Crippling Cardiometabolic Disease with Krüppels

Dr. Jain is Director of the Case Cardiovascular Research Institute at Case Western Reserve University.  He graduated summa cum laude from the University of Buffalo School of Medicine, New York. He then did his Internal Medicine residency at Harvard Medical School, Massachusetts, followed by a Research Fellowship at Harvard. Dr. Jain completed his Cardiovascular Medicine fellowship at Brigham and Women’s Hospital and then joined the faculty from 2000-2006. There he rose through the ranks and eventually became Director of the Program in Cardiovascular Transcriptional Biology at Harvard Medical School.

Dr. Jain is recognised for the discovery of the essential roles of the transcription factor family Krüppel-Like Factors (KLFs) in cellular inflammation and metabolism. Notable findings include the identification of KLFs as flow-inducible factors that orchestrate a gene program that maintains healthy endothelium. In addition, Dr. Jain has already applied his studies to animals and humans, thus implicating KLFs in the physiology of inflammatory and metabolic diseases including vascular dysfunction. As a direct result of this work, KLFs are now increasingly viewed as nodal determinants of cellular inflammation and metabolism.

A recipient of numerous awards, Dr. Jain was elected to the American Society for Clinical Investigation, Association of University Cardiologist, and is a Fellow of the American Heart Association. Dr. Jain has published extensively in peer-reviewed basic science journals and serves on numerous Editorial Boards. He is a highly regarded physician-scientist and is the President-elect of the American Society for Clinical Investigation.

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Professor Mukesh talked about the Krüppel-like factor (KLF) proteins and their role in inflammation and cellular metabolism, making a bridge between science and cardiovascular diseases.

According to the experimental information, there is an inverse relation between serum KLF levels and CV diseases. The American researcher believes that, in the near future, KLF levels can be used as early predictors of CV disease, allowing an earlier treatment of those conditions.

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FRONTAL: What is it like to be the Director of the Case Cardiovascular Research Institute at Case Western Reserve University and President of the American Society for Clinical Investigation? How different is your participation in both?

Mukesh Jain: I would say I enjoy both my roles very much. I moved to Case Western 6-7 years ago because I really had a desire to develop a research programme that would support young researchers. I have been able to achieve that and we have a very strong group of physicians that do fundamental research, almost a dozen now, and about 30 million in NIH funding, which used to be zero.

This new programme allowed me to develop my own vision. I feel very strongly about physicians doing science. If you look at major contributions at the level of Nobel Prizes and other major impacts in human health, many of them have been done by physicians who conduct science. This happens because we are able to see patients, ask questions and then go back from bedside to bench and from bench back to treat patients. The Case Western opportunity was wonderful and I remained, obviously, very active in directing it. As I wanted to start to do something at a broader level, I took the ASCI opportunity. The ASCI is the oldest physician’s scientist society in the USA. It was established over 100 years ago. It has currently 19 Nobel Prizes laureates, 31 Lasker award winners and hundreds of national academy members. It is the scientific elite of America so I am very honoured and privileged to be the President of it. My goal is to really use that opportunity to increase the efforts of physicians scientists in the USA and worldwide.

Taking into account that it is really hard for medical students to do training in Medicine and do Science, I believe that it is an opportunity to really support and cultivate that effort.

F: In your opinion, what is the greatest responsibility in your position and what do you find more difficult to do?

MJ: I think my greatest responsibility is to support young researchers and that is very hard in 2013, because there are large financial challenges in the USA and worldwide. There are very bright people that I want to support because they are the future leaders in the Academic Medicine, who will change the standard of care for human diseases.

They need to be supported and my greatest challenge is to find sufficient resources, by multiple mechanisms, to make sure they are successful. This is both my greatest responsibility and challenge.

F: The Krüppel-like factors (KLF) are being increasingly regarded as key determinants of cellular inflammation and metabolism. What practical use do you envision for them?

MJ: In all sciences, there is a period of fundamental discovery when you understand how a biological system works, whether being inflammation or metabolism. Then, you can use that information to develop therapies.

So I think that we are now at a point where the link of KLF to inflammation and metabolism in CV diseases is being increasingly appreciated and increasingly felt to be quite strong. I think that there will be implications for other diseases: metabolic diseases, neurodegenerative diseases and cancer. Those links will almost certainly be made by our laboratory and others.

That is what we are researching on, in order to make them therapeutical targets. I think that the next 5-10 years have to be focused on the manipulation, activation or inhibition of those factors, in order to have a therapeutic gain.

F: According to some studies patients with vascular dysfunction are already therapeutic targets to drugs that affect the KLF levels. If this is true, how should they be approached?

MJ: I think  that kind of information is not available at this moment. However, we started with patients that have an established coronary disease and we discovered that they had lower levels of KLF. Vascular dysfunction and endothelial dysfunction, which are early steps in vascular disease, have not been  evaluated yet – but it is an excellent question because all our experimental work suggests that KLF are deregulated early. If you could measure the KLF levels you could start therapy in patient with lower serum levels and not after you see the patient with a heart attack. For example, in the lecture I speak about how statins can increase KLF levels. However, in this moment, we often start statins on patients that have clear disease. If we knew that their KLF levels were low, maybe you would start statins in people in their 20s; that is not trivial because, if you look at studies of young people, even at medical student (19, 20, 21, 22 years old), 25-40% of them already have early atherosclerotic lesions.

F: In your opinion, which have been the most remarkable advances in Regenerative Medicine?

MJ: I think the most amazing breakthrough in Regenerative Medicine has to be the induced pluripotent stem cell (iPS) technology; that was Yamanaka’s work in 2006. One of the four factors was in fact a KLF factor, KLF-4, and so we follow that literature very closely. I think that it is one of the greatest breakthroughs of our lifetime but how we use regenerative technology for therapy  still has a major gap: What is the type of cell? What is the condition of the disease? Some diseases may be easier; eye diseases, for example, are amenable to iPS. Heart disease has been tested, as you know, but has not been very successful so far. So, I think we have much more to learn. The great breakthrough is the iPS – the potential and the promise are exceptional but the practical reality will take its time.

Interviewers: Marta Batista, Sara Silva

Writers: Santiago Rodrigues Manica