Dr. Azra Raza, M.D.: Professor and Director of MDS Center, at Columbia University

Interviewer: Scott Douglas Jacobsen

Numbering: Issue 2.A, Idea: Women in Academia (Part One)

Place of Publication: Langley, British Columbia, Canada

Title: In-Sight: Independent Interview-Based Undergraduate Journal

Web Domain: http://www.in-sightjournal.com

Individual Publication Date: June 18, 2013

Issue Publication Date: September 1, 2013

Name of Publisher: In-Sight Publishing

Frequency: Three Times Per Year

Words: 3,865

ISSN 2369-6885

1. What is your current position?

My position is Professor of Medicine and Director of Myelodysplastic Syndrome (MDS) Center at Columbia University.

2. What positions have you held in your academic career?

I earned the appointment of Full Professor at Rush University in Chicago (Age 39).  Subsequently, the University of Chicago appointed me the Charles Arthur Weaver Professor of Cancer Research. The Department of Medicine created a Division of Myeloid Diseases, where I was first Director. I moved in 2004 to the University of Massachusetts as Director of Hematology and Oncology.  They gave me the Gladys Smith Martin Chair in Oncology. I have been in New York since 2007.  Presently, I direct the MDS Center at Columbia University.

3. Where did you grow up?  How do you think this influenced your career direction?

I grew up in Pakistan.  This greatly influenced my career and life.  Post-graduate work in Science was non-existent. I entered medical school as a tangential way of becoming involved in Molecular Biology. However, once I began seeing patients, I knew that I would never give that up.  This led me to the idea of doing translational research. When I felt ready to graduate medical school, it had become abundantly clear to me, even after those three years of clinical work, that if I stayed back in Pakistan, I would not be practicing translational research, but would have no choice other than to become an activist. The conditions under which an impoverished population faces disease are such that one has few other options. I felt that way. Here, I came to understand my primary duty – sincerity to my passion: Science.  In a way, I took to heart the advice of Polonius to Laertes:

“This above all: to thine own self be true,
And it must follow, as the night the day,
Thou canst not then be false to any man.

(Shakespeare, HAMLET, Act I, Scene III).

4. Where did you acquire your education?

Pakistan.

5. What was your original dream?

I became obsessed with ants at a very young age, maybe 4 years old. I used to lie for hours and watch them zip in and out of their little holes in long hot summer afternoons in Karachi and imagine their lives. I constructed imaginary homes for them and social lives complete with romance and all. As I grew and read about biology, I obsessed over Darwin and Freud. In fact, I obtained the first position in my pre-medical examination by scoring high during the viva part of the test, when I engaged the external examiners in a heated debate over Darwinian versus Lamarckian theories of evolution and showing why I was a die hard Darwinian at the ripe old age of 16. If I had grown up in the West, I feel confident I would be a scientist, and not a physician, but I had no way of following my dreams there.  Medical School was the only option to study Biology.  So I went to Medical School.

6. What have been your major areas of research?

I have focused extremely on studying the biology and pathology of myeloid malignancies since the start of my career, even before I started my Residency. This happened because I had come to the US soon after graduation from Medical School and had six months before the start of my Fellowship.  I started working at Roswell Park Cancer Institute (RCPI) in Buffalo New York, where I started working with Acute Myeloid Leukemia patients. On completion of my Residency, I returned to RPCI for my Fellowship and stayed on as a faculty member for another 6 years. During this period, I had an experience with a patient who had acute myeloid leukemia (AML) which had evolved from a prior MDS or a pre-leukemia.  This made me interested in MDS. As a Fellow and young Faculty member, I defined the Cell Cycle Kinetics of Myeloid Leukemia cells in vivo in both MDS and AML by developing a novel technique of studying cellular proliferation directly in patients. These studies led to a startling revelation that the low blood counts in MDS patients were not because of bone marrow failure. Rather paradoxically, the marrow was in a hyper-proliferative state. This led to the logical examination of rate of cell death and we were able to resolve the paradox by showing that the majority of hematopoietic cells in the marrow were undergoing a suicidal self-destruction by apoptosis. Further, this cell death appeared mediated by pro-inflammatory cytokines, especially tumor necrosis factor (TNF). Next, we treated MDS patients with the anti-TNF drug thalidomide, which produced complete responses in 20% patients. Thus, over a course of 10 years, we were able to develop biologic insights into the disease that translated into a novel treatment strategy.

7. What is your most recent research?

I remain completely focused on understanding the Etiology and Biology of MDS and now use the latest genomic technology to interrogate the pathology of these diseases. With the enabling technology, this whole field has become extremely productive and exciting. We are using exome sequencing, RNA Sequence and global methylation studies to carefully study large numbers of patients to identify new drug targets in MDS cells, and hopefully develop novel non-toxic therapies for these malignant diseases of the elderly.

8. If you had unlimited funding and unrestricted freedom, what research would you conduct?

My commitment is to therapy driven research.  How can basic molecular research improve the outcome for my patients? I feel strongly that many effective drugs already exist to treat common cancers, but we do not know how to use them intelligently. Instead of tailoring therapy for individual patients, we blindly treat many with the same drug with the result that 20-30% patients respond.  Usually, we do not know the responders.

The goal would be to match the right drug to the right patient.  A goal for which we need detailed cellular signalling and molecular information. Basic concept: it seems that while multiple signalling pathways that start proliferation in normal cells, cancer cells become addicted to a particular pathway. These pathways of addiction differ between patients. It is critical to identify which pathway a particular patient’s cells are addicted to and then devise ways of interrupting it. If I had unrestricted funding, I would start a dedicated program to perform detailed genomic and methylation studies described above on every patient at diagnosis. Hopefully, this would eventually help identify the vital signalling pathways in individual patients. With this information available, the elegant concept of Synthetic Lethality can be applied where drugs or natural compounds are identified that can interrupt the particular pathway to which the cell is addicted and cause it to stop proliferating. So my dream research revolves around individualized targeted translational research. I would like to give one example here. In a recent patient, we identified a mutation that leads to over activity of the b-catenin pathway of proliferation. I was planning to treat the patient with a monoclonal antibody against TGFb, which is in trial at the MDS Center. However, it turns out that one of the checks on the b-catenin pathway is TGFb. In other words, if I had not performed whole exome sequencing on the genome, I would have treated the patient with an agent that would likely have worsened the disease by allowing the b-catenin to run amok with no checks at all. This information alone, which is the direct result of using genomics is probably life saving for the patient. In addition, we found that one possible way of interrupting the b-catenin may come from using small molecules that interrupt this pathway.  Several of them being in trials in humans already, and also that Vitamin A (all trans-retinoic acid or ATRA) could do the same. In short, we saved the patient from getting a potentially harmful agent.  Additionally, we may have found a perfect treatment for individualized therapy, which is a vitamin! This is my dream research if I have all the resources at my disposal.

As a second dream project requiring unlimited resources, I want to describe the Virome or viral make up of every MDS patient. The goal is to identify all endogenous and exogenous viruses that have become part of each patient’s genome and see whether any of these could have the label of causative. After all, cats regularly get MDS.  In their case, the disease is because of the Feline Leukemia Virus. Practically every cat is infected with this virus, but only a handful get MDS.  There must be
other co-factors involved in MDS causation. Defining the Virome would help all of this research.

9. What is your philosophical foundation? How did it change over time?

Humanism dictates the foundation of my philosophy.  However, the practice and ultimate goals have undergone subtle changes over time. In my formative years, I felt more interest in dedicating myself to grander themes. For example, believing that the thinking and work of a few can change the lives of millions (penicillin is a prime example), I became consumed with a desire to find the cause and cure of cancer. Whether I would ultimately achieve it or not, at least I was ready to dedicate my life to the pursuit of this goal. With age, and one hopes, some level of maturity, the issues for me have transformed to more immediate and individual goals. Human conduct is connected by a series of incidents where one act is the result of another. This necessitated a philosophy that requires a dynamic accounting of one’s knowledge, desires, and deeds, and then to harness these in the service of humanity with humility and forbearance. In other words, instead of the grand designs of curing cancer for many, each individual patient has acquired a special place in my life and caring for their every physical, emotional, and psychosocial need has become far more important. This by no means indicates that my obsession to find the cure for cancer has lessened, but it means my focus shifted from many to one, from cancer patients to Mrs. X, Y, or Z. It is similar to Salman Rushdie saying in Midnight’s Children: “To understand one human, one has to swallow the world.”  For me, the road to understanding and treating the disease is through grasping individual variations at the clinical level and caring for each patient as a special case. Of all the philosophical ideologies, humanism remains mine, but with an altered vision over time about how best to conduct myself in a manner that would be faithful to its basic principles.

10. What do you consider the controversial topics in your field? How do you examine the controversial topics? What do some in opposition to you argue?  How do you respond?

In the current atmosphere of cancer research, researchers study the evolution of a cancer cell rather than its etiology. In at least a subset of patients, I have hypothesized for about two decades that MDS may begin as a viral disease. I committed a form of professional suicide by presenting very early work related to this hypothesis at an MDS Foundation meeting held 19 years ago in Prague. They have not invited me back to that meeting in the last two decades. I learnt a tremendous amount from this experience. For one thing, I became more self-critical and stringent in examining our own data. For another, I started collaboration with the top virologists in the country (Drs. Robert Gallo, Don Ganem, and Joe DeRisi). Finally, it made me more committed to finding the proof for my hypothesis.  In that, instead of throwing up my arms in frustration, by persisting in our search for a virus, we are taking full advantage of next generation sequencing to identify non-human elements in the human genome and re-construct viruses from these pieces. The technology has reached a point where we are poised to unravel possible new retroviral sequences from the RNA Sequence data we have generated.  This will still be only half the battle. The important study will be to prove the etiologic relationship of the pathogen to the MDS under study. This is where all the controversy creeps in again because the pathogens are often known organisms and no one is ready to believe they are the agency for causing the malignancy. Remember that to prove that helicobacter pylori was the cause of gastric ulcers, Barry Marshall had to swallow the pathogen and nurse ulcers in his own stomach before anyone would believe him! (Eventually, he got the Nobel Prize). Now we know that this bacterium is the cause of many stomach cancers. So, in my opinion, the etiologic studies remain extremely controversial and many a career has been sacrificed on the altar of virologic basis of malignancy. I nearly lost my career, but have been able to survive – thankfully.  I continue my studies in the area, always trying for that moment:

“Chance will strike a prepared mind”

11. What advice do you have for young MDs?

A life without work is a life without worth, and this work should be done for the good of mankind as well as for one’s own good. Last year, I was fortunate to win the Hope Award for Cancer Research and in my acceptance speech; I gave advice to my 18 year old daughter which I wish to quote for the young MDs:

“At the risk of being a spendthrift of my own celebrity, I want to address my teenage daughter who is a sophomore at Columbia University and like her parents, plans on a career in science and medicine. You might be wondering why I have to use the 3 minutes allotted to me to do so in this room…well, as Nora Ephron once said, “When your children are teenagers, it’s important to have a dog so that someone in the house is happy to see you.” Actually, it is for two reasons…first because she is a captive audience and second because of the presence of all of you in this room and what this moment means and how indelibly what I say today may be etched on her brain. Sheherzad, as a result of several decades of experience and observation, I have narrowed down the formula for personal success to three cardinal rules: find your passion, find a mentor and then give it everything you’ve got.  However, there is a different kind of success, one which many in this room epitomize. As living beings, we know that death will come inevitably, but thankfully, we do not know the hour of our death. What goes through the hearts and minds of souls who have received a diagnosis of cancer and hear the footsteps of death approaching closer every day? Theirs are the heroic stories of hardiness, ingenuity and resourcefulness. Some of us have the privilege of witnessing on a daily basis, the remarkable dignity with which they face their ongoing ordeals. You have decided to join the ranks of these privileged caregivers. As a little girl from age 3 to 8 years, you have already witnessed your father go through a losing battle with cancer. When faced with such human suffering, your qualifications, your CV or your degrees do not help. What helps is your heart, your sensitivity to feel the pain of others. On this special day, realize that you are fortunate to be in a room full of such compassionate and deeply committed individuals, realize that you will not need magic or miracles to help your patients but you will need serious scientific research and deep sensitivity to their anguish and suffering. Today, I use the honour bestowed upon me through this award to urge you to pledge that even as you will strive for excellence and follow the three rules to guarantee success in your personal life, you will never forget the dues you owe to the patients you will be caring for very soon.”

12. Whom do you consider your biggest influences? Could you recommend any seminal or important books/articles by them?

As far as my personal life is concerned, I am a reader of classics where the themes are grand, the language is noble, and the message is startlingly fresh for all times. When my husband Harvey Preisler died after a five year long battle with cancer, the way I dealt with the loss was to read (and re-read in most cases) the 100 Great Books of the Western Literary Tradition starting with Euripides and Aeschylus and working my way to Rushdie and Morrison. In this, my biggest influences have been the great authors. I feel deeply moved by poetry.  My favorite poets are Shakespeare, Dante, Milton and Ghalib. I come from an oral tradition and committing poetry to memory was a given for as long as I can remember. Currently, I am memorizing the entire 33^rd canto from Dante’s Paradiso during my morning runs. I feel profoundly affected by the thinking of these poets and have translated and interpreted (with my co-author Sara Goodyear) Ghalib’s Urdu poetry for our English speakers in a book, Ghalib: Epistemologies of Elegance. Among the American writers, the books of fiction I admire most are Melville’s Moby Dick and Morrison’s Beloved. Among the Europeans, it would have to be Cervantes’s Don Quixote and Dostoyevsky’s The Brother Karamazov.   Finally, in non-fiction, my two favorite books are both autobiographies called The Confessions written 1000 years apart by Augustine and by Rousseau.

As far as my professional life is concerned, the biggest influence comes from patients.  In particular, I had an encounter starting me on the path to dedicate my life to MDS, when I was barely 30. Here is a short accounting of that episode:

I had just finished my Fellowship in Medical Oncology at Roswell Park Cancer Institute in Buffalo, New York. A beautiful, young 32 years old woman was admitted with a diagnosis of acute myeloid leukemia (AML). The story she gave was rather peculiar. She had become pregnant almost two years before this admission with twins. During the pregnancy, she developed a fetish to smell gasoline. Most days of those nine months, she would go to the corner gas station, buy a dime’s worth of gasoline and smell it all day.  At the end of nine months, she delivered a healthy set of twin daughters, but six months later, she was found to have low blood counts.  Over time, a diagnosis of MDS was made. This was probably in some part at least, related to the toxic exposure she had experienced from smelling gasoline. In any case, there was no treatment for MDS at the time, and she only received supportive care with blood transfusions. Six months later, the disease progressed to AML and that is when she came to see us at Roswell Park.

We gave her high dose induction chemotherapy, to which she responded well and after a rather stormy course, entered a complete remission six weeks later. How sweet it was to see her going home with her lovely daughters at the end of this therapy! We then gave her three courses of standard consolidation therapy.  She did well. During these repeated hospitalizations, and interim outpatient clinic visits, we became very close to each other. During each encounter, we talked to our hearts’ content, and JC shared many of her personal anxieties with me.  I learned to appreciate the challenges of a schizophrenic life torn between fighting a potentially lethal illness at the ripe age of 32 while pretending to be a normal mother to 3-year old girls. At times, it felt heart breaking.  At other times, the sheer force of her courage and sublimity of human spirit was brought home with incredibly graphic detail.

Courage takes many forms. There is physical courage, there is moral courage. Then there is still a higher type of courage; the courage to brave pain, to live with it, to never let others know of it and to still find joy in life; to wake up in the morning with an enthusiasm for the day ahead.

After stopping the final round of chemotherapy, JC returned to her normal life.  She got caught with the daily routine of raising 3-year old twin daughters. Unfortunately, after a year and a half of remission, her leukemia relapsed, and this time around, none of our therapeutic approaches seemed to make much of a difference to her resistant leukemia. She developed a fungal infection of the lungs too. We were not able to give her any chemotherapy for fear of making the fungus spread faster. At this time, she made a wish to be admitted to the Hospital for her terminal illness as she did not want her daughters to be frightened unnecessarily. With a heavy heart, I took her in. It was instructive and astonishing to watch her face almost certain death with such unparalleled grace and equanimity. I noticed on my daily rounds was that she would be writing furiously. Finally, I mustered enough courage to ask her one day, “JC, what are you writing?” The answer she gave me changed my life forever. She said, “I am writing letters that I want my twin daughters to open on their birthdays. I have reached their twelfth. Keep me alive till I reach their twenty-first”.

Alas, we could not keep her alive for the few days she had asked for. I went home that day.  I told my husband that I should study MDSs because this stage precedes the development of acute leukemia in a number of patients. Maybe, I could have saved JC, if I had treated her at the MDS stage of her disease. My idea was that the molecular and genetic lesions in frankly leukemic cell are too complicated. Perhaps, it would be better to start studying the biology of these cells at an earlier stage of the disease, say as in JC’s case when it was still MDS. If we follow the course of the disease and study serial samples, it may become possible to identify the sequence of events that convert a normal cell into a leukemic one. Another advantage of studying MDS would be that if we could effectively treat the patient at this earlier stage of the disease, then the patient would never evolve into the potentially lethal acute leukemic phase. Finally, I felt that at the MDS stage, the drugs required for treatment may not be as toxic as those needed for the acute leukemia stage. For all these reasons, back in 1984, I decided to dedicate myself to the study and treatment of MDS along with my continuing research in acute leukemias.

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