An Eclectic Path to Precision Medicine

Stephen Emerson entered Haverford College with the aim of becoming an astronomer-mathematician. That is, until he met Ariel Loewy, a biology professor on the faculty who encouraged him to change his focus.

“He said, ‘All the asteroids and stars are going to be there for the next billion years—let someone else worry about them,’” Emerson recalled. “Why don’t you study whatever science you want but think about applying it to cells and molecules and maybe someday even people?”

Emerson spent a summer working in Loewy’s lab at the small liberal arts college and was hooked, graduating with a double major in chemistry and philosophy. Since then, his career trajectory has continued to take unexpected turns. He spent 13 years as the chief of hematology/oncology at the University of Pennsylvania, where he became a renowned expert in bone marrow stem cell biology, and his lab’s research in bone marrow stem cell transplantation led to many new medical therapies.

In 2006 he was asked to serve as president of his alma mater. “After saying, ‘Huh?’ but then talking it over, I said I would do it because I owed Haverford my career,” Emerson said. “I loved the college, and I loved serving as its president. But one wrenching stock market crash [in 2008] while running a small college was enough for me.” In all, Emerson was at Haverford just under five years when the call came from Columbia and he returned to medicine full time.

As director of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, he is among a group of Columbia scientists homing in on innovative ways to treat diseases that target a patient’s genome, sometimes called personalized or precision medicine, which President Lee C. Bollinger has made a University-wide initiative.

And despite his 40 years as a scientist, Emerson remains an advocate of the liberal arts education that changed his life. “Honestly, I use the philosophy just as much as I use the chemistry,” he said.

Q: What is precision medicine?

Some people call it personalized medicine, which I think is a misnomer because in a sense we’ve always done personalized medicine—it’s what a good doctor does. What’s new now is we know a lot more about the biology of diseases. And what we’re starting to realize is that what looked like the same disease among patients can actually be different diseases that just happen to look the same. Many of these illnesses are caused by random mutations in someone’s DNA within one cell, which can in turn change the function of a key protein, which makes a cell grow abnormally, as a cancer. Since the site of the mutation on the chromosome will be random, and different, for each cancer, every cancer will be fundamentally unique. One patient’s leukemia will not necessarily be the same as another’s, so the treatment for them should be different depending on the actual cause of the disease in their cells.

Q: What would be an example of that?

There’s a disease called chronic myelogenous leukemia, or CML, which is caused by one genetic change. It’s very rare, but if you get this change—and bear in mind, it’s a single gene change, not two—it turns out that one medicine can control it. In fact, that’s how precision medicine started, in a case where one gene was abnormal. In fact, you don’t need that gene to work at all; it’s like the appendix of cells. You can poison this gene and from then on the patient’s CML cells will behave as if they were normal. The disease is still there, you didn’t cure it, but the cells from then on will grow normally. It’s amazing.

Q: Is it possible to do this with other cancers?

As you can imagine, the success with treating CML based on its single mutation led people to say, “Why don’t we do this for all cancers?” It turns out there are very few cancers like that; usually it’s a combination of two or three genes gone wrong, and they’re all very different. But with DNA sequencing becoming more available, and with better computer power to analyze it, we can now perform a complete DNA sequence for any cancer, analyze it with the best computer power and brainpower available, and combine that sequencing information with what we already know about the genes involved. From there we can take a pretty educated guess as to what key gene is causing the problem, and then go to the shelf and try a medicine that might work in a clinical trial. Or put that abnormal gene into the tumor of a little mouse, try 50 different best guesses as to what medicine might work, pick the one that’s most effective, and use that for the patient.

Q: Is cancer medicine in the vanguard of this effort?

Yes. Oncology is the poster child for personalized medicine right now because you can have cancers that look the same under the microscope but are totally different in terms of what genes have been disrupted, which ones cause the cancer. So you have to use a treatment that specifically addresses that cause. But while this revolution has begun in cancer, it will spread to other parts of medicine in ways we can’t foresee. It’s only starting to be applied to other specialties.

Q: Such as?

Columbia just hired David Goldstein, a geneticist whose focus is seizure disorders. Kids get seizures all the time; usually they’re from a fever and they’re not major health problems. But a few kids have diseases that come with recurrent, severe and debilitating seizures. It turns out that if you sequence their genomes, some of these children have mutations involved in neural functions. There might be a way to prevent their seizures by giving these patients medicine that cures the function of a particular cell. If we know what the gene is, we can study it and maybe we can make it function better.

Q: How far along is this approach?

Just as for cancer patients, we can now perform complete DNA sequences for any patient with recurrent seizures, analyze it with the best computer skills, and identify mutations that distinguish the child’s DNA from those of his or her parents. By combining that sequencing information with what we already know about the mutated genes, one can take a pretty educated guess as to what key gene might be causing the problem. For David and his seizure patients, he can use that technique to identify the abnormal gene and test it out. That sort of approach will expand in medicine in different ways. He and the people he hires, and the next generation, will figure out different ways to identify the genes relevant in all the diseases we have, hopefully, and find diagnostic tools and treatments tailored for them. The same thing’s going to be true in autism.

Q: Are there some diseases that are better study subjects for this approach than others?

I think anything where a child has the gene for a disease and the parents don’t is a good candidate. That child’s disease is likely to be caused by a mutation that arose specifically in the fertilized egg that developed into the child. In fact, if you look at children who are diagnosed with leukemia when they are 8 or 9, and you go back and look at their umbilical cords, you’ll find the same mutation—it just hasn’t grown out yet. And this is where medical ethics come into play, because we don’t necessarily know what mutation will cause which disease. It might never happen. Do you tell the parents before they have children? After?

Q: What attracted you to the study of blood diseases?

When I started to see patients as a medical student, I found the kids and adults who had blood diseases like leukemia incredibly compelling. We didn’t know why they got these diseases; they were desperately ill and they required the best and most sensitive medical care. It was clear to me that it would really matter for patients if I made some progress. It’s also an unusual specialty because when you stain the blood cells on a slide they’re beautiful, they’re just gorgeous. You’re looking at developmental biology in front of your eyes, normal or abnormal. And the connection between the detective side of hematology and patient outcomes was unusually high in hematology. The better job you do at being a “blood detective,” the better your patients do.

Q: Do you still see patients?

I did until I became president of Haverford. And while all my patients from my Penn days have my number on their cell phones, I now refer them to the right people to take care of them. I still speak to my patients often, but I felt it wasn’t fair to them to not be a full-time clinician taking care of them. But I’m still itching to do it.

Q: It’s clear how your major in chemistry has had an effect on your work, but what about philosophy?

The whole Western stream of philosophy is important for medicine and science. The hardest thing, for example, to teach a medical student is how to record and interpret a patient’s clinical history. As you talk to patients, you must think about the potential universe of diagnoses. You have to have a framework before you start to fill it in with data. And we learned about that way of thinking from the German philosopher Immanuel Kant. But the most important idea for me was from a mathematician named Georg Cantor, who created a theorem about different levels of infinity. Without getting into all the details, it boils down to this: We don’t even know what we don’t know yet. The biggest problem for students who are interested in science is that they see so many things to learn, they can’t imagine how will they master it all, much less add to it and discover something new. They get frozen and discouraged. I recently gave a talk at Yale’s M.D.- Ph.D. program, where I went, and the kids were brilliant. But they asked, “What’s going to be left for us?”

Q: And what was your answer?

That we’re just beginning to sort through all of this. If you think about it, cells function by virtue of billions of years of evolution, right? That’s incredibly complex. We haven’t even scratched the surface of what we can learn.

— Interviewed by Bridget O'Brian