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Building the team that performs the work of sequencing the human genome at Baylor College of Medicine was almost as groundbreaking as the science itself. In essence, Richard Gibbs, PhD, his co-director George Weinstock, PhD, and the other key people in the laboratory were faced with breaking the job into tasks and setting up an assembly line of bright people who could be taught to perform the various procedures and were flexible enough to change with the developing technology.
They did not have to be scientists, but they had to have manual skills and the intelligence to learn and to understand how what they did fit into the whole. When Henry Ford set up his gargantuan assembly lines, he drew his workers from the back hills of Appalachia and the urban centers of Detroit. The team that built the human genome and will assemble the genomes of other animals includes college students and recent graduates, women going back into the work force and people changing careers. Young and old, they are part of a team with a spirit best demonstrated by a rousing cheer during a video cast of the White House announcement that the first draft was completed.
Anne Hodgson, PhD is a no-nonsense, unassuming leader in the Baylor Human Genome Sequencing laboratory who began when there were too few people doing too many tasks at a breakneck speed. Her interest in science began in kindergarten when she discovered the thrill of a scientific experiment. When she graduated from college, she spent two years as a tech in the laboratory of Savio Woo, MD, right next door to the lab of Thomas Caskey, MD, who began the genome effort at Baylor. She got her PhD at the University of Texas Graduate School of Biomedical Sciences where she did a rotation with George Weinstock. After a post-doctoral rotation at UT Medical Branch in Galveston, she returned to Baylor and eventually wound up working for Gibbs, who had been the top post-doctoral student under Caskey. She has worked in various roles in the genome center and is now developing ways to speed the process even faster - a far cry from the beginning when she remembers that Caskey's lab had only one machine that could sequence the genome. "What I really like is that this is knowledge that will be used forever," she said. "It's like the periodic table of elements or a map of the planets. It's not something that is going to be ever changing."
Rachel Gill came to the project in June of 1999 with her shiny new bachelor's degree from the University of St. Thomas in hand. When she started, the center employed 75 people. Now there are more than 200. "I started in a small laboratory doing 'bac prep,'" she said. That is the area where bacterial artificial chromosome clones are made. In the interim, she has worked all over the laboratory and learned how to perform all the techniques. "They were hiring like wildfire when I came," she said. "It just happened that I was interested in genetics. They were just looking for people who had the most capability and were willing to do the work.
Margaret "Maggie" Morgan had been in the oil industry almost 15 years when she decided to go back to college and change careers. "I was considering veterinary medicine," she said, but she somehow fell into the research program at the University of St. Thomas. When someone came to talk about the genome project, she was galvanized. "How could you pass that up?" she said. She began working at Baylor in the last semester of her senior year and has been with the project more than two years.
Kim Worley, PhD, is charged with annotating the sequences, pointing out where there are known genes, regulatory regions, repeat sequences and markers that can be used for navigating the genetic landscape. "Annotation is a philosophical thing," she said. "There are straight forward annotations such as repeats of DNA sequences. There are good tools for those.
"Then there is another level in which the annotation is a hypothesis about what might be in a sequence." She is careful with those because everything that goes to GenBank, the public repository of DNA sequences, is her responsibility - even the sequences of the animals such as mouse, fruit fly, and rat. A researcher who lacks the appropriate probe to find where genes are can compare human DNA with that of another species. "For every gene, there will be a species at some evolutionary distance that gives you the most information for the gene of your interest," she said.
Worley began her science work at Baylor in 1988 in laboratory of Edward McCabe, MD, a pediatric genetics expert now heading the department of pediatrics at the University of California at Los Angeles. She finished her degree in 1993 and did her post-doctoral work at Baylor where tools for sequencing the genome were under development. "It was the time when the machines were very new," she said. "Now we have rooms full of these things that just work along. It is a wonderful place to be."
It should surprise no one that George Weinstock, PhD, ended up in science. His father was a "chemist who did physics" and his mother was involved in the testing of metals and chemicals for aircraft during World War II when both were sent to Los Alamos, New Mexico, to help build the "ultimate" weapon and to find a romance sparked by the Manhattan Project.
Yet, said Weinstock, "Science was the last thing I wanted to do," when he started college. However, an inspired lecturer in his first college chemistry class turned him around. He seemed destined for a career in theoretical physics when late in his senior year he realized that was not going to be his forte. His father suggested he consider molecular biology - the next frontier in science. He read a few books by Isaac Asimov and took a couple of biology courses and ended up with a degree in biophysics. At the Massachusetts Institute of Technology in Cambridge, Mass., he did his doctoral thesis in the area of genomics, and has stayed in that field ever since, more or less.
The transition from traditional genetics to the current field where "you can know a DNA sequence, see a DNA molecule and fragments, where we know how big they are, how far apart genes are from one another" was phenomenal, he said. "It reduced the field something concrete, a profound paradigm shift that I don't think anyone realizes."
Today he is co-director of the Baylor center and heavily involved in sequencing the genomes of bacteria. He predicts that "all known infectious disease pathogens will eventually be sequenced, leading to more sophisticated diagnostics tools, vaccines and new antimicrobial medications that will perhaps eliminate concerns about bugs that are resistant to antibiotics.
As the threat of emerging infections becomes more obvious, there is more funding for such work. Weinstock was involved in sequencing the genome of the Treponema pallidum, the spirochete that causes syphilis. The genome of the organisms that causes malaria was recently completed, and other genomes that are most likely to affect populations in the Third World are under similar scrutiny as federal officials recognize that infectious disease outbreaks anywhere are an international problem.
The future will prove the value of the various genome projects, but Weinstock worries how the average physician will keep up with the mounting pile of new information. He expects there will be a time lag. "When the Internet burst upon us, how many people had computers?" he said. "Of those who had computers, how many looked at them and didn't know what they were for? There is a time lag between where the technology is pulling everyone and where the users are. The same thing will be true of the genomic era."
Erica Sodergren, PhD, was doing basic research at The University of Texas Medical School at Houston when the Baylor Genome Sequencing Center came up against problems in its production in the winter of 1999. By March 2000, she was on board helping them overcome some of the difficulties, using her expertise of 30 years. Even though she was working on the genetic sequence of the organism that causes syphilis at UT, she ultimately wants to spend more time looking the interaction between pathogen and host. She finds her work with the genome satisfying. "It will take many decades to mine the information in the human genome," she said. "This is just the beginning, and the beginning has to be there. Now we are putting the time in to develop it."
Ryan J. Lozado came to Baylor's sequencing center with a bachelor's degree in biology. However, the need for people to write computer programs was so great, he started to learn programming when he got to the school. "It's not that much different," he said. "It is all based on logic. Biology and genetics are logical." He has been fascinated with the genome project since it started in the late 1980s. His high school biology teacher talked about it. During his last year at University of Houston, the project's Baylor director Gibbs spoke to his class. When Lozado graduated, he came right to Baylor and applied for a job. "It's a great learning experience," he said. "I have a quest for knowledge and want to go to graduate school at some point."
He was hired to do some of the annotation to the genome before it was sent to GenBank. "I had no idea what annotation was," he said. He ended up teaching himself from the notes of the woman who was supposed to train him and a big book.
As she has since she came to Baylor in 1986, Donna Muzny, MS, wears many hats in the genome center. She co-manages production of DNA for sequencing during the production phase of sequencing the rat genome. Ultimately, she is also in charge of the materials group that produces materials and quality checks the chemicals the production group needs. She also oversees the work of the assembly group that puts together the pieces of the genome sequence so that the information can be submitted to GenBank.
The sequencers are the troubleshooters of the genome center. "They have to be able to problem solve and they have to be tenacious," she said. While the work is done on computers, the people involved have to understand the biology.
Muzny started working at Baylor in the lab of C. Thomas Caskey, MD, and she and Gibbs, have worked together since 1990. She chose to come to Baylor right after finishing her master's degree at Texas A&M University in College Station because she knew the environment at Baylor College of Medicine was conducive to good science. When Gibbs took over the sequencing effort, she knew it was important that Baylor become one of the leaders of the international consortium. "We managed to do that," she said. "Growing and doing that was really a personal goal for me."
The team atmosphere at the genome center is important to its success, she said. In some ways, she said, she likes being involved in management. "There is always a problem to solve, but I never imagined that it would get this big and be involved in doing this much."
Graham Scott, PhD, really never expected to be involved in biological sciences. The New Zealander's bachelor's degree was in physics and chemistry. Then he spent nine years as a pilot in the New Zealand Air Force before deciding at age 28 that he was, perhaps, too outspoken to make a career out of the military. As a result, he went back to school and got a doctorate in physical chemistry. During a post-doctoral stint with Nobel laureate Robert Curl, PhD, at Rice University, he learned of the genome project and after a year at Baylor University in Waco, he accepted a job offer in the center.
"It's exciting to be working on the biggest science project in the world," he said. "It's my chance to make a difference and a real contribution." He credits Gibbs, the center's director, with giving him the chance. "One of the things that Richard did is to consciously say that he didn't want to have a whole lot of biologists. We are a multidisciplinary team." As a result the project is home to people who are chemists, mathematicians, physicists, machinists as well as molecular biologists.
Scott's familiarity with instrumentation such as mass spectrometers, lasers and high vacuum systems made him a natural to run those areas of the genome center. He oversees the operation of all 69 sequencers in the center and the nearly 30 people who operate them as loaders. He also directs operations in an area in which oligonucleotides are synthesized for use in finding specific sequences of DNA and the robotics portion of the center, where machines to speed the sequencing effort are under development.
His research involves everything from sequencing improvement to figuring out a way to study the appearance of hundreds of fruit flies as fast as possible. "The biggest problem is hours in the day," he said. "The job here is one of the most rewarding I've ever had."
Only one other job would tempt him now - that of U.S. astronaut. When he applied earlier, they told him he had to be a U.S. citizen. He'll try again once he achieves that status.
Steve Scherer, PhD, was prepared to begin ramping up the genome effort after the center began its large-scale sequencing in March 1999, and he's been involved in that ever since. In charge of mapping, he begins the actual process of sequencing by determining the approximate location on the genome of the snippet of DNA that is to be sequenced.
Scherer obtained his doctorate in the Graduate School of Biomedical Sciences at Baylor College of Medicine, working in the laboratory of C. Thomas Caskey, MD. After a post-doctorate at the National Institutes of Health, he returned to Houston where Gibbs offered him a job in the genome sequencing center.
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