Radical View | March 2019

Prabhat Goswami, Ph.D.
The University of Iowa

By Ines Batinic-Haberle, Ph.D., Duke University

DOT: When you look backwards as well as ahead, do you feel happy/fulfilled with what you are presently doing, or you would like to explore another topics within redox biology or perhaps out of this field? Do you have any large goals that you have not yet had time to accomplish?

It was certainly not an easy path integrating two independent fields of research: redox biology and cell cycle biology. But I was lucky to have guidance from outstanding academicians who foresaw the significance of the research areas that I am trying to advance. In our profession, we always have additional goals and interests that for one or another reason we had to put on hold for the next available opportunity. I had my training in organic chemistry and then transitioned into biology. If I have the time and resources, then I would like to pursue redox biology of natural products and their effects on aging and cancer therapy. Another area of research that I would like to advance would be that of the redox control of post-transcriptional regulation of gene expression, something that I worked on 25 years ago.

DOT: When did you start to realize that you want to be a scientist?

Growing up in rural India, I did not get exposure to the different career pathways one can take after finishing your education. If you do well in school, it was predetermined that you would eventually follow a medical or engineering path.  My interest in the scientific field didn’t fully develop until I was in college. My college chemistry professor introduced us to Organic Chemistry through a lab experiment where we were given a protocol to synthesize salicylic acid (aspirin). I was fascinated to observe the formation of beautiful needle shaped crystals in the reaction flask. This experiment introduced me to a new way of looking at the world around us, and I wanted to continue to learn how science is integrated into our everyday lives.

DOT: What are the challenges you faced in your transition from an undergraduate and graduate training outside the USA to a postdoctoral position and professorship in the USA? What are the most important aspects of this transition and how did you overcome them?

This is an interesting question. It was not an easy transition, mostly because of people’s perception (reviewers included) of researchers outside of their specific field of expertise as well as the perception of foreign researchers. I can’t imagine how the basic science knowledge I gained in my undergraduate and graduate training in India is any different than what I see my students learning here. Even at this stage of my career, “foreign trained” is a common bias that creeps into the reviews of my research applications.

I view self-confidence and a willingness to work hard to overcome my weaknesses as the most important aspects of my professional success. I am thankful to my mentors and laboratory colleagues for their patience and time teaching me laboratory techniques that I was not familiar with. I put forth more effort to understand those unanticipated results from well-designed experiments. This curiosity led me to the discovery of the existence of “a redox cycle within the cell cycle”. I tell my students to pay special attention to those unanticipated results in their experiments. Very often, those are the results that may lead to new concepts and discoveries.

DOT: What was your most crucial life experience that greatly affected your present career? What is the reason you became a scientist?

My career growth would not have been possible without the guidance and care of my postdoctoral mentor, the late Professor Leonard Tolmach at Washington University in St. Louis, and my faculty mentor the late Professor Larry Oberley here at The University of Iowa. I learned old school cell cycle biology from Len and integrated a molecular biology approach into it. Larry introduced me to the redox biology and chemistry field. He used to comment, “Find out what MnSOD has to do with your cell cycle”. The knowledge that I gained from Len and Larry helped me to integrate the field of redox biology and cell cycle biology, which led me to the discovery of “a redox cycle within the cell cycle” that integrates cellular metabolism to cell cycle progression. Additionally, I am very fortunate to work with an outstanding group of scientists at The University of Iowa.

My parent’s support and confidence in me as well as the scientific training I received from my graduate, postdoctoral and faculty mentors inspired me to pursue a scientific career.

DOT: What has been your most exciting reserch discovery so far?

I consider discovery of the presence of “a redox cycle within the cell cycle” and “chronological lifespan” as the most exciting events of my scientific career. I was studying molecular mechanisms regulating the expression of Topoisomerase II (Topo II) in response to treatments with ionizing radiation and heat shock. Topo II is a molecular target for cancer therapy. We observed that expression of Topo II is specific to the G₂and M phases of the cell cycle. Its expression during the cell cycle is primarily regulated by redox-sensitive binding of proteins to specific RNA sequence-motif in its 3′-untranslated region. Although redox-control of transcription factor activities (e.g. AP1) was known at that time, we were the first to report post-transcriptional regulation of a cell cycle gene that is redox-sensitive. These exciting results led us to query whether the cell cycle itself is redox regulated. These efforts led us to the discovery of the presence of a “redox cycle” within the mammalian cell cycle that integrates cellular metabolism to cell cycle progression. The redox cycle is regulated by post-transcriptional (transcript selection) and post-translational (methylation/demethylation) modifications of manganese superoxide dismutase (MnSOD). MnSOD activity regulates a ROS-switch controlling cellular proliferation: superoxide signaling promoting proliferation and hydrogen peroxide signaling supporting quiescence.

Our research related to cellular aging led us to the discovery of a new mode of aging, “chronological lifespan”. Chronological lifespan is defined as the duration of quiescence during which normal cells retain their capacity to re-enter the proliferative cycle. This mode of cellular aging is independent of mitotic division and telomerase activity, but dependent on cellular redox tone. Normal cells nearing the end of their chronological lifespan exhibit a lower bioenergetics health index, which correlated with significant increases in the steady-state levels of ROS and changes in mitochondrial morphology. An age related decrease in bioenergetics health index was associated with a shift in metabolism from glycolysis in cells from young donors to mitochondrial respiration in cells from older donors. Additionally, our results showed that maintenance of a higher MnSOD activity extends chronological lifespan and delays age-related changes in mitochondrial morphology. We posit that because a majority of normal cells reside in quiescence, our discovery of a chronological lifespan will be of high significance to a mechanistic understanding of aging of normal cells.

DOT: What direction do you think the Redox Biology and Oxidative Stress field is going? Is it going the way you would like; would you offer some advice, directions to be explored? 

Biology is complex and redox is an integral component of both normal physiology and pathological processes. Other disciplines are slowly but steadily embracing redox biology into their research portfolio, at least as a sub-aim in their research applications. In my opinion, the ubiquitous use of the vocabulary “oxidative stress” often confuses readers and reviewers outside of our field. It is very common to hear others commenting on how could the same “oxidative stress” control normal physiology yet having adverse effects. I strongly believe a change in generic vocabulary will alleviate this concern.

I advocated for the use of new vocabulary at the 21st SfRBM Annual Conference in Seattle. I proposed that we should use “eustress” (aka “oxidative eustress” in recent literature) when discussing redox processes that regulate normal physiology and “oxidative stress” (aka “oxidative distress” in recent literature) for redox processes that regulate pathology. The famous Hungarian-Canadian endocrinologist, Hans Selye, first introduced the vocabulary “eustress”, which consists of the Greek prefix “eu” (meaning good) and stress, literally meaning "good stress." We proposed that normal cellular processes such as cell cycle progression are controlled by eustress (oxidative eustress) whereas aberrant proliferation (as seen in cancer cells) is a consequence of oxidative distress.

It is possible that this dual function of redox reactions in oxidative eustress and oxidative distress could be due to the difference in the concentrations (threshold), pulse duration (flux) and subcellular localization of oxidants and antioxidants as well as cell types. I strongly believe that advances in the quantitative redox chemistry and biology research will resolve many of these intriguing questions in the very near future. In my opinion, research in quantitative redox biology of oxidative eustress and oxidative distress will be an important future direction to pursue.

DOT: What do you see presently as “hot” areas of redox biology/oxidative stress?

In my opinion, resurrection of metabolism is a “hot” topic of research currently. Because metabolism and redox biology are intertwined, let us take this opportunity to further advance our knowledge related to redox chemistry of biological processes to promote a healthy lifespan.

DOT: Do you think that pressure due to present shortage in funding affects how freely we exchange our results and thoughts, and therefore precludes fruitful, sincere and productive research environment?

Certainly, shortage of funding impacts our progress and often restricts exchanging our results and thoughts. We all probably have a story to tell about being “scooped.” In my opinion, being “scooped” is not the end of one’s scientific career. I think we can minimize this fear by encouraging more open communication among our peers. Every program has their own format for presentation of research activities, research seminar series, etc. Research personnel and mentors from every lab need to present their research at these regularly scheduled forums. The feedback from these presentations will significantly help advancing one’s research rather than hinder progress. Let us promote good science.

DOT: How do you achieve balance between your personal and professional life?

It is hard. I am very fortunate to have lots of support from my wife and children. They recognize the challenges and time commitment of our profession. I think I am a dedicated husband and father, and enjoying both aspects of my responsibilities and care. I am a dedicated husband because I took my wife to India numerous times to visit her family and continue to keep in touch with her Indian heritage. For my kids, I attended most of their school and outdoor activities. I attended all those parents-teacher conferences, parent’s day and even grandparent’s day. My children were not at all happy when I showed up during their school’s grandparent’s day. Like their friends, our kids were expecting to see their grandparents and not me. Living so far away from India, I had to fill the role of both parent and grandparent.