05:26pm Thursday 14 December 2017

On Auto Attack

 

  click to enlarge Maureen Su, MD (Photo by Max Englund, UNC Health Care)

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On Auto Attack

Fresh off the plane from California, an 18-year-old Maureen Su lugged her bags across the quad to a room in one of Harvard’s ivy-covered dormitories. Down the hall, a gaggle of first-years gathered. Su scanned the door numbers until she got to her assigned domicile. She dropped her bags and heard someone say, “You got Al and Tommy Lee’s room.”

That’s Al Gore – the former vice president turned climate change activist turned media mogul – and Tommy Lee Jones the actor.

Su figured those two guys knew precisely where they were headed in life. She wasn’t so lucky. Su, now an associate professor in the department of microbiology and immunology, as well as pediatrics, had no idea what she wanted to do with the rest of her life when she arrived in Cambridge.

In high school, she wrote a freshman-year essay about wanting to be an advertising executive. “I don’t really know where I got that from,” Su now says. “Maybe from watching ‘Bewitched.”

But in college, as in high school, science came easiest to her, and when she got her first taste of research, she knew she had found her calling.

Today, Su is a rising star in the field of autoimmunity – when immune system cells attack healthy cells. For her research and clinical care of children with autoimmune endocrine diseases, including type-1 diabetes, Su earned the UNC School of Medicine’s Jefferson-Pilot Award, given to exemplary UNC School of Medicine junior faculty. The four-year fellowship carries a prize of $20,000 to support research or teaching efforts.

We sat down with Dr. Su for a Five Questions feature to find out how she wound up as a pediatrician with a penchant for basic research and what her research can tell us about potential treatments for many diseases, including cancer. 

5q-pediatricianWhat was the driving force behind you pursuing medicine, science and in particular an undergraduate degree in biology and a medical degree from Harvard?

I grew up in Southern California. My impetus for going to Harvard was that it was far away and mysterious, kind of like a Hogwarts institution that I never even imagined I’d be able to attend. I went from being this valley girl who put “like” between every word and called everything “rad,” to attending Harvard, which was definitely an inspiring place to be. When I started there, I really didn’t know what I wanted to do. I had great chemistry classes and I thought about going in that direction. But they don’t let you declare a major at Harvard right away; they want you to get a broad-based education first.

In the end, I think it’s the people you’re around that often influence what you end up doing. I was lucky enough to have many great mentors along the way, and I realized that I loved to be in a lab setting. During the summer after my sophomore year, I worked in a genetics lab where I felt most at home. It was like a little family of people; all of us were interested in the same thing.

That was my first experience doing biology-based research.

I stayed at Harvard for medical school because it had a health sciences and technology joint program with MIT, and doing research in this program gave me a chance to work with top-notch medical researchers and made it possible for me to pay my way through a lot of medical school.

I was lucky enough to work with a physician-scientist Nancy Andrews, who was spectacular. I was inspired by her and really liked being on a mission to figure out the cause of diseases we were seeing in the clinic.

The choice to become a pediatrician was pretty natural. At some point, I thought I’d either be a kindergarten teacher or a pediatrician because I always enjoyed working with kids. It was the research part that was sort of a lucky, fortuitous thing.

5q-tcells-yellowWhy did you choose pediatrics and endocrinology as your areas of focus as a clinical fellow, chief resident, and resident at UC-San Francisco?

I do think this has to do with the people you’re around. My family is from California, and my father died while I was in medical school. So there was a big pull for me to go back to California. At UC-San Francisco, there was a strong tradition in endocrinology and a rich diabetes research environment. It was lucky that autoimmune diabetes research was really cutting edge at UC-SF.

When I was there I heard a talk about autoimmune endocrinopathies – [conditions in which the immune system attacks part of a person’s endocrine system, which is responsible for making and regulating hormones.]

As endocrinologists, we’re not really addressing that when we see patients. We address the hormone replacement part. So, kids who have type-1 diabetes don’t make enough insulin. We give them insulin. But we don’t do anything to address the autoimmune cause of that condition.

It was really frustrating to me to know there was an autoimmune disease going on and even though we knew this when a kids came to us in the ER, we wouldn’t do anything to stop the immune response. We let the autoimmunity bear itself to completion and then we’d replace the insulin. We know they still have insulin-producing cells in their bodies when we see them for the first time, but we were powerless to do anything about it.

There was a big disconnect between what we were doing and what we should be doing in terms of trying to prevent or cure disease.

So I became involved in the diabetes center at UC-SF. That was the beginning of my work on autoimmune diseases. I was there from 2000 to 2010.

5q-northcarolinablueHow did you come to join the faculty of UNC’s Department of Pediatrics and the Department of Microbiology and Immunology?

The South was not on my radar. But I did come here a couple times to interview for college and medical school, and I was always struck by how kind people were. When I interviewed for medical school down here, I forgot to bring my contact solution. So I stopped a lady in the hallway to ask if there was a store nearby, and she said, “No, but I can take you to one.” So she drove me to the store and drove me back. This wasn’t someone I was interviewing with; she was just a kind lady in the hall.

I remembered that when my husband was offered a job at Duke. It’s really hard for married academics to find top academic jobs in the same geographic area. Duke had an opening for my husband and UNC had one for me.

I was really impressed by the research going on here. This has turned out a great place for us to start our careers. The academic environment has been great, but also Chapel Hill has been great because we have two kids, and this is a fantastic place to raise children.

5q-shotWhat is autoimmune disease and what has your Aire research project revealed thus far?

Autoimmunity means that your immune system has lost the ability to know what should be protected. It’s already a big problem and it’s getting worse for reasons that are not entirely clear. About 10 percent of the population is currently affected by autoimmunity. Autoimmunity can cause diseases like type 1 diabetes, lupus, rheumatoid arthritis, thyroid disease, adrenal insufficiency, and vitiligo – which is when immune cells attack skin cells.

We don’t know why autoimmune diseases are becoming more common, but we think it’s the way our environment interacts with our genes. This is just speculation, though it’s true that we don’t live the way we did fifty years ago. Most of us don’t live on farms anymore, we eat differently, we don’t walk to work, we don’t ride horses to work.

The most common autoimmune disease I see is type-1 diabetes. What we think is happening is that immune cells whose job is to fight off infections are not just doing that; instead they attack the person’s insulin-producing cells that are usually ignored by immune cells.

In type-1 diabetes, one of the antigens – the things that provoke the immune response – is insulin itself. For whatever reason, the body doesn’t see insulin as part of itself anymore; the body thinks insulin is something that has to be gotten rid of, and it does a really good job of doing so.

We think there are a lot of different genes that contribute to this. In the old days, when humans were exposed to a lot more infectious diseases, we evolved genes that gave us really strong immune systems so we could fight off those infections. One possibility is that those same genes are not being used because we have a much cleaner environment than we used to. So, instead of our immune cells attacking infectious agents; they attack the healthy parts of our bodies.

We think a lot of genes contribute to this. One of them is the Aire gene. If you have a mutation in that gene, then you get autoimmunity in multiple organs. It’s rare, but it’s interesting because we know that a mutation in that one gene is enough to cause autoimmunity in mice and people.

When I was a postdoc we made a mouse model with a mutation in the Aire gene. These mice spontaneously got autoimmune disease. This allowed us to try to understand why people get autoimmunity and test different potential therapies.

The specific mouse model we made was different than what other researchers made; our Aire mutation led to autoimmune peripheral neuropathy – when the immune system attacks nerves. We’ve used this model to find out what immune cells are targeting – a protein called P-zero in the peripheral nerve.

Truthfully, if you want a better treatment, you have to understand what the cause is, otherwise you’re just guessing. So we’re trying to understand what causes autoimmunity in spontaneous mouse models, and then use that information to figure out what kind of therapies would work best in patients.

So that’s the crux of the Aire project.

5q-tealmicroscopeIf the body sometimes naturally attacks “good” cells to cause disease, then do you foresee a way to make these autoimmune cells attack “bad” cells, such as cancer cells?

Yes. I think it’s possible, and we’ve flipped the Aire project on its head to try to do just that because we know that the autoimmune response can be useful. For example, people who have mutations in the Aire gene can develop vitiligo, which is an autoimmune disease of the skin.

People with vitiligo have white patches of skin where there’s no pigment. Sometimes it’s very severe. This hypopigmentation is from T cells attacking [skin cells.] We know that the same antigens that T cells attack are the same antigens that are important in rejecting melanoma. We want to harness this kind of autoimmunity to make those T cell attack the melanoma.

In the last five years, there’s been an explosion of interest in cancer immunotherapy. People are trying to activate the immune system to fight cancer cells.

Because Lineberger is here and cancer immunology research is strong here, we began thinking about whether we could utilize autoimmunity for good. Now, we have evidence that we can use the autoimmune T cell response we see in Aire-deficient mice to fight off melanoma.

We just developed, with our collaborators in UC-San Francisco, an antibody-based therapy that we think can do the same thing the Aire mutation does in people and mice. Therefore, we could use that antibody as a potential therapeutic to make people temporarily autoimmune to fight off their melanoma.

If we can do this, then I think this could be a really good alternative to some of the current therapies, which work in only a fraction of patients. Also, if we succeed, then this could give us insight into how to boost our own immune system to fight other types of cancer cells.

Maureen Su, MD, is a member of the UNC Lineberger Comprehensive Cancer Center, the Thurston Arthritis Research Center, and the Inflammatory Disease Institute.

University of North Carolina at Chapel Hill School of Medicine


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