Chapter 04: A Fellowship and a Risky and Successful Study of Cell Differentiation
In this chapter, Dr. Dmitrovsky talks about the research project that would set him on the path to discover the effectiveness of retinoids in treating acute promyelocytic leukemia. He begins by noting that at the end of his residency, he had decided to focus on hematology/oncology and took a Research Fellowship ('83 " '86) at the National Cancer Institute, Navy Medical Oncology Branch, in Bethesda, working with Dr. Ilan Kirsch. He explains why he enjoyed working with patients with terminal disease during the initial, clinical, year. Next, Dr. Dmitrovsky explains that, at the time, he still believed he would enter private clinical practice. This is the reason that he took on a risky research project during his final two years of protected laboratory time. He explains that the study was to use dimethyl sulfoxide (DMSO) to influence the role of the c-Myc oncogene in controlling leukemic differentiation (how undifferentiated cells become differentiated and capable of malignant growth) with the intention of developing treatments. He explains the technical challenges of conducting this study (the primary reason why all the other fellows at the NCI had declined the project). He talks about the success of the study and the discovery, after publishing the results in Nature, that two other groups had reached the same results, a fact that convinced him of the role of serendipity in scientific discovery.
The Interview Subject's Story - The Researcher; The Researcher; Discovery and Success; Overview; Definitions, Explanations, Translations; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care
Ethan Dmitrovsky, MD:
[So based on that experience, I decided to devote myself to oncology as a career, and then, in part because of the Alsop book that had always intrigued me, I did my fellowship at the National Cancer Institute in Bethesda.] I still felt that I would probably spend my time as a clinician full-time and didn't feel I had innate skills as a researcher, because it doesn't come naturally or easily to anyone. And I knew that it would in order to be versed, in order to see whether I would have the skills I knew it would take a number of years to become trained. So what I'm saying is I've fully trained as a physician, and then say, "Well, I'll try to devote an intensive period of my career to learn about science and to see if I would have the ability to make contributions in that space.And so after a very intensive clinical year, you are given two years of what's called protected time very focused time in the laboratory. And since I felt that I would most likely become a practicing doctor, I was willing to take on ambitious project, because I felt that, since I was going to go into practice anyway, it wouldn't be that much of a risk for me. So the project that I took on I didn't know at the time was a project that had been offered to every postdoctoral fellow in the group, and the greater group was, oh, probably thirty-five people. And I was not told that everyone rejected the project. It's a truthful story. It's not a story, I guess. It's the truth. So the project, in a nutshell, was there was a prevailing view, a hypothesis I came of age, for want of a better word, as a physician- and scientist-in-training right when oncogenes were discovered. And one of the early hypotheses of oncogenes was that one cancer would each cancer would have a different oncogene, or cancer-causing gene, and so this is even before tumor suppressors were discovered. People were interrogating the functions of oncogenes, and so I was asked to study a very well-described model of a leukemic differentiation leukemic cell differentiation where, when a drug called dimethyl sulfoxide, also known as DMSO, was given in culture to these mouse erythroleukemia cells, startlingly, a discovery made by Charlotte Friend then at Mount Sinai she found that these white leukemic cells became red because they produced hemoglobin, meaning the undifferentiated erythroid cells became mature and differentiated, so you could actually see a white pellet become red. And intriguingly, one of the earliest oncogenes ever discovered called the c-Myc C hyphen M-Y-C oncogene precipitously declines after DMSO treatment within a few minutes, and then rapidly rose. And there was a theory that that might be a signal to cause the differentiation. So the idea was to reconstitute the expression of the c-Myc oncogene, prevent the fall, and then treat with DMSO. And would the white cells remain white, or would they become red? That is, would the non-hemoglobin-producing cells be prevented from becoming hemoglobin-producing? And if it were a signal, then that would be the hypothesis. And so the reason it was a challenging project is that these were so-called "floating cells.They didn't adhere to the tissue culture plates, and the technology to transfect floating cells is only evolving at that point, and it turned out it was very difficult to transfect. So there was a new technology that was called electroporation electro, E-L-E-C-T-R-O, poration, P-O-R-A-T-I-O-N and also other forms of transfection. That is a process of taking DNA and putting it into recipient cells, in this case, the c-Myc oncogene. So we did do the experiment, and it did succeed, and it did block differentiation. The white pellets stayed white. And we, since this, at this point, was a very no pun intended visible result, we decided to send it to Nature, and it was accepted. So that was my second project in science. I had a first authorship in the journal Nature, which was a really interesting experience for a lot of reasons. One is that when it came out in the journal Nature, I learned there were two other groups in the world with the exact same result, and all of these papers were published together. And we didn't know about each other, and all had the same result. Oftentimes this was a notable question that many groups were looking at, and the fact that all three groups came with the same result validated the idea that there was a signal. And you would think, with that experience, that it would give you confidence, but it actually did not, because the idea that you could come up with a reasonably attractive hypothesis, conduct the experiment, and have it succeed, and not know that there are multiple groups and we also found out later that there were multiple groups that tried to do the experiment but were not successful that you would sort of gain confidence. "Oh, you can do this, while others couldn't.Actually, that was not my reaction. My reaction was, "It was all serendipity, and it was just being in the right place at the right time.
Dmitrovsky, Ethan MD and Rosolowski, Tacey A. PhD, "Chapter 04: A Fellowship and a Risky and Successful Study of Cell Differentiation" (2015). Interview Chapters. 639.
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