Pitt: World Class Cancer Researchers Facilitate Viral Discovery

Posted on September 30, 2011 by

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For years, Pittsburgh has had disproportionate number of the world’s experts in one specific area of research.  As a community, they represent diverse approaches to understanding the fundamental science behind and clinical outcomes of polyomavirus infection.  This fact perhaps goes generally unappreciated by the general public who, unlike me, don’t have a favorite polyomavirus or even know what they are.  Polyomaviruses are a very common type of virus that you acquire in childhood and stay with you for life.  It’s a happy, healthy relationship with no symptoms for most, unless you become immunosuppressed.  So why are so many Pittsburghers studying these viruses?  It is easiest to explain this by pointing you to the crown jewel in the Pittsburgh Polyomavirus crown: Merkel Cell Carcinoma Virus.

Polyomavirus: Image courtesy of Wikimedia Commons

As the name suggests, this is a virus that causes cancer- it was actually found in Merkel cell carcinoma tumors.  This is a rare kind of skin cancer that is terribly aggressive (~50% mortality rate), but was not well understood until Pitt Scientists Yuan Chang and Pat Moore discovered the link to polyomaviruses.  A couple weeks ago, The American Association for Cancer Research put up an article about the fantastic work being done by Moore and Chang.  One of the current goals of their lab is to understand how the virus causes cancer, so that drugs can be found to stop it.  If you choose to read the above article (which I would encourage), set your jargon-o-meter to stun (AKA, level 4).

I’m not going to discuss the recent findings of Moore and Chang, I actually want to spend a moment explaining why Pittsburgh is such a fantastic place for cancer research, and this kind of research specifically.  And that requires going back to my second year in graduate school.  As a graduate student, I was studying the family of polyomaviruses.  The conversation I had with my grandmother about them went a little like this, “I am studying these REALLY cool little viruses, called polyomaviruses.  They are called that because we used to think they caused cancer, but it turns out, that only happens to mice and hamsters…  But, studying why the virus gives mice tumors has actually taught us some really important lessons about cancer!  No, I don’t actually study cancer.”   I was looking for drugs to treat the diseases that threaten the immunosuppressed. Some 80% of the population carries at least one of these two viruses, and the numbers of immunosuppressed people are increasing.  Yeah, it’s a bit anachronistic to use a cancer model system to study infectious diseases that are fortunately rare-  seriously, even if I found a wonder drug, we are talking about TWO viruses.  And they don’t cause cancer- which is what people mostly use polyomaviruses to study.  Gramma was really supportive though.

Then in 2008 a fantastic thing happened- two papers came out, both from the Moore and Chang lab, describing how they identified the tell-tale signs of a polyomavirus in the Merkel cell carcinoma tumors.  As a graduate student, this was great!  The conversation I get to have with Gramma now goes like this, “I am looking for antiviral drugs that target a specific family of viruses, including one that causes CANCER. Yes! I am looking for the cure for (a) cancer!”

Most importantly, for people who actually get this rare cancer (1500 cases/ year in the US), there is a cause, which means for the first time, some hope of treatment in the future.  And for the field of polyomavirus researchers, it was like a splash of cold water to the face.  There are more than just these two human polyomaviruses?  How many? In the 3 years since the discovery of Merkel Cell Carcinoma Virus, FIVE new polyomaviruses were discovered, including Merkel Cell Carcinoma Virus.

You can imagine, this has been very exciting.  Pitt has long had some of the best Polyomavirus researchers in the field, including the recently profiled Jim Pipas who has spent years understanding how polyomaviruses tip the balance from healthy cells to malignancy, but also Dr. Randhawa at the Starzl Transplant Institute, who revolutionized the way polyomaviruses are detected in patients from an invasive biopsy to a simple urine test, and Dr. Vats, a surgeon at Children’s Hospital who regularly treats immunosuppressed patients who have polyomavirus diseases.  And of course, my old boss in the Department of Biological Sciences, Jeff Brodsky has spent years looking for better drugs to treat these viruses.  Heck, we’ve even trained some fantastic scientists here, too- like Chris Sullivan (now at UT Austin) who was the first to point out that viruses (actually, polyomaviruses) use interfering RNAs to silence gene expression.  But that doesn’t explain the Chang and Moore discovery- it could have been any kind of virus in that tumor.

Drs Chang and Moore were already famous before Merkel cell carcinomas piqued their interests.  They had identified another cancer that is caused by a virus, Kaposi’s sarcoma.  This is another cancer that has conspicuously high prevalence in immunosuppressed patients, which a careful medical scientist will tell you suggests that there is an infectious agent behind the cancer.  Moore and Chang were also working at the University of Pittsburgh Cancer Institute, which provides lab space for researchers who study many aspects of cancer from the clinical to the molecular, and as a result, allows for rapid knowledge sharing that is key to the scientific process.  In addition to being surrounded by other world-class researchers and equipment, perhaps it also gave them some contact with this rare cancer.

Even though it never happens this way, I always like to imagine the moment of discovery.  This virus was found by comparing the DNA of a cancer cell with a non-cancer cell.  They hypothesized that any non-human sequences that stuck out would point to the infectious agent, if there was one.  Karposi’s sarcoma is caused by Human Herpes Virus 8, a virus that is about 30 times bigger than the teeny polyomavirus. I imagine them subtracting away sequences, thinking “It might be another herpesvirus” but there isn’t enough DNA for that, “Do you think it could be a papillomavirus?  Those cause cervical cancer…” and there still isn’t enough DNA for that, but they do have this teeny bit of sequence, that looks like “…Polyomavirus?” And so they would have walked across the hall to the lab of Ole Gjoerup, who studies how polyomaviruses cause cancer in some animals but not humans to ask him what he thinks.  Ole was on my dissertation committee, so I can imagine how calmly he would explain that having the first human cancer caused by the world’s most studied, longest lasting model of cancer that doesn’t apparently affect humans is… probably a big deal.

Now I don’t mean to imply that the Moore and Chang lab wouldn’t have cracked this nut if they had been at any other institution.  They are a fantastic team who’ve attracted a lab full of great scientists, and their publication record shows how they continue to be diligent and insightful in understanding the biology of this interesting virus.  But I’ve been to their seminars, and I’ve seen their students get cornered by other faculty who want to know, “Have you looked for the virus in other tissues? How about the tissues I study?” “Can it replicate new DNA? Would you like to try my assay?” And that is why Pitt is such a great community for this research.  Being surround by experts in cancer biology, virology and the clinic gives all polyomavirus researchers the support and overzealous encouragement that both promotes innovation and supports human health.

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