Dr. Rameen Shakur, MD PhD, is an academic cardiologist, biologist and personalized medicine researcher, the Janson Fellow in Cardiology and Personalized Medicine at the Koch Institute for Integrative Cancer research at the Massachusetts Institute of Technology, and the Founder of Cambridge Heartwear Ltd. His academic research focuses on modeling and understanding cardiac development using iPSCs. We sat down with Dr. Shakur to discuss his work in cardiac personalized and precision medicine, as well as his overall views of the field.
You’ve done some wonderful work in the field of cardiac precision medicine. How did this journey begin?
It all began in Cambridge, UK while I was looking at therapies for inherited heart conditions with a specific focus on genetic muscle disorders called cardiomyopathies. Cardiomyopathies are a disease of the heart muscle that makes it harder for your heart to pump blood to the rest of your body. Even though these diseases have been studied extensively over the past few decades using mouse and other vertebrate models, I was keen to understand why we still lack effective clinical therapies.
What eventual reason did you come up with to explain this lack of effective clinical therapies?
I think the reasons here are twofold. Although mice and humans are phylogenetically related, they have physiological differences. A small rodent’s heart beats at 600 BPM and a human’s heart beats at 60-70 BPM. So the electrophysiological and potentially molecular focus are different. For this reason, translation of these therapies to the clinic has not always been successful.
How did this discrepancy motivate your thinking and your research plan?
I was working in a genetic clinic where patients of all ages were coming to me with arrythmias and symptoms of heart failure. Based on my medical training, I would genotype these patients with familial histories and treat them symptomatically, but I couldn’t discern the biological origins of the disease. It was then that I decided to dedicate my efforts to returning to the fundamental basic science paradigms. I realized that we needed to investigate the molecular dynamics, genetic defects, downstream signaling and physiological output all together.
Did this prompt you to start working with stem cells?
Yes, I was awarded a national Wellcome trust clinical PhD fellowship at the University of Cambridge, which, although competitive, allowed me to pursue my interests. I started working at the Wellcome Trust Sanger Centre and the Laboratory of Regenerative Medicine at the University of Cambridge. My focus was to better elucidate underlying disease mechanisms and instigate a novel therapy platform through modeling cardiomyopathies. It was around that time that the seminal Yamanka paper came out, and people started studying the use of Yamanaka factors to reprogram stem cells. This motivated me to start using patient-derived iPS cells. I soon realized the need for having chemically defined protocols for cardiac differentiation, and in the decade since then, the field has evolved to achieve that. However, I grew more curious about how these signalling cascades could be manipulated at a transcriptional and proteomic level, and with the advent of CRISPR, I had another tool to answer some of these questions.
It took us a few years to put together our work, and in the end we used not just human iPS cells but zebrafish as well. We found that human iPS cells provided the most accessible means to understand the underlying genetic perturbation in patients. This is because, at that stage, we could access iPS cells in feeder free conditions, perform non-retroviral transfection, and produce robust and accessible cells. CRISPR Cas9-corrected and -deleted cells gave us a whole new system to try and broaden our understanding, and we were getting some great insight from a genetic secondary messenger and downstream protein perspective. I was able to produce a platform that was an integration of all the omics: transcriptomics, proteomics and the methylation status of these lines. We extended that work to search for drugs or small molecules that could correct the signalling that was going awry from underlying genetic mutations. Our overall objective was to restore normalcy.
How did this comprehensive platform help you?
Obviously there is genetically a lot at play here in the underlying mutations. But that platform produced a lot of interesting hits that allowed us to look at drugs we had never considered before. It also gave credence to this type of systems physiological testing, and it gave a deep biological understanding through the targeting of downstream signaling from the underlying genetic perturbations. We were able to perturb the system and bring it to some level of homeostasis.
What it also allowed us to do was to have candidate screens from FDA approved drugs, hit upon a few potentials, move them forward and actually test them in a cellular context. And that was exciting because usually drug development takes decades and we were able to showcase the same efficacy in stem cell models and then in smaller animals before moving them to clinical trials. This happened very quickly, because we were picking up drugs that we thought from a cardiovascular point of view were used for other indications, but from a molecular point of view, could be used to perturb genetic indications. We were able to take some of these drugs into clinical trials and we are now learning the outcomes of those trials.
What are the latest advances your team has made using this platform?
A clinical trial was recently undertaken and closed, and we found that we could replicate findings from our original line and findings from smaller animal studies in humans. We found clinically significant results looking at ejection fraction, BMP levels, 6 minute walk tests, electrical output and so on. All sorts of physiological functional tests were performed to see how the patient is doing, and our modelling in silico and in vitro were verified in vivo.
What is your biggest takeaway from all of this?
Three words: Personalised drug therapy. This study has been a good example of personalized precision medicine with a unique data set leading to candidate drugs which lead to biological results.
We also discovered a lot of older drugs in the cardiovascular space that were not as effective at treating the pathological symptoms, but could still perturb the disease at a molecular level. And this led me to my next step, which is combining drug delivery and precision medicine with the help of Bob Langer and Gio Traverso at MIT.
What are your next steps?
We are set to publish some of this data this year. We are also trying to replicate this methodology for other inflammatory conditions, such as myocarditis, and in the cancer setting. We have established initial methodologies that are robust enough, which will allow us to better understand the signaling mechanisms.
Where do you envision taking this research?
I would like to look at signaling and cellular proliferation pathways that haven’t been characterized well before, and use that to understand active targeting for the heart, along with their structural and molecular implications. I want to use chemistry to understand the biochemistry of polymers, underlying cellular targets, cellular membrane interactions and tease away at complex biological signals for effective regeneration.
Thank you for taking the time to discuss your research with us, Rameen! We wish you the best of luck with your future endeavours!
