David Goldstein on the Promise of Precision Medicine

The case of a child afflicted by progressive neurodegenerative symptoms illustrates the clinical potential of precision medicine, says human geneticist and new Columbia recruit David B. Goldstein, PhD. The child’s doctors suspected an autoimmune disorder, but the girl’s condition was quickly deteriorating.

Hoping that a fresh perspective would help, the clinical team and Dr. Goldstein decided to perform whole-exome sequencing, a relatively quick and affordable analysis of the protein-coding components of the genome responsible for roughly 85 percent of known disease-causing variants. “We found that she has this super-rare genetic disease,” says Dr. Goldstein . “Only 50 or 60 people in the world have it.” And treatment was simple: vitamin B2 supplements. Says Dr. Goldstein, “And now, in one of the most amazing experiences of my career, she’s doing wonderfully.”

Author of more than 200 papers on the clinical applications of genomic analysis in AIDS, hepatitis C, schizophrenia, and epilepsy, Dr. Goldstein has been named founding director of Columbia’s Institute for Genomic Medicine, a university-wide program to integrate genetics and genomics into research, patient care, and education at Columbia University Medical Center and NewYork-Presbyterian Hospital. The institute also will develop programs to prepare students to integrate precision medicine into their careers.

Dr. Goldstein begins his new role at Columbia Jan. 1, 2015, but he is already formulating his vision for Columbia’s nascent effort.

In 2008, you told the New York Times, “There is absolutely no question that for the whole hope of personalized medicine, the news has been just about as bleak as it could be.” What has changed?

In 2008, “bleak” was an awesome place to be working, because it could only get better. And it has. Back then, we were doing genome-wide association studies and linking variations to diseases—and in my view we weren’t getting very far in terms of clinical relevance. I’ve always felt that we should be completely transparent, up front, and accurate with the public. We shouldn’t be saying that we’re making more progress than we really are. We should describe the situation as we see it. We’re doing the work very differently now. Now we often find the exact causes of an individual patient’s disease, and that’s a game changer.

Much of your research has been in the field of pharmacogenetics, looking for clues in a patient’s genetic traits or disease profile to predict responsiveness to a particular drug protocol. How is that going?

There has been a lot of enthusiasm and even hype for this work, and the reality is that we still have very few real-world examples. And while I would not want to add to the hype, I do personally expect that to change before too long. There’s every reason to believe that understanding the exact underlying molecular cause of a condition will guide how we treat it, and we in fact already see very clear examples of this in some of the work we and others are doing in epilepsy.

Why the move to Columbia?

The work that needs to be done in precision medicine goes beyond the boundaries of a single investigator’s lab, no matter how big that laboratory is. The vision Columbia has outlined is the most integrative and comprehensive I’ve seen, bringing in the Morningside campus, CUMC, and NewYork-Presbyterian with a charge to pursue clinically applied investigations. As soon as I heard President Bollinger articulate his vision, I knew I wanted to be involved.

What is your own vision for the institute?

We’re going to pick a few key clinical areas where we think we can make a really big difference. One major focus will be on epilepsy and using comprehensive genomic approaches to figure out what’s wrong with kids who have serious genetic diseases. A more general focus will be to carefully interpret the genomes of all patients with unresolved or undiagnosed genetic diseases. My hope in coming to Columbia is that we will be able to ensure that every patient that could benefit from genome sequencing will have their genomes not only sequenced, but carefully interpreted.

How might the institute’s work help someone with epilepsy?

If we sequence a patient with epilepsy and find there’s a mutation in a particular potassium channel gene, we can put the protein that gene encodes into a well-established laboratory protocol and test an FDA-approved drug that targets that protein. My colleagues in Melbourne, as part of the Epi4K and Epilepsy Phenome/Genome Project research teams, are already pursuing exactly this kind of work. You can prove that the effects of a mutation that causes epilepsy can be interrupted in the lab with a particular drug. Then you know to try that drug in patients with that kind of epilepsy.

This is where having an integrated program is so important. If we just get the mutation, we can’t do much with that. We have to understand what that mutation does, biologically, and how it relates to the mutations in other patients, so we can group patients based on the different underlying processes that have gone awry and not just their symptoms. One of my highest priorities at Columbia is to create a mechanism for handing over the mutations to really good biology labs that can investigate how those mutations create the effects that they do.

What do you tell patients about the current realities of precision medicine?

When I talk to families about participating in the kind of research we do, I always tell them that there is a pretty decent chance that we will find out what is wrong genetically, but I also tell them that there isn’t a very high chance that we will be able to do something clinically that will make a big difference. Sometimes we really do learn how to essentially save a kid, just by looking at the genome, and that is the most wonderful thing that can happen. But it is a minority of cases and we have to make that clear.

So why do families still choose to participate?

Most families and patients want to know why. Even if we can’t make a big difference clinically, simply putting a name to a condition, and providing a genetic explanation, is of real value. It provides peace of mind. It provides an explanation. It allows families to reach out to other families that they know have similar conditions, to create support groups, to create advocacy groups. Explaining the basis of disease is a part of practicing good medicine, and genomics is a critical part of that effort.

Where do you draw inspiration in your quest for clinically relevant genomics?

In terms of personalized and precision medicine, cancer treatment is no longer aspirational—it’s demonstrated. Everyone agrees that the future of cancer therapeutics is to target treatment to exactly what has gone awry in tumors. All sorts of great work in that field is already going on at Columbia. My personal ambition is to add a few more disease areas to that roster. I want to make epilepsy next. And I want to make sure we do everything for kids with undiagnosed disease, for complicated pregnancies. Cancer is an example of where we want to be.

Learn more about Dr. Goldstein and Columbia’s precision medicine initiative:

• Dr. Goldstein’s Dec. 1 lecture, Columbia’s Inaugural Distinguished Lecture in Precision Medicine, is available here.
• Read the CUMC Newsroom post about Dr. Goldstein’s recruitment as director of the new Institute for Genomic Medicine.
• View a video about precision medicine.