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Going Behind the Genes

By Michelle Choate
Seth Crosby ’78, M.D., has dedicated his career to examining cells, genes and DNA to help understand humanity’s biggest health challenges.
Seth Crosby ’78, M.D., missed his LJCDS graduation because he was in a lab at Scripps Clinic conducting research on pernicious anemia. The research required him to take blood samples from South African fruit bats at specific times, and had Crosby attended the commencement ceremony, he would have risked compromising the test results. He’d started at the lab when he was 14, working his way up from cleaning rat cages, and he took the experiment very seriously. 

In the ensuing four decades, Crosby has never found himself far from a lab because he believes deeply in what happens there: It’s science at its unbiased, factual best, dedicated to making life healthier and longer.

Crosby now serves as the director of research collaborations for the McDonnell Genome Institute (MGI) at the Washington University School of Medicine in St. Louis. MGI is a world leader in the fast-paced, constantly changing field of genomics and has played a vital role in the field of genome sequencing. MGI was a key player in the Human Genome Project—an international effort to decode all 3 billion letters of our genetic blueprint—ultimately contributing 25 percent of the finished sequence. In 2008, MGI became the first to sequence the complete genome of a cancer patient (a woman with leukemia) and to trace her disease to its genetic roots. This has led the way for the institute’s involvement in new personalized medicine research and discoveries through collaborations with doctors and pharmaceutical companies— and puts Crosby and his colleagues at the forefront of some of the most important developments in the identification and treatment of disease.

“In my world, we involve ourselves in two things,” says Crosby. “One is comfort, in that we try to make living more comfortable and less painful. The other is longev- ity; we hope we can prolong life.” 
 
Science & Longevity Versus Art & Meaning
Though a scientist in practice, Crosby is also a lover of literature, poetry and the arts. His work is about finding ways to lengthen and improve human life. However, he is perhaps rare in the scientific community in that he believes that art and beauty are as important as longevity. Though he spent much of high school in the lab, he did take some important lessons from his time at LJCDS—and from unexpected places. “Strangely, the great influences for me at LJCDS were not in the sciences but in the departments of history and English,” says Crosby. “Will Erickson [English], Roger Weaver [English], Bruce Boston [English] and Tom Vogt [political science] all indelibly influenced the way I perceive art, life and the world. In my mind, health and art are on the same playing field. I would even argue that meaning is more important than comfort and longevity.”
 
This personal creed resulted in Crosby taking a less-than-straightforward path to medical school and his subsequent career. He began his time at the University of California, Santa Barbara, as a biology major but switched to English literature after six months of hitchhiking around the country and reading metaphysical texts. Crosby had decided, at least temporarily, that “science was meaningless. I really love writing in all of its sort of magnificence, so I decided to become an English lit major.”
 
But in a classic “the grass is always greener on the other side” scenario, Crosby ultimately concluded that “science feels so much more important. And I had to face the fact that my most fundamental nature is as a scientist. As much as I like writing and art, I’m not an artist.” 

Breathing With the Greatest Ease
After graduating with his English degree, Crosby realized he wanted to go to medical school, so he went back and completed his undergraduate studies in biology. But doubts of a different kind began to plague him as he neared the end of his med school journey. “I was furiously jealous of my college classmates who had gone into research rather than clinical medicine. I wanted to go back into the lab to study neurobiology. I felt like that was the atmosphere in which I could breathe with the greatest ease,” explains Crosby. “I wanted to focus on scientific problems. The challenge for someone who’s scientifically inclined in medicine is that a lot of medicine is dogma. In fact, it’s legally dogma; if you diverge from certain protocols in medicine, you can be liable for medical decisions that you make. There are places for science in medicine, but science is not the main thing.”
 
Crosby moved on to do a post-doctorate at Washington University in St. Louis and went to work in a laboratory. After three years, he left that lab because “real life came barging in.” Crosby’s wife had just had their second child, and he was burning through the $25,000-a-year he made as a post-doctorate. As he saw it, he could either commit to academia and become a professor, or he could go into the applied science of pharmaceuticals.
 
Pharma seemed like the best decision. Crosby spent 10 years in the industry, working on projects in hematology and microbiology. But it was his assignment to functional genomics that introduced him to what has become his great love: genomic sequencing. 

A Great Love for Genes
When Crosby first dipped a toe into genomics, the Human Genome Project was new. Thousands of genes were being discovered every month, but for 90 percent of them, their function was completely unknown. Says Crosby, “And so began an industry of people who would figure out gene function. One way this is done is by turning a gene up or turning a gene down, and then seeing what changed in whatever system they were looking at. If you make too much of this gene, does it give you cancer? Does it cure you of cancer? Does it give you diabetes? How can I reach in and tweak genes and see what happens to the cells?” And Crosby became part of that group of people.
 
After 10 years of Crosby working in the pharmaceutical industry, the company he was working for at the time, Pfizer, decided to close its St. Louis facility. Fortunately, Crosby soon found himself directing a small three-person genomics laboratory at Washington University, the lab now part of MGI. “I was brought in to help manage the people who did the experiments but also to help analyze all the data coming in. How do you take a million observations and make any sense of it at all?” says Crosby.

A critical part of Crosby’s role as MGI’s director of research collaboration is to develop new business and cultivate research collaborations. Perhaps his most significant accomplishment in this area was establishing a close association with Illumina, a renowned biotechnology corporation that develops, manufactures and markets integrated systems for the analysis of genetic variation and biological function. They have been called the Google of the DNA- sequencing arena, and as they grew into a multinational, multibillion-dollar company, MGI grew along with it, jumping from three staffers to about 100. 

What is Important?
Though what they do at MGI is timely, relevant and has huge implications for human health, the lab is not forming the hypotheses that drive their research. Those come from the doctors, pharmaceutical companies and others they work with. “Doctors will come to us after noticing that one group of cancer patients responds very well to a particular type of immunotherapy, but another group of patients that appear to have the same cancer isn’t doing very well with the same immunotherapy,” says Crosby. “As far as the doctors can tell through their microscopes, the cancers look identical. They ask us to figure out what the difference is. What genes are messed up in these cancers—or in the specific patients—that can explain why the patients behave differently? We may not ask the questions, but we provide the technology to give them the answers.”
 
One of MGI’s important achievements is its sequencing of thousands of cancers for the creation of huge sets of data that highlight all of the mutations found in these different cancers. “A lot of these mutations may not have anything to do with the cancers,” says Crosby. “The hard challenge for cancer doctors is to figure out which of these mutations are causative and which make the cancer happen or make it worse, and which are just ‘passenger’ mutations that we don’t have to pay attention to.” In a similar fashion, MGI will provide pharmaceutical companies with information about the important differences between certain cancers, so the companies can develop drugs that will most effectively treat those cancers.

In their work, MGI uses their instrumentation, computer software and expertise to analyze huge quantities of data that doctors and drug companies cannot—due to cost and time. “Obviously you can’t sit there and look at 3 billion bits of information with your eyes. The data is very complex and difficult to analyze. It requires teams of people and is very involved,” explains Crosby. “Our people use computer programs to separate significant versus insignificant correlations.” In fact, MGI has hundreds of different statistical programs that are used to look at genetic data in order to make the kinds of observations that doctors, pharmaceutical companies, universities— humanity—need.
 
Though a great deal of their work is focused on cancer, MGI is involved in a large array of diseases, projects and studies. Much of the lab’s newest research has involved the human microbiome, which is all the bacteria, viruses and fungi that live on and in human beings. Feces alone contains hundreds of species of bacteria, which can be quickly identified by analyzing the feces’ DNA. Says Crosby, “We are rapidly learning that bacteria has a big impact on many aspects of human health.” MGI recently worked with Jeff Gordon, a world-renowned microbiome researcher, to determine why a group of Bangladeshi children were not growing despite receiving adequate nutrition. It turned out that the children’s microbiome was the problem. “They were missing the ‘right’ kind of bacteria in their intestines and so could not properly use their food,” says Crosby. “In addition, the group determined that food can be tailored to the individual microbiome—an unusual example of personalized medicine.” 

A Way to Wrap Up
As he enters his 60s, Crosby has begun to think about the next phase of his life. “There’s a part of me that misses patient care,” he shares. In part, Crosby has been influenced by observing his wife’s career as one of St. Louis’s top hospice nurses, which he sees as “a beautiful, meaningful life.” As a result, he’s thinking about someday becoming a patient advocate. “I want to help patients find their way through this incredibly dense forest of modern clinical medicine. These days, the healthcare system doesn’t give doctors much time to talk to patients. As an advocate, I could sit with them for a while and help them understand the issues and what their choices are. I think that would be a great way to wrap up my career.”
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