Alumni Spotlight: Sandra Silberman
Sandra Silberman, M.D., Ph.D.We sat down with alumna Sandra Silberman, M.D., Ph.D., who has decades of experience in drug development. She talked with us about translating basic science discoveries into developing new drugs, especially in the cancer field.
Silberman earned her undergraduate and master’s degrees and a doctorate at The Johns Hopkins University’s Krieger School of Arts and Sciences, Bloomberg School of Public Health and School of Medicine, respectively. She then worked with Johns Hopkins oncology expert Richard Humphrey, M.D., after receiving an American Cancer Society postdoctoral research fellowship in oncology.
After her initial training at Johns Hopkins, Silberman earned her medical degree from Cornell University and completed a residency at New York University/Bellevue Hospital and a hematology/oncology fellowship at Brigham and Women’s Hospital and the Dana Farber Cancer Center.
Early in her career, Silberman was an instructor in medicine at Harvard Medical School and an attending physician at Yale University Hospital and in Duke’s hematology/oncology program.
Then, she took her career to drug development at Pfizer Inc., leading some of the first clinical trials of erlotinib — a novel cancer drug that was the first to target a specific protein in cancer cells. She continued in the drug development field at pharmaceutical company Novartis as head of the development of imatinib, and then was the head of oncology at Eisai.
Today, Silberman is consulting with biotechnology companies, helping to initiate and expand clinical trials for new therapies in oncology.
What drew you to begin your career at Johns Hopkins in basic sciences?
I was drawn to the basic sciences because it enables scientists to start with ideas and then pursue answers in the lab. We start with a problem or a question. To find the answer, we need to turn to the laboratory and do the proper experiments. As an undergraduate, I often did a mini semester in a research lab, and it was fascinating.
In the lab, we learned that there were ways to understand the biology of a disease better, and discover what is really happening.
What did you find when you started work in the immunology field?
I was drawn to immunology based on working with a biology professor who introduced a field I had never considered — how does the immune system actually work?
At the time, we knew there were T cells and B cells. That was it. There was no immunology division at Johns Hopkins, and leaders in the field had just started to coalesce.
As an undergraduate, I heard about differences between immune cells. What were these cells, and what were they doing? I started working in the lab to purify a new type of cell involved in the immune system — NK [natural killer] cells — to explore how they worked in animal models.
I was honored to be able to work with professor Kimishige Ishizaka, who discovered IgE (immunoglobulin E), an antibody produced by the immune system. He was incredibly insightful about this new class of cells. We knew that NK cells alone could kill leukemia cells, but they also used antibodies to do this. We did experiments to discover which class of antibodies were involved, and found that IgG molecules that bound to NK cells via the Fc receptor differ in their capacity to destroy cancer cells based on their subclass. This was so exciting to me, as this explored basic science to find underlying aspects of disease.
When I received an ACS [American Cancer Society] fellowship, it was to work at The Johns Hopkins Hospital with Richard Humphrey, who was working on treatments for patients with multiple myeloma using interferon, a protein that had been shown to activate NK cells. In the first clinical trials of this drug, Dr. Humphrey gave these patients interferon, and we looked for activation of NK cells in the bone marrow. The research was challenging, because we did not have the best laboratory tools at the time to differentiate and distinguish between immune cells in the bone marrow. But it was important, and I was privileged to see how he worked with his patients.
How did a foundation in basic sciences prepare you for work in clinical fields?
At the time I went to medical school, we relied mainly on rote memorization skills (just know everything!). But with my background in basic science and research, I looked at how medicine was being practiced and was better able to understand how treatment had evolved based on previous discoveries.
When I was in my residency, it was the first time that we saw people dying from an unknown disease, which, in New York City, was rampant. Scientists eventually discovered that it was based on a virus that led to immunodeficiency, and this disease was subsequently known as AIDS.
So, when I did a fellowship in hematology oncology, I was able to get back to immunology research. I studied T cells that the virus affected.
We now know that helper T cells were being targeted. So, how does this happen? The surface of the virus has a protein called GP-120, which we isolated in the lab. We found that just the GP-120 protein binding by itself could dampen the ability of the T-helper cell to be effective in fighting the virus. This finding got me interested in understanding how something binding to the cell surface can transmit a signal to the nucleus that influences its function.
Now, we’re at another moment in time when immunology is incredibly important in the oncology field, with the discovery of new immunotherapy agents and CAR-T treatments.Have we reached a pinnacle of understanding the immune system and cancer?
Not yet. The biggest problem in science and medicine is that we tend to become attached to the latest discoveries and new drugs that are relevant to this field and neglect the fact that we need to integrate each new discovery into the aggregate of our knowledge. We need to understand the basic biology first. I did this with several of the drugs that I’ve developed, especially the targeted ones; e.g., erlotinib and imatinib. We needed to look more closely at their targets — for example, with erlotinib, the EGFR receptor, and for imatinib, multiple targets on cancer cells — to find out why subsets of patients showed responses.
What did these explorations teach you?
I learned a lot about the biology of cancer. If there is a single mutation in a cell that is driving cancer growth, then you have the ability to develop a single drug that can halt cancer growth (e.g., BCR/ABL gene translocations in chronic myelogenous leukemia). For these cancers, you define the mutation and find the rare cancer that is like a three-legged stool, and by removing just one leg, it will fall.
However, most cancers are like six-legged tables. You can remove some of the legs, but the table will still stand. This suggests that a combination of therapies may be most useful. And understanding this may help describe new targets that could lead to the development of drugs that require combination therapy for the greatest success.
If I’m a scientist thinking about a career in drug development, how can I be most successful?
First, understand the limits of a preclinical model. Second, explore laboratory models that are more translatable to the human condition. However, also recognize that the pathophysiology of disease between individuals can be different, and the microenvironment, which plays a role in the development and growth of tumors, can also be different. It’s helpful to understand these differences when working in a laboratory setting before we bring new drugs to the clinic. But even after a drug is clinically tested, one needs to ask: Can there be a way to refine it and make it better based on the information gleaned from your laboratory work?
What advice would you give trainees looking at the drug development field?
Understand the complexity of diseases; however, know that what you’re working on may be a significant piece in unraveling this.
All of these efforts, especially when put together, can make an incredible difference. Work on one piece, as a goal for a certain stage of research. Then, look at how to push this further. What someone might consider a very small part of the pathophysiology of a disease could be the one thing that makes more discoveries possible.
What did I miss?
I’ve never stopped mentoring throughout my career in all its iterations. It’s one of the most enjoyable and fascinating aspects. When students or new associates ask for advice, I ask them questions about what activities get them excited to come to work each day. I think that’s what has motivated me all my life.
Finally, for new trainees in science and medicine, I give you a world of thanks for going into a field that will ultimately make all our lives better.