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Mahendra Rao: Taking it All in

Whether ascending slopes in a pair of hiking boots or descending them on skis, Mahendra Rao is creating a path and renewing his perspective. His approach to stem cell research has taken a similar course. From stints in academia, industry, regulatory affairs and government, he has gathered more than 20 years' experience for his next endeavor with the National Institutes of Health.

 

While he doesn't get as much time as he would like to recharge from the day's work and a busy travel schedule, 2012 SLAS Asia Conference and Exhibition keynote speaker Mahendra S. Rao, M.D., Ph.D., does try to make time for physical activities such as hiking and skiing – lifelong passions that grew when he lived in Utah's panoramic ski country.

"For me, physical activity has always helped clear my mind and get me away from what was happening on the bench," Rao says. "Where I worked in Salt Lake City, the ski slopes are very close to work. You could set up a gel, for example, in the morning and go up skiing for a half day. You come back later and finish the experiment. It was great to be able to do that. Doing something completely different is good – cooking, playing Sudoku, doing the crossword – anything that can distract me from focusing too much and getting too caught up in work."

He has good reason to explore mind-refreshing pursuits. Since his August 2011 appointment as director for the new National Institutes of Health Intramural Center for Regenerative Medicine (NIH-CRM), Bethesda, MD, Rao's perspective is likely from the window of a jet taking him to meetings and appointments around the world. He is internationally renowned for his research involving human embryonic stem cells (hESCs) and other somatic stem cells.

The NIH-CRM is an initiative to create a world-class center of excellence in stem cell technology on the NIH campus; this includes induced pluripotent stem cells (iPSC), which can have applications in many systems and organs of the body. An initiative of the NIH Common Fund, the NIH-CRM is administered by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). NIH Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research.

NIH-CRM plans to build upon existing NIH investments in stem cell research to advance translational studies and ultimately cell-based therapies in the NIH Clinical Center. The center also serves as a resource for the scientific community, providing stem cells, as well as the supporting protocols and standard operating procedures used to derive, culture and differentiate them into different cell types. In addition to his NIH-CRM director position, Rao holds a joint research appointment in NIAMS and the National Institute of Neurological Disorders and Stroke (NINDS).

For Rao, the NIH position is a return to familiar territory. His previous work included a position as chief of the Neurosciences Section for the National Institute on Aging (NIA), where he studied neural progenitor cells and continued to explore his longstanding interest in their clinical potential.

"I was really lucky at that time to be recruited into the NIA," he comments. "NIA had launched a whole genomics program and was going to conduct large-scale analysis. For me it was a logical fit that we had a new cell type, had expected to grow it in a purified form, and we would now have access to a lot of technology."

The NIA position also offered an opportunity to be there in the beginning to analyze data and view it in a high-throughput fashion by using early editing and sequencing technology. "Because we had early access to unique cell types, people wanted to work with us and share the new technology they had. You can see how it was being in the right place at the right time," he says, adding, "We recognized that we had some unique skill types that allowed things to work together."

Rao's career has been more than government appointments. Most recently, he spent six years as the vice president of Regenerative Medicine at Life Technologies, Carlsbad, CA. He also co-founded Q Therapeutics, a neural stem cell company based in Salt Lake City, UT, that develops novel products to treat debilitating and often fatal diseases of the central nervous system. The company's initial product, Q-Cells, was designed to treat diseases such as multiple sclerosis, transverse myelitis, ALS (Lou Gehrig's disease), cerebral palsy, spinal cord injury, traumatic brain injury, stroke, Parkinson's disease and Alzheimer's disease.

Rao also served internationally on advisory boards for companies involved in stem cell processing and therapy, on committees that include the U.S. Food and Drug Administration's Cellular Tissue and Gene Therapies Advisory Committee, as chair, and as the California Institute of Regenerative Medicine and International Society for Stem Cell Research liaison to the International Society for Cellular Therapy. In a way, it was as if he was digesting as much of the stem cell field as possible in preparation for the NIH appointment.

"The NIH knows that stem cells are a cross-disciplinary field. It's moving forward rapidly in terms of translation electivity," he says. "An NIH goal was to appoint a professional with broad experience in the field."

The Right Place, the Right Time

Many instances of his career Rao describes with the familiar phrase "being in the right place at the right time," but the decision to go into research was something he actively pursued.

"I was all set to become a neurologist, and I practiced neurology as a resident for two years," says Rao. "It was great. One could make a diagnosis, but there was nothing you could do to cure something. I decided that I needed to do research."

His advisors told him at that time that developmental biology was important in understanding how the brain was formed. Armed with this information, Rao launched work on a Ph.D. in developmental neurobiology at California Institute of Technology, Pasadena. "Each time you looked at development, you found that you had to go back earlier and earlier in the development until you reached early stem cells from tissue. My goal was to try to harvest enough cells from early progenitor cells or stem cells to be able to do transplant studies and studies on diseases for which we had no other therapy. I joked that I became a stem cell biologist before stem cell biology was fashionable," he says.

He has remained in the field because he finds it fascinating. "For me the most important thing was when I decided to do research. Most clinicians tend to do clinical trials and study things with which they are comfortable. I decided to do a Ph.D. and chose to go to a college that did not have a medical school attached to it. There was no choice; you had to work in basic science. I was really lucky that I was admitted to Caltech, which, in my mind, was a premier institute. They took a gamble on this guy who had no research experience."

His skill in culturing cells, paired with his interest in stem cells and basic biology questions opened doors. He describes how an opportunity to lecture at Geron, a biopharmaceutical company that was seeking advisors in embryonic stem cell work, gave him access to technology and science he would not have had otherwise. "That talk and collaboration with that company further led me to do things that would have been difficult to do at all," he says.

A Family Tradition of Higher Education

Expanding the educational horizon was a family tradition. Rao's father was a pharmacist and his grandmother was the first Indian woman to earn a degree in English literature while in residence at Oxford College.

While the young Rao knew the family expectation for academics, this did not keep him from holding other interests. As a seventh grade student, Rao admits he had a tendency toward sports, not academics. "I wasn't a hard working student," he laughs. That changed when a wise middle-school teacher decided that Rao needed a challenge to jump-start his potential. He was expected to earn one of the top grades on each assignment or lose points.

"He told everyone in class that he was giving me a handicap in math. It was hard, and I thought it was unfair, but it really pushed me to do something. I really thank him for that. I think I really needed some discipline," Rao explains.

Fortunately, scholarly pursuits took root. Prior to the Ph.D. he earned in developmental neurobiology while at Caltech, Rao earned an M.D. from Bombay University in India. Following postdoctoral training at Case Western Reserve University, Cleveland, he established his research laboratory in neural development at The University of Utah, Salt Lake City.

Relating to the SLAS Community

These experiences make it easy for Rao to relate to the SLAS community, which he perceives as trying to achieve a broad set of goals while working across disciplines. "SLAS is looking at instrumentation and automation and trying to bring together the whole discovery pipeline in some fashion. For me, that is really exciting in terms of what we are trying to do in translational work as well. You need to put together these types of teams and get the expertise from specific parts of the scientific community to be able to work together," Rao says.

He sees an overlap between what the SLAS community is working on and the work of the NIH, particularly in the screening activity. "Everyone is considering a useful direction to go. There are new paradigms in screening that we need to consider given what we can now do that we couldn't do four years ago," he states. These things include making differentiated cell types from any tissue and from any patient who carries a mutation of a particular disease disorder.

"Now we can retrospectively get cells from someone who has a clinical history so we can marry function with the assay, which we couldn't do before," he explains. Another element is genomic repetition, which has reduced the cost of sequencing and sufficiently gathered the whole genomic expression.

"Now you can combine drug screening to get to the mechanism of action with the large scale genomic and proteomic methodologies that we have. Those are fundamental changes in the way that one would do screening," Rao says. "That's going to be important and a challenge for the community. We need to think about how to plan for it."

Rao's keynote address, "Stem Cells for Regenerative Medicine," will be presented during the 2012 SLAS Asia Conference and Exhibition, with the theme of "Advances in Drug and Life Sciences R&D through Laboratory Technology," at the Grand Hyatt Shanghai, China from June 19-21, 2012. Rao expresses that the conference will be a good platform for his message with an audience that is well-suited to receive it.

"I am going to talk about why we need to start thinking about a new paradigm of how to screen and what will be the issues in doing that," he comments. "The big thing is that SLAS, like NIH, also seems to recognize that we have two major issues: Employers don't always train people correctly for the kind of screening and translational activity that needs to be done, and this work requires a wide variety of people to work together. The NIH thinks that this is its primary effort in trying to facilitate translation. We are looking to societies, foundations and groups to help us with making sure these sorts of infrastructure and structural things happen. It can't be done by employers alone."

The Beauty of Creative Thinking

Like hiking and skiing, sometimes moving through the open vista of the mind is refreshing and stirs imagination. Rao mentions that his time spent at Caltech was one of the primary influences on his life and career. In particular, he appreciates the funding of one of the school's donors who wanted students to explore and be creative.

"He set aside a certain amount of money that could be used to do whatever experiment you wanted, whether it was part of your Ph.D. thesis or not. It was not a lot of money, but it was great to have somebody trust you enough to be able to say, ‘it's your thought process and it's your experiment.' It was a huge incentive to think of something elegant to do."

This grant led to one of the first papers Rao wrote and, more importantly, he explains: "It taught me that you have to be willing to take risks. Sometimes you're not willing until you see someone having that kind of trust."

He extends the same trust to students working in his lab. "I tell them: Do whatever project you want; you just have to tell me why you are doing it, and you have to be convincing. I will support you in what you are doing," he explains, adding that this has been a useful approach. His other advice for students and professionals alike? Pursue your passion.

"There are always problems. There is never enough money, there are not enough jobs, industry is cutting down just as you are ready to graduate. Often students ask me if they should change and do a different kind of experiment or whether their training should be different. I tell people: You can't chase what looks good right now. You have to do what makes you happy. If you do that well, opportunity will be there. It's like a Catch 22. You can never do things really well unless you really enjoy them and are passionate about them. That's what makes you happy. If you try to do something else simply because you think that it will make you more money or that it is an easier path, you are never going to be happy enough or committed enough to be able to work hard at it."

June 1, 2012