The Significance of the Human Genome Project

Our guest today is Dr. Euan Ashley, a pioneer in the use of genomic sequencing to solve some of our most puzzling medical mysteries. Medical genomics, and the precision medicine it will enable, has the potential to predict, prevent, and diagnose many common (and uncommon) diseases.

In today’s interview, we discuss:

— Euan’s work with a colleague who was just the fifth person in the world to have his genome sequenced.

— Precision medicine and how Euan has helped establish medical genomics.

— Technological advances that made sequencing cost-effective for individuals.

— How pathogenic labels will transform healthcare.

— The Undiagnosed Disease Network, which includes physicians from across the country who work with patients and families to solve medical mysteries.

— Research from his lab that shows how all forms of exercise, particularly endurance exercise, confer benefits across all domains of health and function.

Euan is a Scottish-born professor of medicine and genetics at Stanford University. He’s also the author of The Genome Odyssey: Medical Mysteries and the Incredible Quest to Solve Them.

Show notes:

[00:02:27] Dawn begins the interview asking Euan if it is true that he was a computer nerd growing up and if his interest in science fiction played a part in that.

[00:03:03] Dawn asks Euan how he was first introduced to computers and what it was about them that hooked him.

[00:03:44] Dawn asks about Euan developing tax software when he was a teen-ager for his father.

[00:04:53] Ken asks if Euan ever developed, or thought about developing, any computer games.

[00:06:34] Dawn asks Euan where he grew up.

[00:06:51] Dawn mentions that Euan’s father is a physician, and his mother a midwife, and that even from a young age Euan told people that he wanted to become a physician, even though his parents did not push him in that direction. Dawn asks Euan what the underlying pull towards becoming a physician was for him.

[00:07:52] Ken asks Euan how he became interested in data and statistics.

[00:09:08] Dawn mentions that Euan graduated with first-class honors in physiology and medicine from the University of Glasgow, and then went for a medical residency and Ph.D. at the University of Oxford. Dawn asks when in that journey he met his wife Fiona, who helped him through medical school and has played a major role in his life and career.

[00:10:26] Ken mentions that Euan and his wife took off for California, where he conducted his post-doc research at Stanford University. Ken mentions that Euan would later join the Stanford faculty in 2006, and asks Euan what made him decide to move to Stanford in the first place.

[00:12:54] Dawn asks Euan what it was that fascinated him about the heart and at what point did he decide to specialize in cardiology.

[00:15:03] Ken asks Euan when he realized that he could combine his career in medicine with his interests in computing and data.

[00:17:38] Dawn explains that Euan’s lab at Stanford is focused on the science of precision medicine, and that he is perhaps best known for helping to establish the field of medical genomics. Dawn goes on to mention that Euan and his colleagues developed some of the earliest tools for interpretation of the human genome in the context of human health and asks Euan to give a short primer on the genome and how the first draft of the human genome sequence was completed about 20 years ago.

[00:20:36] Ken asks what genomic medicine and precision medicine entail.

[00:22:33] Dawn asks Euan about a moment in his life in 2009 when he walked into the office of a friend who was the fifth person in the world to have his genome sequenced.

[00:27:19] Dawn mentions that in 2010 Euan wrote a paper about Steve, his aforementioned friend who had his genome sequenced. The paper described how Euan put together a team to undertake an integrated analysis of a complete human genome in a clinical context. Dawn explains that this was a groundbreaking paper because it asked the question of how one brings together the entirety of the genetic literature and everything that is known about associations between genes and disease and variants of diseases. Dawn goes on to say that Euan built all these questions into an algorithm that could be deployed in the context of a single patient in a primary-care practice.

[00:30:07] Ken mentions that thanks to technological advancements, it is becoming cost effective to not only sequence individuals, but now to begin investigating entire populations. Ken asks Euan to explain the impact that this might have.

[00:32:14] Dawn mentions that in an interview Euan did with the New England Journal of Medicine’s podcast, he talked about how someday we will see a pathogenic label, or be able to order a pathogenic label, on a genetic report. Dawn explains that current commercial tests can already tell if people are at risk for certain diseases. She mentions that Euan has said more advanced genetic reports are on the horizon and that they will provide even greater detail. Dawn asks Euan to talk about these future genetic reports and pathogenic labels and how they will differ from what we see today.

[00:36:34] Ken mentions that Euan often compares the work of physicians and geneticists to detectives, and that’s because patients often present medical mysteries. Ken asks Euan to elaborate on this and talk about how he teaches young physicians to think of themselves in this way.

[00:39:18] Dawn mentions that about 25 to 30 million Americans have a rare disease, which are sometimes referred to as mystery conditions. She goes on to say that Euan has been instrumental in establishing the Undiagnosed Disease Network, established in 2014, which includes teams of physicians across the country who work with patients and families to solve these medical mysteries. The network has identified scores of previously unknown syndromes to date. Dawn asks Euan to talk about some of this work and how the network came about.

[00:43:36] Ken shifts the conversation to Euan’s recent research. Ken mentions that Euan had a study last year that looked at the impact of genetic sequencing in critical-care settings. Because a genetic diagnosis can improve the prognosis of critically ill patients and therefore guide the clinical management of their care, a lot of effort has gone into developing methods that result in rapid, reliable results. In critical-care situations, decisions need to be made in hours, but traditional testing requires weeks and even rapid testing requires days. Ken goes on to explain that Euan’s paper reported on a new method he and his colleagues developed for rapid sequencing of the whole human genome in patients in as little as five hours. This new ultra-rapid genome sequencing has the potential to lead to significantly faster diagnostics. Ken mentions that this study used a technology called nanopore sequencing and asks Euan to explain what this is and how it works.

[00:46:54] Dawn asks Euan to talk about how the sequence of one of the study’s participants was completed in just five hours and two minutes, setting the Guinness World Record for the fastest DNA sequencing.

[00:52:31] Ken mentions that Euan and other colleagues at Stanford are currently working to cut sequencing time in half from their previous record and asks how far off in the horizon that is.

[00:54:05] Dawn mentions that Euan recently published a paper in Nature that introduced COSMOS (Computational Sorting and Mapping of Single Cells), a cloud-enabled platform that performs real-time cell imaging and analysis. Dawn goes on to explain that COSMOS uses AI and microfluidics to achieve high-throughput imaging that can sort cells using deep morphological assessment. Cell morphology has been used by pathologists and clinicians for years as the gold standard for disease diagnosis and prognosis. Dawn mentions that although there have been technological advances in making single-cell characterization at the genomic, transcriptomic, and proteomic levels, tools for assessing high-dimension cell morphology have not kept pace. Dawn asks Euan to talk about the challenges he and others have faced in performing real-time deep-learning assessment and sorting of cells and how COSMOS helps address these challenges.

[00:58:00] Ken asks about future enhancements of COSMOS, given that Euan is using AI predictions to link machine intelligence to cell biology. Ken asks Euan to talk about how this could lead to new insights that could have significant translational and clinical impact.

[00:59:53] As an aside, Ken talks about what makes AI tools effective in the hands of physicians as well as the limitations of AI in physicians’ hands.

[01:01:02] Dawn pivots back to the work Euan did with Steve and his genome. Dawn mentions that Steve pointed out to Euan in that encounter a variant in one of his genes associated with heart disease, a variant that could be life-threatening. Dawn goes on to explain that accurate assessment of cardiac function is crucial for diagnosing cardiovascular disease. In one of Euan’s papers, he addressed the limitations of human assessment of cardiac function. In order to overcome this challenge, Euan and his colleagues developed a video-based deep learning algorithm, EchoNet-Dynamic, which surpasses human observation in several critical tasks related to the assessment of cardiac health. Dawn asks what went into the development of EchoNet-Dynamic and what makes it standout as an assessment of cardiac function.

[01:05:13] Ken explains that IHMC has three primary overlapping research focus areas: artificial intelligence; robotics and exoskeletons; and human healthspan, resilience and performance. He also mentions that IHMC is building a new research complex dedicated to healthspan, resilience and performance research. Dr. Marcas Bamman will be the director of the new complex and will help lead clinical and translational research to advance knowledge on optimizing the performance and resilience of elite performers. Because of this research, Ken was particularly interested in Euan’s paper in Nature last year titled “The Genetics of Human Performance.” The article points out that while we have substantial epidemiological evidence supporting the beneficial effects of exercise, we really don’t know a lot about the molecular mechanisms through which these effects operate. But we do know that exercise extends healthspan. Ken explains that the article reviewed the current understanding of the genetics of human performance, and it begins by pointing out that compared to our recent hominid ancestors, humans seem to have evolved for endurance physical activity. Ken asks Euan to talk about this and why it matters in terms of modern humans.

[01:09:05] Dawn mentions that Euan and his co-authors on the aforementioned paper reviewed the large body of research that has shown that all forms of exercise, particularly endurance exercise, confer benefits across all domains of health and function. The paper goes on to review recent research that identifies specific genetic pathways that may underline the beneficial effects of endurance exercise. Dawn asks Euan to talk about these genetic pathways and the key points of the review and its primary conclusions.

[01:11:31] Ken asks Euan about his thoughts on the significance of the role of the microbiome in enhanced endurance activity.

[01:14:23] Ken explains that while some genetic variants identified to date account for small portions of the variance in exercise training adaptations and/or human performance, it seems the major determinants of inter-individual differences may lie in dynamic expression responses which are largely influenced by the dynamic epigenome. Ken asks Euan what he thinks are the critical paths forward in exercise epigenomics.

[01:16:48] Ken explains that Euan is involved in projects via the Wu Tsai Human Performance Alliance to identify new genetic variants that have larger effect sizes on human performance than those previously identified. Ken asks Euan to talk about the importance of the ELITE project in this context.

[01:19:11] Dawn asks Euan about his book “The Genome Odyssey,” which was described by the Wall Street Journal as an impassioned, firsthand account of the effort to bring genomic data into clinical practice. Dawn asks what Euan was hoping to accomplish with the book.

[01:20:36] Dawn explains that in the Wall Street Journal review of the book, it highlights Euan’s account of the remarkable progress of genetic medicine over the past two decades, and also mentions how Euan believes more wondrous advances are on the way. Dawn asks Euan to talk about some of these advances.

[01:22:19] Dawn mentions that in Euan’s Stanford bio, it mentions that he is a father of three and that in his spare time he plays jazz saxophone, pilots small planes, and conducts research on the health benefits of single malt Scotch whisky.

[01:23:23] Ken mentions that Euan’s bio also says that he is on a quest to better understand American football and asks Euan how that’s coming.

Links:

Euan Ashley bio

Learn more about IHMC

STEM-Talk homepage

Ken Ford bio

Ken Ford Wikipedia page

Dawn Kernagis bio