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For Students at the Icahn School of Medicine, Genomics Is Growing More Personal



By Aaron Krol 

May 23, 2014 | It’s almost summer in New York City, and that means the Whitney Biennial is winding down, it’s nearly impossible to find an empty patch of lawn in Central Park, and at the Icahn School of Medicine at Mt. Sinai, a group of students are bracing themselves for the rare experience of seeing their genomes laid out on a computer screen.

In one month, for the third year running, Mt. Sinai staff will begin taking blood draws from twenty students who won slots for Practical Analysis of Your Personal Genome, a full-time course offered nowhere else in the country. The blood samples will travel to the Icahn Institute for Genomics and Multiscale Biology, where DNA will be extracted and sequenced over a period of two months. Finally, in mid-September, the raw sequencing reads will be delivered back to their donors, who will join the thousand or so people on Earth to personally own their whole genomes. (Tens of thousands more have had their whole genomes sequenced for research.)

Instructors at Mt. Sinai hope that students get not only advanced technical training from the course, but also a new perspective on how genetics will impact the practice of medicine, now and in the future. “Physicians already get some training [in clinical genetics],” says Andrew Kasarskis, Co-Director of the Icahn Institute and Vice Chair of the Department of Genetics and Genomic Sciences at the medical school. “But that’s very different from being asked to deal with, ‘Okay, you have a genome here.’ It’s not a simple test, it’s not just a question you ask – it’s all the questions that could be answered by the genome.”

Sensitive Information 

Just articulating those questions is no easy feat. Physicians in their professional practice are rarely asked to deal with any genetic information more complicated than a diagnostic report, where lab geneticists have listed the most clinically relevant findings along with explanations of their possible link to disease. Behind the scenes, there’s a great deal more being done, especially when you scale up to the level of whole genomes.

“Even in a research setting, this is rarely if ever done by a single person,” Kasarskis tells Clinical Informatics News. “Usually there would be a team of people that include skills such as bioinformatics, variant interpretation, medical genetics, and then some level of specialization with regard to the appropriate biology.” In one semester, students in Your Personal Genome will take on all these roles, guided by an instructor who spends the first half of each two-hour session introducing new analytical tools and techniques before setting the class loose on their own data.

Sinai view 
A view of the Icahn School of Medicine and Mt. Sinai Hospital overlooking Central Park. Image credit: Mt. Sinai 

One such instructor is Michael Linderman, who has been the course director for Your Personal Genome since its debut in 2012. “The arc of the course steps through major topics with [the students] over the course of the semester,” he says. “So we talk about the actual informatics process while it’s running. We talk about ancestry, pharmacogenomics, common complex disease risks, monogenic disease, and so on, in a structured way.”

When students get their genomes, it’s in the form of a FASTQ file, the notoriously difficult text format in which sequencing machines spit out data. From a string of numbers, letters and symbols that signify the DNA bases and read qualities for each short segment of sequenced code, students learn to stitch together an end-to-end genome and flag the variants that distinguish their own genetic makeup from the general population. In the first year the course was offered, students had to learn a great deal of coding to wrangle with this information, but, Linderman says, the industry standard tools have gotten so much easier to use so quickly that even coding-naïve students no longer have much trouble adapting.

“The field is moving so fast that I see a lot of changes year to year driven by what’s going on outside,” he says. “We can spend more time in our practical exercises focusing on the core genomic topic, and not so much getting bogged down in the challenges of making it run.”

Things get more personal once that first bar has been cleared. On any given day, students might have the chance to learn where their ancestors came from, whether their genes could affect their response to certain drugs, what diseases they might pass on to their children, or whether they themselves are at a heightened risk for developing chronic conditions like heart disease or diabetes later in life.

Mt. Sinai is aware that this can be a sensitive, even nerve-wracking experience. Students uncomfortable with learning certain facts about themselves can choose to perform any individual test, or even take the whole course, with a dummy genome instead of their real information. No one at Mt. Sinai ever knows which students take advantage of that option. Even students who do choose to use their own genomes have an opportunity, before their data is delivered, to “black out” areas they don’t want to know about – say, the ApoE gene, a fairly common variant of which has been linked to Alzheimer’s disease.

Nevertheless, Mt. Sinai takes serious precautions to prepare students for the possibility of finding something frightening or unwanted in their genomes. Every student in Your Personal Genome goes through a prerequisite course in the summer that tackles some of the ethical issues and inherent uncertainties in whole genome interpretation, in part by analyzing a publicly available genome. They’re then given several weeks to decide whether they want to go through with having their own DNA sequenced.

Of course, no precautions can prevent the possibility of a student learning she’s at high risk for, say, breast cancer – or, potentially, difficult personal information like non-paternity. Mt. Sinai makes counselors available to the students, both inside and outside the school. In the case of a serious disease risk, the Icahn Institute is also prepared to follow up with a clinical-grade test coordinated with a practicing physician, to confirm the findings.

There haven’t been any incidents like this so far, but if programs like Your Personal Genome continue to run and expand, it’s surely only a matter of time. Mt. Sinai wants to be prepared.

“Before we even start the course, we have reached out to the student mental health resources so they’re aware of what’s going on,” says Linderman. “We do ask the students, who are friends and colleagues and roommates, to be cognizant of their classmates.”

Your Genome Is Not Destiny 

So why offer the course? It’s a substantial financial commitment from Mt. Sinai; in fact, few institutions would have the resources to run a class like Your Personal Genome if they wanted to. The Icahn Institute is a genomic powerhouse, especially by the standards of a clinical setting, with four high-throughput sequencers and a host of other sequencing instruments, plus a supercomputer called Minerva to help process the information. Still, even with a world-class genomics facility, fully sequencing twenty individuals is not pocket change.

“When we started out doing this, we were, like others, expecting the cost of genome sequencing to continue to fall as dramatically as it had been,” says Kasarskis. “Instead it’s been stable for the past two years, although it’s starting to drop again.”

“The expectation is that the cost will be less and less a barrier to entry,” adds Linderman. “So the question really becomes, do we think that offering the opportunity to work with your own data really enhances the educational experience?”

This is the crux of Your Personal Genome – the desire to train professionals who are prepared for a world where genomic testing, even to the level of whole genomes, may someday be commonplace. Mt. Sinai has always been in the vanguard of bringing genetics into medical education. In the 1990’s, the school became home to the country’s first residency program for medical geneticists, and one of the earliest master’s programs for genetic counselors.

The genetic counseling program now attracts around ten new students a year, a large number for this niche career. “With a plethora of genetic tests out there, and a fair bit of press to the effect that it’s almost impossible to get genetic counselors when you need them, it’s really become quite popular,” says Kasarskis.

It’s changed in other ways, too. A profession that was once devoted almost entirely to helping patients understand rare disease variants is now adapting to a much greater diversity of genetic information. Mt. Sinai has made Your Personal Genome a required course for its genetic counseling students, filling about half the class roster with second-year genetic counselors. Students in directly related tracks like medical genetics get the next highest priority, and any remaining spaces can be filled by other students, residents, and even faculty at Mt. Sinai.

Linderman Kasarskis 
Michael Linderman (left) and Andrew Kasarskis (right), both members of the Icahn School of Medicine involved with Your Personal Genome. Image credit: Mt. Sinai 

The school sees simply giving these students the option to look at their own genomes as an important lesson for medical practice. “Being forced to make a decision, in an educated fashion, about whether or not you want to know your own genome sequence is actually really, really relevant for anybody who’s doing genetics professionally in a clinical context,” says Kasarskis. “It’s one thing to think abstractly about whether you’d like to know your genome, or be tested for this, that, or the other thing. It’s another thing to actually sit down and [do it.] This is a decision that people’s patients deal with all the time.” The hope is that physicians who have interpreted their own genomes will gain a more meaningful perspective on how patients receive this kind of information – at once deeply personal, and yet stubbornly inconclusive.

“On some level, [the students] react just like all the other people who have received whole genome sequencing data,” says Linderman. “I think they find it a little overwhelming, in terms of the scope of what we’re talking about. And at times, they can even be underwhelmed. Many of these people have trained and focused on these very serious, deleterious, damaging mutations that are very, very rare, and if you spend all your time thinking about that, a healthy genome can seem a bit underwhelming by comparison.”

“That reflects reality,” adds Kasarskis. “Your genome is not destiny, unless you happen to carry a few hard-hitting mutations that would be likely to predispose you to Mendelian disease. There’s a huge environmental component to who we are.” 

Your Personal Genome is an opportunity to experience that uncertainty firsthand, and to keep abreast of changes in one of the most quickly evolving fields in medicine. Just three years into its existence, the course has already had to adapt to new interests and priorities in the genetics community. “The discussion around secondary findings became a really big part of the course last year, because it was a big part of the discussion more generally in the community,” says Linderman.

The class can also be an opportunity to have some fun with data that most people have some fundamental curiosity about. Students aren’t limited to the analyses presented in class; after all, they are the permanent owners of their own data, and can dip into their genomes any time they like. One popular class session has the students split into groups and design tests that they can teach their classmates to run on their genomes.

“We get everything from stuff about physical traits, curly hair and things of that sort, to percentage of Neanderthal,” says Linderman. “The Neanderthal one went over particularly well.”

A Changing Institution 

Mt. Sinai is also hoping the school itself will benefit from its experience teaching Your Personal Genome. The course is a rare opportunity to interact with people learning about their genomes over an extended period of time. In both formal surveys and informal conversations, the instructors are picking up new insights into how practical experience with whole genome interpretation can change medical professionals’ outlook on their practice.

One survey of a class six months after completing the course found that two-thirds of the students had used something they learned in class in their clinical or research activities. And two years after the first Your Personal Genome course, several students, especially the genetic counselors, have moved on to careers in the field.

“One of the students actually just wrote to me last week to say that she had transferred into a new genetic counseling job with a much heavier genomics focus, and that was partly made possible by her experience with the course,” says Linderman. It’s an encouraging sign that whole genome analysis is really a desirable skill, even at a time when this kind of testing remains quite rare in real clinical practice.

Meanwhile, Mt. Sinai is looking for more ways to bring a genomic perspective to students in the medical school. Both because of the costs of sequencing, and the hands-on nature of the course, Your Personal Genome won’t neatly scale to admitting many more students – nor are the instructors sure it should.

“I think this particular course is really best for people who are going to be future genetics professionals,” says Linderman. “It goes into a depth of detail that’s appropriate for them, and maybe not for others. But I think this laboratory-style approach, and personalization, could be valuable [to others.]”

The school of medicine is in the middle of redesigning its curriculum to bring genetics closer to a range of specialties. Single exercises from Your Personal Genome have been spun off into smaller workshops for a broader audience. For instance, medical students are being offered pharmacogenomics tests, to get a taste of genomic testing in a format that’s likely to impact their practice in the future as more drugs are prescribed based on patients’ genetic profiles.

Course directors are also trying to think of new perspectives on genetics that will be important to the clinicians of the future. “One of the new courses we’ve created here,” says Linderman, “is focused around, what is the economic value of a genome? What is this information worth, and for whom, and who are all the different stakeholders?”

These are questions that Your Personal Genome has really driven home for Linderman and his colleagues. The medical school is investing a great deal in sequencing its students, but it’s also starting to see that the students are not the only people who stand to benefit from the experience. Mt. Sinai is also learning something about how it provides for patients as genomics grows closer to clinical care.

“The instructor staff comes from the genetics clinic here,” says Linderman. “A number of the residents who are actively seeing patients are in the course. And in that sense, both the things they’ve learned technically, and the experiences they’ve had talking about the decision-making process, talking about the limitations, talking about what it’s like to receive this information – all of that has gone back into their direct practice and interaction with patients.”

 

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