Dr. Jay Shendure

Shendure’s lab at the University of Washington School of Medicine sequenced only the exome — the protein-coding regions of the genome, including the exon boundaries — of patients. In the process, he found the gene that causes the Kabuki syndrome.

“The strategy is quickly replacing the other approaches that people have been using for over 30 years because it is much more efficient and cost-effective,” said Jay Shendure, assistant professor of genome sciences, at the University of Washington School of Medicine.

The professor, who is famous for his pioneering work, talked to Uttara Choudhury in New York about how genomics is going to play an increasingly bigger role in bio-medicine and diagnosing genetic diseases. The University of Washington School of Medicine has one of the best departments of genome sciences in America, with faculty members like Shendure who are leaders in their field with a real heart for research.

Most brilliant medical students struggle when making a choice between the rarified academic world of research and being a hands-on doctor. They are not sure whether they prefer the long, lonely road of research or the instant gratification of curing patients. Did you face a tough choice when you earned a Ph.D. degree in genetics in 2005 from Harvard University and an M.D degree from Harvard Medical School in 2007?

“MD-PhD programs are great, but in some ways (they) just force you to put off a decision. It's extremely difficult to do both research and clinical work well these days, simply because medicine has become so complex and research has become so competitive.”

At first, it was an incredibly hard choice, whether to do one, the other, or both. MD-PhD programs are great, but in some ways just force you to put off a decision. It's extremely difficult to do both research and clinical work well these days, simply because medicine has become so complex and research has become so competitive.

As a medical student, I felt that I was doing my patients a disservice by working in a lab at night rather than thinking about them. That, and the fact that genomics was advancing so quickly, ended up making my choice quite a bit easier. At the end of the day you have to go with your gut, and as much as I loved interacting with patients, my gut was clearly pointing me towards research.

There was a lot of excitement when the Human Genome Project costing USD 2.7 billion was officially finished in 2003. Do you believe that human health will benefit not from the first sequenced genome but the genomes that will be sequenced in the future? Is this why your work both at Harvard Medical School and the University of Washington has focused on developing technology capable of sequencing not just one genome but every one’s and making individual genetic printouts cheaper?

The first human genome was essentially an infrastructure project for the research community, and it has paid off in myriad ways. It's amazing how we now take its availability for granted, and many genetics researchers training today will have no idea how challenging some things were to do in its absence. Humans are genetically 99.9% identical to one another, such that the task of sequencing individual human genomes is made much, much easier by the availability of a "reference" human genome. These differences are the basis for the genetic contribution to disease risk, but untangling which differences contribute to which diseases, is an enormously challenging task. Provided we can do it cost-effectively, individual human genome sequencing is going to be a very important part of getting at these sorts of questions.

You previously worked in George Church’s lab in Harvard Medical School developing short-read DNA sequencing technology. Can you talk about the advantages of this method of polony sequencing?

Since 2005, polony sequencing and related technologies (collectively known as "massively parallel", "second generation", or "next generation" sequencing) have enabled a 10,000-fold reduction in the cost of DNA sequencing. The technologies have advanced so quickly that anyone with one of the best next-generation sequencing instruments can generate the same amount of sequencing data that was generated in the entire Human Genome Project, in a single day. Thousands of these instruments are out there, such that there are a large number of researchers with access to a "genome center in a box", as we like to call it.

What are the new methods and tools of looking at biological systems that you are now developing?

“Humans are genetically 99.9% identical to one another…the differences are the basis for the genetic contribution to disease risk, but untangling which differences contribute to which diseases, is an enormously challenging task.”

We have pretty broad interests in genomics technology development and its application. One example of an area we've been successful in is the development of "exome sequencing", which is a way of capturing and sequencing the ~1% of the human genome that encodes proteins, and is usually the part of the genome that is mutated in severe "Mendelian" genetic diseases. In 2009, we demonstrated exome sequencing as a novel strategy to solve Mendelian disorders. The strategy is quickly replacing the other approaches that people have been using for >30 years for this same goal, because it is much more efficient and cost-effective.

Is genomics going to play an increasingly bigger role in bio-medicine and diagnosing genetic diseases?

Absolutely! For example, sequencing of cancer genomes is turning out to be one area where genomics may be directly useful for patients. Also, severe genetic syndromes (i.e. "Mendelian disorders") can be diagnosed using genome sequencing or exome sequencing. There are lots of hurdles before it is regularly used in a patient setting, but things are definitely moving in that direction.

Is the genome sciences department in the School of Medicine in the University of Washington an ideal destination for international students looking at studying cutting-edge, genome technology?

“The first human genome was essentially an infrastructure project for the research community, and it has paid off in myriad ways. It's amazing how we now take its availability for granted, and many genetics researchers training today will have no idea how challenging some things were to do in its absence.”

It is a fantastic department, but yes, it has become highly competitive. However, I would encourage highly motivated and well qualified students to certainly apply.

As a busy professor at the University of Washington in Seattle do you still get time to run marathons?

Sadly not! I miss it quite a bit. The combination of work and family (I now have two young kids) makes it difficult to get in any more than one run a week.

You received the Lowell Milken Prostate Cancer Foundation Young Investigator Award in 2010. Can you talk about your work related to pinpointing the genetic events that cause the start and spread of prostate cancer?

Certainly. Cancer, of all types, is fundamentally a disease of the genome. We, and many others, are applying the same technologies that I described above — exome and genome sequencing, to prostate cancer, in hopes of identifying genes that are recurrently altered in prostate cancer. To do this we sequence the genomes of both normal tissue and cancer tissue from the same individual, and compare. It's an incredibly complex problem, simply because even taking one type of cancer (e.g. prostate cancer), each individual's cancer is so different from that of any other individual with the same type of cancer. This is in part what makes it so hard to treat.