The Geneticist

With his selection to the NIH Council of Councils, Terry Magnuson, PhD, becomes the first UNC scientist appointed to the board dedicated to funding the biggest ideas in medical research.

The Geneticist click to enlarge Terry Magnuson, PhD/Photo by Max Englund, UNC Health Care

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Terry Magnuson, PhD, was a 20-year-old biology major when he saw a call for proposals from the National Science Foundation, an organization he had never heard of, looking to fund student-led research.

Four of his friends also saw the ad, and this group of five students from the University of Redlands in the San Bernardino Valley of Southern California decided they wanted to study pollution in Hilo Bay, Hawaii. To their surprise, the NSF agreed to fund them. Magnuson spent the summer in Hilo studying toxicity in fish populations. He was immediately taken and thought, “If this is what research is – thinking, investigating, discovering – then count me in.”

Forty-three years later, Magnuson is chair of the department of genetics at UNC and vice dean of research at the UNC School of Medicine. He has been elected to the American Academy of Arts and Sciences and also to the Institute of Medicine of the National Academies. This summer he was appointed to the National Institutes of Health Council of Councils, an exclusive group of the top minds in the nation charged with guiding research projects that transcend the focus of just one of the NIH’s centers or institutes.

We sat down with Dr. Magnuson to discuss his path to UNC, his research, the ever-evolving field of genetics research, and his new role on the Council of Councils. What follows is the gist of our conversation:

You were born in the Upper Peninsula of Michigan and chose a small liberal arts school in the desert. How did you wind up spearheading the creation of UNC’s genetics department?

When I was in high school in Southern California, I visited the University of Redlands, which had about 1,600 students. I really didn’t think much about choosing a school, and I didn’t receive much guidance. I majored in biology but wasn’t sure what direction I would be going.

But after that research project in Hilo Bay, I decided research was the way to go for me. And I thought about the biggest problem out there. I decided to study cancer. And I figured I might as well do that in the biggest city in the country – New York. So I applied to Cornell – Memorial Sloan Kettering Cancer Center in Manhattan.

Like that NSF project, my time in New York was transformational. I had no idea what big science was all about until I got there. All in the same area of Manhattan were Sloan-Kettering, Cornell, Rockefeller. Incredible people and scientists all right there.

For my dissertation, I was interested in embryonic development and its relation to cancer. So I picked a lab using mice as a model system. I started learning more about genetics, how cells communicate and what that meant in terms of subsequent development (controlled growth versus uncontrolled growth).

For my post doc, I thought New York was fun, so why not try San Francisco. I was accepted into the lab of Charlie Epstein, a well-known geneticist. That was an exciting time because a floor below Charlie’s lab was Gail Martin’s lab. She was one of the discoverers of how to make embryonic stem cells. I was there when she did that.

I quickly jumped in to work with her and I made the first mutant mouse embryonic stem cell line. A mutant cell line means that the cells have a defective gene that, in a developing embryo, caused death. By making a stem cell line of this, I was able to investigate some of the parameters for why that gene was causing death.

That was really interesting work, and I was selected to make a big presentation at [renowned research institute] Cold Spring Harbor because it was really hot topic at the time.

After my post doc, I started as an assistant professor at Case Western in Cleveland and rose through the ranks. But after 16 years I started thinking about the next step in my career.

I had several offers, but I didn’t even know that there was a position at UNC or what they were thinking with regard to genetics.

But [then UNC genetics professor] Terry Van Dyke called and asked if I’d come down to look at the genome science center concept they wanted to create, as well as the department of genetics, which didn’t exist at the time. Initially, I said no. I told her I was either going to Chicago or Vanderbilt. Terry is a friend, and she wound up convincing me to at least visit UNC. So I did. And the first day on campus I knew this was the place I wanted to be.

I really liked the people and the culture. Vanderbilt and Chicago are great places, but they are very different. UNC seemed to be a very special place with great science. I went home and told my wife that I think I’d like to go to UNC. That was late in 1999.

5q-gene deletionWhat do you consider to be the major contributions of your research?

Three things, I suppose. One was making the mutant stem cell line, which was a real first. The second was in the mid-1990s when we targeted the EGF receptor and made a mutation in that gene by using gene targeting, which is Oliver Smithies’ technology. We discovered that if we changed the genetic background of a mutated gene, then we’d get a very different phenotype, [or observable characteristics].

By “backgrounds” I simply mean genetic differences. For instance, what would happen if I put a mutated gene in you, compared to if I put a mutated gene in me? We have inherently different genetic “backgrounds.”

Different strains of mice also have different genetic backgrounds.

So, in our study, in a mouse with particular background with a mutant gene, the embryo would die before implantation. In another background, it would die midway through gestation. In another background, it lived about two to three weeks after birth.

So we changed the outcome of this mutation by changing the background. That stunned the world in a sense because we showed how the complexity of the genetics really affected the phenotype of a single gene mutation. This crystallized a focus on quantitative complex genetics. This was in 1995. We published in the journal Science.

And the third thing: when I started a lab as an assistant professor I used a whole series of deletions – parts of the chromosome that were missing – to study genes.

These deletions were all generated by scientists at Oak Ridge labs in the 1940s to understand how radiation affected the genome. They created a lot of mice with genetic deletions. They generously sent me a lot of these mice, and by crossing one against another I was able to zero in on what areas of the chromosome were required for normal embryonic development. 

We found one area that really affected the way the embryo was patterned from anterior to posterior. The question was, how can we find the gene? We had to do a lot of really difficult experiments that took a long time, but we eventually found the gene. Then we figured out it was part of this complex called PRC2 complex. This was a Nature paper in 1996. In 2002, a whole bunch of labs figured out that this PRC2 complex caused a specific change in the modification of proteins – the chromatin – that surround the DNA. It’s a major component that keeps genes shut off. Since then, chromatin research has been a major focus of scientists who study the drivers of cancer.

5-q gene networkWhat has genetics research meant to the wider field of medicine?

Terry Magnuson
Terry Magnuson, PhD, department of genetics, Image by Max Englund, UNC Health Care
In the 1980s and 90s, human mutant genes were starting to be identified and cloned, so we knew what genes were causing what kinds of disease. For example, the gene implicated in CF was a big one cloned in the 90s. Understanding what protein is involved helps us understand the physiology of the disease. Also, we can use genetic approaches to figure out whether the protein target is even drugable. This whole area has exploded. 

In most cases, diseases are not caused by single genes; lots of genes are typically involved. This is called quantitative genetics – where networks of genes are involved. 

The sequencing consortium really got underway, and this opened up a whole new way of thinking about genetics. This is one thing that faculty here in the department of genetics have done – the collaborative cross – which has been a major breakthrough in terms of creating mouse models of endogenous diseases, understanding them, and trying to find the complexity of genetic networks involved in a particular disease.

5q-gene sequenceHow has the field of genetics changed over the years, and what has its evolution meant for cancer research?

The sequencing of the human genome changed everything. It took me years and years of work to find that one gene. Now scientists can just sit down in their labs and go on their computers and find anything. Having the genetic sequences of so many organisms and lots of people is just mindboggling. Now, we’re superimposing all of the changes that occur in the chromatin that packages the DNA. The genetics field now gives us the whole genome landscape instead of one gene at a time. That’s been huge.

I remember a lot of people grumbled because the Human Genome Project would cost a lot of money and take money away from other things. But the project was like going to the moon; all the technology that came out of the project has just changed everything that we do.

And now we’re applying this knowledge to medicine. We have clinical sequencing grants aimed at figuring out how to apply this information.

Some patients are now receiving certain kinds of treatments, and when they don’t respond well, they might get their genome sequenced. In some cases, geneticists have found a different kind of genetic mutation, and the patient’s doctor could change the mode of therapy. In some cases this has produced great results. And this is just the beginning. The more we do this, the more we’ll know and the more it will be applicable.

We had an interesting case at UNC where a woman was diagnosed with a condition, and she could barely walk. She came to see Jim Evans, a clinical geneticist here. Her genome was sequenced, and they found a mutation for something very treatable. A drug was already on the market for it. Now she’s not only walking; she’s out dancing.

So it’s an exciting time.

5q-councilWhat is the NIH Council of Councils and what does it do?

The council is made of 30 representatives from the advisory councils of the various centers and institutes within the National Institute of Health. The council oversees the common fund, which is money designated by Congress to support the big ideas in medicine that transcend all institutes and, as a result, don’t have a home in any one institute.

For example, we need to come up with better ways of understanding the nuclear structure of cells in four dimensions – the fourth dimension being time, which is really important in terms of disease and development. The NIH is going to put significant funds into this. Requests for applications from scientists will come out in 2015.

The council consults on projects like that – things that span issues from immediate health outcomes all the way to basic research and everything in between.

Media Contact: Mark Derewicz, 919-923-0959, mark.derewicz@unchealth.unc.edu

 

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