PresenterTitleExcerpt
Kevin Hickerson, Ph.D.‘Who the Hell Ate All the Frozen Neutrons?’ and Other Hilarious AdventuresWhen it’s not too busy being utterly pointless and depressing, The Universe can be funny; really, really, really funny. Just when everything makes sense, nature throws pi in your face, and it turns out we’ve got it all backwards, inside-out, and need to start over from scratch.  Sometimes the best solution is to just sit back and enjoy the joke we call “reality.” In this talk, I’ll share my experience with both real discovery, and the much harder work of explaining those discoveries to as many people as possible, using entertainment and humor. Kevin will talk about his work on movies, (like trying to make a Norse god’s hammer “scientifically accurate”), his “real” work with ultracold neutrons and ambidextrous neutrinos, and his flirtation with standup comedy and podcasting. He’ll share his adventures with actors, comedians, Nobel Prize winning scientists, and applying the scientific method to joke writing.
Jack Scannell, Ph.D.“Damn the Compass, Full Speed Ahead”: Why Quality Beats Quantity in Drug R&DWhy has drug discovery become less efficient as the technologies that most people think are important have improved spectacularly? DNA sequencing is perhaps ten billion times faster now than it was in the 1970s. A single chemist today may make 1,000 times more molecules to test than they could in the early 1980s. X-ray crystallography is perhaps ten thousand times quicker now than it was in the mid-1960s. Almost every research technique is faster or cheaper—or faster and cheaper—than ever. And, there are entirely new techniques that were unavailable to previous scientific generations—like transgenic mice or computer-based virtual models. Yet for every inflation-adjusted dollar spent on drug research in 1950, in 2010 one needed to spend more than $100 to achieve similar success. Our work, applying tools from statistical decision theory to the drug R&D process, suggests an answer. The validity of screening and disease models (i.e., the degree to which their results predict subsequent results in man) must have declined as their brute force efficiency has increased. Compare drug discovery to fitting out a speedboat to find a small island in a big ocean. If one invests too much in the engine (brute-force efficiency) and too little in the compass (validity), efficiency declines because the boat spends its time heading at great speed in the wrong direction. We suspect that the validity of screening and disease models has fallen for two reasons.  First, the best models yield cures, become redundant, so are retired. This leaves uncured diseases, with their bad models, which people continue to use for want of anything better. Second, there may have been too much industrial and academic fashion for simplistic molecular models with low validity. We think that the rate of creation and identification of valid models may be the major constraint on R&D productivity.
Larry Gold, Ph.D.2016 Symposium WelcomeToday I will discuss two transformative events that reflect the goals we have had since we started these symposia. First, after working each year to adjust the balance between hard science (with lots of omics) and the social sciences (which are also hard), we may have finally found the mix that feels right for what we are trying to do at these symposia. I will discuss this a bit so those of you so inclined can send me emails about your own ideas. Our goals continue to be that we reach both scientists and others, and allow the dialogue we crave and need. Second, after lots of discussion with many friends and colleagues, we have chosen a project through which we can contribute to improved health care in Colorado and beyond. We have expanded our core working group and have written a plan for the project, and with only some trepidation I will share the plan with you. I will provide contact information so those of you so inclined can volunteer to help make the project come to fruition. We hope to make the plan into a reality in the next months.
Larry Gold, Ph.D.2017 Symposium Welcome
Larry Gold, Ph.D.2019 GoldLab Symposium Closing Remarks
Larry Gold, Ph.D.2021 GoldLab Symposium Closing Remarks Day 1
Larry Gold, Ph.D.2021 GoldLab Symposium Closing Remarks Day 2
Rebecca Trumbull || Eric Trumbull, Ph.D.23 & Us: Family Ties, Family LiesWhat’s in a [family] name? That which we call a Trumbull by any other surname would feel as sweet? Or would it? Or how about Murphy? Or how about going from thinking your family’s heritage is Spanish to learning that the heritage is Pakistani? And how reliable is that information, anyway? The two youngest Trumbull siblings take us through the journey of their lives as the “mistakes” of the family – though mistakes of a different kind than what they had thought all their lives. What they discover late in their lives is that lifelong family friends were intertwined in ways they had never anticipated. They will explore the nature of “family,” of genetics, of identity, in a world that changed for them a few years ago from the results of DNA testing. What is the significance of our family name? And why does it seem important to us? What influence does it have on our identity? What’s in your name? What difference does biology make? And who, by the way, owns the truth about one’s own self? And what do so many people with “genetic identity issues” mean for the society at large? for the social work community? for the scientific community? for politics and education, finance and social services, etc.?
Lisa Stubbs, Ph.D.A Conserved Regulatory Core — With Species-specific Innovations — at the Root of Shared BehaviorsCertain aspects of early development — including most types of cell-fate decisions and many aspects of determination of the body plan — proceed similarly in all metazoan organisms. Despite the wide diversity of eventual outcomes — specialized adult cell types, organs, body morphs and behaviors — these fundamental steps are also controlled by very similar cohorts of genes. In particular, conserved transcription factors (TFs) have been singled out for conserved and controlling roles. Likewise, certain fundamental aspects of social behavior are also deeply conserved. It seems possible that conserved gene regulatory programs may also underlie those conserved aspects of social response. The overarching interest of our group is to identify gene regulatory network components that control fundamental aspects of development and behavior in mammals, and to examine how those networks have been modified for species-specific diversity. In a collaborative effort with other groups at the Institute, we have completed the first phase of a three-species comparison of neural response to territorial invasion, a social challenge that evokes a very clearly analogous response in most social species. Our studies, involving a gene expression and chromatin-mapping timecourse of brain regions from honey bee, stickleback, and mouse after exposure to territorial threat, reveal evidence of conservation of an ancient regulatory network that has been preserved, with species-specific modifications but with a clearly conserved TF backbone, from the earliest invention of social species. These studies provide new insights into the regulation of social behavior and provide a path to optimally leveraging data from diverse model species to understand social response, both normal and maladaptative, in humans.
Steven Morrissett, J.D.A Curious Collision: Innovation vs. Patent Protection in Health CarePatents serve the Constitutional directive of creating a playing field promoting science and technology. Inventors are rewarded for publicly disclosing their inventions with a grant of exclusivity in their invention for a limited term, now 20 years less the (reasonable) time it takes the Patent Office to process the patent application. As with other political systems, the patent system, in practice, suffers from the effects of being managed by the government, interpreted by judges and lawyers, and ignored by the general public except when they are compelled to serve on jury duty. Recent activities by the courts, Congress, and executive branch seek to level the playing field (or to skew it in the eyes of some). The Patent Reform Bill now in Congress may substantially change the ground rules. The final decision in the Myriad Genetics appeal, now pending, may alter what can be patented. There are no immediate plans to change the biggest unknown on the slope of the playing field: the right to trial by jury.
Thomas R. Cech, Ph.D.A guided discussion with panelists led by Tom CechA guided discussion with panelists led by Tom Cech, Ph.D., Professor, University of Colorado, former President, HHMI
Jo Marchant, Ph.D.A Journey into the Science of Mind Over BodyCan the mind heal us? Thoughts clearly influence physiology, from fear to sexual arousal, but there is much skepticism about the idea of “healing” thoughts and beliefs. Recently, however, scientists from a range of fields have been uncovering evidence that our mental state can play a crucial role in determining both symptoms we experience and underlying processes of disease. Placebos trigger biological changes similar to those caused by drugs. Mood predicts complication rates during surgery. Immune responses are influenced by taste and smell. In this talk, Jo Marchant will discuss the potential—and limits—of the mind in physical health, and ask how might we harness these principles in medical care.
Robin Deterding, M.D.A Journey to Transform Care for Children with Rare Lung DiseaseOpportunities exist today to create new strategies to transform care and find cures. As a pediatric pulmonary specialist, most of my patients have rare disease. Many patients and their families often struggle to find better understanding, care, and treatments for their children. Through the advocacy of patients, physicians, and scientists a collaborative journey to create a roadmap of hope began for children with interstitial and diffuse lung disease (chILD). Examples will be shared that highlight the use of systems, proteomics, genomics, stem cells, and information technology as tools to address the needs of children with rare lung disease.
Sarah GrayA Life EverlastingWhen Sarah Gray received the devastating news that her unborn twin son Thomas was diagnosed with anencephaly, a terminal condition that meant he would not survive long beyond birth, she decided she wanted his death—and life—to have meaning. In the weeks before she gave birth to her sons in 2010, she arranged to donate Thomas’s organs to medical research.  Later curious about how the donations were being used, Sarah embarked on a quest for those answers that took her to some of the most prestigious scientific facilities in the country, including those at Harvard, Duke, and the University of Pennsylvania. Pulling back the curtain of protocol and confidentiality, Sarah met the researchers and scientists who received Thomas’ donations, and learned how they’re being used in cutting-edge research for medical discoveries to benefit humanity.
Richard Lamm, J.D.A New Moral Vision for Health CareTwo major transforming realities have overtaken the health care systems that require us to redraw the health care map. I. Taxpayers now fund approximately 50% of U.S. health care. II. It is now inescapably clear that resources are limited relative to needs. When limited funds meet unlimited demands, they must be budgeted and prioritized. The “rationing” of health care goes from outrage to obligation, from intolerable to inescapable. Those who distribute pooled or taxpayer funds become not mere payment agents but allocators of limited resources who must maximize the health of the group they cover. There is a largely unexplored ethical analysis applicable to the macro-allocation of health resources. Those who allocate limited resources should not mechanically pay for everything within the doctor/patient relationship. As one perceptive author suggests: “…the distinction between macro-allocation and micro-allocation of resources is crucial. More traditional bio-ethical analysis may well clarify the micro-allocation issues, but it is inappropriate at the macro-allocation level and therefore misses the point. …The allocation of health care resources is best understood as a political rather than an ethical issue.” American health policy has missed a crucial point. Medical ethics may control the behavior of health providers, but it should not control the macro-allocation process. Public policy must have its own independent ethical duties. Welcome to the Brave New World of Health Care that is fast heading our way.
Steven McKnight, Ph.D.A Solid State Conceptualization of Information Transfer from Gene to Message to ProteinMost DNA and RNA regulatory proteins consist of two parts. One part enables direct recognition of DNA or RNA, is well folded, and is represented by canonical domains including zinc fingers, homeoboxes, leucine zippers, RNA recognition motifs, KH domains, and pumilio domains. The other part is typified by poorly folded, low-complexity sequences whose mechanistic basis of function has long been enigmatic. When incubated at high concentration, certain of these low-complexity domains polymerize into labile, amyloid-like fibers. My presentation will outline studies indicating that low-complexity sequence cross-beta polymers may represent the organizational basis for the formation of nuclear and cytoplasmic puncta including nuclear speckles, P granules, stress granules, and neuronal granules. It is our speculation that from the birth of a transcript in the nucleus to its ultimate translation in the cytoplasm, the entire pathway of information flow is guided by movement of the message through a solid state pathway of polymeric fibers. This “informational cytoskeleton” is regulated in a dynamic manner by post-translational modification and can be impinged upon in disease states via mutational events that enhance fiber stability.
Sean Eddy, Ph.D.A Tour of the Human GenomeThere is a surprising amount of controversy about the contents of the human genome: junk DNA, pervasive RNA transcription, the role of long noncoding RNAs, and whether 20,000 protein-coding genes suffice to account for the complexity of our biology. Popular accounts often refer to "dark matter,” the idea that only one percent of the genome codes for proteins, the vast majority of the genome is unexplored and unaccounted for, and the key to our complexity may be lurking there. But we know more about the human genome than popularized accounts tend to acknowledge, and two facts are especially important. One is that most of the genome consists of the decaying remains of molecular parasites, a baroque menagerie of different replicating DNA elements that infest all known genomes. The other is that biochemical machines have error rates, and the machines that make RNA will make low-level RNA products even from random DNA sequences. Understanding the human genome requires appreciating that a genome is a noisy, messy, evolving molecular ecosystem. Like a forest, some of it is trees, some is undergrowth, and much of it is decaying into fertile soil.
Dan Dennett, D.Phil.Agents and Homunculi: Does it Take a Village to Make a Conscious Organism?From one biological perspective, a multicellular organism such as a person is better seen as a relatively stable community of semi-autonomous cellular agents, with agendas of their own; this huge population of cells (having thousands or even millions of distinct genomes) normally manages to hold it together for decades. How can an aggregation of trillions of selfish, myopic cells discover the unwitting teamwork that turns that dynamic clump into a person who can love, notice, wonder, and keep a promise? Daniel will not attempt to answer this giant question, but will set out constraints and opportunities for research that will answer it. Hint: there is no Emperor in charge. As one of Dan’s critics once said, in outrage, “For Dennett, it is not a case of the Emperor having no clothes. It is rather that the clothes have no Emperor.” (Voorhees, 2000, pp55-56) Exactly!  There just seems to be an Emperor. There is, instead, a virtual governor.  And how does it come to exist and what does it do?
Cindy Malone, Ph.D.Alternative Pedagogy for the Scientifically Refractive LearnerTeaching in the 21st century brings many challenges, but none more than the population of students who seem to actually try to NOT learn. This is particularly apparent in the non-majors Biology courses, but also, seemingly inexplicably, appears in the majors courses as well. Even more frustrating is the presence of these learning refractory students in upper division biology courses. I often ask, “If you don’t like this stuff and do not find it interesting, why is this your major?” What I have found in the majors is that these students “are going to go to (insert professional school here) and so they do not care about science, they will be (insert doctors, dentists, pharmacists here). It is clear that these students and the non-majors do not share the passion and exhilaration of science that we do. Merely relaying technically complex information clearly is not enough to engage these students. Teaching these students requires so much more. Capitalizing on the human love of laughter, I attempt to MAKE students learn, sometimes it seems, against their will. I use a variety of resources to do battle including video clips, sing-alongs, karaoke, sound bites, costumes, and any other foolishness I can find to entertain them into learning. For the motivated student, I provide fun and helpful incentives to encourage over-achieving in my classrooms. Reaching all students across our educationally diverse population is a challenge that continually requires innovation, experimentation, and pure tenacity in the classroom.
Irene Aguilar, M.D.Amendment 69: ColoradoCare? Yes!Despite repeated Supreme Court challenges and efforts by Congress to repeal it, the Patient Protection and Affordable Care Act (ACA) is into its sixth year of existence. Efforts to undermine its financial sustainability continue; but in the end, which elected representatives will choose to remove guaranteed access to health care from Americans with pre-existing conditions? We in Colorado are finding that the ACA is not as affordable as we’d like. Many people with chronic diseases still struggle to see the doctors they want; and, they can’t afford the medicines they need nor pay their insurance premiums, either. The administrative complexities and hassles are overwhelming for consumers and providers alike. While the focus has been on getting people access to health insurance, the success varies by region of the state with up to 36 percent of people uninsured in some rural areas of Colorado. Coloradans deserve better. Fortunately, starting in 2017, states can opt out of the ACA and design their own health care coverage. The state’s coverage plan has to meet four criteria. The coverage must: 1) Be at least as comprehensive as that offered through the marketplace; 2) Be at least as affordable as that offered now; 3) Be accessible to at least a comparable number of residents; and 4) NOT increase the Federal debt. ColoradoCare or Amendment 69 meets all of these criteria. In November of 2016, Coloradans have the opportunity to continue their leadership in health care reform by voting in a state-based health care system that guarantees access to quality, affordable health care for everyone living in the state. Learn why you should vote YES! on amendment 69, ColoradoCare.
Ted Scambos, PhDAntarctica and Sea Level Rise: We’re In This Boat TogetherUsing satellite data of the polar ice caps allows CIRES to map these regions in new ways, and study the effects of climate change in Antarctica. This data has witnessed the collapse of ice shelf areas and glacier acceleration in the Antarctic Peninsula, ice streams of the Ross Ice Shelf, and wind-snow interactions on the East Antarctic Plateau. A recent study used satellite thermal data to identify the coldest locations in Antarctica, and the processes that set their minimum winter temperatures. In this presentation, Dr. Scambos will recount experiences from his expeditions to Antarctica from unique large dune features in the center of East Antarctica (“megadunes”) to icebergs off the shore of the Antarctic Peninsula, and his work on developing instrumentation to try to better monitor and understand Antarctic climate and ocean circulation in areas of major change
Christopher Walsh, Ph.D.Antibiotics Past, Present, and Future: At the Academic/Biotech InterfaceAs new antibiotics are brought into widespread clinical use for the treatment of life-threatening infections, resistant pathogens emerge as sensitive bacteria die off. Thus, there is a constant need for new generations of antibiotics to combat arising waves of multidrug resistant pathogens. Traditionally bacterial infections have been a target-poor therapeutic arena and many of the large pharmaceutical companies have closed their antibiotic R&D operations. This lecture offers a personal perspective on research at the interface of academic investigators and biotechnology startup companies to address the pressing need for new antibiotics.
Julie Gerberding, M.D., M.P.H.Antimicrobial Resistance: Newest Thugs without DrugsAlexander Fleming noted the importance of drug-resistant microbes when he accepted the Nobel Prize in 1945 for the discovery of the first "wonder drug"—penicillin. Since then, we have benefitted from the development of more than 100 antibacterial drugs and many other products that target viruses and fungi, but unfortunately, the emergence of drug resistance has stayed in lockstep with these discoveries. Initially, most antibacterial resistance was intrinsic—inherent in the particular genomic make-up of the organism. The next wave of resistance emerged through horizontal gene transfer that promotes the spread and accumulation of resistance factors under the selection pressure of antimicrobial treatment, especially in relatively closed populations like healthcare facilities. Today we are seeing an even more ominous phenomenon—the geographic translocation and hence globalization of multiple-resistant organisms on an unprecedented scale. Widespread availability of powerful antimicrobials for human and animal use (often without prescription requirements), urbanization, crowding, social migration, global travel, and medical tourism have produced the perfect storm promoting “superbugs” throughout our ecosystem. Traditional approaches to drug discovery and development simply cannot keep pace with the scale of emergence we are currently experiencing, and finding novel solutions is a global imperative. The domains of innovation must include not only new therapies that target resistant infections in individual human and animal patients, but also bold global geopolitical engagement in effective antimicrobial stewardship efforts. Absent these, we will be left with ominous bugs and no drugs to treat them.
Steve Williams, M.D., Ph.D.Aphrodite and Medusa: Portraying the Beauty of Biology and the Gorgon of DiseaseHow many dimensions are there to Aphrodite or Medusa? Can you describe them in one word or even a short list? Would you even try to do so, when the process of appreciating their complexity is such a positive experience? And if you were blessed with the skills to represent them artistically, would you leave out the bits that the censors didn’t like or the buyers weren’t going to pay for today? And so too medicine and biology. Why do we require our medical portrayals to be in one word, one number, or an incoherent list (such as PSA, cholesterol, blood-pressure, age)? Why are our regulatory and payment systems for diagnostics based on one test at a time? Why do Netflix and Amazon use the latest mathematics and “big-data” to suggest our next trivial purchase but important medical decisions are left to the mind of a single human? Do we really believe that disease, behavior and biology are that simple? Or are we afraid — or worse — complacent? The time has come to embrace the real complexity rather than shun it; to build diagnostic products which are coherent, multidimensional and powerful. Making thousands of protein measurements and coupling them with mathematical analyses, data integration and user-friendly interfaces is close to an ideal solution to these issues, and I will attempt to illustrate that they create a better portrayal of the beauty and horror of biology and disease.
Larry Hunter, Ph.D.Artificial Intelligence and Medicine
Roy Smythe, M.D.Authority, Power and Autonomy in MedicineMoney, science, and technology have been important, but not enough to create and sustain the massive medical-industrial complex. A critical additional force – one responsible for almost everything civilization has accomplished – has been necessary. That force is authority. Authority exists between parents and children, employers and employees, governments and citizens, and between health care providers and those seeking care. At its core, it is someone acting as suggested or directed by another where action would not otherwise occur. While they are two drums beating constantly in the background of civilization - one a staccato snare you willingly tap your feet to, and the other a bass drum struck on occasion with such force you feel the vibration and are compelled to move – authority and power are not the same. Power implies the use of force or coercion and authority voluntary acceptance. The medical-industrial complex has never had power, so society had to grant it authority. In other industries, this is the “right to sell”, and in medicine - this is the “right to treat”. The medical-industrial complex was built on three pillars of medical authority – informational, technical, and moral. Informational authority implies it possesses knowledge laypersons cannot access or understand, technical authority technology laypersons cannot obtain or use and moral authority suggests healthcare providers are somehow divinely empowered. Medical authority has prevented individuals from actively participating in a more effective care model. However, the three pillars are crumbling.
Caldwell Esselstyn Jr., M.D.Becoming Heart Attack Proof and Ending the Coronary Artery Disease EpidemicAt the completion of this talk the participants will appreciate the scope of the coronary artery epidemic and why it does not exist in certain cultures. They will have further insight into the mechanism of plaque blockage formation and an understanding of why plaque ruptures and how a heart attack develops. They will have an understanding of what is our endothelium and how it thrives and how it may be injured. They will grasp how the endothelium manufactures nitric oxide and appreciate the multiple functions of nitric oxide in protecting our vascular health. They will become aware that the intestinal flora of omnivores manufactures atherogenic TMAO which is not the case for those consuming whole food plant based nutrition. They will appreciate that present coronary artery disease therapy is a transient patch job, which does not treat the causation of the disease and is doomed to failure. They will grasp the required lifestyle change to prevent, halt, reverse, and eliminate coronary artery disease.
Nathan Wolfe, Ph.D.Before It Strikes: Viral Forecasting For Pandemic PreventionCurrent global disease control efforts focus largely on attempting to stop pandemics after they have already emerged. This fire brigade approach, which generally involves drugs, vaccines, and behavioral change, has severe limitations. Just as we discovered in the 1960s that it is better to prevent heart attacks then try to treat them, over the next 50 years we will realize that it is better to stop pandemics before they spread and that effort should increasingly be focused on viral forecasting and pandemic prevention. In this talk I discuss how novel viruses enter into the human population from animals and go on to become pandemics. I then discuss attempts by my own research group to study this process and attempt to control viruses that have only recently emerged. By creating a global network at the interface of humans and animals we are working to move viral forecasting from a theoretical possibility to a reality.
Lakshmi A. Devi, Ph.D.Big Science on a Small Budget: Neuropeptide Receptors and Drug DiscoveryReceptors are signal-transducing proteins that sense the cell’s environment and respond to a particular stimulus by eliciting an intracellular response. Due to the importance of their physiological roles, receptors have been major drug targets; they account for about 50-60% of all pharmaceuticals in the market. Hence there is a great interest in identifying new therapeutics by targeting receptors involved in a variety of diseases. Over the last decade, although the amount of money spent towards identifying new drugs has escalated, the number of drugs approved has remained constant. Furthermore, in recent years funding for basic research geared towards the identification of new receptors as targets has continued to decrease both in the public and privatesectors. One approach to carrying out such research during these trying times is to use strategies that maximize publicly available databases and information. For example, data from genomic, proteomic, and metabolomic studies combined with bioinformatics analyses can identify new drug targets. Dynamic collaborations with screening centers for high-throughput screening and/or in silico screening technologies can identify molecules that can serve as tools to evaluate the role of the target in disease as well as leads for drug development. This presentation will describe two examples of these approaches: One example is the identification and characterization of a novel receptor involved in body weight regulation. The other example is the identification of a small molecule that selectively binds to opioid receptor dimers, producing analgesia with reduced side effects.
Simon Lovestone, M.B., Ph.D.Biomarkers for Alzheimer’s disease: Not Necessarily Desirable but Definitely EssentialAlzheimer’s disease is a devastating disorder – to individuals, to families and, as it costs the state more than heart disease and cancer combined, to health services and potentially economies. As life gets longer, things are going to get only worse as more people live to the age of risk. Balanced against this gloomy scenario is the considerable progress made in the last two decades towards an understanding of the molecular pathogenesis of the disease and the rational design of drugs to slow or even halt progression. And here’s the rub – Alzheimer’s has a prodromal or preclinical phase that might be as long as ten or more years. Treat the disease in that phase and there is every possibility that effective treatment will equate to clinical prevention. But in order to treat the disease in this phase, then biomarkers of this preclinical pathology are needed. As conventional trials of disease modification agents in established disease are failing, the options in Alzheimer’s disease are becoming stark: either we will have markers enabling precision medicine in clinically unaffected individuals or we will have nothing. In the search for such preclinical biomarkers most progress has been made in measuring candidate markers, particularly amyloid, using CSF as a test-fluid for immunocapture assays, and molecular PET imaging as an imaging technology. Studies compare people with dementia to those without. As an alternative approach we have been using proteomics and genomics rather than candidates, using blood as a test-fluid and, most important, using a study design focusing on trying to identify biomarkers of pathology rather than biomarkers of clinical disease. Using these approaches we have found a set of genes and proteins that have accuracy in the utility range for diagnosis and have some evidence for very early, or even pre-clinical, detection. These findings have the potential to change our perspectives on Alzheimer’s disease and as a consequence we are changing our services for assessing people with dementia. Gearing up for an era of personalized medicine, at King’s Health Partners we are streamlining assessment and scaling data collection through the electronic medical records coupled to routine collection of samples.
Richard Barker, Ph.D.Bioscience – Lost in Translation?Richard Barker will explore the mystery of our persistent failure in turning great advances in bioscience into lasting and affordable patient benefit. He will lay out five 'gaps in translation' and a strategy to overcome each—with precision medicine the golden thread that runs through his solutions. He believes we can improve the productivity of the medical innovation process by at least an order of magnitude, if we are prepared to challenge and change our innovation ecosystem.
Chunming Ding, Ph.D.Blood-Based Screening to Combat the Rise of Colorectal Cancer in China?Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world, accounting for over 9% of all cancer incidence. In developed countries, the incidence and mortality rates of CRC have dropped significantly in the last twenty years, while these rates in developing countries (such as China) have increased significantly. While lifestyle and dietary changes in developing countries have contributed to the increase in CRC incidence, such apparent discordant trends are largely attributable to the differential screening programs. CRC is ideally positioned for screening, particularly non-invasive blood or stool-based screening. Firstly, CRC often develops over a long period of time, providing an ample time window for detection. Secondly, accurate diagnostic and therapeutic colonoscopies are available as a follow-up for positive screening results. Detecting CRC at an early stage is likely to benefit patients given the much better prognosis. In developing countries, the shortage of competent physicians is severe and it is unlikely to change in the foreseeable future. As such, standardized and cost-effective molecular tests may be the most practical way to combat CRC. As DNA methylation is an early event in carcinogenesis, we performed extensive DNA methylation biomarker discovery using prospectively collected clinical samples to identify about 10 markers with high specificity for CRC in plasma. A single-tube multiplex qPCR assay is subsequently developed to quantify tumor-derived methylation signals in plasma. In several independent cohorts, we demonstrated that the test may have sufficient specificity, sensitivity, and cost-effectiveness for nationwide population screening.
Alan Attie, Ph.D.Bottlenecks in Evolution, Bottlenecks in Type 2 DiabetesWe are in the midst of an unprecedented epidemic of obesity, which is accompanied by a type 2 diabetes epidemic. Whereas >80% of people with type 2 diabetes are obese, ~80% of obese people do not develop diabetes. My laboratory studies this dichotomy by searching for genes that confer susceptibility to type 2 diabetes. This involves genetic screens in obese mice segregating for diabetes susceptibility alleles as well as genomic studies to identify coordinately regulated genes responsible for the pathogenesis of diabetes. Throughout most of human history, famine, injury, and infection were the major causes of death. Some populations experienced exceptionally harsh conditions and thus might have been under strong selection for allelic variants conferring resistance to famine. The thrifty gene hypothesis states that these variants, in the context of overnutrition, may conspire to increase the susceptibility to type 2 diabetes. In type 2 diabetes, there is an increased demand for insulin — usually due to obesity-induced insulin resistance — that confronts a limited ability of beta-cells to secrete insulin. Many potential pathways can play a role in setting this limit. These pathways have an evolutionary history that goes back to single-celled organisms.
Risa Lavizzo-Mourey, M.D., M.B.A.Building a Culture of Health in America: Why Health is EverythingFor too long in America health has been defined as simply not being sick. But health is so much more than that. Health is everything. It is influenced by a complex web of social factors: Where we live, how we work, the soundness and safety of our surroundings, and the strength and resilience of our families and our communities. The U.S. spends far more on health care than other developed nations, yet Americans live sicker, shorter lives than their counterparts. Over the past three decades, obesity rates have reached epidemic proportions. Heart disease, cancer, diabetes, and other preventable chronic illnesses continue to account for most deaths. And across the nation, business loses about $226 billion in earnings each year due to sick, injured, and absent workers. So what can we do differently to build a society in which well-being is a priority? And what will it take to provide everyone in America with the opportunity to live as healthy as possible without leaving some behind? This talk will look at how we can join forces across sectors to build a comprehensive Culture of Health, enabling all in our diverse society to lead healthier lives, now and for generations to come.
Susannah FoxBuilding an Innovation NationThe Chief Technology Officer at the U.S. Department of Health and Human Services is, in a lot of ways, the chief innovation officer, bringing a can-do, creative spirit to government. I will share stories about how the passion and tenacity we associate with startups can be found in every health care setting, from government labs to communities of people living with rare, life-changing, or chronic health conditions. One deceptively simple insight runs like a thread through all these organizations: the internet gives us access not only to information but also to each other. If we leverage this newfound power to crowd-source and communicate, to value the tinkerers and the change makers at every level, we can build a stronger, more innovative health care system. What will happen when everyone has access to the tools and information they need to solve their own problems — and share their ideas with others? My hope: an Innovation Nation.
Marc Feldmann, Ph.D.Can We Define a More Cost-Effective Path to Better Therapy? Reminiscences from the Front LineWith our aging society, medical costs keep on increasing globally. As research has dramatically changed the world we live in, could more effective research diminish the cost of health care? I believe this is not that difficult, if therapeutic research was better organized. Having had an unusually complete view of the generation of a new drug class, the TNF inhibitors—currently the most profitable drug class (sales ~$27 billion)—from defining the hypothesis to proving it in laboratory and clinic, convincing payers of its cost-effectiveness, I can detect major opportunities. Failed experiments, especially in the clinic, and needless duplication result in major costs. Keeping therapeutic research open, academic, non-competitive until target validation and drug and dates are needed will reduce cost as championed by Al Edwards of SGC in Toronto. But the greatest cost reduction would come from more effective therapy, given at an early stage. For this, better diagnostics need to be linked to therapeutics, and we need to learn to develop combination therapies.
Kevin Davies, Ph.D.Cancer, Early Tumor Diagnosis and Tumor DNA moderator
Rob Reich, PhDCarbon Versus Silicon: Professional EthicsThe revolutions in biotechnology (CRISPR and genetic editing) and information technology (artificial intelligence) call into question nothing less than what it means to be human and the place of humans in the natural world. Rapid acceleration on the technological frontier makes it less likely that democratic regulation will be up to the task of installing sensible guardrails so that these revolutions support rather than subvert human interests and democratic stability. As a result, we must look to professional norms within bioengineering and computer science to help steer us. Are these up to the task?
Richard Lawn, Ph.D.Cardiovascular Disease and Drug DiscoveryBleeding and blood clotting are the leading causes of mortality, and represent major areas of focus for drug discovery. Significant advances have been made in the treatment of bleeding disorders, such as hemophilia, where recombinant proteins supply the missing clotting factors. Thrombosis, as manifest in cardiovascular disease, stroke, and other hyper-coagulation disorders represents challenges of high risk and high reward for pharmaceutical science. Atherosclerosis is caused by an excessive accumulation of cholesterol in the artery walls, and the chronic inflammatory reaction thus set in motion. LDL delivers cholesterol to peripheral tissues, and has been the target of very successful therapeutic interventions. HDL removes excess cholesterol from the artery wall. To date there have been some enormous failures to increase the amount of this “good cholesterol” in a safe and effective manner. Several approaches to modulating this “reverse cholesterol pathway” will be discussed. Since the balance of cholesterol transport in and out of the artery wall is at the root cause of atherosclerosis, biomarkers of cardiovascular risk include these lipid measures, and imaging modalities continue to improve the picture of plaque buildup in the arteries. Yet the ultimate plaque rupture, leading to the dire consequences of an arterial thrombus, is still difficult to anticipate. The prediction of such an event, and the classification of people into categories of imminent risk, remain a holy grail for predictive medicine.
David QuammenCarl Woese and the Non-Tree of LifeCarl R. Woese, of Urbana, Illinois, was the man who invented molecular phylogenetics. Although famous to researchers in molecular evolution and microbiology—revered by many, suspect to some—he remains almost entirely unknown to the general public. Even among organismic biologists, ecologists, and evolutionary biologists who study flora and fauna, the name Woese draws a blank. He is arguably, as I’ve often said to such people, “the most important biologist of the 20th century that you’ve never heard of.” It was Woese who discovered a third major domain of creatures, the Archaea. It was Woese who hit upon the notion of using 16S rRNA, at the core of the translation apparatus, as a Rosetta Stone molecule for discerning phylogeny. And it was Woese’s work that led forward to recognition of the scope and the significance of horizontal gene transfer (HGT), as an evolutionary factor, throughout life’s history and across all domains. Because of Carl Woese, we now comprehend that the “tree of life” is not shaped like a tree. Given those contributions, it’s peculiar and somewhat unfortunate that he is so little known. But it’s fortunate for me, because I’ve just written a book about him—with the help of insights and memories generously shared by many of his colleagues and friends, including George Fox, Norman Pace, Ralph Wolfe, Linda Bonen, Ford Doolittle, Harry Noller, and Larry Gold. Drawing on the work, and the memories, I will talk about Carl Woese as a scientist and a man.
Stephen Macknik, Ph.D.Champions of IllusionsDrs. Macknik and Martinez-Conde produce the annual Best Illusion of the Year Contest, a celebration of the ingenuity and creativity of the world’s premier illusion creators. Visual illusions are those perceptual experiences that do not match the physical reality. Our perception of the outside world is generated indirectly by brain mechanisms, so all visual perception is illusory to some extent. The study of visual illusions is critical to understanding the basic mechanisms of sensory perception, as well as to cure visual and neural diseases. The illusion community includes visual scientists, ophthalmologists, neurologists, painters, sculptors, magicians, mathematicians, and graphic designers that use a variety of methods to unveil the underpinnings of illusory perception. This lecture will feature the most exciting novel illusions created by the best and most cutting-edge illusion innovators of the new millennium.
Tony Marion, Ph.D.Chance, Genetics, and the Heterogeneity of Autoimmunity and Disease Pathogenesis in Systemic Lupus ErythematosusPhylogenetic and ontogenetic evolution combine to maximize the potential for the immune system to detect and eliminate pathogens at risk for initiating potentially damaging immune reactions including self-reactivity and autoimmune disease. Innate immune receptors have limited diversity and detect molecules whose expression is exclusive or at least more prevalent among pathogens, for example lipopolysaccharide and DNA with non-methylated CpG, respectively. Adaptive immune receptors, on the other hand, have enormous diversity and include those with reactivity to self. Intrinsic and extrinsic cellular and molecular mechanisms function to prevent maturation of adaptive immune cells with self-reactive receptors and limit and control self-reactive or otherwise harmful innate and adaptive immune responses when they occur. Failure of the regulatory control mechanisms can lead to excessive acute inflammation, allergy, chronic inflammation, or autoimmune disease. Systemic lupus erythematosus (SLE) is a genotypically and phenotypically heterogeneous, systemic autoimmune disease that affects multiple organs and connective tissues. Glomerulonephritis is the most severe disease manifestation in SLE and has the highest standardized mortality ratio among patients. Prominent among the autoantibody specificities in SLE and the specificity most correlated with glomerulonephritis is autoantibody to DNA. Our research in experimental models of SLE have improved our understanding of how autoantibodies to DNA initiate glomerulonephritis and why there is such heterogeneity in kidney disease among SLE patients with otherwise identical serum autoantibody profiles.
Robert Duke, Ph.D.Changing Minds: You Don’t Know the Half of ItFrom inside our own consciousness, it seems to us that our thinking and behavior follow a somewhat linear progression in which we perceive the world around us, gather information, interpret what we perceive, decide, and act. From this perspective it’s possible to believe that if we all had access to the same information (and understood it) we’d all reach the same conclusions. But human decision-making is complicated by the fact that our minds are products of the genetically-determined wiring that has evolved over millennia and our individual histories of past experiences, all of which contribute to what we notice, what we think, and what we do. Of course, the structures of human brains evolved in ways that advantaged survival and procreation at a time when the circumstances of human existence were very much unlike those of contemporary society. And as brains developed in even the earliest epochs of human evolution, older structures were not replaced with newer ones; newer structures and enhanced capacities for cognition complemented what was already in place. This combining of older and newer ways of thinking are at the heart of the seeming complexity of how we think, decide, and act. In a series of five etudes and a culminating discussion, our goal is to reveal the multiple dimensions of human thinking and behavior, illuminating aspects of our perceptions and decision-making that in many ways function outside of our conscious awareness. To quote Professor Gold: “These issues will dominate what our society does about healthcare, quite independently of what our hot-shot science leader thinks flows automatically from omics.”
Scott DanielsonChanging Minds: You Don’t Know the Half of ItFrom inside our own consciousness, it seems to us that our thinking and behavior follow a somewhat linear progression in which we perceive the world around us, gather information, interpret what we perceive, decide, and act. From this perspective it’s possible to believe that if we all had access to the same information (and understood it) we’d all reach the same conclusions. But human decision-making is complicated by the fact that our minds are products of the genetically-determined wiring that has evolved over millennia and our individual histories of past experiences, all of which contribute to what we notice, what we think, and what we do. Of course, the structures of human brains evolved in ways that advantaged survival and procreation at a time when the circumstances of human existence were very much unlike those of contemporary society. And as brains developed in even the earliest epochs of human evolution, older structures were not replaced with newer ones; newer structures and enhanced capacities for cognition complemented what was already in place. This combining of older and newer ways of thinking are at the heart of the seeming complexity of how we think, decide, and act. In a series of five etudes and a culminating discussion, our goal is to reveal the multiple dimensions of human thinking and behavior, illuminating aspects of our perceptions and decision-making that in many ways function outside of our conscious awareness. To quote Professor Gold: “These issues will dominate what our society does about healthcare, quite independently of what our hot-shot science leader thinks flows automatically from omics.”
David Fajgenbaum, MD, MBAChasing My Cure: Lessons Learned as a Physician-Researcher-Patient-AdvocateDavid will share about his journey from fighting for survival against idiopathic multicentric Castleman disease (iMCD) during medical school to conducting research leveraging the SOMAscan proteomic platform and ultimately collaborating with dozens of physicians, researchers, and patients to accelerate progress for Castleman disease patients worldwide. His presentation highlights the incredible power when patients, physicians, advocates, researchers, caregivers, biopharmaceutical companies, and drug regulators unite to leverage cutting-edge technologies and turn our hope into action. At 25 years old, Fajgenbaum presented with life-threatening multi-organ dysfunction for an unknown cause. Without a diagnosis and no hope for survival, a priest read him his last rites. Fortunately, the diagnosis was made and multi-agent chemotherapy saved his life, but he went on to have multiple deadly relapses. When he learned about the limited research funding, lack of resources, no FDA approved treatments, and no drugs in development beyond anti-IL-6 therapy, he co-founded the Castleman Disease Collaborative Network (CDCN) in 2012. In parallel, he began searching for insights into the pathogenesis of iMCD and potential new treatment approaches. Combining omic technologies such as SOMAscan with single cell profiling, tissue immunostaining, and bioinformatic tools, Fajgenbaum has discovered novel predictive biomarkers of treatment response and novel treatment approaches, including one (an mTOR inhibitor) that is saving his life and others. Through his roles as a Board member for the Reagan-Udall Foundation for the FDA and Co-Chair for the CURE Drug Repurposing Collaboratory, Fajgenbaum is also advancing drug repurposing to ensure that all currently FDA-approved drugs are utilized to treat all diseases that can benefit from them. Though incredible progress has been made chasing cures, important work remains to identify treatments for all patients suffering from incurable conditions and we hope attendees will join us in this work.
Emanuel Petricoin, Ph.D.Clinical Proteomics for Diagnostics and Precision Medicine: Applications in the Post-Genome EraWhile DNA is the information archive, the proteins do the work of the cell and constitute most of the cellular machinery. Functionally, nearly all of the FDA-approved drugs work by modulating protein expression and/or protein activity/location. Moreover, many of the biomarkers that are measured in the clinic for routine disease detection to more esoteric testing are proteins. This backdrop provides context to the exploding field of proteomics in the post-genome era; however, proteomics is constrained by technological and biochemical limitations: lack of a PCR-equivalent technology to amplify low-abundance proteins and relative analytical insensitivity of mass spectrometry, lability of proteins in vivo, and massive dynamic range and complexity of the human proteome. To help deliver on the promise of clinical proteomics, we have developed new technologies that can amplify low-abundance proteins for discovery and point-of-care testing. We have also developed new types of protein arrays for precision medicine-based applications. Case studies of these technologies as applied to the bedside will be presented for breast cancers and infectious diseases to emphasize the clinical impact that could be achieved as well as highlight the global potential for incorporation into the early detection and precision medicine workflow.
Neil Siegel, Ph.D.Closed-loop Healthcare Processing: The Use of Proteomics and Information Technology to Improve HealthcareClinical care decision-making can be improved though the use of a “closed-loop” information processing cycle that integrates sensed and recorded data on individuals (initially centered around a combination of highly-multiplexed, longitudinal protein measurements, and electronic healthcare records). This approach applies, analyzes, and visualizes those data using “causality cases” (authoritative findings about how sensed data relate to diagnosis), so as to enable personalized diagnostic and treatment guidance for consideration by the patient, the care team, and the healthcare administrator. We integrate scans of the proteome with a “learning” information processing system. The resulting system, soon capable of measuring thousands of proteins simultaneously from very small blood sample sizes, can be the basis for significant improvement at the system level in the healthcare system, helping improve average outcomes while decreasing total costs. Advances in both data processing technology and biotechnology have reached a level that make this approach feasible, and if applied broadly and effectively, can provide a scalable mechanism for achieving the “triple aim” of simultaneously improving care outcomes, lowering costs, and enhancing the patient experience.
Larry Gold, Ph.D.Closing RemarksLarry Gold gives the closing remarks for the 13th annual GoldLab Symposium.
Larry Gold, Ph.D.Closing Remarks 2010
Larry Gold, Ph.D.Closing Remarks 2014
Phyllis M. Wise, Ph.D.COLS UpdatePhyllis Wise is a leader in higher education and biomedical researcher. She recently accepted the position of Chief Executive Officer of the Colorado Longitudinal Study, an ambitious project to create the largest repository in the world of biological specimens and corresponding data on the social determinants of health. Phyllis has previously served as chief executive officer and chief academic and budgetary officer at pre-eminent research universities, including the University of Washington and the University of Illinois at Urbana-Champaign. She has been a passionate advocate for public research universities and the role they must play in meeting society’s greatest global challenges. With over thirty years of research funding from the National Institutes of Health, among other funding agencies, Phyllis’s research focused on issues of women’s health and how hormones influence learning and memory and protect the brain against neurodegeneration. Phyllis has significant corporate and foundation board experience and currently serves on the NIKE and the First Busey Corporation Boards of Directors. In the non-profit sector, she serves on the Robert Wood Johnson Foundation Board of Directors and the RAND Health Board of Advisors. She was recognized as a “Woman of Influence” by the Puget Sound Business Journal and has received several awards that recognize her leadership in education including the Asian Pacific Americans in Higher Education Leadership Award and the Chang-Lin Tien Educational Leadership Award. Phyllis received her bachelor’s degree from Swarthmore College and her Ph.D. from the University of Michigan. She holds honorary degrees from Swarthmore College and the University of Birmingham (England). She is a member of the National Academy of Medicine and the American Academy of Arts and Sciences.
Ian Billick, Ph.D.Complex Systems, Idiosyncracy, and Scarce Data: Observations from the FieldField biologists face the daunting task of generating fundamental truths based upon scarce data from complex systems that are idiosyncratic in time and location. How do field biologists make progress and are there lessons to be learned? Drawing upon my experience with the Rocky Mountain Biological Laboratory and the Organization of Biological Field Stations, I briefly describe what it is like to be a field biologist and where field biology is headed. The challenge of studying complex and idiosyncratic systems, which include individuals and particular ecosystems, is that the number of relevant factors and their interrelationships (the dimensionality of a system) overwhelms our capacity to measure the system. Field biologists escape this paradox by “looking around corners.” They combine a mechanistic understanding of complex systems with contextual information in order to generalize and predict. For example, a study of fish and mayflies can provide insight into the reintroduction of wolves in Yellowstone and how governments should respond to terrorism. Finally, I argue that a greater emphasis on juxtaposing fundamental research with predictions and/or decision-making within the context of Bayesian statistics provides opportunities for accelerating fundamental discoveries in the field sciences. In keeping with the theme of this Symposium, I will attest to our capacity to make progress understanding complex systems, from Charles Darwin’s efforts to understand the “tangled web” of nature, to the work of clinical researchers to improve human health.
Larry Hunter, Ph.D.Computational Bridges over the Chasms between Science, Medicine and HealthMae West said, “Too much of a good thing can be marvelous.” So why hasn’t the torrent of molecular data produced by systems biology, the clearinghouses of computerized clinical records, and the explosion of health information available on the internet turned out to be so wonderful? The problem isn’t finding relevant information so much as making sense of all of it. While computers have demonstrated power for searching, merging and transforming enormous datasets, computational support for developing good explanations or generating significant hypotheses about that data have, to date, been more modest. However, the transition of scientific publication into the digital era, the somewhat slower computerization of clinical information systems, and promising developments in artificial intelligence are converging to give hope that computational tools may soon help scientists, clinicians and patients better understand more of the factors that determine human health.
Robin Dowell, D.Sc.Cracking the Regulation CodeDr. Francis Collins, director of the National Institutes of Health (NIH), describes DNA as the “language of life”. It’s a language written in a cryptic, simple four-letter biochemical alphabet. The NIH has spent millions to record, or write down the code in books, a.k.a. genomes. Volumes with titles as exciting as “Human”, “Mouse”, and more recently “Owl monkey” have been release over the last 20 years. Reading those books is the next major challenge of biology. In December of 2020, code breakers announced they had finally deciphered a message left 51 years earlier by the Zodiac Killer. Some find it astonishing that it took years to decode this one message. The time commitment necessary to crack the Zodiac’s cipher is just a fraction of what it will take to crack the code of life. Deciphering the human genome, with all its complexity, is a far more challenging task than breaking the Zodiac’s code. Each human genome encodes massive amounts of information in billions of bases. Readout of the genome results in not only a startling diversity of cell types, tissues, and systems, but also how each cell responds to its environment. Our challenge is to decode the genome and understand how it is regulated. This challenge requires some patience and dedication devoted to the Zodiac’s message. While it is not a fast process, it is a necessary and thrilling ride. Ultimately, decoding the genome has vast implications for agriculture, ecology, and medicine.
Craig J. Mundie || Mira Murati || Larry Hunter, Ph.D.Craig, Mira, Larry HunterCraig, Mira, Larry Hunter, and Larry Gold will discuss philosophical and technical aspects of AI. The audience is welcome to ask questions through Slido on the right hand panel.
Stephan WolfertCry HavocCry Havoc is an award-winning, critically acclaimed one-person play by military veteran, Stephan Wolfert. Wolfert seamlessly interweaves Shakespeare’s most famous speeches with personal experience to help us understand the national crises we face when we “wire for war but never un-wire from war”. “It chews you up and spits you out, as it were. It gives you chills while swathing you in empathy. Its horrific images of warfare are countered with angelic theatrical effects as the human heart is exposed. You haven’t quite been to a place like this, yet it’s homey and warmly embracing. A nightmare with raw nerves; it’s a plea for understanding and healing.” -Houston Press
Greg LaGana, M.D., F.A.C.P.Damaged Care: The Musical Comedy About Health Care in AmericaDamaged Care: The Musical Comedy About Health Care in America, written and performed by Greg LaGana, M.D., and Barry Levy, M.D., focuses on health care issues of concern to everyone, ranging from the erosion of the doctor-patient relationship to "superbugs." During the past 19 years, they have performed Damaged Care almost 140 times in 28 states and Canada, for organizations ranging from the American Medical Association and many state medical societies and hospital associations to the Federal Reserve Bank of Boston. They have also performed on Capitol Hill and frequently Off-Off-Broadway in New York. Damaged Care has been featured in the New York Times and the Boston Globe, on CNN Headline News, and ABC Nightline. More information about Damaged Care can be found at: www.damagedcare.com.
Barry Levy, M.D., M.P.H.Damaged Care: The Musical Comedy About Health Care in AmericaDamaged Care: The Musical Comedy About Health Care in America, written and performed by Greg LaGana, M.D., and Barry Levy, M.D., focuses on health care issues of concern to everyone, ranging from the erosion of the doctor-patient relationship to "superbugs." During the past 19 years, they have performed Damaged Care almost 140 times in 28 states and Canada, for organizations ranging from the American Medical Association and many state medical societies and hospital associations to the Federal Reserve Bank of Boston. They have also performed on Capitol Hill and frequently Off-Off-Broadway in New York. Damaged Care has been featured in the New York Times and the Boston Globe, on CNN Headline News, and ABC Nightline. More information about Damaged Care can be found at: www.damagedcare.com.
Stephan WolfertDE-CRUIT® Treating Trauma Through Shakespeare and ScienceRecruited at a psychologically malleable age, young men and women are indoctrinated using a systematic process that “wires” them for war. But, there is no training to undo this indoctrination. Returning veterans are vulnerable to persistent and pervasive effects of traumatic stress largely due to the challenge of reintegrating into civilian life. Up to 68% of veterans drop out of clinical treatment for post-traumatic stress disorder (PTSD). Veterans, on average, are 4-6 times more likely to be homeless, 2-3 times more likely to commit suicide, more likely to commit a violent crime, be addicted, receive harsher, longer prison sentences, and have PTSD rates which far exceed those of the general population. Over-reliance on pharmacological treatments, along with the isolation commonly experienced by returning veterans, is compounded by dominant treatment approaches which adopt an illness-focused model rather than focusing on sources of resilience within veterans’ various communities.  DE-CRUIT® is an interdisciplinary program designed to help military veterans overcome the obstacles of transitioning from military service back into their communities. Countering the military’s intense indoctrination and training, as well as the extreme trauma so commonly experienced as part of military service, DE-CRUIT delivers: a safe, non-judgmental outlet for processing military-related trauma without focusing solely on the trauma or on an assumed pathology within the individual veteran. DE-CRUIT® uses routinized techniques derived from principles of classical actor training (e.g., experiential analysis, symbolic representation, and techniques of breathing and spoken verse) to transform military camaraderie into camaraderie among treatment group members to communalize the process of healing from the trauma of war. The DE-CRUIT® treatment protocol integrates state-of-the-art therapeutic techniques from cognitive science and narrative therapy within a regimen of nutrition, writing, and analyses of trauma as represented by numerous veteran characters in Shakespearian texts. Treatment group members learn to narrate their own stories of trauma through a strengths-based approach that fosters the development of life skills, self-efficacy, and post-traumatic growth.   Stephan will discuss DE-CRUIT®, its steps and their latest data from the scientific evaluation, which shows the incredible efficacy of the program.
Daniel KleinDeath and Its PrequelBeginning with a joke-riddled marathon tour of how the great philosophers viewed Death, this presentation moves on to a more serious contemplation (although not completely joke-free) of how philosophers view old age. This second part looks particularly into the teachings of Epicurus, who viewed old age as the pinnacle of life.
Clyde Hutchison III­­­, Ph.D.Design, Construction, and Analysis of a Minimal Bacterial CellClyde’s team used whole-genome design and complete chemical synthesis to minimize the 1079–kilobase pair synthetic genome of Mycoplasma mycoides JCVI-syn1.0. An initial design, based on collective knowledge of molecular biology combined with limited transposon mutagenesis data, failed to produce a viable cell. Improved transposon mutagenesis methods revealed a class of quasi-essential genes that are needed for robust -growth, explaining the failure of our initial design. Three cycles of design, synthesis, and testing, with retention of quasi-essential genes, produced JCVI-syn3.0 (531 kilobase pairs, 473 genes), which has a genome smaller than that of any autonomously replicating cell found in nature. JCVI-syn3.0 retains almost all genes involved in the synthesis and processing of macromolecules. Unexpectedly, it also contains more than one hundred genes with unknown, or poorly defined, biological functions. Progress in defining the functions of these genes will be discussed. JCVI-syn3.0 is a versatile platform for investigating the core functions of life and for exploring whole-genome design.
Kenneth E. Sharpe, Ph.D.Designing for Patient Centered Care When There Is No CurePalliative Care medicine was not a field or a specialty in the 1980s. Advocates of such end of life care, often inspired by the then emerging hospice movement, struggled to bring palliative care into hospitals and cancer clinics. Their efforts frequently faced reluctance, even resistance, from medical professionals who lived in a culture of treatment and cure. This clash of cultures between “cure” and “care” was reinforced by reimbursement incentives which made continued treatment and procedures “rational” long beyond their usefulness. Despite the desire of many patients to receive better end of life care, and receive it at home, most ended up dying in hospitals — unguided and unsupported in their choices, and unable to get the palliative care they would have chosen. In the last two decades the hospital doors that were closed against palliative care were wedged open by its proponents and palliative care nurses and doctors began to set up shop. This is a story of how a new paradigm got through the door and what it takes to begin to change a culture and an institution — to design for care in situations in which there is no cure.
Kenneth E. Sharpe, Ph.D.Designing for Practical Wisdom: How Can Medical Organizations Encourage Practitioners to Learn the Character and Judgment They Need?Good health care demands good science, good research, good drugs, good technology, and medical staff with first-rate technical skills. But data, technology, drugs, and algorithms are not enough. Good judgment is a critical capacity that medical practitioners need if they are to successfully make tough, everyday decisions about how to care and how to work with each other in teams. At the heart of this judgment is not just academic knowledge and technical expertise but something Aristotle called phronesis or practical wisdom. What does this practical wisdom mean concretely? It demands being motivated by the right things: medical practitioners need to have the virtues of character that motivate them to seek the good of patients. It demands the ability to notice, to see: the capacity to listen not only to what their patients are saying but what they are actually feeling. It demands the ability to reflect and deliberate about the tough decisions, big and small, involved in everyday care and major illnesses—to figure out how they and their teams can diagnose and treat each person given the particular context of their lives, hopes, and fears. It demands the will and capacity to empathize, to counsel, to deal with uncertainty, to balance empathy with detachment, to balance honesty and kindness, to balance hope with truth-telling, and the courage to keep trying and learning in the face of inevitable failures. Such practical wisdom is only learned through experience. But not any experience will do. So how do you design the right kind of experiences? How do you create systems that encourage the learning of practical wisdom? How do you design medical institutions and medical education to encourage practitioners to learn the character traits and judgment skills they need to care for us? I’ve got three stories to tell: one takes place in an intensive care unit in a major Boston Hospital; one takes place in an inner-city health clinic; one is a story about a program in a major medical center that provides palliative care. Each story will help elaborate how medical organizations can be re-designed to encourage clinicians to learn the practical wisdom they need.
Carl Morris, Ph.D.Developing a Gene Therapy for Muscular DystrophyDuchenne muscular dystrophy (DMD) is a severe, progressive, fatal muscle disorder caused by loss-of-function mutations in the DMD gene that leads to the absence of the dystrophin protein. Without dystrophin, the structural link between the actin cytoskeleton and extracellular matrix is broken and muscles are highly susceptible to contraction-induced damage. Direct dystrophin replacement has thus far been unsuccessful due to the large size of the DMD gene. At present, there are only limited treatment options available to DMD patients. Gene therapy is an approach that addresses the root cause of certain genetic diseases by replacing a non-functioning, mutated gene with a functional version. Adeno-associated virus (AAV) mediated gene therapy is an ideal treatment strategy to slow or even stop progression of the disease in most patients. AAV vectors are non-pathogenic viruses that have been designed to enable the safe, systemic, wide-spread delivery of a functional gene. However, there are significant limitations to use of AAV in gene therapy including its genome carrying capacity of approximately 5000 base pairs, ability to manufacture in large scale, and targeting of all affected tissues. Solid Biosciences, a company focused solely on DMD, is developing an AAV micro-dystrophin vector (SGT-001) that may overcome many of the gene therapy barriers, including manufacturing, with the goal to enter clinical trials for DMD. The program is based on extensive research on the dystrophin protein to develop shorter yet functional micro-dystrophin variants that can fit into the AAV, and to deliver genes to the majority of affected muscles. Solid is developing SGT-001 as a viable therapeutic option for all DMD patients, regardless of mutation.
Jay Wohlgemuth, M.D.Diagnostics in the Reference Labs: Putting the Patient FirstTechnologies are rapidly maturing, which enable evaluation of disease specific and informative molecules with high sensitivity and on a large scale. The rate of new marker discovery is therefore advancing rapidly and so focus on diagnostics with high value for individual patients is at risk of being lost in scientific excitement – more is not necessarily better. In addition, individual patients and physicians are interested in accessing diagnostics which are useful to detect, diagnose, select treatments, and monitor multiple diseases in a comprehensive manner. Finally, as diagnostics are developed, cost of testing and ability to access results in a timely manner to impact patient care are crucial. With these challenges in mind, there are emerging examples of comprehensive and highly clinically valuable diagnostics that represent a distillation of the right information for the right patient at the right time. These examples represent technology innovation to enable proactive medicine.
Paul R. Ehrlich, Ph.D.Diet and Hunger: The Weakest Parts of the Global “Health Care”In the U.S, and the rest of the world, it would be more honest to call the “health care” system a “health repair” system. Today some two to three billion people are food-insecure. Roughly 800 million are hungry and another perhaps two billion are micronutrient malnourished. Almost all of these people have weakened immune systems and are more susceptible to disease. Interactions between the biophysical and social dimensions of the food problem are daunting. Meeting human nutritional needs means increasing agricultural production some 70% to 100% by 2050 in response to a growing population, rising demand in emerging economies for meat-rich diets, and increasing competition from biofuels. Such a production increase will create pressure to expand the already-dangerous fossil fuel subsidy to agriculture. The results will be more greenhouse gas emissions, land degradation, and likely higher food prices. Perhaps the biggest uncertainty is whether key politicians will recognize the population-food-health crisis and provide the leadership necessary to avoid a calamitous loss of food security and, thus, the loss of health and well-being.
Elizabeth ScarboroDispatches from the Frontiers of Modern MedicineWhen my first husband Stephen was born with cystic fibrosis in 1968, the average life expectancy for a person with his illness was 10 years. By the time I met him at age 17, the average life expectancy had doubled. In 1986, the first successful double-lung transplant was performed, radically altering the possible life course for CF patients. In 1989, the gene causing CF was discovered, spurring research into new treatments. Adult CF clinics sprung up at hospitals, as patients began surviving into adulthood. We lived in this shifting landscape, experiencing the cutting-edge of medicine first-hand. When Stephen was 22, he participated in the first trials for the drug DNase, which (by a different name) has become a standard part of CF treatment. He received a double-lung transplant in 1997, when the chances of surviving five years were one in two. He spent time at two university hospitals, where scientific investigation went hand in hand with care. Together, we navigated the frontiers of modern medicine, grappling with the questions that arose from this strange place: What constitutes a life worth living? When is intervention worth pursuing, and at what cost? How does our experience of health care shape us, and how can we shape it? Join me as we explore what it means to live and die well on medicine’s frontiers.
Ray Schinazi, Ph.D., D.Sc.Disruptive Discoveries for HIV, HCV, and HBV InfectionsHIV and Hepatitis B and C (HBV and HCV, respectively) viruses cause significant morbidity and mortality worldwide. HCV and HBV kill more people annually than the next 60 reportable infectious diseases combined. HCV related deaths have set new records in every year since at least 2003. The continued rise is alarming given that the vast majority of these deaths are preventable with the wide range of safe and effective oral treatments available since December 2013 when Sofosbuvir received U.S. FDA approval. Sofosbuvir is considered best in class because of its safety, high potency, pangenotypic activity, and high barrier to resistance. Ray will discuss ultrashort 3-week treatment with three potent direct acting antiviral agents (DAA) resulting in 100% SVR in genotype 1b HCV infected individuals that could increase compliance, and reduce costs, while reducing the required frequency of multiple doses and leading to a complete cure. He will also advocate for fully funded “HCV Test & Treatment as Prevention Programs” to eliminate HCV globally. In addition, he will discuss how he discovered the most commonly used drugs for HIV; the nucleoside antiviral agents Emtricitabine and Lamivudine. Finally, Ray will discuss recent efforts to develop HBV capsid effectors that may offer an opportunity to cure HBV, a virus that affects over 250 million people globally.­­
Matt FitzgeraldDo We Need a Theory of Healthy Eating?Many of the popular diets that Americans follow are based on sweeping theories that neatly separate food types into categories of “good” and “bad.” The Paleo Diet, for example, classifies foods humans are presumed to have eaten before the agricultural revolution as “good” and foods that are presumed to have entered the human diet within the past 12 millennia as “bad.” All theory-based diets share the common assumption that it is possible to predict the effects of different food types on human health on the basis of a single principle derived from general knowledge. None of these theories stands up to rigorous testing, however. In each case, there are discrepancies between the lists of foods that, according to the theory, “ought” to be healthy or unhealthy and those that actually are. What if we were to abandon a comprehensive theory of healthy eating and instead define it heuristically through the identification of eating patterns common to the healthiest humans? I will employ the science of self-organizing systems to explain why this approach is more sensible than the theory-based approach and will reference the dietary patterns of elite endurance athletes to identify universal dietary best practices for humans.
Allen Lim, Ph.D.Doped and Duped: Deviance, Coercion, and Irony in both Sport and MedicineThrough my own experiences working as a coach and scientist on the Pro Cycling Tour for athletes like Floyd Landis and Lance Armstrong, I will be discussing how the legal drugs the public are fed for better health are as dark, dirty, and ineffective as the illegal drugs used to enhance performance in sport. This discussion will be more human experience than science. I’ll be giving a point of view that is based on my own beliefs, which, at present, don’t match mainstream scientific consensus. But, consensus forming in science relies on skeptics. I will be telling stories, presenting evidence, and asking questions that make me very skeptical about drugs in both sport and medicine. I don’t believe doping improves athletic performance. In the world of professional sports, this view doesn’t make me a moralist, it makes me the village idiot. Likewise, I don’t believe the technocentric and reductionist paradigm of Western medicine is making us healthier. Instead, it is my belief that our reliance on this paradigm is only making us weaker and sicker. In our effort to make the world a better place, we must be mindful of the dark side of our ambition—a culture of deviance and coercion that I found deeply traumatic in sport and that I now see as the great trauma of modern medicine.
Grazia M. Cereghetti, Ph.D.Drp1: A Link Between ER Stress and ApoptosisLive imaging of mitochondria with fluorescent probes unraveled their restless shape restyling all along cell life. Chopping and reconstructing of mitochondrial membranes was soon attributed to large GTPases of the dynamin family and appeared to accompany crucial pathways, from the distribution of mitochondria to daughter cells during cell division, to making release of proapoptotic molecules from mitochondria easier during programmed cell death. Recently, fusion and fission events were shown to apply to other subcellular organelles, including peroxisomes. In addition, proteins modeling mitochondrial morphology were observed on other organelles. A single shared shaping machinery appears to be suitable to the coordination of relevant pathways involving different organelles. Here, we describe our recent discovery of the involvement of the fission protein Drp1 in shaping morphology of the endoplasmic reticulum: morphological defects impinge on ER performances, in particular the ability of the cell to couple ER stress and apoptosis.
Tim Harris, Ph.D., D.ScDrug Discovery and Development: It’s All about Human Genetics ReallyThe ability to stratify patients and their disease by understanding the genetic basis of their disorders is a very powerful paradigm for drug discovery and development. All the phenotypic tests that have been developed are all a consequence to some extent of the genetics of the patient. The biomarker literature is littered with false associations owing to small sample sizes and inadequate controls. In contrast, the analysis of inherited disease by the application of both Mendelian genetics and association studies with very large data sets has led to very robust findings. In other words, “Genetics never lies”. This important fact has driven, and will continue to drive, novel drug discovery, development and patient stratification. There are good examples for using somatic cell genetics for drug discovery in oncology (leading to crizotinib and vemurafinib) that are showing the way. The same concept applies to other diseases such as multiple sclerosis and amyotrophic lateral sclerosis. But it is more difficult.
John Swindle, Ph.D.Drug Discovery: Infinitely Complex but Don’t Overthink ItAbsent safe and effective therapeutics, many diseases remain untreatable or are treated with limited success. Why has the discovery and development of new drugs been so difficult? Setting aside our poor understanding of the human biological system, one significant problem with many small molecule drugs is that they lack sufficient selectivity for the intended target leading to unwanted and at times, unexpected side effects. Traditional discovery technologies rarely identify selective drug candidates because the technologies used typically focus on the catalytic or active site of the target protein – structures that are frequently conserved within a protein family or across a whole target class. Biotherapeutics begin to address this problem since they exhibit good selectivity. However, they pose a different series of challenges including complex manufacturing, poor absorption into cells, low tolerance and compliance and sometimes, adverse effects from unexpected individual immune responses. At CompleGen, we use a simple genetic based discovery system that does not depend on a deep understanding of biologic networks. Nonetheless the system can efficiently identify target selective small molecule inhibitors that differentiate targets even within highly conserved protein families. In most cases, these small molecule compounds target non-conserved regions of the protein and inhibit allosteric regulation rather than catalytic activity, hence the exquisite specificity. Consequently, our drug candidates have all the advantages of small molecules coupled with the target selectivity of biopharmaceuticals.
Yvonne Monique Kobayashi, Ph.D.Duchenne Muscular Dystrophy: A Not-So-Rare DiseaseDuchenne muscular dystrophy (DMD) is a rare and devastating muscle disease caused by mutations in the X-linked dystrophin gene, DMD. Since the first identification of the disease in the 1800’s, the clinical course of this complex disease has not changed; however, clinicians, scientists, and patients worked to improve the natural history of these patients. Together, we still continue to learn more about the patient and the disease. Novel therapies are continuously being investigated. One of the biggest gaps for testing new therapies for DMD and other diseases is the lack of verifiable biomarkers. Serum biomarkers for DMD and other diseases hold significant potential as objective phenotypic measures of disease state, deeper insights to disease pathogenesis, new therapeutic approaches, and responses to therapeutic interventions. Clinicians and scientists continue to learn from the history of DMD and past therapeutic approaches. The identification and use of verifiable biomarkers will provide a rich body of valuable information in the search for new diagnostic, prognostic, and therapeutic approaches for patients with DMD and other diseases.
Diana Chapman Walsh, Ph.D.Educating Our Smartest Kids to Tackle the Big Problems in HealthcareI was intrigued by the topic Larry Gold suggested in his email inviting me to speak, so I have taken it up as my title, with variations on his theme. I plan to reflect a bit on the nature of the problems we face--his “big problems”--in health care and beyond, a bit on the kind of leadership those problems demand, and a bit on the educational culture in which I think the needed leadership qualities have a chance of flourishing. I’ll draw on some experiences as a college president, on some readings, and on some of what I am able to see from a perch on the governing boards of five nonprofit organizations.
William J. Rutter, Ph.D.Empowering Individuals to Control Their Health Status: Improving the Efficiency of the Healthcare System at all LevelsThe explosive increase in knowledge of biology and medicine at the mechanistic level has not been accompanied by an increase in the efficiency of medical care. Indeed, innovations seem to increase medical costs rather than the opposite. The uncertainties associated with drug discovery and development, including clinical trials and regulatory issues, all combine to make biopharmaceutical efforts a risky business. Despite the high cost of drugs and medical devices, the major cost of healthcare is associated with “ care” itself. Payments are tied to procedures and treatment protocols, and the major healthcare plans support and perpetuate that system. My colleagues and I believe that empowering individuals to manage their health through specific diagnostic and software protocols, which organize health information from multiple sources, can catalyze change in the biomedical industry at all levels. We will present two Synergenics companies: Numera and ReLIA. Both companies aim to empower individuals to control their health, through prevention and effective monitoring, while encouraging more effective interactions with their physicians and health care providers.
Stephen Ansolabehere, Ph.D.Energy and Climate Policy and the Lessons for HealthcareIn 2009, the Obama Administration proposed major legislation to restructure two key areas of the American economy: health care and energy. Both present enormous challenges for American society in the decades ahead, and addressing the problems posed by each will require foresight and planning. We face a substantial transformation of the energy sector in the United States in order to deal with increasing demand, changing technology, the growing obsolescence of current energy facilities, and mounting local and global environmental problems. Building on recent reports issued by the American Academy of Arts and Sciences, this presentation discusses the path toward an alternative energy future, and its parallels to and implications for the health care sector.
Bob Weinberg, Ph.D.Epigenetic Programs and Cancer ProgressionThe current interest in sequencing the genomes of cancer cells has distracted attention away from the role of epigenetic programs, which may in the end be responsible for the lion’s share of distinct cancer cell-associated phenotypes. One type of epigenetic program derives from differentiation programs of the normal cells-of-origin of cancer cells, which continue to influence the phenotypes of derived cancer cells. A second type of program is represented by the epithelial-mesenchymal transition (EMT) program, which operates in normal epithelial tissues that undergo wounding and dominates the behavior of carcinoma cells at various grades of tumor progression. When activated by heterotypic signals that carcinoma cells receive from the adjacent tumor-associated stromal cells, the EMT program confers a variety of malignancy-associated phenotypes, including motility, invasiveness, a resistance to various therapies, an ability to disseminate to distant sites in the body, and tumor-initiating ability, the last being the trait of cancer-stem cells (CSCs). This association between stemness and the EMT program operates in a wide variety of normal and neoplastic epithelial cell types, and enables cancer cells to serve as founders of metastatic colonies. Experimental activation of the EMT program in primary carcinoma cells enables their dissemination and blocking of this program prevents such dissemination. As tumor progression proceeds in the mouse mammary gland, the Slug EMT-inducing transcription factor (EMT-TF) expressed in normal SCs is replaced by its paralogous cousin, Snail, albeit in a different cell layer. Accordingly, the resulting CSCs do not arise from normal tissue SCs. Residence of mammary carcinoma cells in epithelial (E) or mesenchymal (M) cell states holds important implications for their responses to immune attack: activation of anti-checkpoint immunotherapies results in blocking the growth of tumors composed of E carcinoma cells but not of M carcinoma cells. Hence, the current limitations of checkpoint immunotherapies in the oncology clinic may be due in no small part to the representation of more M carcinoma cells within tumors under treatment. These biological complexities reveal how limited are the insights gleaned from focusing exclusively on the somatically mutated genomes of cancer cells.
Paula L. Hoffman, Ph.D.Everyone Knows About Alcohol–But What Do We Really Know?Alcohol is an “addictive” drug, but its use is condoned by government, and it is used by many individuals who enjoy social drinking and never become dependent on it. However, about 7 percent of alcohol drinkers 18 years of age and older in the U.S. develop what is now called Alcohol Use Disorder (AUD). In addition, many men and women drink alcohol at “hazardous” levels, which can lead to organ damage and is responsible for more than 3 million deaths per year worldwide. AUD is psychiatrically defined by the presence of 11 signs, and the number of signs during a 12-month period defines the severity of AUD. These signs include the narrowing of repertoire to focus on obtaining, using, or recovering from alcohol effects; unsuccessful efforts to reduce alcohol use; alcohol use resulting in failure to fulfill major role objectives; continued use despite adverse consequences and craving (a strong desire or urge to use alcohol) (DSM-V criteria). Many of these criteria also apply to other addictive drugs, and alcohol can produce many of the same neurobiological effects as the other addictive drugs. But, alcohol also has unique characteristics and mechanisms of action in the central nervous system. The effects of alcohol in the brain derive from alcohol’s ability to interfere with the activity of the two major neurotransmitters, GABA (the major inhibitory neurotransmitter) and glutamate (the major excitatory neurotransmitter), and the interaction of these transmitters with other modulating systems that contribute to the rewarding effects of alcohol. Maladaptations of these systems occur with chronic alcohol use and lead to the signs and symptoms of AUD. However, not everyone who uses alcohol, even at hazardous levels, develops AUD. Numerous studies have estimated that the genetic constitution of an individual can contribute up to 50 percent of the likelihood of the development of AUD, and human genetic analyses have suggested particular subsets of genes that may underlie this vulnerability. A conceptual transition has occurred over the last 10 years, in that rather than looking for a gene responsible for complex phenotypes such as AUD, it has become common to consider that interacting genetic elements (i.e., networks of gene products) are responsible for the complex phenotype. Our current work uses a systems genetic approach to understand the transcriptional and signaling networks in the brain that influence alcohol drinking, a prerequisite for development of AUD. The characterization of this genetically controlled “brain connectome” promises to provide the basis for developing rational pharmacological approaches to reducing alcohol consumption and the craving for alcohol in individuals suffering from AUD. 
Scott MacDonnell, PhDExploring Cardiovascular Physiology to Uncover Novel Therapeutic Strategies Using Human Inducible Pluripotent Stem Cell Derived Cardiomyocytes and Human Engineered Cardiac TissuesBuilding more relevant human model systems to explore complex cardiovascular biology is essential as we work to uncover new therapeutic treatment options for heart failure. Dr. MacDonnell will share the rationale and development of human-based cardiac cellular and tissue model systems.
Neal Copeland, Ph.D.Exploring the Evolutionary Forces Driving Tumor DevelopmentCancer genome sequencing has identified a level of complexity unimaginable only a few years ago. We now know that cancer often develops through a step-wise but non-linear process of clonal evolution, generating a bewidlering array of inter- and intra-tumor heterogenetiy, with only a limited number of driver mutations shared among tumors of even the same histological subtype. We also know that cancer-specific alterations can occur at a number of regulatory levels, which can influence gene function and expression. It is perhaps not surprising then that recurrent driver mutations in coding genes found by whole-exome or whole-genome sequencing sometimes constitute only a small contribution to the genetic component of cancer. It is therefore important to use other methods for characterizing cancer genomes that are better suited to capturing the full complement of the genetic complexity present in tumor cells. One powerful and unbiased method for capturing this genetic complexity involves transposon mutatenesis in mouse models of cancer. Transposons can identify genes that are somatically mutated in human cancer as well as those that are deregulated by transcriptional or epigenetic means. In my presentation, I will explain how transposon mutatenesis is helping us to elucidate the evolutionary forces driving tumor development and how this information might be helpful in developing new treatments for human cancer.
Mathias Uhlen, Ph.D.Exploring the Human Protein Atlas to Study Biology and DiseaseThe human genome has approximately 20,000 protein-encoded genes. An import quest for the future is to characterize the expression, localization, and modification of all the human proteins. The current version 9.0 of the Human Protein Atlas (www. proteinatlas.org) contains more than 15,000 validated antibodies targeting 12,200 genes corresponding to more than 60% of the protein-encoded genes in humans. The Protein Atlas contains more than 12 million high-resolution images generated by immunohistochemistry and confocal microscopy. The antibodies have been generated to regions of low homology. The long term objective is to generate paired antibodies towards the protein targets with separate and non-overlapping epitopes. Pilot projects have been initiated to also generate recombinant affinity reagents, a pilot version of a Rodent Brain Protein Atlas, and to study human biology. In addition, we have developed a targeted MS-proteomics strategy based on the recombinant protein fragments (PrESTs) generated within the frame-work of the Protein Atlas project. We have used the human protein atlas to study the global protein expression patterns in human cells, tissues and organs, as well as a discovery tool to find potential biomarkers for diseases, such as cancer.
Mark Fishman, M.D.Extreme Clinical Phenotypes in Drug Discovery and Medical EducationDiscovery of impactful new medicines rests upon a base of strong fundamental science. Translation from discovery to therapeutic takes decades, not so much because drug discovery per se is hard (which it is) but because the relevance to disease is obscure. The clearest translational path, we have found, often is via a rare disease, where patients have a strong phenotype and genetic predisposition, and in whom clinical trials can be brief and convincing. Subsequently, it is feasible to expand utility of such novel therapeutics to subsets of disorders that are more common and heterogenous. This approach can work quite well in oncology and immunology, where we have a reasonable grasp of underlying molecular pathways. But how can we approach diseases such as autism, where genetics are complex, expressivity variable, and which are subject to powerful phenotypic influence from development and the environment? We are exploring ways that computer vision can be used to quantify behavior in the zebrafish, and lead to understanding of the fundamental biological principles of social behavior and, potentially, the discovery of new therapies for psychiatric disorders. Physicians-in-training routinely encounter patients with phenotypically extreme disease whose disorder may speak well to underlying pathways. Unfortunately, residents today have little time to turn clinical observation into new scientific directions because they must deal with increasing acuity of care, rapid patient turnover, and burdensome documentation needs. As part of the medical residency training program at the Massachusetts General Hospital (MGH), we have introduced a rotation dedicated specifically to patients with extreme and/or confusing constellation of phenotypes. Residents synthesize data, including from scientific and clinical experts around the world, and formulate testable hypotheses about the underlying molecular pathways. These investigations have proved clinically valuable to the patient and have led to novel lines of fundamental investigation.
Elodie Ghedin, Ph.D.Frenemies: Microbial Interactions in Respiratory DiseasesNo microbe exists in isolation. When we become infected with a respiratory pathogen, like influenza, our bodies harbor not just the current influenza strain making the news; they share space with other drug-resistant variants and bacterial species. Together, these “bugs” set off a complex set of interactions that impact viral evolutionary dynamics and skew clinical outcome and can lead, for example, to pneumonia. They also keep bad company with other infections that likewise can affect the host’s immune response, such as HIV, which can modulate the interactions among the members of the respiratory microbiome. For all the damage they do, however, these interactions in the human respiratory tract are essentially uncharted territory in the scientific realm. Our work has begun to make inroads into this territory by characterizing in animal models and clinical samples the microbial ecology in the upper and lower respiratory tract in the context of two infections—influenza and HIV—and lung diseases like chronic obstructive pulmonary disease (COPD). What we have found so far is a restructuring of the microbial environment during disease, including interactions among and between bacteria and fungi. The latter, which are often present at a much lower abundance, nevertheless play a leading role in the organization and stability of the microbial community. I’ll show how this works and how we plan to probe the microbial environment and networks of interaction so that we can develop predictive modeling of disease severity, potentially leading to novel therapies.
Leslie Leinwand, Ph.D.From Bench to Bedside: The Role of Science in Treating a Deadly DiseaseLeslie was fascinated by human genetics by the time she went to college and has been passionate for decades about unraveling genetic contributions to disease. A long path that took a few twists and turns ultimately led her to a longstanding goal: to develop treatments for genetic diseases where none existed. It started with mapping genes to human chromosomes. The next phase led her to be an academic scientist. At the University of Colorado, Leslie’s lab studied how certain muscle mutations lead to disease. In other words, how a small DNA change leads to an often fatal crisis in the heart. It is this kind of work, sometimes called basic research, that lays the foundation for the bridge from bench to bedside. The disease that her lab continues to study is called familial hypertrophic cardiomyopathy, a long way of saying a big sick heart that runs in a family. This disease is most notable for killing young athletes, sometime with no prior symptoms. Geneticists identified what genes, if mutated, cause this disease. What Leslie will do today is to share how a great deal of searching led to the first FDA approved drug in 2021 by MyoKardia, the company she co-founded in 2012. MyoKardia has since been acquired by Bristol Myers Squibb. Prior to this drug, the only effective treatment for this disease was a heart transplant. In fact, familial hypertrophic cardiomyopathy is the leading cause of sudden death in young people. Once tools became available, it was possible to determine which members of a family carried that mutant gene, frequently after someone in the family suffered a cardiac arrest. Having the knowledge of your genotype is an important advance. But, what do you do with that information when there is no treatment? Many were told to stop athletic activity; others were followed by a cardiologist, but this was a very anxious way of life. Leslie’s talk will tell the story of finding a treatment for a fatal genetic disease of the heart.
Joy Hirsch, Ph.D.From the Autistic Brain to the Autistic Mind and BeyondAutism is a complex developmental spectrum disorder currently estimated to affect as many as 1 in 100 children, and is 4 times more prevalent in males than in females. It is defined by a constellation of behavioral symptoms that include limited social interactions and profound language disabilities. However, the underlying neural causes for these severe disabilities are only recently beginning to be understood. Due to both the high prevalence and the severity of the disorder, this gap between understanding neural mechanisms and treatment constitutes a critical unmet clinical need. In this talk I will address the question of why language and interpersonal interactions are so difficult for autistic individuals based on previous neuroimaging studies, and describe current and future research directions aimed at early diagnosis and therapeutic approaches.
Sarah Burgamy, Psy.D.Gender Re/Evolution: Navigating Developmental, Psychological and Social Facets of Pink and Blue in a Purple WorldHow do you know your gender? From Time to People, cradle to grave, few aspects of human identity have exploded into our current collective and visible consciousness as transgender, gender variant, gender expansive, and gender creative identities across the human lifespan. Is this a new phenomenon in human development? Is it identity fad or phenomenon? What are we to do with the upending of our psychological and sociocultural organization of “pink” and “blue” when the world appears to have gone “purple”? Given the inherent nature of human neuropsychology to organize, categorize, identify, and associate, what are we to do with the potential end of a binary system of gender—boy/girl, man/woman, male/female—when few aspect of human identity have as much sociocultural “currency” as gender, gender identity and gender expression? The veritable “alphabet soup” of sex, gender, sexual orientation and gender identification terminology only further appears to confuse and confound our collective wisdom regarding these aspects of development—LGBTIQQA… Welcome to the gender re/evolution.
Terry Fry, M.D.Gene-Modified T Cell Therapy for Pediatric Cancers: Where Do We Go From Here?T cells genetically modified to express chimeric antigen receptors are highly effective at eradicating malignant B cells resulting in recent approval for the treatment of refractory B cell acute lymphoblastic leukemia in children and B cell lymphoma in adults. However, a substantial number of patients will relapse or not respond and extension of CAR T cell therapy to other forms of cancer has met challenges. Terry’s presentation will review the status of current CAR T cell therapy for human cancer;and, highlight strategies to optimize CAR T cells to improve remission durability and to address barriers to success in other forms of cancer.
Jennifer McCreaGenerosity Becomes YouThere are more than enough resources—money, networks, time, creativity, life experiences—to be mobilized in support of all of the important work to be done in the world. We simply block them through various obstacles, like our relationship with money, power dynamics, and fear that the problems are too big. In this presentation, we'll identify and unpack the various obstacles and learn how to remove them to get resources moving quickly, efficiently, and, most importantly, joyfully to your causes.
Allan Jacobson, Ph.D.Genetic Nonsense: From Bench to BedsideThe genetic code includes specific “start” and “stop” signals that respectively demarcate the beginning and end of the information comprising a gene. Mutations that cause premature stops are called nonsense mutations and genes which harbor such mutations are essentially nonfunctional. Such genes still produce messenger RNA (mRNA), the template for protein synthesis, but cellular quality control pathways ensure that their defective mRNAs are rapidly eliminated. We have been studying an mRNA surveillance pathway in yeast that we dubbed nonsense-mediated mRNA decay (NMD) because it targets and degrades the mRNAs encoded by genes harboring nonsense mutations. The trigger for NMD is premature translational termination by the ribosome and this led to the recognition that premature translational termination and normal translational termination must differ mechanistically. One consequence of this difference is that it was possible to use genetic tricks in yeast that allowed the ribosome to bypass or “read through” premature stop signals, but not normal ones, thereby restoring function to genes otherwise inactivated by nonsense mutations. Such restoration is known as nonsense suppression. Given the large number of individuals collectively afflicted by nonsense mutations (15-20% of the alleles of all inherited diseases, including those causing cystic fibrosis [CF], Duchenne muscular dystrophy [DMD], hemophilias, and lysosomal storage disorders), a therapeutic approach to their suppression could be of considerable medical benefit. Stuart Peltz and I thus attempted to apply the principles of yeast nonsense suppression to pharmaceutical development for humans. We started PTC Therapeutics Inc. and the company developed ataluren as a novel therapeutic for genetic disorders attributable to nonsense mutations. Encouraging results in clinical trials of patients with nonsense-mediated CF and DMD suggest that ataluren not only encompasses a new approach to treating these two diseases, but also has the potential to treat multiple life-threatening inherited disorders.
Charles R. Middleton, Ph.D.Giving the Patient a Choice: Democratizing Medical ServiceWith the expansion of healthcare that is attendant on the passage of the Affordable Care Act and the aging of the population generally as the baby boomers hit 65 at the rate of 10,000 per day, there will be a premium on providing high quality, readily accessible, affordable healthcare. This presentation will look at the emergence of highly effective healthcare teams and the role that pharmacists will play in one key aspect of this process: medication therapy management. It will focus on the recent developments in this area of care and also on the advantages of locating these teams in non-traditional sites that are accessible to patients seven days a week, twenty-four hours a day.
Casey Greene, Ph.D.Gone FishingAt the 2016 GoldLab Symposium, Tom Blumenthal described how our understanding of the world, and specific maladies, improves when scientists metaphorically go fishing. However, the term "fishing expedition" is primarily used as a pejorative when applied to scientific projects. I'll provide my perspective on why science could become more accurate and efficient once we rescue this term. Scientific fishing expeditions are valuable because they can take research in new directions. Looking at other people’s data can provide researchers with a new perspective on their area of study. But analyzing individual experiments from other labs is difficult. Instead of single datasets, our lab builds "nets" that we and other scientists can use to go fishing in large collections of public data comprised of many experiments. We've put these to the test on a few recent expeditions, and I'll share one or two stories from our own work. Finally, I'll discuss why I think large collections of public data are a uniquely valuable resource for the process of scientific discovery. Our fishing expeditions are possible because of the robust data sharing culture in genomics. This has allowed a public data commons, akin to the medieval English common lands, to emerge. It may seem obvious that scientists should always share the data that support their conclusions. But this point of view remains contentious in parts of the scientific community. I'll highlight the important role of data sharing and reanalysis in the process of scientific discovery. I'll discuss recent efforts to recognize those who participate in this sharing and reanalysis ecosystem.
David M. Lawrence, M.D.Growing Pains: The Evolution Toward Consumer-Driven MedicineThe piece-parts now exist. The context supports disruptive change. Advances in molecular science and personalized medicine will further increase consumer demand. Private investors are seeking promising opportunities in care delivery. Major non-healthcare players are looking for opportunities to bring their know-how in scale, high performance, and technology infrastructure to health care. What stands in the way of this transformation; of the creation of a robust new front end to health care: the “Consumer Health Ecosystem?” Several critical barriers will be identified and approaches to addressing them discussed, including: consumer readiness, the creation of successful business models, the need to deliver disruptive levels of performance and cost compared to the traditional care delivery solutions, the resistance of the traditional care system to changes that threaten their well-being, the ability to scale, and the ability to create integrated primary health platforms that combine the individual applications.
Harriet WarshawHaving the Conversation: Is It Really That Important?Too many people are dying in a way they wouldn’t choose, and too many of their loved ones are left feeling bereaved, guilty, and uncertain. It’s time to transform our culture so we shift from not talking about dying to talking about it. It’s time to share the way we want to live at the end of our lives. And it’s time to communicate about the kind of care we want and don’t want for ourselves. The Conversation Project is dedicated to helping people talk about their wishes for end-of-life care. We believe that the place for this to begin is at the kitchen table—not in the intensive care unit—with the people we love, before it’s too late. Together we can make these difficult conversations easier. We can make sure that our own wishes and those of our loved ones are expressed and respected. If you’re ready to join us, we ask you: Have you had the conversation?
Jandel Allen-Davis, M.D.Health: The Heart of Health Care ReformSince March 2010, the nation has worked hard to implement the Affordable Care Act, the largest expansion of health care coverage and access since the creation of the Medicare and Medicaid programs in 1965. This landmark legislation continues the journey of providing health care to Americans while attempting to reform our inefficient and expensive health care delivery system. Yet, there are residual problems and issues regarding “health” that the law cannot and does not address. Factors that affect our health status and impact the cost, quality, and experience of people seeking care are not always obvious and are described as the “social determinants of health,” defined by the World Health Organization as circumstances in which people are born, live, work, and age, as well as the systems established to deal with illness. “Fixing health care won’t fix health care.” But what if there were a fertile verge, where the traditional health care system and the innovative entrepreneurial community meet to create new processes and new technologies that address health and improve the health care system? Let’s imagine what’s possible and explore the components of this “green space” or “blue ocean.”
Ruth Crowe, M.D., Ph.D.Healthcare on the Ground: New Challenges for PhysiciansThe global enterprise of human health has changed rapidly and radically over the past 25 years. Diverse forces are altering the landscape - economics, changing demographics, and technological breakthroughs shift the interests of the stakeholders responsible for keeping us healthy: patients, physicians, payers, policy makers, and innovators. Our global health economy is growing faster than the gross domestic product. The question is: is this all leading to better health? The roles of health care providers are evolving to address the changing needs and perceptions of our society. For many reasons, the goal of physician training and practice is transforming from treating illness to managing health in order to meet the challenges of the world ahead.
Peter Ganz, M.D.High Levels of Growth Differentiation Factor 11 Are Associated With Lower Prevalence of Left Ventricular Hypertrophy, Heart Failure and MortalityBlood levels of growth differentiation factor 11 (GDF11) decline in mice with age, accompanied by development of cardiac hypertrophy. Treatment of old mice to restore GDF11 to youthful levels regresses cardiac hypertrophy (Cell 2013: 153, 828–839). Thus, GDF-11 is a potential therapeutic target for preventing or reversing left ventricular hypertrophy (LVH), but no data are available on GDF-11 in humans. To determine whether circulating GDF-11 levels are associated with LVH, heart failure, or death in humans, we conducted a prospective cohort study (Heart and Soul cohort) in 885 outpatients with stable coronary heart disease (CHD) recruited from 12 clinics in the San Francisco Bay Area between 9/00 and 12/02. We measured plasma GDF-11 level in baseline blood samples using an aptamer-based proteomic platform (SOMAscanÔ, SomaLogic, Inc.) and assessed LVH by echocardiography. We followed subjects for heart failure (HF) hospitalization and all-cause mortality for an average of 8.9 years. LVH was present in 40% of our cohort. Both in unadjusted models and after multivariate adjustment, high GDF-11 levels were associated with lower prevalence of LVH. A total of 161 heart failure hospitalizations and 353 deaths occurred during follow-up. High levels of GDF-11 were associated with lower rates of both HF hospitalizations and deaths. In the Heart and Soul cohort of patients with stable CHD, higher levels of GDF-11 are associated with lower prevalence of LVH and lower rates of heart failure hospitalization and death. These findings are consistent with GDF-11 as a circulating factor that protects against LVH and reduces cardiac risk in humans.
Patti Brennan, R.N., Ph.D.High-Reliability, Person-Centered Health Care: It Can’t Happen without the National Library of MedicineAs health care migrates from the hospital and clinic to the home and community, so to must the National Library of Medicine (NLM). In 2017, the NLM established NLM Strategic Plan 2017-2027: A Platform for Biomedical Discovery and Data-Powered Health, which will position the Library to carry out its congressionally mandated mission and support the important work of the National Institutes of Health (NIH) by creating a future in which data and information transform and accelerate biomedical discover and improve health and health care. The strategic plan focuses on three essential, interdependent goals that will help guide the Library’s priorities over the next 10 years its mission is to collect and integrate an expanding set of information resources, and enables them to be analyzed by tools emerging from the informatics and data science research front. Those goals are to: 1. accelerate discovery and advance health through data-driven research; 2. reach more people in more ways through enhanced dissemination and engagement; and 3. build a workforce for data-driven research and health. What’s new, different, and exciting for the NLM here is: … a discovery process energized by the concepts of open science … a commitment to engage with persistence … a recognition of the central role of people and patients in the workforce of the future
Wendy Sue Swanson, M.D., M.B.E., F.A.A.P.How 140 Characters Are Changing Health CareDigital tools are auspiciously changing health care forever. It's a novel time when it comes to seeking advice about your health. While widespread social media and evolving online networks change access to information for patients and their families, they also dramatically shift physician and provider responsibilities. Improved communication is the future of smarter health care. With the change emerging technologies have presented to everyday life, clinicians must problem-solve with patients as partners and share expertise unlike ever before. We’ll discuss how new technologies wed with patient involvement are disrupting the health community. Through my work as a pediatrician, my experience sharing health information in social and traditional media, and my leadership running a team in digital health and innovation at Seattle Children’s Hospital, I’ll share lessons learned, tips for technology implementation, and the rich opportunities that reside in patient and family co-designed solutions.
Craig J. MundieHow Machine Intelligence Could Accelerate Holographic Medical ImagingThis talk is a short primer on the evolution from classical statistical analysis through machine learning and ultimately toward Artificial General Intelligence. With this in mind, Craig will demonstrate new ways of doing holographic medical imaging and explain how these techniques can be put into production in the future by exploiting these evolving capabilities in machine intelligence. He will demonstrate the current state of the are in holographic medical imaging using Microsoft Hololens and some images prepared at the Case Western Reserve University.
Robert Duke, Ph.D.How We Learn… and How We Don’tChanges in the functional capacities of learners are visible manifestations of changes in the physical structure of the brain. Although we seldom think of learning experiences as brain-reorganization activities, they most certainly are precisely that. We will look at why formal education often fails to make substantive and lasting changes in how learners think and behave, and we’ll consider how to design learning experiences that lead to advantageous changes in cognition, affect, and behavior, all of which are components of expertise in every discipline.
Richard A. Spritz, M.D.Human Genetics and DiseaseThe past 30 years have seen a revolution in knowledge of the basis of genetic disease. While early efforts focused on single gene, Mendelian disorders, efforts over the past decade have focused on common, complex diseases, empowered by new technological and statistical approaches in genomics and genetics. From linkage studies to candidate gene association studies to genomewide association studies (GWAS) to genome sequencing, each new approach to complex disease has yielded only partial success, the result of both technical limitations and the biological and genetic nature of the problem. GWAS have, for the first time, yielded remarkable successes for many diseases, identifying over 2000 confirmed disease susceptibility loci and/or causal variants. Nevertheless, for essentially all diseases studied the total loci/variants identified appear to account for only a small fraction of the total genetic risk of the disease. Progress towards identifying the genetic causation of complex disease will be considered in the context of the strengths, weaknesses, and flaws of these experimental approaches, with a view towards the near future based on high-throughput DNA sequencing of candidate genes and full genomes.
David Housman, Ph.D.Huntington’s as a Metaphor and a Serious DiseaseIn my presentation I will discuss with you my experience in unraveling the challenges presented by several diseases which are each caused by a common mechanism, the unstable expansion of a three base pair repeat in DNA including Huntington’s Disease, myotonic dystrophy and fragile X syndrome. I will visit the ways in which DNA sequence expansion impacts on the lives of people and families in which these highly mutable DNA sequences are transmitted from one generation to the next. I will discuss with you the challenges presented in attempting to provide effective therapeutic intervention for these disorders. I look forward to dialogue with you on the issues, scientific, social and ethical presented by the continually improving understanding of this group of genetically based challenges to us and our families.
Melissa Haendel, PhDIf We Cannot Count Rare Disease Patients, They Will Not CountThe phenotypic, genetic, and environmental characteristics that define a given disease are established in different demographics, regions, contexts, and databases. Different knowledge sources model the attributes of a disease and their relationships differently. For example, one resource may include the variant-to-disease association, whereas another records only the phenotypic features and their onset associated with the disease. Further, patients are an often underrecognized source of disease knowledge. As our collective knowledge advances, there is also a philosophical debate about what constitutes a disease, and when to “lump” or “split.” Our analysis has revealed that prior estimates of the number of rare diseases, at ~7,000, dating back to the 1983 United States Orphan Drug Act, grossly underestimated the number by approximately 3,000 diseases. A rare disease harmonization initiative, Mondo, aims to reconcile rare disease knowledge globally. Patient-level characterization supports improved data sharing and disease definition. The end result is a suite of resources that can be used in diagnostic and discovery tools, where every patient will have an equal opportunity for a diagnosis no matter where they live.
David SnowImproved Interventions: Drug Use and Best PracticesMedco is a leading pharmacy benefit manager (PBM), with the nation’s largest mail order pharmacy operations. Through advanced pharmacy, Medco improves the health and lowers the total cost of care for clients and their members, helping to ensure that millions of Americans have access to affordable, high-quality prescription healthcare. No two people respond to the same drug in exactly the same way. In a typical population, there can be as much as a 20- to 30-fold variation in responses to a particular drug. Among the key reasons for such a wide variance are the genetic differences between individuals. Tests for these genetic variations offer physicians a set of powerful predictive tools. By helping to anticipate a patient’s response to a medication more precisely, these tests can help physicians provide truly personalized medicine—selecting the right drug and the right dose for the right patient more quickly, safely, and effectively.
Michael J. Joyner, M.D.Is Reductionism Killing Biomedical Research?Biomedical research has been increasingly informed by the reductionist notion that genotype=phenotype. This view persists even though the “common-disease common-variant” hypothesis has been rejected as an unintended and unexpected finding of the Human Genome Project. It also reflects deep ignorance of ideas from fields like integrative physiology and epidemiology on biological redundancy and the nature of human phenotypic variation. In parallel, the genotype=phenotype worldview has also led to the breeding or engineering of rodent models where genotype does equal phenotype. These models then lead to false discoveries of treatments or “cures” that fail in clinical trials. In my presentation, I will critique both the current biomedical research landscape and discuss alternate approaches.
Molly BurhansIt’s the End of the World as We Know It (and I feel fine)Despite dire warnings about human-driven global ecosystems collapse, our efforts to curb environmental destruction continue to fall short. What we do over the next decade will determine the fate of life on earth. Human’s unique physical and cognitive capacities have enabled our increasingly efficient exploitation of the environment through technology. Civilization’s advancement relies on the concomitant development of technology and science. These advances have improved the quality and duration of life for an increasing percentage of the human population. They have also led to our current planetary predicament. Technology and science today allow us to measure and track the state of our environment. We now understand the extent of damage caused by human activity and the critical situation we find ourselves in. The continuation of civilization will be enabled not by our collective regression, but by using our best technology, most advanced science, novel collaborations, and creativity to reframe our relationship with nature. GoodLands is one of the most internationally recognized emerging efforts among an increasing number of institutions, organizations, and individuals whose work embraces this integrative approach. Molly Burhans is the founder of GoodLands. GoodLands is a social enterprise that helps organizations use and manage their properties to restore ecosystems and increase the well-being of people in their communities. GoodLands’ model has been recognized by the United Nations as one the most innovative, feasible, and scalable approaches to ecosystem restoration. It uses cutting-edge technology to integrate a community’s needs and ideas with a foundational understanding of their property portfolio’s current and potential impacts. Our solutions incorporate emerging research from public health, environmental sciences, and economics. GoodLands services were initially developed for the largest nongovernmental landholder in the world; the Catholic Church. Molly quickly learned that The Church also had not updated their record-keeping systems in a long time. It turned out that the Vatican’s last map update was during the Holy Roman Empire. Before the age of thirty, Molly led the development of the first digital map of the Catholic Church in history. She has since received Papal approval to trial-run a geographic institution in the Vatican. Goodland's created a climate solution that can be used to transform my organization’s real estate portfolios into positive forces for planetary change. The story behind how this all came to be is a wild adventure that has led Molly through the halls of Vatican palaces, slums in Nairobi, forested mountains owned by monasteries, and beyond. Like most of life’s great stories, this one begins with DNA replication stress.
Jonathan Shay, Ph.D.JUST ONE CRITTER: Brain, Mind, Society, Culture at the Same Ontological LevelPhilosophic conclusions from work with psychologically and morally injured combat veterans: brain, mind, society, and culture are co-evolved. The four encompass the complete human phenomenon, but are not reducible to the physical brain. None of the four is ontologically prior to the others. All four are each other’s environments with obligatory cross boundary flows, each with each in both directions. Rigorous, but non-reductionist interdisciplinary research in the vein of “EvoDevo” in embryology is called for in the study of the human phenomenon. Moral injury is present when the following three things are present: Betrayal of what’s right (according to the local culture) by someone who holds legitimate authority (in the social system) in a high stakes situation (the stakes are held and their changed condition anticipated and appraised in the mind). The body (mainly run by the brain) codes moral injury as physical attack and responds accordingly.
Jian Han, M.D., Ph.D.Learning from the Best Doctor in the World: Our Immune SystemThe process of developing a diagnostic is slow and expensive because identifying disease signal requires knowledge, and detecting the signal relies on technologies. A shortcut to this classical approach is to learn from the best doctor in the world, i.e., our immune system. In nature, our immune system has already acquired the skills to diagnose and treat diseases. Each of our immune cells, T or B cells, is equipped with a disease sensor, a receptor that recognizes and binds to disease antigens. Human beings are capable of making an astronomical number of receptors by shuffling and recombining a small group of genes. For the past ten years, we have been developing high throughput sequencing methods to study immune repertoires. We have studied more than 40,000 normal and patient samples and our database accumulated several billions of receptor sequences. We have developed many clinical applications. For example, we developed the Sharing Index for diagnosing diseases. The Sharing Index describes a person's immune repertoire overlapping with a disease signature; we have developed the Delta Index for treatment monitoring by measuring the repertoire turnover rate; we have developed the Diversity Index for evaluating repertoire diversity and capacity. We have also developed the Response Index that can recognize those responding to cancer immune therapies. One exciting application is the Wellness Index. Instead of evaluating health status by referring to diseases, we measure health by analyzing immune reserves. To make these applications widely available, we have developed a fingertip blood collecting method and lab automation solutions. We also developed a mobile app, allowing consumers to have direct access to the technology. The repertoire sequencing method could become "the ultimate diagnostic": taking one non-invasive sample, running one test, detecting many diseases. Our immune system, like our national defense, needs resources and has a budget. When we were young, our immune system had the maximum capacity and focused on fighting external infectious agents; when we get older, the immune system had the maximum efficacy and focused on maintaining internal integrity. To sustain health, therefore, is to balance these needs, managing the transitions, and to do so without breaking the immune bank.
Tom CathcartLogic, Science, Death, and Trolley SafetyTom Cathcart will explore the intriguing connections between 1) logic, 2) science, 3) death, and 4) trolley safety, while demonstrating how to monetize a 1961 bachelor’s degree in philosophy in today’s global economy.
David M. Lawrence, M.D.Looking Back: Peeking Into the FutureAt the first GoldLab Symposium, Dr. Lawrence argued that a “consumer health ecosystem” was emerging that marries ubiquitous information and communications technologies, advancing analytic sophistication, molecular science, and the growing challenges the traditional care system faces in meeting the needs and expectations of the population. In the current session, Dr. Lawrence will review the progress towards the creation of that new ecosystem. He will discuss the implications of the presentations at the 2012 Symposium for addressing the needs of the population and offer additional observations about the direction of the care delivery transformation now underway.
Sendhil Mullainathan, Ph.D.Machine and Human Intelligence: Algorithms as a Source of Bias or InsightAlgorithms can be useful aids in medicine, but they are not foolproof and without bias. This presentation uses three “stories” to illustrate broader lessons for AL and medicine. The key takeaways from these compelling stories is that 1) Data not algorithms are the scarce resource; 2) AI breaks because the data is broken; 3) unrepresentative data can lead to biased results; and, 4) data can be used appropriately for prediction, but not emulation.
William Robinson, M.D., Ph.D.Malignant Melanoma: The Tumor That Used to Give Cancer a Bad NameMalignant melanoma is more than just a skin cancer. It is primarily the result of damage to the melanocytes from intense sun exposure in childhood and adolescence. These transformed melanocytes have the capacity to invade the blood and lymphatic system and spread widely, if not caught early. Unlike many other cancers, once melanoma had spread beyond the skin, standard treatment is usually ineffective. A number of laboratories have recognized that melanoma cells have the ability to “paralyze” the immune response—particularly the cytotoxic T cell response—via several mechanisms. At the same time, understanding of the molecular events that occur with the initiation and progression of melanoma has led to the development of new molecularly targeted therapies, particularly agents directed against mutated BRAF. Unlike the immune therapies, which have to be given intravenously, these targeted agents can be given by mouth often with dramatic clinical responses. Combinations of targeted and immune therapies are now being investigated in advanced disease. In the space of 10 years, malignant melanoma has gone from the most dreaded cancer in humans to a model for development of more rational and effective cancer treatment.
Gene Robinson, Ph.D.Me to We: Searching for the Genetic Roots of SocialityTrue societies are very rare in biology, but have evolved repeatedly in a group of insects that include the ants, bees, and wasps, with the honey bee widely considered a paragon of sociality. In this lecture, I will use the honey bee and related bee species to demonstrate how the new science of genomics enables the study of social life in molecular terms, with examples of mechanisms relating selfish behavior that have evolved to promote cooperation, and connections between socially responsive genomes and human health.
Nebojsa Janjic, Ph.D.Measuring Proteins with DNA. Twisting the Central Dogma for Better Understanding of Biology.Information in biology, according to the central dogma, flows in a defined order: DNA, the master copy that contains all genes, is transcribed to RNA, which is then translated to proteins. It is proteins, the final product of this process, that execute most of the instructions encoded in the genes. Unlike DNA, which is relatively static through life, protein composition changes dynamically as the organism goes through various stages of development, responds to a variety of stimuli, and cycles through health and illness. Much of biology is driven by interactions among three-dimensional objects. Through shape recognition, enzymes transform their substrates, cell-surface receptors transmit signals after binding to their ligands, ions travel through pores of precise dimensions, and genes are activated by transcription factors. To better understand biology, we need a large collection of shapes with which to measure other complementary shapes. In humans, there are 20,000 genes that encode proteins. If we want to fully understand dynamic changes in the body, measuring many proteins at the same time is crucial since proteins do not work in isolation but rather operate in networks. For this task, we have employed aptamers, affinity reagents made of single-stranded DNA. The realization that a large collection of sequences of single-stranded nucleic acids can be thought of as a large collection of shapes, from which rare molecules capable of binding to other molecules with high affinity and specificity can be selected, arose independently in two labs. This notion, initially considered to be of questionable utility, proved to be both robust and applicable to a wide range of molecular targets. Over time, aptamers have been improved through chemistry to incorporate molecular features typically found in proteins, which further expanded the range of molecular targets for which a useful aptamer can be identified. Three decades on, aptamers have found many uses in research and medicine. They have also turned out to have several unique advantages for simultaneous measurement of many proteins, which has led to a better understanding of health and wellness, as well as progression to disease. The common denominator in this adventure has been the commitment to ask open-ended questions, to make and test all possible solutions, and to view biology as being more complex and surprising than we often appreciate.
Evelyn Resh, M.P.H., C.N.M.Men, Women, Sex, and Power – How Health, Confidence and Pleasurable Living Support Sexual DesireMaintaining sexual desire throughout life can bring angst, sadness, and confusion to men and women of any age and in any stage of life. This lecture applies a new paradigm to describe the necessary prerequisites for sustained sexual desire, health, and satisfaction – regardless of age or partnered status. Six markers of emotional well-being and a commitment to leading a deeply sensual life on a daily basis are explored as necessary ingredients for sustained and satisfying sexual engagement. The importance of prioritizing health, giving and receiving undivided attention to ones’ self and beloved, and the integration of daily sensual sacraments are included in the lecture content. The inherent sexiness of self-empowerment, confidence, and health and their connection to sexual desire are included in the lecture content. A review of the coercive and destructive behaviors that erupt in the absence of emotional health and confidence and which lead to a loss of interest in sex altogether will be included. The lecture concludes with suggestions and recommendations for keeping ones sexual identity and activity alive, well, and easily accessible.
Jane Salmon, M.D.Mice and Mothers: Understanding Pregnancy Complications in Patients with AutoimmunitySystemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and presents during their childbearing years. Pregnancy in these women is dangerous both for mother and offspring, and, in the past, patients were advised not to have children. Among complications frequently seen in women with lupus is preeclampsia (also known as toxemia of pregnancy), preterm birth, markedly underweight newborns, and fetal death. Identifying women destined for complications remains challenging and limits our ability to counsel and care for pregnant lupus patients. There is currently no effective treatment for women with these high-risk pregnancies; treatments to prevent poor pregnancy outcomes require an understanding of mechanisms of injury. Our research in an animal model that mimics the human condition shows that the blockade of well-established mediators of inflammation prevents adverse outcomes. To translate these discoveries to lupus patients, we launched the PROMISSE Study (Predictors of Pregnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) to determine which pregnancies were at highest risk for adverse outcomes. Over 20% of pregnancies in patients with SLE resulted in an adverse pregnancy outcome. We discovered a specific auto-antibody that can be detected in the blood before pregnancy or in the first trimester, confers a 10-fold increase in risk of complications. Furthermore, we found that early in pregnancy, measurable alterations in the balance of angiogenic factors (proteins that circulate in blood, promote proper placenta development, and are required to maintain the health of the mother’s vascular system) are highly predictive of preeclampsia and other pregnancy complications. The results of the PROMISSE Study provide models for early risk stratification to allow physicians to identify patients early in pregnancy who are at low risk and reassure them that their pregnancies were likely to be uncomplicated and their babies healthy. Conversely and importantly, we can reliably predict which patients are destined to have poor pregnancy outcomes, and we are working to offer patients at the highest risk an experimental therapy to prevent placental dysfunction. Treatments to prevent poor pregnancy outcomes require an understanding of mechanisms of injury. Experiments in mouse models have enabled us to embark upon a trial of a potential treatment.
Gilbert Omenn, M.D., Ph.D.Molecular Diagnosis and Prognosis for CancersMolecular analyses of cancers can reveal critical information about the particular mechanisms of initiation and progression of cancers and provide the foundation for clinical tests. There are several aims of such tests: correct diagnosis, earlier diagnosis, prognosis/likelihood of metastasis, responsiveness to specific therapies, and recurrence after successful treatments. Cancers are very heterogeneous in causation, progression, and risk of metastasis and death. Gene expression, genomic, epigenomic, proteomic, and metabolomic studies are complementary “omics platforms” for development of clinically useful tests. It is a long path of discovery, confirmation, validation, clinical trials, and FDA approval to establish the validity and utility of proposed tests. Examples of biomarker discovery and test development for breast, ovarian, and prostate cancers will be presented.
Steve Williams, M.D., Ph.D.Monitoring Wellness: Blood Tests for Many DiseasesThe dream of transforming medical practice by measuring individualized actionable medical and lifestyle data for all common conditions from a single blood test has not been realized. Genetic approaches alone can never accomplish this promise despite the billions spent. Obstacles to accomplishing it are technical, human, and economic. Technical obstacles include poor productivity in multiplexed technologies for new biomarker discovery, poor management of false discovery in highly dimensional data, and inadequate large-scale biobanking of multi-year samples. Human obstacles include a jaded view of new technologies because of failures in the past, intellectual snobbishness about the higher value of making predictions in the future over measurements of what is happening now, lack of agreement about performance standards and validation, inadequate decision support for patients and physicians and precautionary regulatory approval processes based on one test at a time. Economic obstacles include reimbursement processes geared towards a single a-priori diagnosis rather than multi-disease screening, an intellectual property thicket which may be impenetrable to highly dimensional tests, and the cost and time of discovery and validation. Nonetheless, there is a glimmer of hope; new techniques such as SomaLogic’s 850-plex proteomic assay can overcome some of these obstacles with the potential that early versions of the wellness chip could be 5 years away.
Alan Russell, PhDMuscle Adaptation Gone Wrong – How Duchenne and Becker Muscular Dystrophy Cause Amplified Muscle Damage Revealing a Novel Therapeutic TargetThe human body has evolved with an ability to rapidly adapt to physical challenges by allowing controlled injury and repair of skeletal muscle as a way to increase muscle size and strength. Different skeletal muscle fiber populations exhibit different thresholds for this type of remodeling with an aim towards maximizing the speed of adaptation while minimizing the potential for detrimental effects on existing function. In serious inherited muscle diseases such as Duchenne and Becker muscular dystrophy, loss or mutation of the supportive muscle protein dystrophin results in an amplification of adaptive injury processes and uncontrolled damage in response to normal daily activities. With time, this leads to fibrosis, muscle loss, disability, and early death from cardiac or respiratory muscle weakness. In this presentation, Russell describes how muscle has evolved into two major fiber populations – fast and slow, and his thoughts on why one of these populations, the fast fibers, are more susceptible to injury. He will detail how loss of dystrophin amplifies activity-driven muscle injury and how the nature of this injury creates an opportunity for a novel medicine to improve muscle health in these devastating diseases. To evaluate how this therapeutic approach impacts muscle health, Russelll also describes how proteomic profiling can be leveraged to measure muscle injury signatures in Becker muscular dystrophy.
Bill Burhans, Ph.D.My Life Over and Under the Microscope as a Cancer Scientist and PatientCancer is a genetic disease—that is, it is caused by alterations (mutations) in the genetic information encoded in genes that determine the structure and function of proteins and other macromolecules. In cancer cells, these alterations lead to uncontrolled cell division that results in the formation of solid tumors or in excessively high levels of certain types of blood cells. Recent studies indicate that somewhat unexpectedly, the majority of genetic alterations leading to cancer arise as a consequence of mistakes that occur in the duplication of the genetic material—that is, DNA—required for cells to obtain a complete and accurate set of genetic instructions when they divide. However, cancer is also caused by mutations in the DNA of germline cells that are inherited from parents from one generation to the next. This includes, for example, mutations in the breast cancer genes BRCA1 and BRCA2, which cause breast and ovarian cancer in women at an elevated frequency. Many clinicians are not aware of the fact that inherited mutations in the BRCA1 and BRCA2 genes can also cause other types of cancer, including prostate and breast cancer in men. For the past 28 years, Bill’s laboratory’s research has focused on genetic pathways that are frequently altered in cancer, including those that require of the function of the proteins encoded by the BRCA1 and BRCA2 genes. Not surprisingly given a strong history of cancer in his family, in 2013 Bill was diagnosed by his colleagues at the major cancer center where he works (Roswell Park Comprehensive Cancer Center) with an aggressive case of prostate cancer driven by a pathogenic mutation in BRCA2. In addition to his treatment at Roswell Park, he has also been treated at Sloan-Kettering Cancer Institute in New York City and participated in clinical trials at Dana-Farber Cancer Institute in Boston. In his talk he will describe his experiences as a cancer patient and as a cancer scientist who has spent most of his career studying defects in genetic pathways that lead to cancer. His talk will include descriptions of his efforts to educate clinicians and patients on the genetics of prostate and other types of cancer.
Scott Russell Sanders, Ph.D.Nature as MedicineFor millennia, humans have turned to nature for medicines to treat a host of ailments, and the search continues today. It is estimated that nearly half of the pharmaceuticals now in use are derived from plants, animals, fungi, or microbes for conditions ranging from headaches and hypertension to malaria and cancer. Researchers are actively seeking medically-useful compounds in the world’s tens of millions of species. The value of nature as a pharmacopeia is well known. Less well known is that contact with nature itself can have a healing effect—all the more so in our increasingly hectic urban and electronic world. Recent research suggests that contact with nature—gardens, parks, forests, companion animals, potted plants, even a view of trees through the window—can be useful in treating attention deficit disorder, post-traumatic stress disorder, anxiety, depression, dementia, and other afflictions. This talk will explore efforts to foster nature-contact in hospitals, nursing homes, prisons, schools, and inner cities. It will also speculate on why contact with nature—the world that humans do not manufacture or control—is vital for health as well as happiness.
Leilani Raashida Henry, MANavigating in a White World at the Bottom of the EarthLeilani Raashida Henry is the author of the book The Call of Antarctica: Exploring and Protecting the World’s Coldest Climate. She utilizes the diaries of her father George W. Gibbs, Jr., the first person of African descent to set foot on the continent of Antarctica, to explore this beautiful and desolate part of the world. Leilani will talk about the expedition on which her father served (Admiral Byrd III), the continent itself, and its importance to the global environment.
Rick GuidottiNeglected Diseases are All of UsRick’s Positive Exposure photo and video presentation explores the social and psychological experiences of people of all ages and ethno-cultural heritages living with genetic, physical and behavioral conditions. Rick’s presentation embraces our shared humanity and celebrates the richness and beauty of human diversity. The lecture provides new opportunities to see individuals living with a genetic difference first and foremost as a human being with his/her own challenges rather than as a specific diagnosis/disease entity.
Anna Marie Pyle, Ph.D.New Defenses for the Body’s Own Armor: RNA Weapons Against RNA VirusesHumans evolved in a world that is swarming with pathogens. To survive as a species, we developed remarkably good defense mechanisms for fending off diverse, ubiquitous organisms that evolve faster than we do. However, as societies become more mobile, and the genetic soup of whole ecosystems is stirred up by environmental change, human societies are becoming increasingly exposed to lethal infections to which we cannot adapt. Because there is not enough time to find a strategy to fight each new germ, humans must improve their body armor. We come remarkably well equipped with antiviral sensors that prowl our cells in search of invaders. These Pattern Recognition Receptors (PRRs) provide our first line of defense by recognizing and responding to molecules that are unique to viruses and other pathogens. In my lab, we have developed customized RNA molecules that trigger this early warning system in mammals, thereby preparing the immune system to combat both known and emerging pathogens. By generating a new generation of antiviral therapies and vaccines based on synthetic RNA, we hope to reinforce the excellent security system that is already included in the basic human package.
David Rosenman, M.D., M.B.A.New World. New Doctors. New TrainingThe medical curriculum in this country emerged from a document written 100 years ago. Medical schools have built upon this scaffolding, improved curricula, and adapted to mind-boggling biomedical advances. Yet before our eyes, emerging global networks are bringing to health care a new and breathtaking change. The roles of health care providers, patients, families, and researchers are evolving. The Preclinical Block at Mayo Medical School is taking into account these changes, introducing students to key principles of innovation, and preparing them for the new and ever-changing world ahead.
Charles Cantor, Ph.D.Noninvasive Personal GenomicsWhenever there is cell death, apoptotic cell free DNA fragments appear in the circulation of the host. These fragments, typically 145-160 base pairs in size represent a minute fraction of total DNA in the host circulation. If care is taken to avoid host cell breakage, the apoptotic DNA fragments can be analyzed to provide information about the genome of the cells that produced them. In pregnancy, analysis of apoptotic DNA fragments has allowed the development of very effective noninvasive aneuploidy testing. Indeed it is possible to reconstruct the entire fetal genomic DNA sequence from these fragments. In cancer it is possible to view copy number, sequence, and epigenetic differences between the tumor and the host by analyzing circulating free DNA. While this work is still at early stages it is reasonable to predict that an array of useful noninvasive cancer diagnostic tests should soon result from such studies. It is furthermore likely that a careful search for informative apoptotic DNA fragments that differ in methylation from DNA in the circulation of a normal host might lead to methods for the early detection of other clinical situations that are characterized by inappropriate cell death.
Steven Reed, Ph.D.Novel Adjuvants For New VaccinesSafe and effective adjuvants for prophylactic and therapeutic vaccine use are resulting from the identification of small molecules and optimization of their formulations. For a new adjuvant to be widely accepted and used, however, non-clinical safety and efficacy are not the only important aspects to be considered. Also helpful are detailed knowledge of mechanism of action, local and systemic effects on immune activation, magnitude and duration of effects, as well as quality, manufacturability, and stability of the active ingredients and excipients used in the final adjuvant composition. Effectively engaging macrophages and dendritic cells (DC), leading to T cell responses is essential for developing a new generation of T cell vaccines (e.g. tuberculosis, malaria, HIV), as well as for improving the quality and duration of antibody responses (influenza, HPV, HIV, etc.). The most advanced approaches to new adjuvant development consist of using TLR ligands (TLRL), which when properly formulated can be used in minimal amounts to achieve desired effects. The manner in which TLRL are formulated dramatically influences the nature of the immune response they induced. We have developed formulations of synthetic of several TLR4L and have evaluated a variety of these, including oil/water emulsions, micellar, and liposomal, in non-clinical and clinical studies. Formulations have been developed with desirable adjuvant properties, adjustable potency, focused Th1 or balanced Th1/Th2 responses, down-regulation of Th2 responses, induction of CD8 T cells, induction of mucosal immune responses, and effective broadening of specific antibody responses. We have also shown that cells from elderly individuals strongly recognize formulated TLRL, producing cytokines in a manner qualitatively and quantitatively indistinguishable from cells from healthy adults. Thus, selective molecular synthesis and formulation may lead to a new generation of TLR4L- based adjuvants with improved qualities over natural products. Non-clinical and clinical data using these and other novel adjuvants in development will be discussed.
Elvir Causevic, D.Sc.Novel Models of Biotech IP Licensing: How Early Can it Start?Dramatic events in the Intellectual Property (IP) world of the past 18 months have created a new landscape. These included passage of the America Invents Act (new patent law), Nortel patent auction sale for $4.5 billion, Google acquisition of Motorola for its patents for $12.5 billion, and a series of fundamental federal and Supreme Court decisions. Coupled with changes in life science VC funding, “new rules” at the FDA, reimbursement challenges, and Large Co. R&D gap, this opens up thrilling opportunities for IP-savvy biotech leaders of all sizes. Novel IP licensing modalities will be explored, with case studies from lifescience and other industries, finishing with a “how to” session.
Matt Might, Ph.D.One of a Kind: What Do You Do When You’re the First?The widespread availability of sequencing is creating an explosion of “one of a kind” disorders. Patients are being told in record numbers: “You are the first and only we’ve ever seen.” Not long ago, the diagnosis and discovery of these "n=1" disorders would have been devastating. But, social media and precision medicine are making it possible to fight and win against even the rarest diseases. My son was the first patient to be diagnosed with the novel disorder N-glycanase (NGLY1) deficiency. Using targeted social media for case-finding made it possible to find undiagnosed and misdiagnosed NGLY1 patients as far away as India in mere months rather than years. Two-and-a-half years later, a tight-knit community of 26 NGLY1 cases has established a global, patient-driven research coalition that is rapidly bringing the disease to heel through breakthroughs in understanding the biology of the disorder. Ultimately, the global NGLY1 community seeks to discover more than a cure for N-glycanase deficiency; it also seeks to discover a sustainable, scalable model for understanding, treating, and curing the rarest of diseases.
Larry Gold, Ph.D.One to Five, Six to TenTransitions always are frightening, and this is a transitional year. We have done five symposia so far, and I have looked backward at what we’ve done with pleasure—almost 80 presentations about so many things that matter. I learned a lot, which is as good as it gets for me, and I got to laugh, deeply. Now we are seeking to change these symposia to have even more impact on health care. This outrageous idea has grabbed our hearts, so I will tell you what we have done and how the next five years—starting today—might be different. One may have already seen this change evolving last year, and now we are officially in the midst of that transition. The GoldLab Foundation has evolved as part of this effort. We still will have fun; we still will think about important things that need our attention; we still will listen to great science that touches medical practice; and, we will add in more and more “soft” stuff in the context of improving health care.
Matthew Todd, Ph.D.Open Source Drug Discovery – A Limited Liability TutorialFinding effective medicines is hard. A model we have used in the past is one based on competition and some level of secrecy. New moves by the pharmaceutical industry, called “open innovation”, are operating along similar lines. Are we discovering the drugs we need quickly? No. I will describe an alternative model of drug discovery based on open source - all data and ideas are freely shared and anyone may participate at any level. This mechanism avoids patents. A project with the World Health Organization has been completed using this research model that found a way to improve an important drug used to treat Bilharzia. A new project is now underway attempting open source drug discovery, in this case for malaria. Some technological and psychological barriers to working in an open arena will be described, as well as some of the thrills.
Larry Hunter, Ph.D.Opening RemarksLarry Hunter gives the opening remarks for day 2 of the 13th Annual GoldLab Symposium.
Larry Gold, Ph.D.Opening Remarks
Larry Gold, Ph.D.Opening Remarks 2010“The Ins and Outs of Personalized Medicine” Today Personalized Medicine is available, technically, and yet the infrastructure needed for full implementation is inadequate, the challenges are large, and society is unready for (perhaps even hostile to) what is possible. The concept of Personalized Medicine is nevertheless intriguing. Most scientists have not considered how different one person is from another, nor even how different one set of cells in an individual is from a different set of cells in the same person. Personalized Medicine — “the right drug at the right dose at the right time for the right person” — faces the complexity of human biology. Just how different are any two people on the planet? There are perhaps ~1033 different possible fertilized human eggs on the present earth, an astounding number. Six billion people provide 9 x 1018 potential mating pairs (as they are called, delicately) and each sperm and oocyte can contribute one of 8 x 106 (223) possible chromosome combinations to a fertilized egg. Additionally a fertilized egg divides perhaps 1014 times from embryo to adult, providing vast opportunities for somatic mutations that cause cancer and other diseases. That is, 1033 different possible fertilized human eggs have another 1014 cell divisions in which to progress, through mutations or environmental insults, toward disease. Humans are different from laboratory mice. While humans seek out breeding opportunities, laboratory mouse strains are inbred to the point of being nearly identical at the level of DNA. This is one dilemma of Personalized Medicine – the Ins and the Outs. Genomic differences make us persons with a variety of medical conditions and destinies. We experiment on mice who are nearly identical, and then on humans who might as well be from different solar systems. Genomics matter greatly, yet the dimensionality of human genomics is staggering. One hopes (and can begin to see) that vastly different genomics push people toward diseases with common attributes that will be the Achilles heels for medical interventions.
Larry Gold, Ph.D.Opening Remarks 2011“Our Dialogue, One Year Later” Despite the urgency of our mission, the past year has seen millions of friends and strangers fall out of health. Mortality will always be a reality, but we know in our guts that most illness can and should be treatable, if not preventable. Yet disease in all its forms continues to pile up the score in its favor against our efforts to restore and maintain wellness. Keeping score in this mortal game is a sensible thing. However, an impartial referee would be dismayed by how slowly important things change with time, and might be tempted to yield the court to the silly people who dawdle, who trifle away our important time, who prefer window-dressing our broken healthcare system to making real progress. But we cannot allow this to happen. Time matters to us all. Nonetheless, I remain an optimist ever since – or even before - the day in 1963 that I handed in my paper at Yale for Religion 24b, called, regrettably, “A Study: Part One.” What was I thinking? Similarly, what do I think today about our healthcare dialogue, and what hopes can we have for progress? This year our Symposium probes both the acute/common and rare/neglected diseases that strip us of health, imagines the tsunami of diseases that are amassing for invasion at our borders, looks at the growing empowerment of groups of patients banding together to help themselves through the internet, and analyzes the possible impact of patent law and large data bases to restore urgency to the dialogue. This year we have also included several discussions about our brains and behavior, a quite daunting topic of immense importance – medical progress will not happen if human behavior resists what is possible. To help the discussion, several speakers from last year return to both moderate sessions and to maintain the thread of logic for these Symposia. Last year we started with “omics” so that a common ground for improved evidence-based medicine was clear. The picture is more clear this year than last. Our shared goals remain to implement things that help people live healthier lives, and also to implement steps toward lower healthcare costs. This is a tough dialogue, to be sure, but one that calls us all to the table to contribute, to listen, and – most importantly – to act.
Larry Gold, Ph.D.Opening Remarks 2012“The Pace of Personalized Medicine Development: The Narcissome in Action” Many changes have occurred since our last Symposium – biomedical science is more powerful (which happens every year), the world of “omics” is broader, and deeper thought is happening about the connections between great research and medical applicability. Several stunning clinical trials have been reported in the past year, including trials of a single individual (n=1). Such trials make an odd but interesting connection between “clinical” and “personalized,” though they also appear to elevate anecdotal evidence to the level of science. But if such work is done carefully, it can provide another view of one’s biology, with an emphasis on human differences rather than similarities. Although the nature of epistemology will be tested by this so-called “n=1 paradigm,” the application of rigorous scientific method could lead to significant medical breakthroughs, which in turn could change the very nature of how we decide on best medical practices.
Larry Gold, Ph.D.Opening Remarks 2013“Complexity: Rube Goldberg was merely linear” Sociology is multi-dimensional and operates outside the known laws of chemistry and physics. Social structures contain the history of human culture, constrained in some unclear manner by human biology. Human biology also contains history, in this case the evolutionary history of biology on our planet (both the early history of all species for over 3,000,000,000 years, and then, the far briefer history over the less than 10,000,000 years during which the non-human primates evolved into our human species). That recent history can be understood to be the initial biology palette that constrained human evolution; humans were granted a narrow palette compared to the broad biochemistry and physiology used by all creatures on earth. There are several implications of those broad statements for healthcare. While we acknowledge the imperfections of human culture, we are far less likely to acknowledge the imperfections in human biology. Yet both of those “imperfections” are present as we try to fi x healthcare. If we understood human biology perfectly, we would immediately know the right drug for the right patient at the right time – an often-used definition of personalized medicine. If we understood human sociology perfectly, we would quickly implement solutions that provide health and well being to people. But we are far from those understandings, and we may remain far from them for a long time. The purpose of this year’s GoldLab Symposium, as in prior years, is to confront what we know and cannot know and make plans to do the best we can. This year we have more than the usual number of people who are not simple technology wizards, but are in fact interested in the sociology that limits our progress. In my brief introduction I will describe the impact of complexity on the things we wish to do, and then we will again have two days of extraordinary pleasure as we listen to and debate with the generous people who have come to Boulder for these discussions.
Larry Gold, Ph.D.Opening Remarks 2014“These Symposia as Evolving Creatures” Here we are, about to start our fifth event — who would have thought we would try this and keep it going? Our intentions (from the very first moment) have not changed, but we know more today about the healthcare issues that make change so difficult and so slow. I will try to use examples of profound healthcare changes that have occurred over the last two decades to see if we can glimpse the pressures that made it so painful to implement what we now see as obvious and good. I will also explain, ever so quickly, how a team of us decided for #5 to do an experiment, without a net. Each year I promised we would do “something” that might facilitate improved healthcare, an idea that we could do real science — focused on omics and drugs and diagnostics (with omics including comics…) — and also comprehend how our brains work (both biochemically and behaviorally) because we are sure that we could do better healthcare if we behaved better. And so these last couple of years many of us read a lot about behavior. You will see (and enjoy, however uncomfortable we get) that there are ways to do better so we can all be healthier and get and give more out of our lives.
Leslie Greengard, M.D., Ph.D.Opportunities and Challenges for Big Data in Biology: The Good, the Bad, and the UglyNew opportunities for discovery through data analysis, modeling, and simulation are constantly emerging within the biological and biomedical sciences, as well as in traditional physical and social sciences. A realization of the last decade, however, is that our ability to cope with this data influx has not kept pace and that the creation of tools that allow us to process large-scale data sets judiciously is one of the central challenges of the present age. We will discuss the kinds of challenges scientists are facing, some examples of success, and some of failure.
Garret A. FitzGerald, M.D.Opportunities and Challenges in Translational TherapeuticsWhile the number of new therapeutics approved by the FDA has remained relatively constant over the past 60 years, the cost of this endeavor has increased in a log linear fashion. This mainly reflects the exploding cost of failure of a model that is clearly unsustainable. Experience in the altruistic sector has illustrated the temporal and scientific efficiency of a globalized modular approach to drug discovery and development where (i) behavior is incented by altruistic ideals and a pot of money and (ii) intellectual property barriers are collapsed by the perception of there being no money to be made. Can this model be exported to the for-profit sector? There is some movement in that direction as Pharma seeks to outsource some of its activities, although still retaining most of the control -- a touch of perestroika with a whiff of glasnost. However, more radical reform is likely, driven primarily by crisis rather than the prospect of opportunity. This will require a fundamental revision of assumptions around intellectual property, an increased capability of academic medical centers to play in this space, a redeveloped workforce with skills in translational medicine and therapeutics, regulatory reform of incentives in drug development and a bioinformatic infrastructure capable of sharing heterogeneous information in a secure and compliant manner across distinct organizational structures and on a global scale.
Larry Lasky, Ph.D.Pathway-Specific Medicines: 21st Century Solutions to Unmet Medical NeedsCancer remains one of the great unmet medical needs with high morbidity and mortality. Older therapies relied upon exceedingly toxic methods, such as chemotherapy and radiation, which had marginal therapeutic indices. Since the discovery of the oncogene, biochemistry, and cell and molecular biologists have discovered a diversity of deregulated pathways in solid and liquid tumors. These discoveries have ushered in the era of patient- and pathway-specific oncology therapies, including, for example, Herceptin for breast cancer and Gleevec for chronic myelogenous leukemia. In today’s talk, I will discuss the approaches utilized by three early-stage biotechnology companies who hope to further explore other oncogenic pathways that may be involved in a large number of tumors. Proteolix has developed a modulator of a protein-degradation pathway that has shown efficacy in hematologic tumors. Intellikine has generated an inhibitor of one of the components of the PI3 Kinase pathway, one of the most mutated pathways in both solid and liquid tumors. Finally, Oncomed has developed monoclonal antibody inhibitors of early developmental pathways, such as Notch and Wnt, in order to eliminate the cancer stem cell. Together, these three stories will highlight the newest trend in oncology: patient- and pathway-specific medicines.
James HeywoodPatient Driven Real Time Outcome Management and ResearchPatients are closest to their health status. With well designed self-reporting scales, they can provide rich and detailed information about their illnesses, symptoms, co-morbidiies, treatments, and background. This information can be used to monitor clinical practice, adherence to guidelines, and even the effectiveness, and risks of treatments in real time.
Scott DanielsonPatient-Centered Care Perspectives: Views from Where We Stand, Sit, and Lie DownThere’s a lot of buzz these days about patient experience. Lots of talk about becoming the Apple, Nordstrom, or Starbucks of health care. But what is the “patient’s perspective” and how is it relevant to the care provided? How can we see it, know it, capture it? What can we interpret from it? How can a patient’s perspective inform care delivery innovation? And while good design thinking, like good science, informs the practice of medicine every day, too often the long-tail patient experience is inconsistent, jarring, insensitive and downright scary. Consider how a deeper understanding of patient experience can inform care delivery, and ultimately improve care outcomes.
Lloyd Fricker, Ph.D.Peptides, Drug Discovery, Serendipity, and Basic SciencePeptides are amazing molecules. In the body peptides are used as chemical messengers to signal between cells as hormones (such as insulin) and neuropeptides (endorphins). Peptides are also used as toxins to defend us against bacteria, and in other species, to kill predators or prey. In addition to these roles for endogenous peptides, synthetic peptides have been used as research tools to alter protein-protein interactions that are essential for cellular functions. Because of their importance in biological processes, peptides have been the focus of research aimed at developing drugs for a wide range of conditions. The first step of drug discovery is target identification. Using a novel peptidomics technique, we have identified hundreds of peptides, including some that function as neuropeptides involved in food intake and body weight regulation. Other peptides found in the peptidomics screens are not likely to function as neuropeptides, but may instead play a role in regulating protein-protein interactions within cells, a novel role for endogenous peptides. A new class of anti-cancer drugs -- the proteasome inhibitors -- greatly alters the intracellular peptidome, raising the possibility that this contributes to the mechanism of action of these drugs. The focus on peptides will be related to the issue of drug discovery in general, and the need for retro-translational research—going deeper into basic science to understand mechanisms of drug action.
Thomas R. Cech, Ph.D.Personalized Medicine
Matt Might, Ph.D.Personalized medicine is personal – moderator
Daniel Kracov, J.D.Personalized Medicine: Facilitating a Partnership with the FDAThe path to personalized medicine traverses a largely uncharted legal and regulatory landscape that offers both challenge and opportunity. As we advance rapidly into an era of medical treatment tailored to individuals with information from increasingly sophisticated diagnostic tests, the FDA and other regulators are faced with a new paradigm that includes labeling of approved drugs with companion diagnostics and the co-development of drugs and companion tests. As diagnostic technologies grow more complex, laboratory-based tests that do not require FDA clearance present a certain opportunity to industry and a challenge to regulators. Possible legislative proposals for incentives for co-development of drugs and companion diagnostics create potential new challenges and opportunities for regulators and industry. Personalized medicine will also play an increasing role in studying post-market drug safety. The healthcare system, including providers, payers, and patients face equal challenge and opportunity in the changing legal and regulatory landscape of personalized medicine. This includes the roles of comparative effectiveness initiatives, possible limitations on payment for tests and physician services, as well as patient privacy issues. The success of personalized medicine demands knowledge and careful navigation of this legal and regulatory landscape.
Michael Teitell, M.D., Ph.D.Photothermal Nanoblade and Nucleic Acid Import into Mitochondria: Can We Improve Bioenergetics for People?Numerous diseases result from mutations within the mitochondrial genome. A functional decline due to mtDNA mutations could lead to reduced oxidative phosphorylation and other untoward effects on mitochondrial activities. Strategies that restore mitochondrial function could potentially diminish the ill effects of mitochondrial-driven diseases. In this presentation we will discuss two strategies for repairing mtDNA mutations. In one approach we are developing a photothermal nanoblade to introduce whole mitochondria containing functional mtDNA into cells. In a second approach, we consider targeted mitochondrial import of corrective ribonucleic acid (RNA) to compensate for mtDNA mutations. RNA import into mammalian mitochondria is considered essential for replication, transcription, and translation of the mitochondrial genome but the pathway(s) and factors that control this import are poorly understood. Previously, polynucleotide phosphorylase (PNPASE) was localized in the mitochondrial intermembrane space, a location lacking resident RNAs. In recent studies we have shown a role for PNPASE in regulating the import of nuclear-encoded RNAs into the mitochondrial matrix. These recent studies show an unanticipated role for PNPASE in mediating the translocation of RNAs into mitochondria and provide a potential therapeutic route for halting or reversing the decline in mitochondrial function in human disease.
Elizabeth Fenn, Ph.D.Pox Americana: The Great Smallpox Epidemic of 1775-82Elizabeth Fenn tells the gruesome, riveting story of smallpox during the era of the American Revolution. Few people know that a terrible epidemic ravaged North America in these years, influencing the Revolutionary War, dashing the dreams of freedom-loving African Americans, and wreaking havoc on Native Americans across the continent. Elizabeth also addresses eighteenth-century biological warfare in her talk.
Aaron Clauset, Ph.D.Prediction and Its Limits in Scientific DiscoveryThe desire to predict discoveries, to have some idea, in advance, of what will be discovered, by whom, when, and where, pervades nearly all aspects of modern science, from individual scientists to publishers, from funding agencies to hiring committees. The successes and failures of predicting scientific discoveries -- the creation of new knowledge -- have broad implications for understanding the nature of knowledge itself, and the likely future role that computers and artificial intelligence can play in its creation. In this talk, I'll begin with a simple conceptual framework for thinking broadly about prediction and its limits for scientific discovery. I'll then do a dive deep into two areas where accurate predictions would be highly useful for science policy: the predictability of researcher productivity over an entire career, and the predictability of when in a career scientists make their most important discoveries. To close, I will draw some broader conclusions from these results about the future of science, and I'll describe strategies and dangers for scientific discovery in the age of big data.
James Robinson, PhD, MPHPricing Drugs for Innovation and AffordabilityDrug prices need to be high to finance research and development but low to ensure affordability and access. Attempts to balance these conflicting imperatives are bedeviled by scientific uncertainty as to product effectiveness at the time of initial launch and the subsequent evolution of clinical evidence. The combination of multiple goals and scientific complexity creates one political firestorm after another, exemplified most recently by the accelerated FDA approval, budget-crushing manufacturer’s price, restricted Medicare coverage decision, and broad physician rejection of Ahuhelm for Alzheimer’s disease. In this presentation, Robinson describes how drug prices are negotiated by innovators and purchasers in the context of rapidly evolving scientific knowledge. He then describes a model of dynamic prices that adjust to changes in the evidence of a drug’s safety and effectiveness, to be applied to products such as Ahuhelm that are launched through FDA’s accelerated review and Medicare’s conditional coverage pathways.
David M. Lawrence, M.D.Primary Care for the Twenty-First CenturyAt the 2010 GoldLab Symposium, I discussed the challenges facing medical care systems as they try to build physician-centric primary care systems. Shortages of trained physicians force a rethinking of traditional solutions. Emerging technologies provide a host of new ways to respond. In this presentation, I will reprise these arguments briefly and discuss the most promising technological advances, then present an alternative model for primary-care delivery that builds on patient and consumer-based solutions, rooted in the family and community. The model offers significant advantages in identifying and supporting people at risk of, or afflicted with, one or more chronic conditions. As this subpopulation represents the majority of the country's disease burden today and even more so tomorrow, the opportunity to influence both demand and overall costs of health care in our country is large.
William Rom, M.D., MPHProtein Biomarkers: A Blood Test for Early Stage Non Small Cell Lung CancerLung cancer is the leading cause of cancer deaths in the U.S. at 160,000/year because most cases are diagnosed in later stages and the disease is histologically heterogeneous. New clinically effective diagnostic methods are urgently needed to identify lung cancer in earlier stages when surgical resection has the potential for curative therapy. Of concern is that the U.S. cigarette smoking rate increased from 19.8% in 2007 to 20.6% in 2008. Environmental carcinogens also cause DNA-adducts at “hot spots” in TP53 and KRAS that correlate with mutations. Furthermore, mutated receptors lead to up regulation of signaling pathways P13K and p38 kinases. CT-scan screening can identify non-calcified nodules in over half of high-risk smokers. A panel of blood biomarkers may distinguish malignant from benign nodules including auto-antibodies, anti-glycan antibodies, serum proteins, PBMC multiple gene expression or methylation of promoters. Using a new proteomics technology based on SOMAmers, modified DNA aptamers with very long dissociation rates, we conducted a multi-center study on 281 NSCLC and 1035 controls matched for age, gender, and smoking. After evaluating 813 proteins/subjects, a 12-protein signature achieved 91% sensitivity and 84% specificity with an AUC of 0.91 in the training set, and 89% sensitivity and 83% specificity in the testing set. A blood protein biomarker panel has potential for identifying individuals with a history of cigarette smoking who are at increased risk for early stage lung cancer.
Don Kripke, M.D.Psychiatry: Is It Different? If So, How?For centuries, the mentally ill were regarded with a combination of awe and fearful superstition, predominantly the latter. The enlightenment introduced them to humane compassion but left them subject to both isolation and faddish remedies. The prevalence of serious mental illness in the United States now exceeds 5% of the population. Less than half of those afflicted receive minimally adequate treatment. This serious problem derives from residual stigma, unreliable availability of resources, and inequality in insurance coverage. In recent decades, the science of psychiatry has advanced, and the field has entered the territory of evidence based medicine. But in both theory and practice, it still suffers from diagnostic vagueness and uncertainty. Partly as a result, psychiatrists confront burdensome administrative demands, and the field struggles with the heterogeneity of mental health practitioners, the majority of them outside the field of medicine. Psychiatrists, psychologists, other licensed therapists, and their patients are thus vulnerable to discriminatory reimbursement policies. Hence, we have on-going political and social advocacy to achieve parity through education, development of effective treatment programs, and legislation. These factors, more prevalent in psychiatry than in other medical specialties, may illuminate certain general themes in the quest for equitable and effective health care for our country. Psychiatry’s challenges may reveal certain patterns of resistance to change that might otherwise remain obscure.
Ted J. KaptchukPursuing the Placebo EffectThis talk will emphasize clinical research into placebo effects and discuss several experiments that Ted Kaptchuk has led. The talk will present studies that suggest that the ritual of therapy can be administered in a manner analogous to dose dependence (BMJ 2008), that placebo outcomes may not be dependent on deception or concealment (PloS One 2010), that placebo responses may be primarily limited to self-reported symptoms (New England Journal of Medicine 2011) and that switching meaningful words on labels of pills can significantly modulate pharmaceutical and placebo treatment outcomes (Science Translational Medicine 2014).
Dennis Lo, M.D., Ph.D.Pushing Forward the Biological Understanding and Diagnostic Applications of Circulating DNADr. Dennis Lo's group reported the presence of cell-free fetal DNA in maternal plasma in 1997. Since then, this technology has been developed into a platform for noninvasive prenatal testing (NIPT) that can be used for the screening of multiple types of fetal chromosomal aneuploidies, various types of single-gene disorders and even for fetal whole genome sequencing. Apart from circulating fetal genetic markers, recent work has also led to the development of fetal epigenomic and transcriptomic analyses from maternal plasma. Excitingly, the global success of NIPT has triggered researchers in other fields to explore the use of circulating nucleic acid technology in multiple areas, notably in the liquid biopsy of cancer. Circulating nucleic acid technology has therefore brought about a paradigm shift in diagnostic medicine.
Sharon TerryRare and Neglected Diseases: The Time is Now!Traditionally, Mendelian (single gene) disorders have been categorized as ‘rare’ and considered ‘orphaned’ in more ways than one. In addition, diseases in emerging nations, that don’t affect developed nations, are called neglected diseases and are also victims of inattention. These distinctions, defined in legislation and policies in some nations, are not helpful in a number of ways – including for the affected individuals, the clinicians who serve them, the researchers trying to mitigate the effects of the disease and companies involved (or not). The intersection of biology and informatics, in the form of genomics integrated with clinical medicine, offers a pathway to a new world of collaboration toward the development of diagnostics and therapies for all diseases. In the dawning age of stratified medicine, all diseases are rare. It is time to join forces on multiple levels and create new paradigms for the solutions that will elude us if we continue to create orphans. We’ll consider the history of rare and neglected disease research and advocacy. We will also consider recent formation of the International Rare Disease Research Consortium and other efforts. Finally, we will consider the need for a collaborative effort using the long tail as a vehicle for citizens to create the revolution that is needed to radically accelerate disruptive strategies to provide insights to understanding and treating disease.
Mark Messenbaugh, J.D.Realizing SomaLogic’s Dream: Plans to Deploy Large Scale Proteomics to Guide Best HealthFor nearly 20 years, SomaLogic has been guided by Larry Gold’s vision of the Wellness Chip – a simple blood test that can read out a person’s state and trajectory of health broadly, with the precision needed to guide effective action. The platform is now even more exciting than he envisioned. We will soon deliver “Wellness Chip v1.0” to patients and care teams within the UK’s National Health Service. Mark will explain how the company is using the disruptive SOMAscan(r) health information platform to enable forward-thinking health systems, consumers, and others to improve the management of human health around the globe.
Tim Snyder, PhDReflections on Current Events in UkraineTim Snyder reflects on the state of the conflict in Ukraine and his view on the importance of the outcome for the rest of the world.
Dan Shefet, J.D.Regulating AISince the Symposium in 2019, we have witnessed a clear trend towards stronger privacy protection both in the US (especially California) and in Europe. In addition, the influence of platforms on behavior and ultimately democracy has been recognized. The European Commission’s Digital Services Act was published on the 15th of December 2020 and creates a new liability standard for such platforms. The latest development in tech regulation is the Commission’s draft Regulation on Artificial Intelligence (published on 21 April). This presentation will focus on this recent initiative,e which may be seen as the logical sequel to privacy and accountability regulation.
Jessica Mathews, Ph.D.Rethinking U.S.­ Foreign PolicyFor decades, three competing worldviews have battled to define American foreign policy. Neocons want the U.S. to act as global policeman and to judge others based on their domestic as well as their international policies. Realists believe we should be focused on the small number of other great powers on matters of war and peace. Liberal Internationalists see U.S. security in the age of globalization as rooted in international cooperation, embodied in alliances, agreements, and robust international institutions. All three narratives are rooted in a century-old tension between the interest-driven policies of Teddy Roosevelt and Woodrow Wilson’s idealism. As the decades have passed, the debate has continued with remarkably little change, getting more stale and less productive, as conditions in the world have totally transformed. It is time to discard these too-familiar isms and proceed instead from the bottom-up. Notwithstanding how hard it is to make predictions, especially where rapid scientific and technological change is involved, why not discard ideology for an empirical approach, trying, instead, to identify the forces that will shape geopolitics over the coming decades and then derive an international approach to fit these new realities. It should be possible to identify the major forces likely to drive economic, social, and political change with some degree of confidence and to indicate the broad direction and scale of change. Here is once such attempt to peer into the future and to attempt
Roy Parker, PhDRNA Abnormalities in Human Diseases and How They Might Be CorrectedRNA molecules, and their regulation, are central to the functioning of human cells. Moreover, abnormalities in RNA regulation can lead to human disease. For example, in bone marrow failure diseases, such as dyskeratosis congenita, the telomerase RNA required for chromosome maintenance is abnormally degraded. Understanding this degradation mechanism has suggested possible therapies to reverse this process and provide treatment for this disease. Similarly, neurodegenerative diseases such as ALS and Alzheimer's disease involve alterations in proteins that regulate RNA, leading to RNA abnormalities in these diseases. Determining how RNA regulation is altered in these diseases is an important area of research, and determining how those alterations can be reversed may lead to new therapeutic approaches.
Susana Martinez-Conde, Ph.D.Sleights of MindMagic tricks fool us because humans have hardwired processes of attention and awareness that are hackable — a good magician uses your mind’s own intrinsic properties against you in a form of mental jujitsu. The insights that magicians have gained over centuries of informal experimentation have led to new discoveries in the cognitive sciences, and they also reveal how our brains work in everyday situations. If you’ve ever bought an expensive item you’d sworn you’d never buy, the salesperson was probably a master at creating the “illusion of choice,” a core technique of magic. The implications of “neuromagic” go beyond illuminating our behavior; early research points to new approaches for everything from the diagnosis of autism to marketing techniques and education.
David Eisenberg, DPhilStructure-based Discovery of Small Molecules that Disaggregate Tau Fibrils from Alzheimer’s DiseaseFailing the development of effective drugs for Alzheimer’s disease (AD), millions are destined to die with dementia. AD is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. This suggests that disaggregation of tau fibrils could be a therapeutic approach to AD. The capacity for the polyphenolic small molecule EGCG, abundant in green tea, to disaggregate tau and other amyloid fibrils has long been known, but EGCG has poor drug-like properties and fails to fully penetrate the brain. Here we have cryogenically trapped a high-energy intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure. The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define AD. Treating the EGCG binding position as a pharmacophore, we computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain tau fibrils. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases, perhaps portending chemical interventions for Alzheimer’s akin to those so effective for treating cancer and metabolic disorders.
Howard-Yana Shapiro, Ph.D.Stunting, Caused by Chronic Hunger and Malnutrition, is a Crime Against HumanityThirty seven percent of the children under the age of 5 in rural Africa are stunted due to chronic hunger and malnutrition. Improving the nutrition of the fundamental food system of Africa, which has not been studied by science, and the translation to scale are crucial to eradicating stunting. The African Orphan Crop Consortium (AOCC) is an uncommon collaboration which includes the African Union Commission (AUC) and African governments (through NEPAD), international organizations (FAO, UNICEF), companies (Illumina, Google, Mars), scientific bodies and civil society organizations working to improve the nutritional values of the food crops that 600 million rural Africans depend on. The AOCC hopes by the end of 2019 to have sequenced the genomes of 101 crops. Its third class of African plant scientists will graduate in 2018 from its African Plant Breeding Academy (AfPBA) led by UC Davis, in Nairobi, hosted by the World Agroforestry Centre. These scientists are trained at no cost to them on the world’s best equipment to re-sequence the genomes, breed more nutritious and resilient varieties for African farming families.  Graduating scientists have returned to their home countries to establish national and regional orphan crops consortia. Currently there are 81 breeding programs in place. What has to happen to make sure we go from discovery to translation to scale?
Jeremy Nicholson, Ph.D.Supersystems Biology and Systems Medicine in the Clinic: A Translational JourneySystems biology tools are now being applied at individual and population levels to understand integrated biochemical function of complex organisms including man. Metabolic phenotyping offers an important window on systemic activity and both NMR and mass spectrometric methods have been successfully applied to characterize and quantify a wide range of metabolites in multiple biological compartments to explore the biochemical sequelae of human disease. There also is extensive cross-talk between the host and the gut microbiome at the metabolic control and signalling level that is modulated in exquisitely complex ways by genes and environment and link to disease risk factors. These symbiotic supraorganismal interactions greatly increase the degrees of freedom of the metabolic system that poses a significant challenge to fundamental notions on the nature of the human diseased state, the etiopathogenesis of common disease, and current systems modelling requirements for personalized medicine. We have developed new scalable and translatable strategies for “phenotyping the hospital patient journey” using top-down systems biology tools that capitalize on the use of both metabolic modelling and pharmaco-metabonomics for diagnostic and prognostic biomarker generation to aid clinical decision making at the point-of-care. Such diagnostics (including those for near real-time applications as in surgery and critical-care) can be extremely sensitive for the detection of diagnostic and prognostic biomarkers in a variety of conditions. They are a powerful adjunct to conventional procedures for disease assessment that are required for future developments in “precision medicine.” Many biomarkers have deeper mechanistic significance and may also generate new therapeutic leads or metrics of efficacy for clinical trial deployment. Furthermore the complex and subtle gene-environment interactions that generate disease risks in the general human population also express themselves in the metabolic phenotype. As such the “Metabolome Wide Association Study” approach gives us a powerful new tool to generate disease risk biomarkers from epidemiological sample collections and for assessing the health of whole populations. Such population risk models and biomarkers can also feedback to individual patient healthcare models, thus closing the personal and public healthcare modeling triangle.
George Poste, D.V.M., Ph.D.Sustaining Healthcare Innovation in an Era of ConstraintRapid progress in molecular biology offers the promise of major gains in the detection, treatment and prevention of diseases and for targeting therapeutic interventions to match the molecular and pharmacogenetic profiles of individual patients (personalized medicine). Molecular diagnostics, next-generation imaging and miniaturized on body: in-body sensors will assume increasing importance in the healthcare value chain as powerful technology platforms for earlier disease detection, optimum selection of treatment, and for remote, real-time monitoring of treatment compliance and individual health status. These emerging diagnostic, imaging, and health monitoring platforms will generate data on an unprecedented scale. Academia, industry, regulators, and healthcare systems are ill prepared for the technical, financial, organizational, and cultural implications of large scale computing initiatives in healthcare. Longer term, advances in tissue engineering, synthetic biology, and materials science will catalyze a new era of regenerative medicine and the design of bio-mimetic devices with dynamic physiological traits and self-repair capabilities unmatched by current mechanical systems. Agility in forging new alliances between the hitherto separate sectors of pharmaceuticals, diagnostics, devices, computing, telecommunications, and consumer social media networks will radically reshape the future competitive landscape. Technical innovation has been, and will remain, fundamental to progress in healthcare. However, the anticipated acceleration of new discoveries will also generate complex economic, social, and ethical questions regarding the ‘value’ of innovation, how much new technology society can afford, and how priorities for the allocation of expensive healthcare resources are set.
Phil Holliger, Ph.D.Synthetic Genetics: Beyond DNA and RNASynthetic biology seeks to probe fundamental aspects of biological form and function by construction (i.e. resynthesis) rather than deconstruction (analysis). Synthesis thus complements reductionist and analytic studies of life, and allows novel approaches towards fundamental biological questions. We have been exploiting the synthesis paradigm to explore the chemical etiology of the genetic apparatus shared by all life on earth. Specifically, we ask why information storage and propagation in biological systems is based on just two types of nucleic acids, DNA and RNA. Is the chemistry of life’s genetic system based on chance or necessity? Does it reflect a "frozen accident", imposed at the origin of life, or are DNA and RNA functionally superior to simple alternatives. I’ll be presenting recent progress on the development and application of strategies to enable the enzymatic synthesis and reverse transcription and hence replication and evolution of novel synthetic genetic polymers, which we term XNAs. We show that eight different synthetic polymers, based on nucleic acid architectures not found in nature, can also mediate genetic information storage and propagation1. Beyond heredity, we demonstrate a capacity for Darwinian evolution by the de novo selection of specific ligands (XNA aptamers) and catalysts (XNAzymes) based on entirely synthetic backbones1, 2. Thus, key hallmarks of living systems, including heredity and evolution are not limited to DNA and RNA but can be implemented in synthetic polymers and are likely to be emergent properties of polymers capable of information storage. I’ll also be presenting our progress in the engineering and evolution of RNA polymerase ribozymes towards a general polymerase and self-replication capacity, We have discovered RNA polymerase ribozymes that are capable of the templated synthesis (i.e. transcription) of another simple ribozyme3 or RNA oligomers exceeding their own size (>200 nts)4, a key milestone on the road to self-replication.
Paula Cannon, Ph.D.Targeted Nucleases—Human Gene Therapy 2.0?Targeted nucleases, which include zinc finger nucleases and CRIPSR/Cas9, are poised to revolutionize gene therapy by potentially offering safer and more precise methods to engineer human genes. Although several different nuclease platforms are available, they all act in the same way, by first introducing a DNA break at a specific targeted sequence. Subsequent repair of the break by host cell pathways can then be exploited to achieve three possible outcomes—gene disruption, gene editing (mutation correction), or the regulated addition of new genetic material at a defined genetic locus or “safe harbor.” The gene editing and addition outcomes also require the introduction into a cell of a homologous “donor sequence,” to serve as a repair template to direct such changes. My group is using targeted nucleases in hematopoietic stem cells (HSC), with the specific goal of developing anti-HIV therapies. Our initial efforts focused on disrupting the CCR5 gene, which codes for an entry co-receptor molecule used by most strains of HIV. We demonstrated using humanized mice—immune-deficient mice transplanted with human HSC—that CCR5 disruption could suppress HIV replication without any adverse impact on human hematopoiesis. A clinical trial based on knocking-out this non-essential human gene is now enrolling HIV/AIDS patients. More recently, we have also developed methods that allow us to edit genes in HSC at high frequency. At some loci, we can reach levels that are comparable to those achieved with more standard gene therapy tools such as lentiviral vectors, but without the concern that randomly integrating vectors could drive insertional mutagenesis events. This capability, combined with a growing clinical experience with zinc finger nucleases, means that targeted nucleases are poised to be applied to other diseases of the blood and immune system, and beyond.
Jean FeracaTeaching Plato in PrisonIn Plato’s Allegory of the Cave, human beings live all their lives in an underground cave with their legs and necks chained so that they cannot move or turn their heads. They can only see their own shadows, or the shadows of one another, which a fire, blazing behind them, scatters across the cave wall. Jean teaches the Allegory in the UW-Odyssey Project, a humanities course which offers hope to people living at the margins. Three years ago she began teaching the Allegory in Wisconsin prisons. A more powerful transformational text can hardly be imagined. Odyssey students identify readily with the plight of prisoners shackled and fettered and kept underground all their lives. Plato insists that “the unexamined life is not worth living.” In the intensive give and take in the Odyssey Project, students begin to examine their lives, develop critical thinking skills, discern new possibilities for the life of the mind. They move from reaction to reflection, experience breakthroughs and arrive at a sense of hard-won self-worth, many for the first time. Plato makes his meaning clear: “the prison house is the world of sight, the light of the fire is the sun and the journey upwards is the ascent of the soul into the intellectual world.” At the end of the Allegory, Plato admonishes those who have experienced freedom not to remain in the upper world but to descend again among the prisoners. The clearest sign that students have internalized the meaning of the Allegory is when they volunteer to go back down into the cave. Eugene Smalls, whose mother died giving birth to him in prison, is now a prison chaplain. James Morgan, who just turned sixty and was incarcerated for most of his adult life, works to rehabilitate men recently released. The journey does not end with self. As Cicero said a thousand years ago, “we are born for one another.”
Judith Kimble, Ph.D.The Ambiguity of Sexual Fate DeterminationDogma tells us that we become females if we have two XX chromosomes and males if we are XY. Dogma also tells us that this bimodal gender specification occurs early in life. Yet reality may not be so simple. My laboratory has investigated the molecular basis of sex determination in a small nematode worm, often thought of as the “E. coli of animal development.” Over the years, we’ve found a network of genes that regulate sexual fate and figured out ways to turn many of them on and off at will. The surprising result is that we can reverse the sexual fate of a tissue even in adults, breaking the dogma that these fates are fixed early in development. Digging deeper, we’ve found genetic ways to create a molecular signature that is intermediate between male and female, even when cells “look” and “act” male or female. What is perhaps most astonishing is that tissues with these intermediate signatures are poised to switch sexual fate upon environmental exposure to specific chemicals. Just a few hours of chemical exposure can flip the sexual switch. We speculate that gender fates may be similarly induced to flip in tissues within humans. Although clearly speculation, the vast genetic variation in the human population coupled with many chemicals in our environment make this possibility seem entirely plausible.
Richard C. Levin, Ph.D.The American Research University: Achievements, Challenges, and ResponsesThe output of research universities has been a source of American economic leadership since the Second World War, but today American leadership is threatened by (1) declining and volatile Federal government support for research, and (2) dramatically declining state government support for education in our public universities. This talk provides data illustrating that economic growth depends on technology derived principally from university-based scientific research. It documents the success of the unique U.S. system for the organization of science, and examines data that suggest that increased public spending on healthcare is responsible for the erosion of support for science and public education. Proposed solutions include (1) providing steady, predictable increases in research funding, (2) making research more efficient through reform of the Federal grant programs, (3) using technology to lower the cost of education, and (4) solving the healthcare financing problem.
Benjamin Coles, Ph.D.The Anthropocene Chicken and the ‘Wicked’ Problem(s) of Contemporary FoodContemporary food provision presents a series of contradictions. Enormous increases in food production, as well as availability, over the last century have enabled populations to grow, becoming healthier, with longer lifespans and increased quality of life. Technological developments, often associated with food’s globalization, have all but rendered seasonality and Nature obsolete. It’s possible to not only supply food year round, but to mitigate against age-old problems such as famine. In the global North and West, food is so abundant that for many of us, scarcity means popping out to the shop or getting take out on a Friday night because what we want to eat is not readily available in the fridge or cupboard. Indeed for many of us here, true scarcity has fallen out of intergenerational memory. Corresponding with the Great Acceleration—the massive and continued surge in the production and consumption of nearly everything that some suggest marks the beginning of the anthropocene—this remarkable period for food is marred by contradictions. Social inequality at all scales has increased alongside increased production. Wealthy populations tend to suffer from diseases of over rather than under-consumption, whilst vast swathes of the ‘bottom billions’ are still starving. Embedded within a nexus with water and energy, food production itself, a great marvel of the 20th Century, is driven by a carbon economy—an economy that has colonized nearly every space of the globe, and an economy that we know we cannot continue to exploit. Through the lens of the anthropocene chicken, a distinctly modern form of food production, this presentation examines these challenges. I will argue that the wicked problems of food, and of the food-water-energy nexus as a whole, are not only social and economic but spatial. Thus, they require spatial solutions. I close with some recent examples from the field that should give us hope in these unprecedented geologic and geographical times.
Lucy Shapiro, Ph.D.The Bugs are Winning in our Changing Global Health LandscapeThe conjunction of emerging infectious diseases, the rapid rise of resistance to antibiotic and antiviral drugs, and the sluggish pipeline for new anti-infectives puts us at the eye of a perfect storm. This talk will explore the environmental and societal challenges that are responsible for the global surge of novel pathogens as well as old pathogens in new places. How is the healthcare industry dealing with this new reality? How, as a global community, are we to deal with (when not if) pandemics, quarantine laws, and the critical development of radically new anti-infectives.
Estelle Smith, PhDThe Calamity Prayer: Computational Spiritual Support as a Whole-Human Centered Approach to HealingIn the literature and practice of medicine, especially chronic, palliative, and end-of-life care, spirituality and spiritual care are known to be of fundamental importance to patients’ wellbeing. Yet the healthcare institution is ill-equipped to provide affordable and equitable access to sufficient spiritual and mental health care for all patients. With ever-rising rates of mental illness, overdose, and suicide in a world shattered by pandemic, war, and societal fragmentation, what can be done to support the spiritual healing–and moreover thriving–of both individuals and society? In this talk, Dr. C. Estelle Smith will share a research path toward a more humane future, guided by the principle that sociotechnical systems (e.g., social media, online communities, medical software) should be intentionally designed to support spiritual wellbeing, healing, and connection. Couched within her personal experiences of lifelong mental illness and losing her mother to cancer in 2015, Estelle will synthesize insights from her studies of both existing and prototypical systems for health support, especially focusing on CaringBridge.org (a nonprofit social media platform that offers free health journaling services to over 40 million users annually) and Reddit (an ecosystem of diverse topic-based online communities, with over 50 million users annually). Estelle’s work with CaringBridge provides an empirically-derived definition of spiritual support that can inspire a whole-human centered design approach. She will discuss how approaches from User Interface Design, Machine Learning, Artificial Intelligence, and Data Science offer promising new mechanisms for facilitating spiritual support, focusing on opportunities to: (1) engineer new models of delivery for evidence-based spiritual and mental health care; (2) encourage prosocial behaviors in online spaces where deeply held spiritual values may clash; and (3) augment community assets and capacities for connection and support. By explicitly honoring spirituality in the design of the online systems that now shape our social worlds, Estelle hopes to rebuild a virtual universe that can help humanity transform our collective calamity into collaboration, kindness, and care for all. Content Warning: Talk includes discussion and personal disclosure of physical and mental illness, suicide, and death/dying.
James O. Hill, Ph.D.The Challenge of Healthy LivingThe high rate of obesity in the US and worldwide is a marker for unhealthy lifestyles. These lifestyles are leading to chronic diseases such as diabetes, heart disease and cancer and are driving up health care costs. They also are reducing quality of life for many people. While almost everyone would like to be healthier, and despite the high awareness of the problem, few people have achieved a lifestyle that optimizes health. Our challenge is to help people achieve healthy living in an environment and a culture that unintentionally supports unhealthy lifestyles. A big missing piece of the puzzle is the “why.” Why do people want to change their behaviors, their environment or their culture? I will discuss how we can start in providing motivation for change and in creating demand for a healthy environment.
Michael Rosbash, Ph.D.The Circadian Rhythm Story: Past, Present and FutureThe last 35-40 years has seen a sea change in the field of circadian rhythms. This modern era began with work in Drosophila (fruit flies), which has been a leading genetic system for more than 100 years. Michael and his colleagues discovered the clock mechanism that underlies circadian timing, and it turned out that the genes and mechanism are conserved in all animals. This circadian system governs a large fraction of all gene expression, once again extending from fruit flies to humans, which explains why so much animal physiology (biochemistry, metabolism, endocrinology, behavior, sleep, etc.) is under temporal control. The broad reach of circadian biology indicates that it will continue to be important to many aspects of human well-being and will become increasingly relevant to medicine as more knowledge and applications accrue. Michael will also touch on unusual and interesting features of the 150 adult fly brain clock neurons, which is of major interest to his current lab. They play an important role in regulating sleep and wake behavior. Their small numbers present a challenge, as many molecular methods of interest are biochemical and therefore difficult to apply to these neurons. (There are in contrast about 100,000 total neurons in the adult fly brain.) Insha’Allah, Michael will have sufficient time at the end of his remarks to make some philosophical and political comments about behavioral genetics as well as to address the contemporary research landscape that we all currently inhabit.
Phyllis M. Wise, Ph.D.The Colorado Longitudinal Study: A Road to Better Health and Health EquityOne of society’s greatest challenges today is to improve health and achieve health equity for all at lower cost. I will speak about the plan of the Colorado Longitudinal Study (COLS) to create the largest, longitudinal repository of biological specimens and associated community and public health data in the world. I will discuss how we plan to recruit one million participants in Colorado to donate blood and urine annually for a 10-year period. COLS will also ask participants to provide comprehensive information about their health, behaviors, mood, and environment over time allowing researchers to study the interaction between biology and lifestyle in unprecedented ways. The impact of this will be more than additive, it will be multiplicative. The COLS repository will be unlike any other in the world. It will revolutionize the way we approach health, health care, and health equity. It will allow researchers to ask questions that they have never been able to approach before. We hope you will become as passionate about our vision as we are.
Gregory Petsko, Ph.D.The Coming Worldwide Epidemic of Neurological Disorders, and What We’re Doing About ItThe rapid aging of the population in most developed countries will eventually produce a world in which almost a third of its inhabitants will be over 60 years of age. Coincidentally, 60 is the age at which the incidence of neurodegenerative diseases such as Parkinson’s Disease, Alzheimer’s Disease and stroke begin to rise exponentially. Effective treatments are lacking for these and nearly all of the major neurologic disorders, which, taken together, cost the U.S. over $330 billion per year. We have created a new approach, which we call structural neurology, to bring the techniques of structure-guided drug discovery to bear on a number of these diseases. A highlight of our strategy is the use of what we call pharmacological chaperones to increase the steady-state concentration of neuroprotective proteins – we are not only limited to finding inhibitors of neurotoxic ones. We will give examples of this approach in the treatment of Gaucher Disease and the prevention of Parkinson’s Disease.
Larry Hunter, Ph.D. || Mira Murati || Craig J. MundieThe Evolution of Machine IntelligenceEach presenter will speak for 20 minutes in order to set the stage of the past, present, and future of Artificial Intelligence.
Larry Hunter, Ph.D. || Mira Murati || Craig J. MundieThe Evolution of Machine Intelligence: Panel Discussion
Keith Gottesdiener, M.D.The Gardasil Story: A Vaccine to Prevent Cervical CancerHuman Papillomavirus (HPV) is a potent carcinogen strongly linked with cervical cancer, but which also causes other benign and malignant diseases such as genital warts, and vulvar, vaginal, penile, and head and neck cancers. HPV Types 6, 11, 16, and 18 cause the preponderance of HPV disease burden, being responsible for ~70% of cases of cervical cancer and 90% of genital warts. Over the past 10-15 years, a remarkable story of the development of a quadrivalent HPV vaccine has led to the first vaccine specifically targeted to prevent cervical cancer. This vaccine has shown strong prophylactic efficacy in young women and adolescents and has also been studied in other populations, such as adult women and males. In this presentation, the clinical efficacy and safety of the quadrivalent HPV vaccine will be reviewed, and future implications will be discussed.
Don Jones, J.D., M.B.A.The Healthcare Ecosystem: Connecting the PartsThe wireless industry is revolutionizing Life Sciences by partnering with medical device companies to create innovative, connected health solutions. Wireless body-worn sensors, environmental sensors, medical implants, and smart phone apps are increasing the efficacy and efficiency of medical solutions. Whether it is enabling real-time streaming of a patient’s biometric data, in-body drug delivery systems, wireless pills, or remote diagnostics and monitoring systems, the possibilities for truly personalized medicine are endless. By applying the power of wireless to medical devices, applications and services, we are effectively placing everybody on the net.
Ann Thor, M.D.The Host Cancer Interface: Obesity and Diabetes Promote Cancer Development and May Reduce Treatment EfficacyObesity and type 2 diabetes (T2D) are common and comorbid diseases, reflecting significant dysregulation of human carbohydrate and lipid metabolism. These are well known risk factors for cardiovascular disease, whereas their association with cancer risk and poor cancer outcomes are less well known. The process of cancer development is complex, influenced by many factors, and typically takes years to occur. Patterns of obesity associated risk for cancer are influenced by gender, although there is significant overlap. T2D further enhances risk of cancer. Ethnicity, inherited genetic factors, socioeconomic variables, some infectious diseases, environmental exposure, access to healthcare and geography also influence obesity associated cancer risk, so that different subpopulations may experience dissimilar patterns of cancer development even in the same organ. Cancer cells are adaptable to both their environment and mechanisms of energy generation, utilizing both aerobic and anaerobic respiration even under conditions of relative hypoxia. Cellular free energy has been shown to be an important predictor of cancer cell survival and replication (growth). Obesity and T2D, as well as energy excess provided through and sugar and fat rich diet appear to facilitate this process. Modern medicine promotes diet and exercise, as well as pharmaceutical agents to treat patients with diabetes and/or obesity. Metformin is an oral agent that has minimal toxicity and is available worldwide at low cost. There is abundant evidence that metformin reduces the risk of cancer and improves cancer associated outcomes in patients with metabolic dysregulation. This is in contrast to all other diabetes drugs including insulin, that promote rather than reduce the risk of cancer. Given its potent anti-cancer activity, there have been numerous clinical trials of metformin in cancer patients with some apparent benefits. The Thor lab has focused on the mechanisms of metformin action against breast cancer for well over a decade. We have shown that metformin induces unique biological and molecular responses in the various subtypes of breast cancer, that it is especially potent against triple negative cancer. Additionally, we have shown that metformin targets stem cells, receptor tyrosine kinase signaling, Stat3, erbB2/IGF-1 receptors, cell cycle inhibition, glycolysis, fatty acid and cholesterol biosynthesis, glucose transport proteins, organic cation transported 2, motility associated cytoskeletal proteins, TGF-ß signaling, internal and external mechanisms of apoptosis and GM1 lipid raft stabilization. Furthermore, its effects are influenced by extracellular glucose homeostasis (critical in the diabetic patient) as well as deletions or polymorphisms of the OCT1 gene. Finally, we and others have shown that metformin may interact with anti-cancer agents to enhance cell death and improve patient outcomes.
Glenn J. Treisman M.D., Ph.D.The Limits of Evidence Based MedicineThe term “evidence-based medicine” was originally used to describe the broad scientific and experiential underpinnings of medical practice, as opposed to personally held views, limited personal experience, or “how I was taught.” Unfortunately, it has become a faddish term to describe the focus on randomized trials and meta-analyses as the primary drivers of medical practice. The term is now used to limit access to care and to try to develop menu-like algorithms for treatment of complicated patients. Data from clinical trials is filled with artifacts and design flaws that go un-criticized. The field is now plagued more and more by errors in selection because of increased emphasis on reliability with decreased emphasis on validity. The need for true expert input on research and design is obvious from a review of these problems.
Thomas R. Cech, Ph.D.The Long Road to Personalized Medicine: How Mutations Activate a Telomerase Gene and Help Drive CancerThe goal of personalized/precision medicine is to unleash the power of genomics, proteomics, and other omics to improve human health and combat disease. The road from scientific discovery to personalized medicine is exciting, but travel is slow. I will tell the story of my trip down one such road, which involves the molecular machine that builds out the DNA at chromosome ends and allows cells to divide continuously. This trip is still in progress, but the desired destination is clear: improved diagnostics and treatment for multiple cancers.
Elio Riboli, M.D., M.P.H.The Nutrition and Cancer Research Journey: From Chemical-Physical Carcinogenesis to Metabolic CarcinogenesisA growing body of scientific evidence has accumulated supporting the role in cancer aetiology of factors often labelled as “metabolic” that include diet, anthropometric characteristics, physical activity, metabolic syndrome components, and some aspects of sexual maturation and reproductive life. The need to investigate these complex lifestyle and metabolic factors justified the development of large prospective cohort studies. The European Prospective Investigation into Cancer (EPIC) was initiated in the mid-1990s, coordinated from IARC in collaboration with research centers in 10 European countries. It enrolled 521,000 participants, mostly aged 35-70. After 20 years of follow-up, EPIC has accrued over 80,000 incident cases of cancer, 26,000 cases of CHD and stroke, and 26,000 cases of type 2 diabetes. The EPIC database has become a shared research infrastructure used by hundreds of researchers in Europe and across the world. EPIC largely contributed to the identification of the role of overweight and obesity in increasing cancer risk, particularly for the colon and rectum, gastric cardia, oesophagus (adenocarcinoma), breast (after menopause), endometrium, ovary, kidney, liver, gallbladder, pancreas and thyroid. Sedentary lifestyle and lack of physical activity had been known for a long time to be related to higher risk of cardiovascular diseases and type 2 diabetes. Their possible link with human cancer was originally suggested by some case control studies on colorectal and breast cancers, however, substantial doubts surrounded these results, due to the scepticism on the validity of retrospective assessment of physical activity levels in cancer patients compared to controls. Cohort studies with measurement of physical activity conducted years before diagnosis provided strong and consistent evidence on the protective effect of physical activity on several cancers. These results have recently been corroborated by the results of mendelian randomization analyses showing that genetic variants predicting higher physical activity also predict higher risk of cancers of the colon, rectum and breast. The mechanisms linking diet, obesity and sedentary lifestyle with cancer are not fully understood, however there are promising research lines including insulin sensitivity deregulation, triggering of inflammation processes, deregulation of various tissue growth factors and cell cycle. Overall, diet, obesity and sedentary lifestyle have emerged as major worldwide causes of cancer, other chronic diseases as well as of premature death. This knowledge paves the way to new opportunities for primary and secondary cancer prevention.
Charles Cantor, Ph.D.The Oxygen Paradox—A New Approach to Treat Neurodegenerative DiseasesHumans can only survive a few minutes without breathing oxygen. Oxygen is converted in the mitochondrial membrane to water and the energy liberated by this process helps power most bodily functions. Unfortunately, the conversion process occurs in several discrete steps and the intermediates in these steps are extremely toxic and damage (oxidize) the polyunsaturated fatty acids (PUFAs) required in mitochondrial membranes to give them the fluidity needed for proper function. The damaged PUFAs must be continually replaced, and because humans cannot make these PUFAs biosynthetically they have to be ingested in large quantities in the diet. In a young, healthy person the process of minimizing PUFA damage and replacement is adequate to repair damaged membranes but as people age, or in many age-related disease states, the PUFA damage exceeds the repair. As a result, the mitochondria and the cells that contain damaged PUFAs lose function and die. Numerous attempts have been made to use antioxidants to reduce the production of damaged PUFAs. However these have not been effective enough to combat disease. This approach has been all but abandoned by the pharmaceutical industry, especially in their attempts to treat neurodegenerative diseases. An alternative therapeutic approach which is showing great promise in many different neurodegenerative indications is to replace 15-20% of the body’s natural PUFAs with deuterated derivatives (dPUFAs) which are much less readily oxidized, but otherwise retain and support all normal cellular functions. One compound known as RT001 is currently in clinical trials and has also been made available through an expanded access program for use in selected clinical indications, including those where increased PUFA oxidation drives disease processes. These studies show promise not just in potentially slowing the functional decline, normally seen in these indications, but also in providing initial evidence of functional restoration. The drug candidate RT001, appears to be safe and well tolerated at the dosages used and is predicted to achieve therapeutically efficacious exposure levels. Remarkably, humans and animals appear to treat RT001 like the normal nutrient: i) it appears to be distributed to the right places in the body; ii) it is metabolically modified as if the deuterium substitution were invisible; and iii) preclinical and clinical evidence indicates that oxidative damage is curtailed. We anticipate that if current clinical trends are reproduced in longer duration and larger studies it will become feasible to consider using these dPUFA materials to prevent the damage caused by a range of neurodegenerative diseases and thus eliminate one of the major challenges to cost effective health care.
Pat FurlongThe Parent Project: Advocating for Children’s HealthParents have children. They notice things, little things that just seem to separate their child from other children. They express these concerns to their healthcare providers and are often dismissed for months or sometimes years. And then, on what was supposed to be an ordinary day, there is a diagnosis, unfamiliar and often difficult to pronounce, accompanied by a definition that accurately describes the symptoms, now so familiar. Advocacy is born out of necessity. It presents both challenge and opportunity. It includes speaking up, drawing attention to an issue, and directing decision makers toward a solution. This talk will focus on the stakeholders and the tools they utilize for success: Leadership development, Coalition building, Networking, Political lobbying and leveraging support – the IN’s of advocacy: INFORMED — INVOLVED — IN TOUCH — IN FRONT — INFLUENTIAL
Daniel KleinThe Philo-Gag Perspective ITo recap the Friday program, we will discuss philosophical challenges in data analysis, or why you should think twice before undergoing a surgical castration to cure your headaches.
Tom CathcartThe Philo-Gag Perspective ITo recap the Friday program, we will discuss philosophical challenges in data analysis, or why you should think twice before undergoing a surgical castration to cure your headaches.
Daniel KleinThe Philo-Gag Perspective IITo recap the Saturday program, we will discuss epistemological conundrums in science, including the puzzling case of the herring that didn't whistle.
Tom CathcartThe Philo-Gag Perspective IITo recap the Saturday program, we will discuss epistemological conundrums in science, including the puzzling case of the herring that didn't whistle.
Franklyn Prendergast, M.D., Ph.D.The Problems, Premise, and Promise of Personalized OncologyIn the “Emperor of all Maladies” Mukherjee eloquently summarizes the utter complexity of this mélange of diseases described spuriously under the single label of “cancer.” Modern biology reveals that biological and patient heterogeneity, with all that implies, summarize the challenges facing both patients and their care givers. The heterogeneity is at times almost stultifying in degree and complexity, making it seemingly impossible to conjure even precise diagnosis let alone truly effective disease prediction, prevention, or personalized therapy, or to effect accurate individualized prognosis. But there is promise for meeting the challenges that are inherent in the high density, multidimensional biologic data (genomic, epigenetic, metabolic and proteomic) now realizable, provided we have the smarts to design the computational tools necessary to tease out the underlying both normal biology and mechanisms of disease.”
Emmanuel E. Baetge, Ph.D.The Scientific Challenge of expanding the Frontiers of NutritionThe Nestlé Institute of Health Sciences (NIHS) was founded to conduct biomedical research employing holistic systems biology approaches to improve our understanding of health and to further develop medical nutrition strategies for slowing the onset of chronic disease. Our main research axes are brain, metabolic and gut health with a special emphasis on cognition, diabetes, obesity and the gut microbiome. Some of the distinct scientific features of NIHS are the implementation of integrated systems biology and modeling, the establishment of human cell models and the conduct of longitudinal dietary challenge studies in humans. Recently the NIHS joined the EU-funded DioGenes consortium - the largest multi-centre dietary intervention study on weight management undertaken in Europe. The NIHS team is further analyzing clinical samples to better understand and describe the interplay between genes, diet and metabolism for weight management. Ultimately, the NIHS will provide scientific knowledge underpinning the development of concepts that combine medical nutrition with patient targeting or diagnostics designed to delay the onset of chronic diseases such as Diabetes, Obesity, and Alzheimer’s disease. The institute is based on the university campus of the world-renowned Ecole Polytechnique Federale De Lausanne (EPFL) in Lausanne, Switzerland and is part of Nestlé’s global Research & Development network.
David Krakauer, Ph.D.The Stupid Ways That We Have Thought About IntelligenceWhat does it mean to be smart and why is it so hard? Could we imagine a world where being smart was easy and being dumb was difficult? Why do we think that someone is intelligent because they can solve a chess problem effortlessly (an easy task for a computer), but think less of someone who can effortlessly throw a ball or climb an uneven surface (very difficult for a robot)? And why have we been so stupid in the way we test for intelligence and in our anthropocentric disregard for intelligence in non-human animals? It is time we completely rethought intelligence. Our future health depends upon it.
Krzysztof Fidelis, PhDThe Theoretical Acceleration in Identification of Protein StructuresKnowledge of protein structure significantly aids in the investigation of macromolecular function, interactions, and biochemical pathways. It also impacts our understanding of human disease, and the development of therapeutics. Major developments in both modeling and experimental determination of protein structure are dramatically changing the landscape of structural biology. First, advances in the utilization of multiple sequence information using coevolution analysis and machine learning have led to major breakthroughs in modeling of protein structures. Second, progress in cryo-EM has facilitated the determination of high-accuracy structures for large proteins and complexes. The CASP (Critical Assessment of Structure Prediction) initiative assumes that progress in any field depends on being able to accurately assess the strengths and weaknesses of current methods, and that in modeling, methods can only be effectively assessed when models are produced without knowledge of the answers, i.e. the corresponding experimental structures. Results from the most recent edition of CASP show dramatic improvement in computing the three-dimensional structure of proteins from amino acid sequence, with many models rivaling experimental structures in accuracy. We will examine the recent breakthroughs through the lens of DeepMind, a research company behind the deep learning advancements, as presented by Demis Hassabis, the company’s founder and CEO, and John Jumper, the lead of the AlphaFold2 project. These results suggest that deep learning approaches will also be effective for a range of related structural biology applications, including macromolecular assemblies, ligand docking, alternative conformations, disordered states, interpretation of genetic variants, and protein design. In drug discovery, better ligand docking methods should speed up the identification of lead compounds, including drug repurposing opportunities.
Kevin Davies, Ph.D.The Thousand Dollar GenomeTen years ago, shortly after the publication of the first draft of the Human Genome Project, researchers coined the catchphrase “the $1,000 genome” designating the ambitious target to fully realize the fruits of human genomic research by means of routine genome sequencing. Remarkably, that goal is almost a reality. Companies are already sequencing and annotating complete human genomes for less than $10,000 and we are witnessing more and more examples of whole genome (or exome) sequencing in the clinic, particularly in pediatrics and oncology. These suggest a dazzling future for genomic medicine, although we cannot underestimate the regulatory, ethical and downstream informatics challenges, or what some refer to as “the $1-million interpretation.”
Jesse Gillis, Ph.D.The Transcriptional Legacy of Developmental StochasticityX-chromosome inactivation is an epigenetic process that regulates gene dosage in females. Occurring as a random coin-flip early in development, the status of inactivation is then stably inherited down cell lineages via DNA methylation. The degree of “skewing” toward one chromosome over the other has been researched intensively, and importantly it has been linked to disease, where female carriers of X-linked disorders can have differential disease penetrance as a function of skewing. But what about the autosomes? Is the allelic expression of autosomal genes epigenetically regulated? And if so, could it have an impact on disease risk? In this work, we uncover one major axis of random variation with a large and permanent regulatory influence on the allelic expression on autosomes: developmental stochasticity. By assaying the transcriptome of wild monozygotic quadruplets of the nine-banded armadillo, we find that persistent changes occur early in development, and these give rise to clear transcriptional signatures which uniquely characterize individuals relative to siblings. Our central experimental strategy is to measure gene expression over time and look for signatures permanently distinguishing siblings from one another. As an aggregate readout of gene regulation between the genetically identical individuals, gene expression serves as a likely intermediate to capture purely non-genetic regulatory variability with an influence on phenotype. We find that purely stochastic variation in development has a large and permanent impact on gene expression. Using allelic imbalances, we timed the contribution of developmental stochasticity within our data to the assignment of tissue-specific epigenetic marks. Using expression profiles, including co-expression and human twin data, we determined conserved functions affected by developmental stochasticity. Comparing these results to human twins, we find the transcriptional signatures which define individuals exhibit conserved co-expression, suggesting a substantial fraction of phenotypic and disease discordance within mammals arises from regulatory stochasticity occurring early in development. We examine regulatory basis of the largest effect size changes in single cell data. Genetic variation, epigenetic regulation and major environmental stimuli are key contributors to phenotypic variation, but the influence of minor perturbations or “noise” has previously been difficult to assess in mammals. By using armadillos as a model, we control for genetic and environmental factors and reveal early developmental stochasticity as a major source of variability between individuals.
David Juncker, Ph.D.The Transformation of Society by Microchips and Scalable Technologies: From Computers to HealthcareMicroelectronic chips have been scaled up in complexity and down in size over decades, and this progression led to a transformation of our daily lives, society, and even our way of thinking. More recently, bio-chips have transformed genomic analysis, heralding a new era of personalized medicine. Diseases, however, ultimately manifest themselves at the level of protein dysfunction and proteins thus serve as the preferred target for diagnosis and therapy. Yet current protein microchip technologies lack precision and are not scalable. I will present our efforts to develop scalable protein chips for discovering protein disease markers, and microfluidic chips for protein analysis at the point-of care. Finally, the potential of these technologies for transforming healthcare, as well as major challenges that remain, will be discussed.
Alexandra DraneThe Unmentionables: Is “Life” the Missing Link?Most of us toiling away in the health industry feel enormously driven to improve the health of society…and yet, with all the best intentions, there remains a gaping yaw between the health we seek for humans and the health reality we experience. Often that goes not just for those we seek to impact, but for ourselves as well. Why? Because many of us ignore a fundamental truth: Health is life…and when life goes wrong, health goes wrong. Maslow’s hierarchy reminds us that if our most basic needs are not met, it becomes difficult to prioritize (or even care about) much else. If your mother with Alzheimer’s just moved in, you hate your boss, and you’re pretty sure your partner is having an affair, are you really thinking about your diabetes? This is not a novel concept—in 1998 the Adverse Childhood Experiences study demonstrated a clear link between life experience, and health—and the data has only grown from there. Alexandra will review her own work in this area, as well as the increasing body of evidence suggesting that treating life challenges with as much intensity as we treat traditional health factors just might be “the missing link.”
Tom Blumenthal, Ph.D.The Unrealized Value to Society of Understanding Down SyndromeIf we can’t cure Down syndrome, why, then, is research into this complex and highly variable syndrome worth pursuing? I will argue that people with Down syndrome are an underappreciated gift to biomedical science and to society. As a group, they are prone to autoimmune diseases, autism, Alzheimer’s disease, childhood leukemia, heart malformations, and several other maladies. However, even though they all have exactly the same chromosomal triplication—an extra copy of the smallest human chromosome—most don’t suffer from most of these issues. Furthermore, they seem to be protected against the two biggest killers: cardiovascular disease and cancer. An understanding of the molecular genetics of people with Down syndrome will teach us key aspects of the causes of all of these diseases, both those they get at higher frequency and those they get at lower frequency. We can leverage a molecular understanding of Down syndrome to a molecular understanding of the most devastating human diseases. And of course any progress we make in this effort will benefit those with Down syndrome. For example, if we can come to understand Alzheimer’s, a disease that most people with Down syndrome will eventually contract, by studying this unusually vulnerable population, everyone will benefit, especially those with Down syndrome. I will discuss what we know now about the molecular biology of Down syndrome and what we still need to discover. I will also include some recent results about what makes people with Down syndrome unique at the level of proteins in the blood.
Joan HenneberryThe Value of Medicaid: Trends and Threats in 2018What are the market, policy, and financing trends that will impact how states manage Medicaid in 2018 and beyond? How are states connecting the need for health care coverage with improving the overall health of a community? How are changing demographics and the graying of Colorado impacting the services and expenses associated with our Medicaid program? What has been the impact of the current administration on the relationship with states and how they manage Medicaid in their own markets and regulatory environments? Medicaid is a partnership between states and the federal government and has become the nation’s largest health insurer. Yet it is regularly misunderstood and under attack at the state and federal level. At the same time Medicaid has the potential to anchor needed changes in the way we pay for and deliver health care in the U.S., and numerous states are leveraging Medicaid’s purchasing power to drive innovation and disruption in healthcare.
Fintan Steele, Ph.D.Time: Personalized Medicine’s Final FrontierDespite current excitement, the truth is that medicine has always been “personalized.” However, traditional personalized medicine has been based on both an extremely limited knowledge of presenting phenotype and an even more limited number of effective therapeutic possibilities. The current interest in a new kind of personalized medicine comes as emerging technologies are pushing back the frontier of phenotype, while at the same time opening up new therapeutic and diagnostic possibilities. However, the current public understanding of personalized medicine often relies heavily – if not exclusively – on knowledge emerging from genomics. Although highly promising, genomics is unlikely to deliver truly personalized medicine in the sense it has always been practiced: With a few exceptions (e.g., at least some cancers) it tends to lack the immediacy of the diagnostic and therapeutic expectations of patients and their physicians. Genomics is a powerful way into understanding complex biology and disease, and perhaps can even deliver preventive possibilities in some cases, but the very real promise of a new molecular-based personalized medicine will not be realized until actual “in the moment” phenotypes can be readily assessed and effectively addressed.
Lee Niswander, Ph.D.Too Much of a Good Thing? Considering Gene-Environment Interactions in Health and DiseaseNeural tube defects (NTDs), like spina bifida, are a devastating and common birth defect, with current rates ranging from less than 1 to 10 per 1,000 births worldwide. Environmental factors influence the risk for NTDs. Certain medications, diabetes, obesity, and nutrient deficiencies are associated with a greater risk for NTDs. A key public health breakthrough was the recognition that low folate levels can increase the risk for NTDs and that taking synthetic folic acid (FA) could help prevent NTDs. Currently, more than 80 countries have implemented mandatory FA fortification campaigns. Key questions remain as to what role FA plays in affecting neural tube closure rates, and how FA may modify the underlying genetic risks for NTD. Moreover, the combination of FA fortification and multiple supplements has significantly increased FA intake, yet the consequences for human health are debated and it is unknown whether particular genetic backgrounds may be sensitive to FA levels. We have been exploring these questions starting with mouse models of NTDs and multi-generational diets that differ only in FA levels to better mimic the multi-generational exposure of the human population to FA since mandatory fortification in the early 1990s. Our results show predicted beneficial effects, as well as some surprising effects including unexpected loss of mutant embryos early in development as well as an adverse effect of increased NTD risk with FA supplementation. We have honed in on a biological process that appears particularly susceptible to increased FA intake. Mutations in cilia genes in both mouse and human result in ciliopathies and NTDs. We find that mice carrying mutations that affect cilia form and function respond detrimentally to enriched FA diets. On the positive side, moderate FA diets can prevent NTD and other ciliopathies. We have extended these findings using cells from ciliopathy patients. Mechanistically we suggest that FA through its role in methylation may lead to epigenetic changes and transcriptional variability. While it is clear at a population level that FA fortification is beneficial for preventing NTDs in humans, our studies raise the possibility of unintended consequences of increasing FA levels, and that perhaps some cilia-related deficits could be ameliorated by the moderation of FA levels.
Peter S. Kim, Ph.D.Towards an HIV VaccineDeveloping an HIV vaccine remains an important, unanswered challenge: one in 200 people on earth are infected with HIV. In order for HIV to infect a cell, the membrane surrounding the virus needs to fuse with the membrane surrounding the cell. Our approach to HIV vaccine development is to target this membrane-fusion process. Studies of the membrane-fusion proteins from several viruses, particularly the influenza hemagglutinin protein and the HIV-1 envelope glycoprotein, reveal a general mechanism for enveloped-virus membrane fusion. In this “spring-loaded” mechanism, a major conformational change results in the formation of a transient “pre-hairpin” intermediate in which the membrane-fusion protein spans both the viral and cellular membranes. This pre-hairpin intermediate is vulnerable to inhibition. Previously, a monoclonal antibody was identified that binds to the HIV gp-41 pre-hairpin intermediate and inhibits the replication of HIV-1 clinical isolates, providing proof-of-principle for our vaccine approach. Because the pre-hairpin intermediate is transient, a stable mimetic is required to elicit an immune response. We have designed peptide mimetics of the gp41 pre-hairpin intermediate. The polyclonal antibody responses to these mimetics in preclinical experiments will be discussed.
Susan Fisher, Ph.D.Transforming Prenatal Care: Personalized Medicine Begins in the WombOften times pregnancy is considered to be a natural process that should unfold with little medical intervention. Thus, prenatal care is largely observational consisting of growth measurements and monitoring for signs of pregnancy complications. One reason this should change is our growing understanding of the developmental origins of adult diseases. Low birthweight, a by-product of many pregnancy complications, is associated with substantially increased rates of coronary heart disease, stroke, hypertension and non-insulin dependent diabetes. Thus, life in the womb is an important variable in the equation that determines an individual’s overall health. Additionally, prenatal genetic testing for common aneuploidies is limited to women over the age of 35, when the risk of the procedure equals the risk of having an affected child. How can we devise a strategy for developing much-needed clinical tests for the routine monitoring of pregnancy? We can take advantage of the fact that the placenta—a transient fetal organ weighing more than a pound at the end of pregnancy—is inserted into the maternal blood stream. Furthermore, many pregnancy complications and all aneuploidies are associated with abnormalities in placental structure and function. Accordingly, we hypothesized that these changes alter the repertoire of placental proteins in maternal blood. To test this theory, we used an unbiased mass spectrometry-based approach to analyze the plasma proteome of women with preeclampsia (maity for the diagnosis and prediction (at 20 weeks gestation) of this important pregnancy complication. Our work demonstrated the feasibility of this approach for developing biomarkers to monitor the health of a pregnancy. Discovering sentinels of other pregnancy complications and expanding this work to detecting fetal aneuploidies would raise the standard of clinical care for pregnant women to the acceptable norms for neonates, children and adults.
Dan Theodorescu, M.D., Ph.D.Translating Cancer Biology into Novel TherapiesRalA and RalB are small GTPases that support malignant development and progression in experimental models of lung, pancreatic, colon, prostate, and bladder cancer. However, demonstration of their clinical relevance in human tumors remained lacking. Hence, we developed tools to evaluate Ral protein expression, activation, and transcriptional output and evaluated their association with clinicopathologic parameters in common human tumor types. To determine the relevance of Ral activation and transcriptional output, we identified and evaluated a transcriptional signature of genes that correlates with depletion of RalA and RalB in vivo. The Ral transcriptional signature score, but not protein expression as evaluated by immunohistochemistry, predicted disease stage, progression to muscle invasion, and survival in human bladder cancers and metastatic and stem cell phenotypes in bladder cancer models. In prostate cancer, the Ral transcriptional signature score was associated with seminal vesicle invasion, androgen-independent progression, and reduced survival. Together, Dan’s team’s findings demonstrated for the first time the clinical relevance of Ral in several human cancer types and provided a rationale for the development of Ral-directed therapies. Therefore, they used protein structure analysis and virtual screening to identify drug-like molecules that bind a site on the GDP-form (inactive) of Ral. Compounds RBC6, RBC8, and RBC10 inhibited Ral binding to its effector RalBP1, Ral-mediated cell spreading in murine fibroblasts and anchorage-independent growth of human cancer cell lines. Binding of RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasma resonance and 15N-HSQC NMR. RBC8 and BQU57 show selectivity for Ral relative to Ras or Rho and inhibit xenograft tumor growth similar to depletion of Ral by siRNA. These results show the utility of structure-based discovery for development of therapeutics for Ral-dependent cancers.
John L. Rinn, Ph.D.Transposable Elements Modulate Human RNA AbundanceTransposable elements (TEs) have significantly influenced the evolution of transcriptional regulatory networks in the human genome. Post-transcriptional regulation of human genes by TE-derived sequences has been observed in specific contexts, but has yet to be systematically and comprehensively investigated. Here, we study a collection of 75 CLIP-Seq experiments mapping the RNA binding sites for a diverse set of 51 human proteins to explore the role of TEs in post-transcriptional regulation of human mRNAs and lncRNAs via RNA-protein interactions.
Julia Vitarello || Timothy Yu, M.D., Ph.D.Truly Personalized Medicines for Ultra-Rare Diseases: New Opportunities in Genomic MedicineOver 30 million patients in the United States live with a rare disease. Genome sequencing is revolutionizing their diagnosis, but 95% still lack effective therapy. With over 7,000 conditions to tackle, new and creative frameworks will be necessary to address this gap. Julia and Tim will present the recent case of a six year old girl who suffered the sudden onset of vision loss, seizures, and neurologic regression after several years of more insidious symptoms. After an extended diagnostic odyssey, her medical team arrived at a diagnosis of CLN7 Batten disease, a rare neurodegenerative disorder of lysosomal storage. No treatments exist for CLN7 Batten disease, and unchecked, it is rapidly progressive and ultimately fatal. We will describe how arriving at a precise molecular diagnosis prompted a collaborative effort to design, test, and deploy a novel, custom-made antisense oligonucleotide drug to try to save her. Implications of this work for other patients and the further development of individualized genomic medicine will be discussed. Dialogue with Julia and Timothy moderated by Art Krieg, M.D.
Calvin TrillinUnencumberedCalvin Trillin will discuss his experiences in medicine as a patient, an observer, and a diagnostician who is unencumbered by medical training.
Pippa Marrack, Ph.D.Vaccines: How They Work and Whether They are Good for YouVaccines are universally used to prevent certain infections or pathology caused by certain bacterial products -- for example diphtheria toxin. In order to do their job, vaccines must contain not only a portion of their target infectious agent but also an adjuvant. In the past adjuvants have been used quite randomly in different vaccines and without any knowledge of how they function. Recently we and others have begun to find out what adjuvants actually do. Now the goal of many vaccinologists is to create vaccines that contain an adjuvant that is best suited to protect against the target infection. With that in mind, we have recently designed a vaccine that might provide some protection against influenza, regardless of the strain of flu circulating in any given year. Often the public is nervous about vaccines, thinking that they may have unwelcome side effects. We will discuss this problem.
Emmanuel Mignot, M.D.Waking Up Narcolepsy and Brain AutoimmunityNarcolepsy has fascinated scientists for centuries, as it a unique disease where reality and REM/dreaming sleep get confused with each other. Patients experience sleepiness, vivid dreaming bordering on hallucinations, sleep paralysis and cataplexy (muscle weakness triggered by emotions). Type 1 narcolepsy affects 0.03% of the population, and most often starts in children or adolescent. When I started to work on narcolepsy in 1987, nothing was known, and it was considered exceptionally rare. Thinking that finding the cause of the disease could reveal new sleep mechanisms and that the field was without competitors, I plunged myself in this topic of research. Working with a dog model of narcolepsy that transmitted the disorder as a single autosomal gene, we positionally cloned mutations in two dog breeds in 1999, at a time the dog genome was a no men land. The study revealed mutations in a G-Protein coupled receptor called hypocretin/orexin receptor 2, a receptor for a recently discovered peptide believed to be involved in appetite (thus the misnomer “orexin”). Since then, this system has become a major target for hypnotics (blockers), and a promising new treatment of narcolepsy itself (agonists under human clinical trial)is emerging. Remarkably, patient with narcolepsy who don’t have hypocretin are hypersensitive to these drugs, so that smaller dose than in normal individuals have disease reversing effects. In parallel with this work, after finding that the hypocretin/orexin pathway was involved in canine narcolepsy, we discovered that in humans, the disease is not due to mutations of the receptor, but rather the result of an autoimmune disease destroying the 20,000 neurons containing hypocretin, not unlike type 1 diabetes and insulin. More studies have shown that this process is the result of T cell molecular mimicry between hypocretin itself and specific flu epitopes, with no involvement of antibodies as far as we know. This explains seasonal onset in the spring, and in a unique instance, post vaccination cases following a specific swine flu vaccine called Pandemrix. These discoveries are also opening a new field, that of CNS autoimmune mediated disorders. Indeed, many new brain diseases such as anti NMDAR, anti-LGi1, anti-GAD, anti-CASPR2 diseases are increasingly recognized and found to be amendable to immunotherapy. This field is also exploding although mechanisms behind CNS-specific immunity remain poorly understood. Autoimmunity seems to also play a role in neurodegenerative disorders such as Parkinson’s disease and Alzheimer dementia. CNS immune therapies have a bright future considering the rapid progress of immunotherapy in cancer. My research is described at mignotlab.com.
Stanley Feld, M.D., F.A.C.P., M.A.C.E.We Know How to Fix the Healthcare SystemThe Healthcare System’s business model must be changed. The dysfunction in the healthcare system has to be dis-intermediated as iTunes dis-intermediated the music publishing industry and Amazon dis-intermediated the book publishing industry. Dr. Feld will explain how this can be done in the healthcare industry to align all the stakeholders incentives using information technology and social networking. This solution will alleviate the stress all the stakeholders are experiencing, most of all patients. Consumers will receive better access to care and a better quality of care at an affordable cost of care. The new system will revitalize the patient/physician relationship which is a key to successful treatment outcomes.
Larry Gold, Ph.D.Welcome to the 12th Annual GoldLab SymposiumChairman and Founder of GoldLab Foundation, Larry Gold, gives his opening remarks for day 1.
Larry Gold, Ph.D.Welcome to the 13th Annual GoldLab SymposiumChairman and Founder of GoldLab Foundation, Larry Gold, gives his opening remarks.
Larry Gold, Ph.D.Welcome to the 9th Annual GoldLab SymposiumWelcome to the 9th Annual GoldLab Symposium.
Larry Gold, Ph.D.Welcoming RemarksWelcome This one’s a biggie—ten years. Thank you all again. Every year we think we are finally in the transition to being helpful on a broad canvas. Maybe this year is “the year”. Putting our collective dreams aside, we are so fortunate that so many great people have joined us for the weekend. We have old friends and new friends, repeat visitors, and people in the room who seem energized by being here. Please enjoy the talks and the discussions. Perhaps our odd blend of science and a deep, shared human need will do some good.
Ajit Singh, Ph.D.What Can Galapagos Teach Us About Innovation?Off the coast of the islands of Galapagos, new life and new species are created there at a remarkable pace. It is Nature’s platform for innovation. Where is its analog in the man-made world? What are the catalytic conditions that make disruptive innovation happen? We will use the metaphor of nature to propose a framework for innovation. We specifically demonstrate how it applies to clinical diagnostics. Through some case studies we will illustrate the disruptive power of the coming generation of diagnostics — both in the micro, as it pertains to an individual, as well as in macro, as it pertains to an economy.
Kathryn Paige Harden, PhDWhy DNA Matters for Social EqualityFor several years now, scientists have shown that DNA makes us different in ways that matter: for our personalities, our health, and our educational and economic success. Presenting the research that led to her book The Genetic Lottery, Kathryn Paige Harden introduces readers to the latest genetic science, dismantling dangerous ideas about racial superiority and challenging us to grapple with what equality really means in a world where people are born different. Weaving together personal stories with scientific evidence, Harden shows why our refusal to recognize the power of DNA perpetuates the myth of meritocracy, and argues that we must acknowledge the role of genetic luck if we are ever to create a fair society.
Tobias Kollmann, MD, PhDWhy Do Newborns Die and What Can We Do About It? Shift Focus From Pathogen to HostNewborn death due to infection remains one of the biggest threats to life across the human life span and across the globe. Vaccination can save millions of lives every year, but vaccines given to newborns a) induce protection too late, and b) do not cover the many pathogens that can infect newborns. We need to change our approach to begin making a difference. Increasing the newborn’s resilience to infection, i.e., focusing on the host rather than the pathogen, is one such alternative approach. For example, we have shown that the vaccine targeting tuberculosis (BCG) increases newborn resistance to a broad range of pathogens far beyond tuberculosis that are causing severe infection in newborns (sepsis). While supported by ample data, the dogmatic thinking amongst many vaccinologists (‘one vaccine targeting one pathogen’) is what stands in the way to make this pathogen-agnostic approach benefit all. Thus, the paradigm shift required now is to allow policy to be guided by data rather than dogma.
Jack Szostak, Ph.D.Why RNA? A Rationale for RNA as the First Biopolymer of LifeRNA is ubiquitous in biology today, from its role as a primer in DNA replication to its multiple roles in protein synthesis and its even more diverse roles in regulation. Most of the viruses that continue to plague us to this day are RNA viruses, while it is RNA based vaccines that provided the first and best weapons to fight these plagues. But why RNA? Why are we immersed in the biology of RNA? The answer lies in the early history of life, and its origins in the chemistry that led to RNA as the first biopolymer of life. Why did life begin with RNA, and not DNA, or TNA, or ANA, or any of the myriad other nucleic acids (collectively referred to as XNAs) that look as if they could transmit genetic information and fold up into aptamers and catalysts? Part of the answer comes from the recent advances in prebiotic chemistry that describe plausible pathways for the synthesis of ribonucleotides on the early earth. However, many noncanonical nucleotides would have been generated together with ribonucleotides in ratios depending on the environmental conditions. If these noncanonical nucleotides were present with ribonucleotides in some prebiotic pool, and exposed to activating chemistry, their oligomerization would have led to a highly heterogeneous collection of oligonucleotides containing different types of nucleotides. To add to the complexity, these nucleotides could have been connected by a variety of different types of backbone linkages. How could anything resembling modern RNA, with a relatively homogeneous composition, have possibly emerged from this primordial heterogeneity? It now appears that the chemistry of nonenzymatic template copying would have strongly enriched for RNA over the course of multiple cycles of replication. Jack’s laboratory has studied the chemistry of template copying using a simple model system in which an RNA primer bound to an RNA template is extended by reaction with activated ribonucleotides. In order to understand whether this copying chemistry would still work under more realistic conditions, we began to study the kinetics of copying using nonstandard nucleotides either as activated monomers, or when incorporated into the primer and template oligonucleotides. What we found surprised us: in all of the cases we have examined so far, chemical copying with ribonucleotides is faster than copying with alternative nucleotides. Furthermore, nonstandard nucleotides or backbone linkages in the template are readily copied into native RNA with ribonucleotides. Our results suggest that nonenzymatic copying served as a chemical selection mechanism that allowed relatively homogeneous RNA to emerge from a complex mixture of prebiotically synthesized nucleotides and oligonucleotides. The resulting RNA oligonucleotides could then have served as the genetic raw material for the emergence of the first RNA based protocells.
Lynne Wolfe, M.S., C.R.N.P., B.C.Why Would Anyone Study Rare Diseases?Rare disease is defined as a disorder impacting fewer than 200,000 people. There approximately 7,000 rare diseases that impact 25-30 million Americans. Rare diseases can have a known or unknown genetic basis or occur spontaneously and are identified across the lifespan. New rare disorders continue to be identified. The majority of rare diseases are not formally tracked in any way and therefore we know very little about how to treat them or support families and patients living with them. Identifying, formally tracking, and learning about the natural history of these diseases is the only way to improve care for patients and find effective treatments. The National Institutes of Health (NIH) supports research of people with rare diseases across 27 institutes and centers. There is even the NCATS Office of Rare Diseases Research (ORDR) to assist in coordinating research for rare diseases. Additionally, the Food and Drug Administration (FDA) has an Office of Orphan Products Development (OOPD) that provides incentives for drug companies to develop treatments for rare diseases.
Lucy SandersWomen and Technology InnovationTechnology innovation is changing the world in a wide variety of ways—smart homes, smart cars, smart health, smart education, smart cities, and so much more. Computing is a field unique in its societal impact, as computational advances impact everything from scientific discovery to energy, war, and security. Despite women’s early participation in computing, the expansion of women’s career choices into many fields that were not traditional for women, and women’s increasing participation in the private sector, today only 19 percent of all software developers are female. Of that 19 percent, very few are found in technology leadership roles that would enable them to make truly innovative contributions. While ample evidence exists to support the benefit of diverse thinking in computing innovation, numerous social and cultural influences impede women’s contributions to technical innovation teams. Hence, women are essentially “absent” from technology innovation—absent because of low participation, absent because the world doesn't experience their potential contributions, and absent because when women do make a technical contribution, they are often ignored, not recognized, and not given credit for their ideas. Recognizing women as innovators requires explicit, conscious effort. This talk explores the influences negatively impacting women and technology innovators and describes adoptable practices that can mitigate these impacts.
Sara Sawyer, Ph.D.Zika, Ebola, and Dengue: Viruses Emerging from the Human – Animal InterfaceThe 2012 MERS, 2013 Ebola, and 2015 Zika epidemics give testament to the increasing pace at which viruses are emerging from nature. The vast majority of new human viral diseases, including these three, emerge when humans come into contact with animal reservoirs. It has never been more important to rapidly characterize virus biology so that drugs, diagnostics, and vaccines can be quickly developed. The Sawyer Lab is establishing techniques that fit into the “rapid response” pipeline on which we must now rely in the face of endless new viral emergence events. We are focusing in three key areas. First, we are applying techniques to discern which viruses in nature pose the most threat to humans. Second, we are applying novel computational techniques, including machine learning, to quickly understand the biology of new viruses once they start to make people sick. Finally, we are focusing on principles that can reveal which animal models will lead us most quickly to drugs and vaccines that will protect us against these viruses.