1. Neff Newitt, Valerie

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Eirini Papapetrou, MD, PhD, traded games and baby dolls for printed pages when she was growing up in a small town outside of Athens, Greece.

Eirini Papapetrou, M... - Click to enlarge in new windowEirini Papapetrou, MD, PhD. Eirini Papapetrou, MD, PhD

"I was able to read at the age of 4, and I was a bookworm," said the formerly studious little girl who grew up to become Associate Professor at Icahn School of Medicine at Mount Sinai, New York, N.Y., and an elite researcher focusing on genome editing and blood cancers. "I spent so much time with books that my parents were concerned that I didn't play enough. But now I feel like I am playing all the time because I love my work so much. I am always playing."


Married and mother to an infant son, Papapetrou laughed at the idea of indulging in any actual hobbies. "Right now I have one little human hobby, exclusively. He is the one and only. Before him, I just worked all the time," she said. "In fact, I really don't 'get' hobbies. I don't 'do' hobbies."


Finding Her Path

Papapetrou said there were no doctors or researchers in her family, nor anyone who had gone on to graduate school to influence her future career. But, "medicine seemed important-meaningful enough to pursue," she recalled. She earned an MD in Europe, but soon knew an MD would not be enough. "I realized there are so many cancer patients we can't really help beyond giving them support and comfort. But support and comfort don't change the course of a disease," she said. "I remember telling this to my then-professor of hematology, and I was hoping he would say, 'No, no, you are wrong.' But instead he said, 'So, you already have figured that out...'"


About that time, there was a major breakthrough in hematology with the development of imatinib, a tyrosine kinase inhibitor for chronic myeloid leukemia.


"I was an intern in the clinic and I saw how revolutionary this inhibitor was. I experienced a true 'before and after,' seeing how a disease can be impacted when a good drug is developed and how outcomes can completely change," Papapetrou told Oncology Times. "I saw how a lethal disease can become a chronic manageable disease, with patients living for decades. That experience really 'registered' and reinforced in me the fact that I could have a bigger impact doing research than patient care.


"Sure, patient care is more rewarding in the short-term-you go home in the evening and you feel like you did something good. Rewards from the lab are much longer-term. They may take months or years, and sometimes they never come. But if and when rewards do come, they are great."


Armed with an insatiable intellectual curiosity, Papapetrou entered a PhD program in Europe and found the research more intellectually stimulating, whereas being a clinician seemed routine and repetitive sometimes. "It was a gradual realization. I went back and forth from the bedside to research for a few years before I recognized what my proper path would be," she revealed.


Once she set her sights on research, Papapetrou sought out the best environment for cancer research and believes she found it at Memorial Sloan Kettering Cancer Center in New York, N.Y. "When I first visited and interviewed for a postdoctoral position, I knew I wanted to be there."


Innovating iPS Cell Usage

Since her arrival, Papapetrou has emerged as one of the first investigators to produce induced pluripotent stem (iPS) cells, "master cells" that allow an extraordinary opportunity for deepening research.


"When scientists study a disease, they typically use animal model systems simply because we cannot do certain things in humans or ask certain questions of human systems-we can only observe and learn," said Papapetrou.


While she was doing postdoc research in hematological diseases using mouse models, a major breakthrough in stem cell research and technologies came about. A Japanese researcher discovered that pluripotent stem cells can be made in a lab. "These cells are unique in that they are cells we take from an individual, from any part of the body. We put them through a reprogramming process and they become like naturally occurring, early embryonic cells-cells that can make everything," she detailed.


Papapetrou realized the implications of this capability could be huge for many fields of medicine and biology, and hypothesized the cells could be used to create disease models that could fill in the gaps in the limitations of existing animal models.


"I thought we could take this technology and adapt it for use in studying leukemia. Taking blood cells from patients with leukemia and turning them into iPS cells would give us an opportunity to study the cells and to keep them in the lab-forever," she explained. "We then could culture them to make blood and study them to see how leukemia is developed in a way that is closer to what happens in real life, in real patients. This would be in a human model, not an animal model. At the same time, we would be able to do whatever experiments we want with this same material in the lab."


When this idea first came to Papapetrou, "it might have seemed to others a little crazy to do. Maybe it would work, maybe it wouldn't," she noted. "But work or not, I thought it would be very interesting, unique, and novel to try. Fortunately, over the past 7 years, we have managed to make a lot of additional refinements in this technology to assist in the study of leukemias. So now my entire lab is based on these techniques."


Right now her lab is primarily focused on creating, characterizing, and understanding different models, with hopes of developing different assays so that scientists can use them to learn even more. "We have a lot of things in progress right now," said the researcher.


One effort that has been published is the use of new models to study chromosomal deletions. "Chromosomes are very different between humans and other model organisms. It is very difficult-if not impossible-to study chromosomal abnormalities in mice or other model organisms," Papapetrou explained. "So now we have made several human models in which to study deletion of chromosome 7, which is very common in human leukemias."


Understanding Disease Progression

Another recent effort of the lab, published last year, involved building models of the progression of leukemia through distinct stages of pre-leukemia.


"This allows us to study leukemia at a very early stage before it has developed to full-blown leukemia. Most models don't really capture that; they capture late stages when the disease is already fully developed," detailed Papapetrou. "We can use these models to see how blood cells go from being completely normal to acquiring some early mutations that make it not exactly leukemia yet, but not normal either. We want to see the gradual stages of disease development as it becomes a cancer-a leukemia."


Eventually, this understanding may lead to development of a test to determine at which stage of disease a patient is, and if the disease can be inhibited.


"We know people acquire mutations in their blood and that some of them will develop leukemia. But some will not, and we don't know why. What is different in those that develop leukemia?" she asked. "We hope to see if we can predict which patients with pre-leukemic mutations will go on to develop leukemia, and of course ultimately to find ways to prevent this from happening."


The researcher said that as understanding increases around the processes that drive the disease, there also will be more opportunity to find drugs to target it.


"My lab is using iPS cell models to perform drug screens," she noted. "We are taking libraries of active compounds, not known to have activity against leukemia, and testing them. Some may be drugs that are already in use for other diseases and some just may be chemical compounds with some activity that we don't understand. From both of those approaches, we hope to find new drugs for leukemia and earlier stages [of leukemia] that would either prevent the progression to leukemia or just treat the leukemia once it develops."


Looking to the horizon, Papapetrou hopes her research will yield information about disease, new treatment approaches, and drugs that will change the course of leukemia from a lethal disease to a manageable or curable disease. "This is a very high bar, but that is my aspiration from all of this," she said with conviction.


Papapetrou thinks of herself as one of a few investigators who are now pioneering and spearheading the use of human-based models for studying cancer. "Over the past 3 decades, a lot of good medical and cancer research has used the mouse as a fundamental tool, because at that time there was very little that could be done with human materials.


"A lot was found, but also a lot of information was missed," she added. "We realize now that mouse models have limitations. We joke that we have become very good at curing cancer in mice-mice are very lucky. But that hasn't necessarily translated into benefits for humans.


"Now we are introducing a new era of cancer research that uses human models as the primary discovery platform. And conceivably, by using human models as a primary platform for drug development discovery, we can really speed this process and increase the percentage of potential therapeutic agents that turn out to be efficacious and helpful."


And that is, once again, "meaningful enough to pursue."


Valerie Neff Newitt is a contributing writer.


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