Search Magazine October 01, 2013

A new normal

Charles Lee's vision for genomic medicine

Charles Lee has great things in mind for JAX Genomic Medicine, including work that benefits medicine and society as a whole.

"I'm sorry for having to do the interview this way," says Charles Lee, Ph.D., battling Hartford, Conn., rush-hour traffic with one ear listening for the next GPS direction. "I'm on my way to a reception with the governor."

Lee, recently named director of The Jackson Laboratory for Genomic Medicine in nearby Farmington, is used to urban New England traffic, having moved from Boston. But he doesn't know Hartford yet, and at one point he interrupts himself with a "darn, I think I might have taken a wrong turn" and apologizes again for the drive-time interview after getting back on course.

"It's been crazy busy." He laughs. "I guess this is my new norm."

Change of focus

Lee has a formidable record of success in human genetics research. So what led him to travel a different route, leaving an established and prestigious research position at Harvard Medical School (among other appointments) to lead what is essentially a start-up project in Connecticut?

"This is a really exciting opportunity to gather some of the best scientists from around the world spanning different disciplines and provide them with state-of-the-art technologies to further genomic medicine," says Lee.

And why JAX, so well known for its genetics work with mice, when Lee's career has focused on human genetics?

"Over the past few years, as we have amassed a huge amount of data from human genetics, we are also realizing how little we actually understand," says Lee. "About four years ago, I was talking with some senior scientists and they were adamant that with the advances in genome sequencing and analyses, we didn't need model organisms anymore, we just needed to sequence more people. Now we see that's not true. We need good model organism research to understand the biological implications of the sequence variants that are being uncovered."

Lee's move to JAX Genomic Medicine was greeted with enthusiasm at JAX and throughout the biomedical research community. According to JAX President and CEO Edison Liu, M.D., Lee "is uniquely qualified to lead our entire effort around the clinical implications of genomic medicine. He represents the next generation of scientific leaders in translational science with national and global recognition."

Perseverance

Lee didn't set out to be a next-generation scientific leader. In fact, he was gearing up to be a medical doctor in college. But a brief foray into biomedical research after graduating from the University of Alberta in Canada in 1990 led to the co-authorship of a paper based on his summer research project.

"I think a lot of people get ‘a rush' out of seeing their name in print for the first time," says Lee. "I did too, but more than that—I got a great deal of satisfaction knowing that I was uncovering some new knowledge (no matter how small) for the very first time. I couldn't shake that excitement, so I stayed in research and never did go to medical school."

Lee stayed in Alberta for his graduate work and obtained an M.Sc. in experimental pathology in 1993 and a Ph.D. in medical sciences in 1996. His postdoctoral work took him to Cambridge University in England, then to Harvard Medical School in Boston, where he trained and became board certified in clinical cytogenetics. His training went well, but it came with hardship and sacrifice.

"I went to Harvard Medical School with my wife Cecilia and my newborn daughter Annabelle, but the cost of living in Boston is quite high, and it was difficult to survive on my postdoc stipend alone," says Lee. "So my wife had to work, and she got a part-time job as an administrative assistant at the main Harvard campus in Cambridge, working mornings Monday-Friday. Daycare was too expensive for us, so I'd go to the main Harvard campus with Cecilia, and sit in the car in the parking lot, taking care of Annabelle—sometimes just reading scientific articles in the car while Annabelle napped—then go to work until 11:00 p.m. or midnight and certainly on weekends to get everything done. That went on for almost a year." Lee continues, "I loved my work, but it didn't come easily to me. I had to put in the hours. It was very difficult, and even eventually led to some health issues, but it was just . . . just what we had to do."

The benefits of technology

With his postdoc complete, Lee became an instructor at Harvard Med in 2001 and then an assistant professor in 2003. As he built up his laboratory, he set out to understand more about the human genome. The opportunity to run a laboratory meant that Lee could dive headfirst into another key interest of his—technology. And early on, that interest yielded a significant discovery.

One of the newest technologies that Lee pursued and acquired at that time was array CGH (array-based comparative genomic hybridization), which was developed to survey gene copy-number variations—additions and deletions—across entire genomes. Lee and a postdoc in his lab, John Iafrate, got it on board and began to examine human clinical samples. They expected to see additions and deletions in some patient samples, especially in tumors, but were very curious to see if they saw additions or deletions when they compared the genome of one healthy individual with the genome of another healthy individual. When they saw what Lee now calls "blips" in the data—DNA gains and losses throughout the genomes of even healthy control samples—Lee was actually not surprised.

"I previously attended a talk by a pioneer and inventor of array CGH, Dr. Dan Pinkel, and one slide in his talk showed the same ‘blips' in his control experiments," Lee recalls. "However, Dr. Pinkel did not point out the blips in his control experiments, but rather focused on the gains and losses in the cancer specimens. When I asked him about the blips in the control experiments, he seemed annoyed at my question and dismissed them as technical artifacts."

However, those "blips" weren't artifacts; they were real gains and losses of DNA. Lee's discovery that copy number variants (CNVs) are common in genomes of healthy individuals was a crucial step in human genomics research, and it has shaped the field in the decade since. The exact biological implication of most CNVs is still unclear, but it is now widely recognized that CNVs are very important to understanding human health and that single base changes or small mutations alone do not determine disease states and human individuality.

The discovery was also crucial for accurately interpreting the tens of thousands of genetic test results performed around the world every year. Knowing what gains and losses are found in healthy individuals helps to differentiate those gains and losses that directly cause certain human diseases and medical conditions.

"My lesson from this experience was to never assume anything," says Lee. "Let the data speak for itself. It sounds easy, but it is actually hard advice to follow. It's something that I keep reminding every student that comes through my lab. But I sometimes wonder how many of the approximately 40 students that I have had over the years got it—really got it—the ‘don't assume anything' concept."

Lee considers himself a simple man, and he tries to keep his research papers and scientific presentations simple as well. He also has a simple philosophy: focus on merit, seek quality over quantity, and value the students and staff who sacrifice a lot to perform good research, just as he has done. He reminds them that a scientist's reputation is built over a lifetime, but a single careless mistake can have profound implications to that reputation.

A bright future

Lee's research in Boston gained him international accolades and a heavy workload. He received the 2008 Ho-Am Prize in Medicine, one of the highest scientific awards in Korea. He also won a Chen Global Investigator award from the International Human Genome Organization and is now an elected fellow of the American Association for the Advancement of Science. He ultimately carried appointments at Harvard Medical School, the Harvard Cancer Center, the Broad Institute and Brigham and Women's Hospital before joining JAX Genomic Medicine in August 2013. But it's clear he's lost none of his enthusiasm for discovering something new.

"There's still so much work to do in structural genomics," he says. "I'm fascinated by how structural variants can actually cause new phenotypes [traits]. We just published a new paper that looked at structural variation across primate species, and we found a gene in which there was a different copy number and a whole new function in rhesus macaques that wasn't there in other primates studied, including humans. In some cases, errors in DNA replication or DNA repair duplicates a portion of the genome, which leads to a new gene function, or activity in a new tissue where it was not originally meant to be."

In his leadership role, Lee sees several keys to JAX Genomic Medicine's success. In addition to recruiting leading researchers across several disciplines—and early recruiting has already built a stellar faculty nucleus—the researchers must actively interact with one another and have access to the latest genomic tools as well as massive computational and bioinformatics capability.

It's a huge undertaking, but Lee's commitment and expertise are translating well at JAX Genomic Medicine. David Valle, M.D., director of the Institute of Genetic Medicine at The Johns Hopkins University School of Medicine and JAX Trustee, notes, "Charles Lee is an internationally recognized leader in molecular cytogenetics and the application of genomic medicine. His clinical expertise will advance the translational focus of JAX Genomic Medicine, and his international presence will broaden JAX's visibility globally."

Leaving the comfort zone

Having concluded his interview and safely navigated his way to the reception site, Lee is officially welcomed to Connecticut and JAX Genomic Medicine by Connecticut Gov. Dannel Malloy and JAX President and CEO Edison Liu, M.D. During his speech, Malloy, who threw his full support behind building JAX Genomic Medicine in Connecticut, jokes that he was very impressed with what Lee had accomplished in a very short time in Boston, but he expects even more now that Lee is in Connecticut. Then it's Lee's turn to talk.

"When I spoke, I confessed to the governor and the others in the room that I was way out of my comfort zone, that I didn't like being the center of attention," says Lee. "But to make a difference, to start a bold project like JAX Genomic Medicine, it required a lot of people having to leave their own comfort zones. The governor and his staff had to move the state out of its comfort zone and make significant investments to bring JAX Genomic Medicine and other important bioscience initiatives to Connecticut. Dr. Liu had to step out of his comfort zone in Singapore and return to the U.S. to become the first non-mouse geneticist to lead JAX. The leadership and scientists at JAX in Bar Harbor had to step out of their comfort zone of focusing mainly on mouse genetic research to venture more into the realm of clinical and human translational research.

“Indeed, there are many that needed to take risks for us to be here. As a result, we are now all here, working hard every day, to make a difference in the lives of patients burdened with a genetic disorder or other illness. I feel such positive energy from all of the JAX Genomic Medicine faculty and staff every morning that I come into work, and I realize that it's all worth it."

Lee's trip to the governor's reception foreshadows his work at JAX Genomic Medicine moving forward, embracing a new normal that is simultaneously difficult and rewarding.

"It's a privilege to have the opportunity to do something that goes far beyond ourselves, to contribute to breakthroughs that will benefit mankind," Lee says. "I'm really looking forward to taking this exciting journey ahead together, with my new colleagues at JAX and with my new neighbors in Connecticut."