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Lokvani Talks To Dr. Ram Sasisekharan

Ranjai Saigal

Ram Sasisekharan, Ph.D. is a Professor, Biological Engineering Division at Massachusetts Institute of Technology, (M.I.T.), Cambridge, MA. Ram Sasisekharan is a pioneer in sugar-sequencing research and his highly innovative approaches to studying carbohydrates and modifying sugars have the potential to yield novel therapeutics based on carbohydrates. Sasisekharan's work focuses on the role complex sugars play in the immune system, human development, and diseases such as cancer. Understanding how specific sugars bind to pathogens, or creating maps of where different sugar molecules are located on the surface of a cell, could help researchers better understand the molecular basis of diseases and design drugs that target those sugars more effectively. He has shown that the sugar jackets of cancer cells can be tailored to inhibit tumors. His powerful technique for determining the composition of complex sugars like heparin has led to a cascade of potential medical applications that could significantly impact the multibillion-dollar heparin-based therapeutics industry and improve outcomes for patients undergoing major operations such as coronary bypass surgery.

Sasisekharan obtained his Bachelors' in Physical Sciences from Bangalore University and PhD in Medical Sciences from Harvard Medical School. Based on technologies emanating from his lab, he is a co-founder and board member of Momenta Pharmaceuticals and sits on the Steering committee of Momenta Pharmaceuticals/Sandoz-Novartis Joint Venture. Dr. Sasisekharan is a member of the Steering Committee of the International Consortium for Functional Glycomics and has served on different panels of the National Institutes of Health. He is a Core Member of the Nanotechnology Laboratory and Center for Biomedical Engineering, MIT. His other activities include, being the Chief Advisor, MVM Ventures, UK, and being on the International advisory board of the Princess Chulabhorn Research Institute, Thailand. Dr. Sasisekharan has won numerous awards, including the Burroughs Wellcome Fund Young Investigator Award: Awarded to the most promising young faculty members who bring new ways of thinking and new experimental approaches to life sciences; Beckman Foundation Young Investigator Award: Awarded to the most promising young faculty members in the chemical and life sciences (this is one of the most prestigious awards or recognition for a junior faculty member in the U.S); is a three-time recipient of the CaPCure Award, awarded by the CaPCure Foundation to outstanding prostate cancer research programs and the Global Indus Technovator Award. He is a named inventor on 45 issued or pending patents and has authored or co-authored over 100 publications.

In an interview with Lokvani, Sasisekaran spoke about his work and his life and most importantly his desire to use technology to improve the lives of people.

Lokvani: How did you get interested in sugars at a time there was so much excitement and energy in the field of Genomics and Proteomics?

Sasisekharan: After my undergraduate degree in India, I came to study at Harvard University.  At that time I attended a talk by Dr. Robert Langer. I was so inspired by his talk that I decided to do my Ph.D under his guidance.  Being excited by challenges, I asked him to give me a project that others did not want to work on.. He asked me to work on sequencing—or unravel the arrangement of components in—heparinase. This important enzyme cuts up sugars in the heparin-like family, which surround all cells. I was able to solve the problem and it got me my PhD. Later I turned my attention to creating a faster way of sequencing sugars in general. While many people at that time did not see a value in it, I always had a gut feeling that understanding sugars was an importance piece of the puzzle of modern life sciences.  I am pleased to see that now , Glycomics or the study of sugars has gained a lot of attention

Lokvani:  Why is understanding sugars such a complicated problem?

Sasisekharan : The main reason is that complex carbohydrates come in many  “flavors.” Unlike a simply organized, linear string of connected units (DNA, for example), complex carbohydrates can be both linear and branched. They look something like trees, with branches big and small extending in different direction. What’s more—unlike our DNA, with its strings of  “letters ,” and our proteins , made of chains of amino acids—carbohydrates are not made from a blueprint . Rather, the body makes complex carbohydrates through a sort of community effort, via the collective work of different enzymes acting in ways that remain complicated for researchers to understand or predict.

Lokvani: What helped you succeed in developing the technology to characterize sugars?

Sasisekharan: I realized very early on that problems, such as these which are very complex, need to be tackled in a multiple different way using different approaches.  We had some key breakthroughs. Apart from conviction and drive, success in part was also to integrate the different perspectives to address the complexity of the problem. Dr. Ganesh Venkataraman, who co-founded Momenta with me and I, were able to assemble an incredible team and this was key to practically translating the technology.

You started Momenta while continuing to be a Professor at MIT. What motivated you to start a company rather than just stick to research?

Sasisekharan : I was drawn to the philosophy of translating technical contributions into something of practical value. It is one of the effective ways to impact the world. Exploiting the practical potential lets the technology be of use and hopefully make a difference.

Lokvani: At a time when there is a lot of disappointment in the promise of Biotech, Momenta has come out as a success story. To what do you attribute the success of Momenta?

Sasisekharan : Momenta has been successful going public and raising money because of the commercial potential of the technology. The business model is one where Momenta technology can be applied in a fashion leading to both near term and long term product opportunities.  While there are many applications to our work, the ability to sequence sugars can be helpful to easily understand and characterize complex molecules.  Such characterization can enable us to create generic versions of complex drugs which can be taken to the market quickly and start bringing revenues.

One example is the heparin drug class.  One of the most widely-prescribed low molecular weight heparin (LMWH) in the world, is Lovenox.  Lovenox is a heterogeneous mixture of complex sugar chains that has not been adequately analyzed to date. Under FDA guidelines, a generic product must demonstrate that it has the same active ingredients as the branded version. Momenta’s ability to sequence and analyze complex mixtures of sugars has enabled us to analyze the branded low molecular weight heparin, Lovenox, and develop a process that can be used to make a generic version that will meet the FDA requirements for generic approval. Momenta has formed a collaboration with Sandoz, a division of Novartis, to jointly develop, manufacture, and commercialize the generic version of Lovenox.

Lokvani:  What are other applications of Glycomics and what are the other areas that you work on ?

Sasisekharan :  There are many. My wife Uma who is an oncologist and an assistant professor of hematology and oncology at New England Medical Center in Boston has helped point me in the direction of fighting cancer.  Anecdotal evidence suggested that some sugars slow tumor growth, while others accelerate it. We decided to  investigate this further. Because heparinase releases sugars from the surface of cells, our team injected a couple of versions of heparinase into mice with cancer. We found that one class of enzymes , heparinase III, inhibited tumor growth because of the particular sugars it released from cancerous cells. We hope this knowledge can be used towards the development of new anti-cancer therapies.

We are also working on areas like stroke recovery in collaboration with clinicians from MGH. This is an area with unmet medical or clinical needs and we are actively pursuing ways to develop newer approaches to treat stroke patients. One of my students recently won the coveted Lemelson-MIT Student Prize “for his inventive research with a new protein and a common coagulant that may help both stroke and cancer patients”.

Lokvani: Your father is also a great scientist and a professor who has done a lot of work on DNA. Is he responsible for your interest in science?

Sasisekharan : Very much so. I was very much drawn to his insight, way of thinking and questioning. He is a true inspiration. He also motivates me to make sure that whatever work I do can make a difference in the world at large.

Lokvani: You and your wife have very busy careers. Your second child was just born.  How do you manage to have time for family while leading such a busy life?

Sasisekharan : I think setting priorities and managing one’s time has been an important aspect of our life.  Family is very important for us and even though we have busy careers -  my wife and I always make sure that family gets top priority.  This is a hard thing to do and by no means an easy balance – but one that you strive hard to achieve as much balance as possible.

Lokvani: You have accomplished so much at such a young age. What are your hopes and plans for the future?

Sasisekharan :  There is so much to be done in my research area I plan to continue to work in my field.  I am quite interested in translating research ideas into real world applications and this is another area that I do hope to spend quite some time on, especially in India and other south asian countries.  Part of my job entails teaching and mentoring scientists and engineers which I find as a very rewarding experience. I am involved in these kind of activities in especially in that part of the world with the hope of giving back in anyway I am able to.

Lokvani: Thank you for you time.

Sasisekharan: Thank you very much.

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