|Moving Genomics into the Clinic, One Experiment at a Time|
When Terry Magnuson was just an undergraduate science major, he wrote his first research proposal – which was promptly accepted. Because of that winning entry, the National Science Foundation footed the bill for him to spend the summer in Hawaii with his fellow classmates studying pollution. Cynics might say it was just a case of beginner’s luck, but they wouldn’t know that Magnuson has secured scads of research funding -- over $28 million to UNC-Chapel Hill alone – in the years since.
Magnuson, whose list of titles is just as impressive as his accumulation of funding, says that it was that first experience that hooked him on research. He has served as the Sarah Graham Kenan professor and chair of the department of genetics, the director of the program in cancer genetics of the Lineberger Comprehensive Cancer Center and, until recently, the director of the Carolina Center for Genome Sciences. He relinquished that role to take on a new one as Vice Dean for Research, where he will also help lead the NC Translational and Clinical Sciences Institute (NC TraCS) as PI extender for basic research.
Of Mice and Men
Long before he became a fixture in the UNC School of Medicine, Magnuson had decided to focus on research that was medically oriented. He applied and was accepted to graduate work at one of the top two cancer centers in the country, Memorial Sloan-Kettering in New York City. To Magnuson, the move was a much-appreciated culture shock.
“It was going from a small place out in the middle of nowhere to the biggest city in the country,” he said. “Being at Sloan-Kettering was a pretty amazing transformation because walk downing 68th Street and seeing all these tall research buildings, I was just surrounded by this great environment for biomedical research. That is where I started learning how mouse models can be used to study cancer and how genetics is a very important component of developing mouse models.”
So when it was time to do his postdoctoral fellowship, Magnuson chose to go to the University of California at San Francisco and work for Charles Epstein, who was known for his discoveries in mouse genetics. Working with Epstein and a researcher one floor down, Gail Martin, Magnuson made the first mutant embryonic stem cell line. The exciting advance set the stage for him and other researchers to use genetics as a tool for studying the development of disease in animal models. And he has spent the rest of his career doing just that.
Because Magnuson has gained so much expertise over the years in the manipulation of these controversy-provoking stem cells, The National Academies asked him to serve on a committee to write guidelines for working with embryonic stem cell lines. The voluntary guidelines were adopted by virtually every university conducting this type of research during the Bush era.
“It was exciting to be a part of the committee because it was an extension of the work that I started long ago,” said Magnuson. “The guidelines really set the ground rules for how ES cells should be used in the laboratory and in animal models, and eventually tried to lay the path of how these cells get into the clinic.”
Once Obama came into office and issued an executive order expanding stem cell studies to include federally funded research, the National Institutes of Health wrote their own guidelines, using the recommendations of Magnuson and his fellow committee members as a framework. Magnuson currently sits on the NIH stem cell working group that makes sure that all stem cell lines used in research meet those guidelines – including verifying that they were derived from leftover embryos from assisted reproduction that otherwise would have been discarded.
Recently a federal judge overruled Obama’s order, placing on hold the research efforts of many investigators at UNC and elsewhere who are looking for cures for illnesses like Alzheimer’s disease, diabetes and paralysis.
"Such rulings stop the work of those NIH-funded investigators that have been working in good faith to understand the promise of stem cells in regenerative medicine,” said Magnuson. “As a result, very exciting work is halted and screening for new drugs is affected. It can be a major setback for U.S. scientists.”
Magnuson’s own work is conducted in embryonic stem cells from mice and not humans. He has used the cells to “knock-out” specific genes in mice to track how mutated genes might affect the development of an entire organism and infer a gene’s role in disease. Magnuson’s over 150 publications span a seemingly disparate assortment of research topics: transgenic mice, X-inactivation, tumors, stem cells and even autism. But the one thread that ties them together is epigenetics – the study of how genes can be turned on and off without actually changing their DNA sequence.
The typical science textbook’s portrayal of a double helix only tells part of the story of how genetic information is stored. Those strands of DNA can be tightly wrapped around proteins, and those proteins can be tagged with different chemical groups to either wrap or unwrap the DNA to be read. Using his transgenic mice, Magnuson discovered one of the genes – called Eed for embryonic ectoderm development -- that is a key component in this process. Researchers such as UNC’s Stephen Frye are now looking for ways to tweak these epigenetic mechanisms as a way to combat disease – turning on a tumor suppressor gene here, turning off a neurotoxic gene there.
But taking genomics into the clinic isn’t going to be easy. Research is complex, especially research that delves into the understanding of biological systems, says Magnuson. To understand such complex biological mechanisms requires significant experimental approaches and data collection and analysis. And, sometimes, a willingness to fail.
“I think one has to have the right personality for research, because nine times out of ten one goes home thinking nothing was accomplished because the experiment didn’t work,” he said. “Instead, I go home and mow the lawn because then I could see something that was completed. But it is also like being a detective, because when one does an experiment that doesn’t work it is telling something, the researcher just has to figure it out.”
The detective work – doing experiments, collecting data, and developing hypotheses -- is what first drew Magnuson to research. And though the pace of scientific progress often seems slow at times, he recognizes that a number of advances have been made in the field since he conducted that first experiment.
“As I think back when I started my career, it took me literally 10 years to clone one gene,” Magnuson said. “Today, you don’t have to clone any genes, they are all done, so students just have to go on the computer, and they are able to find what they need to find. So that is a huge increase in speed. Having the genome sequenced, and the tools to analyze the sequence, transformed the field -- it is like going to the moon in terms of technology development and what you can do. Things are a hundred times faster now than what you could do 10 years ago.”
|By Marla Broadfoot|