Using Genetic and Genomic Tools to Study Rare Diseases:
A Chat with Pediatrician, Geneticist and “Medical Detective”, Dr. Wendy Chung

Recently, the Wall Street Journal profiled Wendy Chung, MD, PhD, the pediatrician and world-renowned geneticist who runs Columbia University’s DISCOVER Program—short for Diagnosis Initiative: Seeking Care and Opportunities with Vision for Exploration and Research. Dr. Chung is a medical detective (her expertise is genetic and genomic analysis)—and, Dr. Chung, the Kennedy Family Associate Professor of Pediatrics and Medicine, has discovered 28 rare, genetic diseases.

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Even the WSJ couldn’t resist comparing Dr. Chung and her team to television’s Dr. Gregory House and his team—which Dr. Chung finds, at the same time, a bit cringe-worthy but not without its similarities. “I’m more focused (than House) in the sense that we are using genetic and genomic tools for identify diagnoses,” said Dr. Chung, who started medical school the year (1990) that the human genome project commenced.

“I’ve been able to take a less biased view and a more holistic view of the genome,” she said. “Twenty years ago, we didn’t have the ability to look at all genes, so we had to make bets and look at the few genes we understood. Now we have the ability to look at all genes and realize that some bets were right while others were wrong.

Before the DISCOVER Program, Dr. Chung and colleagues at the Berrie Center (including Berrie Center Co-Director Rudolph Leibel. MD, the Christopher J. Murphy Memorial Professor of Diabetes Research and Dieter Egli, PhD, the Maimonides Professor of Diabetes Research) were applying techniques discussed in the WSJ article to identify the genetic etiologies of diabetes and obesity in their patients. (One unusual technique, for example, is gene editing to reproduce in cells, the laboratory or in mice some of the genetic mutations associated with patient’s diseases in order to test possible treatments and even cures.)

Last month, Dr. Chung talked about her work as it relates to diabetes and obesity. What follows is an edited version of what she had to say:

Question: What have you discovered, using genomic techniques about genetic forms of diabetes and obesity?

Dr. Chung: Through the years we were seeing patients at the Berrie Center who didn’t fit the classic profile for type 1 or type 2 diabetes. This made it more difficult to treat. Doctors were beginning to recognize that “monogenic” or single-gene forms of diabetes were in play. About 10 years ago, one of the things I wanted to understand, was how common this was, so we asked these patients if they wanted to participate in a research study.  We have had about 250 people participate in our research study over that time.  

The research study generally often has an empowering effect on patients. It has helped many patients tailor their treatment to their genetic form of diabetes and do the same for other family members, including taking several children off of insulin. For example, my favorite monogenic diabetes problem is something called MODY2 or glucokinase, because, as it turns out, patients need minimal or no medication but only monitoring of diet and exercise in order to maintain good glycemic control.

What are you learning about monogenic obesity?

There are rare forms of obesity—the most common of the rare obesity illness is called Prader-Willi—in which the brain is not correctly sensing satiety, and not correctly regulating body weight.  The exciting thing is we’re getting new treatments for some of these rare genetic forms of obesity.  A paper was recently published a paper in the New England Journal of Medicine about a medication that works on the brain to deliver the satiety signal with ensuing weight loss for one genetic form of obesity. Now, a targeted treatment for some obese patients is looking very promising.

How can you move the science of rare diseases forward?

When we do identify one of these rare genetic forms of—be it obesity, or diabetes, or any other illness, we want to be able to study it at a very high level.  But we don’t want to do biopsies of the pancreas to look at your beta cells or brain biopsies to see how the brain is wired. So increasingly we have ways of doing this by simply taking cells from the patient and recapitulating that organ within a petri dish. 

You could create a whole library of petri dishes and grow neurons or brain cells and even “organoids” or models for organ. We’re starting to be able to make “tissues on a chip” to look at how well certain medications will work on different individuals.

We’re also engineering mice that mimic the illnesses of people. You can create exactly the same mutations in mice as in patients. When I first got started as a medical student we were starting with mutations that the mice had and eventually being able to understand the human physiology based on that. Now we’re actually going in the reverse direction finding mutations in humans and then making the mouse models, so we can study how diseases evolve.

Will your research on rare diseases have an impact on more common diseases?

The idea is for some of these conditions is that many of these single gene models will eventually generate therapies that work, not just for rare genetic conditions, but they may also work for more common forms of diabetes and obesity. In other words, understanding how these genes and molecules work gives us profound insight also for the average person with diabetes. If you can figure it out in one very specific case, you may just have the insight you need to help the majority of patients.

To read the WSJ article in its entirety click here: http://www.wsj.com/articles/the-doctors-who-solve-medical-mysteries-1478544865