Michael Snyder does not look like a man with Type 2 diabetes.
Snyder, chair of the Stanford University School of Medicine’s Genetics Department, is not overweight, nor is he African American, Hispanic, or Native American—ethnic groups that are at higher risk for this chronic disease. Looking back at his family medical history, none of his relations, as far as he is aware, have been diagnosed with diabetes. His own physician, when Snyder first mentioned concerns about elevated glucose levels, told him: “There’s no way you have this. You don’t fit the profile.”
It’s easy to see why. Trim and rangy, Snyder looks more like the type of man who squeezes in a run before biking to the office each morning. He comes off as a person that naturally gravitates toward the salad bar, who manages to avoid sweets despite living in a house with young children. Yet, as the single participant in a groundbreaking study which offers a glimpse of what the future of medicine may look like, Snyder not only learned that he personally was at high risk for diabetes, but assessed and reported the activation of unique biological pathways as he developed the disease.
Michael Snyder does not look like a man with Type 2 diabetes. But with his diagnosis and the creation of his own “integrative personal omics profile”—iPop, for short—he is fast becoming the face of personalized medicine—and showing scientists and clinicians that we may be better able to prevent and control disease with the data gleaned from a sequenced genome and the regular donation of a few milliliters of blood.
That is, as long as those scientists and clinicians are willing to deal with the thornier ethical issues surrounding “omic” interpretation.
“I live by the motto that more information is always better than less information. I’m the kind of person who wants to know if I have a terminal disease so I can plan appropriately.”
FOR YEARS, THE MEDICAL world has been talking about the promise of “personalized medicine.” Currently, medical diagnoses are based primarily on the presentation of clinical symptoms, with the addition of the odd lab test or imaging result. Treatments for those diagnoses are often symptom-centric as well—pills or tonics that confront the accompanying sniffle but largely ignore underlying conditions. This type of health management is reactive at best—and can be less effective, more time-consuming, and more expensive than simply preventing disease altogether. But prevention, for many years, seemed like nothing but a medical pipe-dream.
Why? For the most part, healthy people don’t go to the doctor’s office. We’ve been conditioned to wait until we’re sick to make our appointments. But even for those of us who dutifully show up for our annual check-up, physicians can offer us very little information about our current health state.
“Typically, when doctors try to figure out if you’re healthy, they give you a standard physical exam and then also take a blood test,” says Snyder. That blood test is usually the chemistry panel, which measures common biomarkers like your cholesterol and glucose levels, as well as your liver and vascular status.
With advances in genetics and genomics, however, scientists now not only have the ability to sequence the genome, but also to measure thousands of different biomarkers. And with that, a health care paradigm shift to focus on disease prevention seems more than just possible—it seems inevitable. With a better understanding of the genetic and molecular contribution to myriad disease states, scientists hypothesize that many chronic health issues can be averted altogether. Or, barring that, at least result in quick and reliable diagnoses that can be treated with gentler, more effective therapies specifically tailored to each patient.
While thousands of genome-wide association studies have been published in the past few years linking gene variants with particular conditions ranging from schizophrenia and breast cancer, a comprehensive, longitudinal look at an integrated biological profile of a single healthy individual—a personalized medicine proof of concept, if you will—had yet to be done. Until, that is, Snyder volunteered himself to be the guinea pig in his very own pilot study.
SNYDER WANTED TO MONITOR a person’s health state at a resolution that no one had ever attempted before.
“Your health is definitely the product of your genes. But it is also the product of all the things you are exposed to—what you eat, the pathogens, the viral infections and life stressors and those sorts of things,” he said. A genetic profile, he argues, can only give you a partial look at your overall health picture. And so Snyder, with the help of his colleagues, opted to integrate his genomic sequence with over 40,000 other biological data points, or “omics,” including auto-antibodies, metabolites, proteins, and RNA measures. This combination of genomics, transcriptomics, metabolomics, and proteomics makes up the so-called iPop.
“It was something we’d been thinking about doing for a long time. We’re one of the rare labs that does both genomics and proteomics so we knew we could do this at the level we wanted to,” says Snyder.
Snyder, now 56, did not always dream of being a geneticist. Growing up in the heart of Pennsylvania’s prime farm country, he remembers fantasizing about being an astronaut or a professional ping pong player in his youth. But by the time he was accepted to the University of Rochester on scholarship, he had his heart set on some type of scientific career. He thought it might be chemistry—he graduated with a dual degree in chemistry and biology—until recombinant DNA came on the scene.
“I was very intrigued by the idea of cloning genes, trying to understand gene structure and organization,” he says. That intrigue took him to the California Institute of Technology for graduate school, working under the esteemed Norman Davidson, a National Medal of Science recipient known for pioneering work in genomics. After a post-doctoral stint at Stanford, Snyder accepted a professorship at Yale University, where he stayed for 24 years, contributing to the Human Genome Project and directing innovative research on the importance of DNA’s structure in relation to disease.
When Snyder left Yale University in 2009 to helm both the Department of Genetics at Stanford University School of Medicine and the University’s Center of Genomics and Personalized Medicine, he decided it was time to stop simply thinking about the potential of iPop and start doing the work. With his new laboratory in place, he had the tools at his disposal to start tracking omics and correlate them with various health states over time.
But tools aside, the idea of genomic sequencing in health remained very controversial. Despite the prevalence of genome-wide association studies, very few “smoking gun” type genes, or genes that could be causally linked to specific diseases, had been discovered. Researchers were quickly learning that most medical issues usually stemmed from the complex interactions of dozens, if not hundreds, of different genetic factors.
“There remained a question about what one could really learn from genomes. Maybe you wouldn’t learn anything. Maybe you might learn things that would be harmful, like learning that your father isn’t really your father or that you’re going to get Huntington’s disease,” says Snyder. “People were very concerned about these things. They still are. These issues have not gone away.”
So when it came time to find the person to profile for the iPop study, Snyder realized that he was the ideal candidate. “One, I was accessible and motivated. We needed someone who would be very easy to reach since we’d be taking samples both during healthy times and not healthy times—the person would have to be willing to be dragged in while they were sick so we could take blood from them,” he says. “But it was also that I understood the risks, I understood all the issues. I’m a big believer in this being an important part of the future of health care. I can see the advantages of this as part of managing health. And to me, those advantages far outweigh the disadvantages.”
Over the next 14 months, Snyder gave blood approximately 20 times—once every two months while healthy and then even more often when he fell ill. His team analyzed over 40,000 different proteins and biomarkers from each sample—integrating it with the information gleaned from his genomic sequence. He remained accessible and motivated enough to drag himself into the lab fora half dozen or more blood tests even when felled by nasty viral infections. He was accessible and motivated enough to freely share his own personal health information with his team, including the elevated risks for conditions like basal cell carcinoma, aplastic anemia, and Type 2 diabetes uncovered by his genomic sequence. He was even accessible and motivated enough to ask his 82-year-old mother to have her own genome mapped, so they could compare and contrast sequences as they attempted to interpret the different patterns of data that emerged.
In hindsight, it is difficult to see how his lab could have found someone more ideal to study.
“I’ll go against the medical tradition here and say I believe that we’re all responsible for our own health. To me, the doctor of the future is more of a health coordinator in a cooperative practice.”
SNYDER IS A BIG fan of puzzles. It’s one of the things he loves about science—the opportunity to try to figure out he unknown on a daily basis. “I like jigsaw puzzles and problem-solving,” he says. “It’s a lot of fun to try to figure out how things work.”
As his various omics were tallied, a veritable glut of data, Snyder had thousands upon thousands of data points to try piece together—the ultimate scientific jigsaw puzzle. “You’re looking for genes that you think predict risk and you’re integrating over lots of genes to make those predictions,” he says. “Then you have to analyze your blood components. You try to put it all together and follow the various biological pathways that are going up and down over time. It’s very much a research project but, with more data, I do think we’ll see different markers associated with different health states.”
While Snyder is confident that more research will one day be able to more accurately differentiate a biomarker indicative of impending disease as opposed to a simple genetic outlier, the ethical questions remain. Is it possible that having this much information at the “omic” level may ultimately be more harmful than helpful? When I pose the question to Snyder, he answers thoughtfully.
“You can never be sure of what your genome is going to tell you,” he says. “But I live by the motto that more information is always better than less information. I’m the kind of person who wants to know if I have a terminal disease so I can plan appropriately. Yet, I recognize that’s not for everyone.”
Yet while Snyder was able to recruit his mother to participate in his study, he has not collected iPops for either of his two children—at his wife’s request.
“She was perfectly happy to let me sequence my genome. But she hasn’t gotten her own genome sequenced,” he says. “And she felt it was more appropriate that our kids get to make their own decisions when they are older about whether they want to do it. I can see some advantage to sequencing them now to help us, as their parents, be on the alert for potential issues. But they’re healthy right now and there’s no urgency.”
Yet later, he tells me that he thinks the right age to start iPop profiling may be at birth so that potential health issues can be identified and tracked early. When I ask again about deciding not to profile his own children, he shrugs. “I don’t know that I have all the answers yet. But I do think, at the end of the day, people should own their own sequences.”
SNYDER HAS CERTAINLY OWNED his own sequence. By keeping a detailed iPop, Snyder was able to catch his own diabetes very early and make the necessary lifestyle changes before any lasting damage was done. Which is the point, he says—and how, ideally, health care should work in the future.
“I’ll go against the medical tradition here and say I believe that we’re all responsible for our own health. To me, the doctor of the future is more of a health coordinator in a cooperative practice where multiple players help interpret and assess your omics. But then it’s really up to you,” he says. “We need to shift medicine from the current symptom-based scenario to one of early detection or prevention. And for that you have to have more elaborate tests than we have now. That’s where the iPop comes in.”
Yet he concedes that this particular puzzle is not yet finished—there are still many missing pieces to the iPop, the need for more research to accurately interpret all of the omic information and, eventually, the need for automated processes to translate that interpretation so it is useful to clinicians.
“Clinical interpretations are a lot of effort. People talk about the $1,000 genome. We’re not there yet—but we’ll get there,” he says. “But it costs $20,000 or $30,000 to interpret that same genome properly, to go in and look at all of the variants and understand what they are doing. That’s the real bottleneck, as I see it, for personalized medicine right now.”
To that end, Snyder is one of the founders of Personalis, a new company that is working to create packages that will clinically interpret an individual’s genome and convey that information back to the health care provider. “This is something that can help everybody. Since we did this, we have lots and lots of people asking us to do the same thing for them. As an academic lab, we don’t have the staff or the funds for that. And we want to focus on our research, as we should,” he says. “But commercial ventures are great for this kind of thing and there is a lot of possibility here.”
Despite the ethical concerns, Snyder sees a future where there will be millions of iPops linked to a million electronic health records, changing our understanding of health states (and face of modern medicine) for good. While Personalis works to bring clinical interpretations of those data points to the masses, Snyder is continuing on with his iPop work. His next study will track the omics of 250 pre-diabetic patients, or individuals with a genetic predisposition for Type 2 Diabetes over a five-year period. “We know that about one-third of them will convert over that time. So we’d like to follow and see what is happening there, what events are actually triggering the diabetes. Maybe it’s a viral infection like me, maybe there’s something else there,” he says. Given his own experience with the disease, he believes that tracking these molecular signatures may uncover the subtle differences between each diabetic that can help inform more customized and effective treatments. “By understanding the molecular basis of these different diseases and, perhaps, their etiology, we can treat them to according to what they really are. That’s the power of personalized medicine—being able to tailor treatment to every individual according to their own profile.”
Snyder will also continue adding more data to his own iPop. When I ask Snyder just how long he plans to continue tracking his omics, he answers immediately. “I’m sure I’ll be doing it for the rest of my life. There’s always more information that comes in that needs to be interpreted. There’s no such thing as too much data,” he says. “The longer we do it, the more we’ll learn about how to interpret the data. The longer you can follow a person, the more you’ll learn about their health states, the more you can do to help them stay healthy. That’s the way it should be.”
