Top of the Line - Five questions with Dr. Sharpless
Ned Sharpless isn’t your garden variety scientist. He’ll quote St. Thomas More on the importance of being principled. He’ll mention George Washington when describing how to run a lab. He’ll point to a picture of the devil tempting Jesus to show that the easy road is not the best road. And he’ll use The Clash—yes, the band The Clash—to illustrate the benefit of breaking through conventional wisdom.
Self-effacing and funny, Sharpless can discuss his research with anyone and make it interesting. But those attributes aren’t what earned him his new job as director of the UNC Lineberger Comprehensive Cancer Center. A first-class researcher with exceptional leadership skills and a penchant to think well beyond the next grant or paper, Sharpless is an innovator and entrepreneur whose research inspired the creation of two companies aimed at helping people in his home state of North Carolina and around the world.
We sat down with Dr. Sharpless two weeks before he took the helm at UNC Lineberger on January 1 to ask him about his journey from UNC as an undergraduate to UNC as a professor and now director of a research organization with 300 scientists from 25 departments across campus. What follows is the story of how Dr. Sharpless landed at the helm of one of the nation’s oldest and largest cancer centers.
Why did you pursue math as an undergraduate and then go to medical school, both at UNC, and then choose to become a cancer researcher?
My undergrad and early med school careers were characterized by a strong lack of planning. I was a bit immature for my age. Many people have a plan, and they’re on a mission to get something done. I wasn’t really like that, though I did like college. I was initially an English and math major but that became unworkable. At some point, it became easier to fulfill my major requirements for math.
I remember in some upper level math classes, they gave us two problems and a week to do them. That was really fun. No one could help you; there was no internet back then. You really had to figure it out yourself. But I also loved physics, English, and political science. I just had a great, well-rounded education at UNC, and I still believe in that. I think that writing essays on Shakespeare as an English major has helped me to write crisp, clear, terse explanations of my science, and that’s really good for grants and scientific papers.
As for medical school, well, I was a pretty good undergraduate student but I didn’t work in a lab, or shadow a physician, or volunteer in the hospital. I wasn’t 100 percent sold on the idea of being a doctor, though deep down I think I knew I’d always become a doctor. My parents were physicians and I knew what that life was like.
During my senior year, I applied to the Peace Corps but didn’t quite fill out the application correctly. Also—this was the 80’s—I applied to work at investment banks, which back then were looking for mathematicians. They paid these absurdly high salaries, but they worked you to the bone and most people quit in despair. That also didn’t work out. So I had two choices: take a gap year or go to medical school. I had applied to a couple of medical schools and only got into one of them: thank goodness for UNC.
When it comes to research, the really formative year was when I took a year off from med school to work at the National Institutes of Health as part of the Howard Hughes Medical Institute NIH Research Scholars Program. Within two weeks, I was telling people that science was what I was going to do. This was the first time I ever did any biomedical research. It was almost like being an artist, but at the same time it was data driven and you got to use math and talk to people. You could work at 3 a.m. if you wanted. I had total control of my life. The experience just appealed to everything about me.
I worked on AIDS and HIV. I was first author on two papers as a medical school student. Six months in at NIH, I was telling people that this was the best year of my life. There were about 30 of us in that program; these were clearly my people. Some of them are still my closest friends.
My third year back at medical school after the NIH, that’s when you really learn how to be a doctor. I enjoyed it and I think I got pretty good at being a doctor, but for the rest of my training, I was one those residents who would sneak off to the library to read the journal Cell. I really had the research bug.
You were in Boston for ten years as an intern, resident, instructor, physician, and a research fellow. What was the most rewarding part of your time there, and did you always plan to or want to return to UNC?
The best part of my 10 years in Boston was when I ended up in Ron DePinho’s lab. He’s now the president at MD Anderson Cancer Center in Houston. Back then he had just started his lab at Dana-Farber Cancer Institute at Harvard Medical School. This is when I learned how to become an independent scientist and that’s because Ron was a great boss. He not only trained us how to be scientists and get our experiments to work, but how to manage people, write grants, write papers, how to handle editors—real world skills at which he particularly excelled.
It was exhilarating but scary. I remember waking up at 3 a.m. terrified that I was out of my depth. I would go run in the snow—in Boston, in February—and when I returned home my wife would say, “What are you doing? You’re crazy” And I’d say, “I just couldn’t sleep.” Running has always been how I decompress.
As for UNC, no, I didn’t plan on coming back. I was in Ron’s lab, productive and happy and learning from great scientists at Harvard. When I got a job offer after I published some papers, Ron wasn’t fully supportive at first because he thought I should stay in the lab a few more years. But to his credit, he said, “Well if you’re going to look at one job, you better look at five. Because if you look at one, you’ll get a crummy offer and you’ll take it and it will be a career-ender.”
So he made some calls and put me on a plane. My first interview was at a prestigious school of medicine in the Midwest. Before I went, I told Ron I was just testing the waters, but I wasn’t serious about leaving his lab. That was on a Thursday. On Monday, I marched back into his office and told him, “I’m out of here.” Once I saw what sort of lab resources I could have and what life would be like as an independent scientist, it was hard to refuse.
Ron and my clinical mentor Bob Mayer (now Dean of Harvard Medical School Admission) recommended several schools as a good place for me to start as junior faculty, and the only one on both of their lists was UNC.
Ron knew that UNC had a terrific history of mouse cancer genetics with people like Oliver Smithies, Terry Van Dyke, and Terry Magnuson. And Bob knew that UNC Lineberger was a really special place. He was on the advisory board for a while and knew that this place was on a great trajectory. And I probably wouldn’t have considered UNC had Ron and Bob not recommended it because when I left here in 1993, it was kind of sleepy in terms of cancer research. A couple doctors were putting people in clinical trials, but UNC wasn’t the research juggernaut that it became throughout the decade I was gone.
While I had been away, they built all these research buildings and really began funding basic science. I hadn’t been aware of that. So when I came back for a job interview, I was impressed. I hadn’t realized the depth and size of things here. And that great trend has continued: when I returned in 2002, UNC had climbed to 14th nationally in total NIH funding. Now we’re 7th.
You’ve said, previously, that some colleagues advised against pursuing aging as a topic of research when you came here as an assistant professor in 2002. Why did they say that and why didn’t you take their advice?
That’s standard advice given to young faculty, and I’ve given it to young faculty myself: when you start a lab you have to pick something at which you’ll be competitive, and focus on that topic. So people said I should focus on melanoma—melanoma biology, melanoma mouse models—and they said I should be a melanoma doctor. And I did that to a degree. I worked on cancers, like melanoma, that are deficient in the p16 tumor suppressor protein, which was my research interest. But I also wanted to look into this other thing I thought the p16 gene might do—I thought it might contribute to a decline in the cellular capacity to replicate during aging. Only a few of us believed it played a big role at the time. So people thought I was crazy to pursue this odd topic. I didn’t have training in gerontological research. Colleagues thought I’d be perceived as a dilettante.
So, now I modify that advice; I tell young scientists to work on something in which they’re really interested, and that they think could turn out to be important. If it’s a boring topic, it won’t matter how plausible it is or how good you are at the science because you won’t get funded and you won’t stay passionate about the work.
The reason I didn’t take that advice is because of an odd result I got while still at Harvard. P16 is supposed to be important in pancreatic cancer, so we studied the pancreatic tissue from mice I had generated lacking p16. There, we noted that expression of p16 seemed to modify beta cell function of the pancreatic islet, which produces insulin. We later showed in my group that p16 is highly expressed in beta cells in an age-dependent way. In young mice, there’s no p16 and the beta cells can divide. When mice get old, there’s lots of p16 and the beta cells stop dividing. We believe this explained why beta cells “got old” and why type II diabetes became so much more common with aging. We published that in Nature in 2006. It was one of the first big papers out of my lab.
The diabetes doctors I knew were polite at the time. They were focused on how the liver and muscle used glucose, and didn’t think our findings were really that important. They said our results were interesting but probably not relevant in humans; they said, “It is probably a rodent-specific result, silly oncologist.”
But we got the last laugh because when the genome-wide association studies happened and researchers determined the alleles [alternate forms of genes] that caused susceptibility to common human diseases, type II diabetes was one of the first diseases studied. And the second strongest hit out of those unbiased genetic screens was p16. The importance of the locus in determining diabetes in large populations of normal people has been really unexpected, even to us.
And we’ve since learned that p16 does another good thing besides preventing cancer – its expression also appears to prevent atherosclerosis, an association my lab first discovered. The lower the production of p16 and related genes, the more atherosclerosis people get. This suggests to me that one aspect of atherosclerosis is like cancer: it’s a disease of too much cell division. In atherosclerosis, we believe it’s the macrophages that divide too much inside arterial plaques. These macrophages don’t divide very fast, but there’s plenty of replication to cause a disease over 20 years. So, p16 has become a hot topic outside of cancer, also in diabetes and heart disease.
It’s been really exciting. I’m glad I didn’t listen to those people who told me not to work in this area.
You are a co-founder of two start-up companies. What are the goals of each and what progress have they made toward their goals?
The first company is called G1 Therapeutics. We’re trying to use small molecule kinase inhibitors in a pill or IV medicine to prevent the toxic effects of chemotherapy on normal cells. We have evidence that by making cells stop dividing by inhibiting the enzyme CDK 4, we can make cells resistant to DNA damage. In simple terms, if you put cells to sleep – cells in bone marrow – then chemo won’t be so toxic to them.
G1 has been successful. We have received a lot of government funding and two rounds of venture capital. And we expect to use the drug in clinical trials in 2014.
The other company is called HealthSpan Diagnostics. It’s a harder road, but the science works. We can measure p16 in people and it goes up as we age. And if you have toxic events – such as years of smoking – your p16 level goes up even more. And we believe that your level of p16 can predict your ‘molecular age’ and risk of bad, age-related things happening. We’ve gotten to the stage where we have to make the assay [the experimental procedure] perfect. And that’s not something we can do in my lab; the assay needs to work better than it does, and that’s what the company is working on.
What excites you most about the future of cancer care and research that will hopefully lead to better treatments?
As new director of the UNC Lineberger Comprehensive Cancer Center, I am excited about several areas of rapid progress. Cancer doctors have a number of promising new therapies for a wide variety of diseases that I once thought were very hard, such as metastatic colon or lung cancer. These now have new effective therapies, and we’re seeing patients respond well. I am especially excited about the Cancer Center’s new commitment to tumor immunotherapy, an approach to make the immune system fight the cancer. I’m also very excited about surprising work in cancer epidemiology – what causes certain types of cancer, what are the risks of getting certain types of cancer? Also survivorship issues – how can we give patients a better quality of life after treatments? These latter two are areas in which UNC particularly excels, and where we benefit from the great work at UNC Gillings School of Global Public Health.
I’m particularly interested in the translation of basic science into clinical care at a much more rapid pace. UNC has really bought into this idea. So now, if a scientist at UNC Lineberger has a great idea, we know how to make that into a treatment. Instead of just publishing the Cell paper and moving on, we know how to turn that finding into a device, or diagnostic test, or treatment that can help people. And this is an area of great interest for our pharmaceutical and industry partners.
And the last thing that I’m particularly interested in is the intersection between cancer and aging. That’s becoming real. A number of UNC oncologists like Hy Muss have looked at this and said, well, most patients that get cancer are over 65. And they have a special set of issues that don’t happen in younger people. How will a better understanding of the biology of aging allow us to take better care of people with cancer? That’s one of the great research questions left in cancer biology. And that’s what my lab will continue to work on.
Norman E. “Ned” Sharpless, MD, is the Wellcome Distinguished Professor of Cancer Research and professor of medicine and genetics in the UNC School of Medicine. He has been a member of the UNC Lineberger Comprehensive Cancer Center, including his most recent position as deputy director, since 2002.
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