As gene science transforms our understanding of disease, the Nevada Institute of Personalized Medicine pursues the dream of DNA-based healthcare — and considers the dilemmas
“What do you think the No. 1 human need is?” Martin Schiller asks me. “I’m always surprised that everyone gets this wrong.”
Food?
“Avoidance of pain,” he says. “People will do anything to avoid intense pain.”
His office in UNLV’s White Hall is mostly desk. A hull of ornate wood amid the institutional gray, it looks like the desk of a philosophy professor. Schiller goes on to muse about the particular pain of disease, its physical, emotional and financial ravages that have driven some of medical science’s greatest innovations. And he believes that precision medicine — tailored to individual genetic makeup and the impacts of lifestyle and environment — will be as world-changing an innovation as the internet. But he’s not merely philosophizing. As a scientist and founding director of the Nevada Institute of Personalized Medicine, Schiller is helping lead that transformation.
NIPM launched in early 2015 as a two-person operation with about $6 million in seed funding from UNLV and the Governor’s Office of Economic Development. It has since garnered $19 million in grants, including a recent award of $11.4 million from the National Institutes of Health to build a Center of Biomedical Research Excellence. That work will engage NIPM’s seven specialized faculty, supported by two adjuncts, five staffers, 21 affiliated faculty, and a cohort of 35 students, postdoctoral fellows and trainees. Tackling human health really does take a village, Schiller says, and NIPM is part of a growing global force advancing gene science and its applications.
Perhaps reflecting the complexity of its mission, the institute isn’t one specific building. Radiating from Schiller’s massive desk, it’s a network of labs, offices, and computer clusters touching many disciplines and areas of campus. The core team is Schiller; development officer Jim Timmins; medical geneticist Dr. Michael Nasiak; and active researchers Xiangning Chen, Jingchun Chen (no relation), Mira Han, Edwin Oh, and Qing Wu. They hail from institutions including the Mayo Clinic, Johns Hopkins University School of Medicine, Virginia Commonwealth University, Duke, UCLA, and Cedars-Sinai Medical Center, and their expertise ranges from functional genomics and bioinformatics to molecular diagnostics.
Research is just one pillar. NIPM offers genome-sequencing services to faculty and others in the field, and it is affiliated with the UNLV School of Medicine’s Medical Genetics Clinic for patients struggling to identify and address their disorders. The institute’s charge includes commercializing discoveries, educating health workers, and acting as a community resource. Three years in, Schiller says, some of the headway made stands up on a national level.
“Our impact isn’t very large at this point, but this research and building things take time. … We’re young, obviously, but we are contributing,” he says.
What seems like modesty is just as much an appreciation of the immensity of their project — and the remaining barriers to the dream of precision medicine. Schiller has done the math on yet-to-be-parsed puzzle pieces related to the genome’s 3.1 billion DNA base pairs, finding they far outnumber all the particles in the universe.
Known unknowns
There are more than 12,000 human diseases that we know of. The majority of them are rare disorders with associative or causative links to gene mutations. Such links are found in many common afflictions, from cancer and Alzheimer’s to diabetes. And gene interactions with treatments can cause adverse reactions or make them more or less effective in certain patients.
So targeted healthcare depends on cataloguing genetic variation, a tall order, considering the thousands of mutations that are possible within each of humanity’s roughly 25,000 genes. It’s not as simple as pinpointing variants that are pathogenic. Body to body, the same mutation might manifest different expressions or severity of the disease — or nothing at all. Science must sort through layers of variability across individual biology, ethnicity, and environment. That’s a lot of needles in a lot of haystacks.
On top of the unknowns, there are only about 1,000 medical geneticists qualified by the American College of Medical Genetics and Genomics to interpret sequences. Genetic counselors, who help patients understand the analyses, number only in the thousands.
“We’re not at the point where you can sequence someone and predict whether they’ll have a disease 20 years later. Probably doing exercise regularly has more predictive power,” NIPM researcher Mira Han says. Her background is in genome evolution, but she’s working on a signaling system of DNA modification and RNA expression in tissue cells to find primary sites of metastatic cancers.
Cancer is a good example for illustrating the mind-boggling scale of genomic investigation. Consider BRCA1, a tumor-suppressor gene thought to cause breast and ovarian cancer given the presence of certain mutations. It is the most-studied gene, and of its 38,000 possible variants, scientists know 3,000 to 4,000 to be pathogenic and the same number to be benign. Roughly 80 percent have yet to be cracked.
“That’s a gene we’ve been studying for 30 years,” Schiller says, adding that complex disorders like cancer can be associated with hundreds of genes.
‘Everybody is a mosaic’
“I was scuffing the floor saying, ‘I have to decide what I want to do with my career,’ and out of the blue I get a telephone call, that moment! My jaw hit the ground. Genomics institute. UNLV. New school of medicine. Really? How wonderful! Nevada so badly needs this,” he recalls.
Nasiak oversees the med school’s Medical Genetics Clinic, which immediately resonates in the community and public consciousness. He has seen more than 500 patients, referred to him by doctors who suspect a heritable condition is present.
“It takes a referral, and it takes a while to get in,” Nasiak says. At any given time there are 100 to 200 patients on the waiting list. Among those seen so far, a new diagnosis has been made for about one in five. “They usually come to me as a last resort, and I get half a telephone book full of notes.”
The better we understand the genetic underpinnings of these tough cases, the more therapies can be directed. But blaming genes misses something essential. No gene is there to cause disease, Nasiak says, paraphrasing science writer Matt Ridley. Every day in every cell at the rate of about a thousand base pairs a second, our genes replicate and repair DNA. This task is constant, and mistakes are usually harmless. But if they happen in the right region of a particular protein-coding gene, there can be deleterious effects.
“These are people minding their own business in life who unfortunately, usually by random fate, contract or have a genetic condition. That’s one of the hardest things when you see these patients sometimes, the guilt that they have. It’s like, you’ve done nothing wrong!” Nasiak says.“Mutations are happening all the time. … They keep coming, and they will keep coming.”
“If you were to take DNA from multiple places in your body and compare them, you’d probably find differences, different somatic mutations that have been acquired throughout your lifetime,” Han says. “People are realizing that everybody is actually a mosaic.”
Many of the patients Nasiak sees are children. After arriving late to our interview, he says it’s because he’d just found a cancer gene in a young patient.
“The mother has it too; that means it needs to be chased,” he says. “I found a dysrhythmia issue today in a child. … I can’t promise anything other than being a value add-on to (existing care), but sometimes I’m remarkably fortunate in being able to discover causative reasons in their genome related to their health conditions.” Even in those instances, a diagnosis might come with no clinical action to take from there. Still, knowledge is empowering, Nasiak says, adding that breakthroughs are reliably on the horizon. When X-ray technology hit, he says, doctors could finally diagnose pneumonia — but antibiotics to treat it took another 50 years.
“First you have to know a condition exists and understand its phenotype … and then over time medical science will, and I really mean the word will, find ways to maximize patient outcomes,” he says. “The ability to do this degree of sequencing that has all happened within a generation is awe-inspiring. But they were so good at the technical aspect, it has exceeded our current ability to understand it completely. We could have a problem staring us right in the face if you look at the code, but we’re not smart enough to know that yet. We’re getting there.”
Wanted: genomes
The easiest path forward is sequencing a lot more people, so genetic connections to diseases and spectrum disorders become statistically apparent. That drives the U.K.’s 100,000 Genomes Project and the U.S. VA’s Million Veteran Program, the world’s largest genomic database at 500,000 and counting.
In May, the NIH made its own call for 1 million or more volunteers for All of Us, a carryover from President Barack Obama’s Precision Medicine Initiative intended to gift diverse data to the cause. (Researchers can apply for access, granted at a committee’s discretion.) Through such national efforts, smaller trials, clinical care, or commercial avenues, NIPM neurogeneticist Edwin Oh thinks that in 10 to 15 years, 99.9 percent of people in developed countries will have undergone some kind of sequencing.
Cost is the only reason he wavers. Through a certified lab, whole-genome sequencing is $5,000-$7,000, and adding clinical interpretation quadruples the price. Doing just the exome, or the 1.5 percent of the genome coding proteins for growth, development, reproduction and function, is $2,500-$6,000 for sequencing and analysis. And you can’t just walk into a lab. A doctor must send you, even if you’re paying out of pocket. Insurance covers only a handful of clinical-use cases.
If you volunteer for a public research project or private clinical trial, you won’t necessarily own or even know the results (unless they’re really bad). “Recreational” genetics service 23andMe delivers health and ancestry data for $199, but the level of investigation and insights can’t compare.
“The cost of sequencing is easily outweighed by the personnel costs of having the experts on staff to do everything right, and the interpretation is definitely tens to hundreds of man-hours of Ph.D.s and M.D.s that sit down and really try to dig into what’s going on. It’s like solving a little Sherlock Holmes mystery every single day,” says Gabe Rudy, a bioinformaticist with Montana biotech company Golden Helix and member of NIPM’s external advisory board. “The quip you hear at conferences is that we’ve gotten to the $1,000 genome with a $100,000 interpretation.”
Progressive health systems Geisinger (Pennsylvania) and Sanford (South Dakota) are testing ways to provide genetic services to subscribers at much lower costs. The Grand Forks Herald reported in May that Sanford would roll out a $49 blood test for about 60 disease markers and 30 drug-gene interactions. Earlier that month, Forbes reported Geisinger was doing exome sequencing at a few pilot clinics, footing the $300-$500 bill to test the model’s cost savings.
“We’re going to watch what they do closely and communicate that to our Las Vegas healthcare institutions,” NIPM’s Jim Timmins said when the Geisinger news broke.
In addition to being a product of MIT’s MBA program in tech management, he’s one of biotech’s early players, holding patents going back to the late ’80s. Timmins sees consumers as the market movers, even more so now that the FDA is blessing the use of publicly accessible variant databases to validate sequencing-based services. The intent is to streamline data aggregation, product development, and public access to reliable results.
It’s a regulatory win for businesses, one Timmins thinks will help democratize genomics as startups emerge and costs scale. But there are pitfalls to sharing potentially grave information with consumers who may not see the whole picture. In April, when the FDA cleared 23andMe to sell a test for markers of 10 diseases (Alzheimer’s and Parkinson’s included), Scientific American writer Dina Fine Maron observed: “If disease risk news is delivered at home—without a genetic counselor or doctor on hand to offer context—many geneticists fear it can lead to unnecessary stress, confusion, and misunderstandings.” In July, a New York Times article headlined, “The Online Gene Test Finds a Dangerous Mutation. It May Well Be Wrong,” considered the dangers of false positives and negatives when limited test results are uploaded to third-party sites. Commercial outlets, it posited, are not subject to the quality controls of certified labs because they’re not making diagnoses. But looking at the website for 23andMe, there is a disconnect between disclaimers about provided data (“it is not intended to diagnose any disease”) and insinuations of its marketing (“I truly believe it saved my life.”)
To tell or not to tell?
It’s obvious why coalitions of experts are discussing the impacts of sharing heavy details they can’t fully define, how to counsel frightened patients and care for them if they choose not to know.
Dr. Robert Green is among them. The medical geneticist and physician scientist directs the Genomes to People Research Program in the Division of Genetics at Brigham and Women’s Hospital, the Broad Institute, and Harvard Medical School. He’s also a board member of the Council for Responsible Genetics and part of prominent oversight boards in the space. Green has done pioneering work on how people react to exploring their genomes.
“Find an otherwise entirely healthy young man with a Long QT Syndrome mutation — increased risk of sudden cardiac death. Do you tell him not to exercise, to get an EKG every six months or year, an implantable defibrillator, or to go home and not worry? We don’t know. Right now we have lots of information,” he says, “but not always lots of knowledge associated with it.”
Because of this, Green says, sequencing healthy people is controversial, especially infants. He explains the notion of the human right to an “open future,” to not be saddled with knowledge that could suck the joy out of life. But early detection being the key to prevention, there’s an obvious dilemma.
In his patient surveys, Green has found that users of direct-to-consumer genetic testing have “surprisingly good comprehension of the information,” and that many of them are interested more in familial conditions they know they have or may have than predicting future disease.
Perhaps the most interesting finding: “Most people did not experience distress even when they were given scary information.” Green did indirect studies on consumer behavior after finding a modest risk increase, and his data didn’t show panic driving overuse of medical resources. Fewer than 1 percent of respondents stopped or changed medications without consulting a doctor.
Fears are real and relevant, Green says, and thoughtful consideration is going on at high levels. He advises that people using 23andMe have a responsibility to educate themselves. These outlets offer some good information, but you have to read the fine print and follow up with experts to verify actionable findings.
Despite the scarcity of experts such as Nasiak, resources are emerging for consumers who want help reading their genetic files. Green cofounded a telemedicine service called Genome Medical, which will soon be licensed nationwide to advise people on ordering tests and applying results. It’s not the only outlet pursuing this concept, though one-on-one services come at a cost.
NIPM hopes to fill some gaps for Southern Nevadans with free expertise. During Research Week at UNLV, on October 8, Schiller will host a session on navigating recreational genetics. And he says that by early fall, the institute launch a monthly segment on UNLV TV and KUNV covering topics of general interest within precision medicine. Additionally, the public should watch for a podcast and visit social media channels for dialogue with NIPM.
“UNLV should be the lead on something like this, because where it’s happening now is only in major medical centers that have very well-established research units and clinical units,” Schiller says. “It’s a health disparity based on location. If you’re close to an academic health center you have access, and if you’re not, you don’t, and you don’t even know.”
‘I just followed the science’
In all my conversations with Schiller, there was only one time when his surface mellow rippled.
We were talking about the potential of a technology he developed with postdoc Ronald Benjamin Babu, called the GigaAssay. Combining gene editing, molecular barcoding, a reporter assay, and other techniques, it generates all mutations of any gene in isolated cell cultures, then reads out function. If a mutation impedes DNA repair, for example, it’s likely a pathogenic change for cancer.
“The business concept is to create that encyclopedia, lock it down, and sell it to (diagnostic) companies like Myriad who can then go and say, ‘Whatever you throw at us in terms of your mutation, we’re gonna tell you whether it’s going to knock down DNA repair or not.’ … So Marty will eliminate, with this system’s promise, any variants of unknown significance in any gene,” Timmins says. “So we’re prioritizing the genes we’re going to go after based on commercial impact, mostly cancer genes to start.”
Timmins says it accomplishes what traditional gene cloning does, with two people instead of an “army,” and in a few months instead of a few years. It’s very expensive to run an experiment, and the first one revealed a few kinks. But if the data bear out, the system could be applied to any of the 1,800 genes thought to be associated with all major human disease. The institute recently licensed GigaAssay to Heligenics, a startup jointly owned by Schiller and UNLV.
“We’re working with StartUp NV on a seed round of investment. … I’m like, freaking out,” Schiller says with a smile. A lot of experimentation and data validation remain, but he says that even if competing intellectual property beats his team to market (Timmins knows of two other research groups using different approaches to achieve the same outcome), contributing to precision medicine feels good.
I ask what drew him to this field, long before it was in the news every day. There is no colorful tale of heartbreaking loss or muse on youthful desire to save humanity.
“I just followed the science,” Schiller says.
Asked the same sort of question, Oh gives the same sort of answer.
“Scientists are just ordinary beings interested in a question,” he says. “And depending on the opportunities around us, we’ve either transformed them into something of utility or we haven’t. I’d like to think that Las Vegas is a place with opportunities not as many people have the time or background to recognize.”
One such opportunity is NIPM’s partnership with the Cleveland Clinic Lou Ruvo Center for Brain Health. Its ongoing study on degenerative brain disorders in former fighters is rich in data from a diverse cohort. Through the Medical Genetics Clinic, Oh and Nasiak are recruiting patients for a study that will crosscheck variants involved in rare disorders with cases across the globe to better guide therapies.
Public engagement in scientific enterprise is vital to broad, rapid progress in precision medicine, but laws governing genetic discrimination (GINA, HIPAA and the ACA) don’t cover every peephole onto our essential biological selves. You can be denied life or disability insurance for genetic reasons, and there are rumblings about the same scenario occurring with health insurance. Police can subpoena your files from commercial sites (Golden State Killer), and the military can use them in determining your service.
Even if you willingly submit to sequencing, your data may end up somewhere you didn’t expect if you skip or don’t understand the fine print.
“Most of the commercial genomics companies, they don’t really advertise it, but they’re amalgamating the (anonymized) data from these 10 million people and reselling it to drug companies,” Timmins says of Ancestry and 23andMe users, projected to be 100 million within two years. “I think society is going to increasingly want a get-back on that.”
In June, genealogy site MyHeritage was hacked. Genetic files for more than 92 million affected users weren’t compromised, but the thought sent the media into a frenzy.
Green says that so far, he hasn’t seen any widespread examples of eugenic privacy breaches or insurance discrimination. Yet a quarter of the people in one of his research studies cited fear of these things in thinking about participating in scientific enterprise. He mentions that insurance companies have their own fears about public opinion and haven’t really used their bandwidth to underwrite on the basis of genetic information.
Schiller believes the gains from precision medicine will outweigh direct or indirect downsides. “I don’t think it is stoppable. It’s the new Wild West,” he says. “In a funny way, it will be as reactive as medicine is now, identifying problems and working backward to fix them.”
Oh points out the tendency in human history to launch life-changing innovations without having everything figured out.
“These are all great ideas, right? Do they all have the potential to lead to something damaging? Absolutely. So then the question is, what do we do?” he says. “Do we spend a few more years trying to perfect it in the lab … knowing there are 10 other countries that will just move forward ahead of us? Or do we launch it and be open-minded to the fact that there will need to be new iterations of how we think and act on information?”
Oh’s grandfather has Parkinson’s. If he knew that would be his fate, he says, he might take steps to prevent it. Might. If preventing it required him to become vegetarian, for instance, he wouldn’t do it. “That’s a choice — how do you want to live your life?”
Many of us will face a similar choice. It is Schiller’s view that one in 10 people will have a genetic condition we can identify now, and that everyone is likely to have three or four once we’ve unraveled the entire kite string. Variation makes us who we are. We just need to know ourselves better.
WHO’S BEING SEQUENCED
NIPM’s Sequencing Service Lab is a resource for faculty, their research collaborators, and contract partners. While it’s not open to the public, NIPM is working on certification to offer diagnostic tests/interpretation with a doctor’s prescription.
“I think the biggest impact of this stuff is in prevention, not just diagnosis. Unfortunately that level of access isn’t out there at the moment, but I think it will be in the near future,” says NIPM director Martin Schiller, adding that the institute hopes to offer its first test next spring and build a medical genetics staff to counsel patients. For details about volunteering for a clinical trial, email nipm@unlv.edu.
YOU ARE WHAT YOU (SHOULD) EAT
Live Your Code is a platform for diet recommendations based on genetics, created by NIPM director Martin Schiller. Anyone with a file from Ancestry, 23andMe, or its peers can upload to the site for a complimentary, personalized plan for optimizing health through food. It’s at foodgenesandme.com.
All of Us is a National Institutes of Health project recruiting 1 million people to be sequenced to advance precision medicine. It will examine biology, lifestyle and environment. allofus.nih.gov
Healthy Nevada Project is a community population study by Renown Health and the Desert Research Institute. Phase 2 is recruiting 40,000 Nevadans in the Reno/Sparks area and 10 rural sites, whose genomes will be examined along with environmental, socioeconomic and personal health data. healthynv.org