Dr. Azra Raza, Recent research, Unlimited Funding, and Philosophical Foundations
Author(s): Scott Douglas Jacobsen
Publication (Outlet/Website): The Good Men Project
Publication Date (yyyy/mm/dd): 2017/08/24
Dr. Azra Raza is a Professor at Columbia University. Here we talk about current position, growing up, acquisition of education, original dream, and more, part 2.
Scott Douglas Jacobsen: What is your most recent research?
Dr. Azra Raza: 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.
Jacobsen: If you had unlimited funding and unrestricted freedom, what research would you conduct?
Raza: 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.
Jacobsen: What is your philosophical foundation? How did it change over time?
Raza: 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.
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