By Carla Mellough
About this month’s Featured Principal Investigator, Joseph Wu. Joseph is the Director of the Stanford Cardiovascular Institute and a Professor of Medicine (Cardiovascular) and Radiology at the Stanford School of Medicine. He received his medical degree at Yale and, following his medical residency and training, took a PhD in molecular pharmacology at UCLA. His clinical focus is congenital heart disease and cardiovascular disease and his research is centered upon the development of novel cardiovascular therapies through greater understanding of the biological mechanisms of embryonic, adult and induced pluripotent stem cells. His work has received significant international acclaim in high impact journals including Cell Stem Cell, Nature Medicine, Science and recently in Stem Cells. Prof. Wu has been the recipient of many prestigious awards including the Burroughs Wellcome Foundation Career Award in Medical Sciences, Baxter Foundation Faculty Scholar Award, American Heart Association (AHA) Innovative Research Award, AHA Established Investigator Award, National Institutes of Health (NIH) Director’s New Innovator Award, NIH Roadmap Transformative Award, and Presidential Early Career Award for Scientists and Engineers presented by President Obama at the White House Office of Science and Technology. Fascinatingly, he was also part of the team which was recognized by Center for the Advancement of Science in Space (CASIS) with a grant award under the request for proposals titled ‘The Impact of Microgravity on Fundamental Stem Cell Properties’. He sits on multiple editorial boards including the Journal Clinical Investigation, Circulation Research, Circulation Cardiovascular Imaging, Human Gene Therapy, Molecular Therapy, Stem Cell Research, and Journal of Nuclear Cardiology. We are both fortunate and grateful to have Joseph take some time out from his numerous commitments to bring you this month’s Featured Interview on the Stem Cells Portal.
How and when did your fascination of the cardiovascular system and stem cells originate?
I became interested in cardiovascular medicine when I was a medical student at Yale University School of Medicine. I had always been interested in the heart growing up, because it seemed to be the simplest and yet most mysterious organ of the body at the same time. At Yale, I was able to explore this interest by working with Dr. Albert Sinusas and Dr. Barry Zaret on cardiovascular pharmacology and cardiovascular imaging by using large animal models. After my internal medicine training at UCLA, I became a cardiology fellow and enrolled in the UCLA Specialty Training and Advanced Research (STAR) program. This is a unique program designed for optimal training of physician-scientists. My interest in the heart continued with PhD research working with Dr. Sanjiv Gambhir to develop what was then very novel molecular imaging technology, tracking cardiac gene therapy and cardiac stem cells in living subjects.
As a practicing cardiologist, what was your original motivation for pursuing a parallel career in research? How has this motivation evolved? Has this changed your clinical practice?
I decided to pursue a parallel research career for 2 main reasons. First, I did not want to associate patient volume with my clinical income as in private practice. Second, I wanted the flexibility to investigate interesting fundamental science questions, which would have been difficult to do as a busy physician and without proper research training. I feel that this has been the right choice for me, because over the years, I have had the privilege to work on important topics in cardiovascular and stem cell biology and collaborated with many innovative investigators in the US and internationally.
Your work has reported on many aspects of cardiovascular disease, treatments and enhancing the survival of stem cells following transplantation. In your opinion, what has been your favourite experiment and which has caused the greatest impact?
When I was working on my PhD, I was extremely excited to see the first acquired images of cardiac reporter gene expression in the heart using optical bioluminescence imaging (Wu JC et al, Circulation 2002;105:1631-1634) and later using positron emission tomography imaging (Wu JC et al, Circulation 2002;106:180-183). This is a vastly powerful technology and will continue to transform and accelerate research related to stem cells and other fields into the clinic. In one recent study, we applied imaging technology in heart failure patients to show that early CD34+ cell engraftment can be used to predict late functional improvement (Vrtovec B et al, Circ Res 2013;112:165-173). We have also used imaging technology to help us understand which catheter delivery technique (transendocardial vs. intracoronary) provides better stem cell retention in patients (Vrtovec B et al, Circulation 2013;128:S42-S49). These days, it is just gratifying for me to see that the field of cardiovascular molecular imaging has taken off and to see many investigators adopting this technology to understand the biology of transplanted stem cells in vivo.
What, in your opinion, is successful research?
As a physician scientist, my goal has always been trying to solve questions that are at the interface of science & medicine. Hence in my opinion, successful research is working on intriguing scientific questions that also have significant clinical value for patient care. In my opinion, it is important to strive for both aspects whenever possible.
You have already achieved great success in your roles as clinician and scientist. What do you currently strive towards? What are your main goals?
I would like to use my basic-translational-clinical research expertise to show that patient-specific stem cells can have a significant impact on improving cardiovascular care. In particular, the iPSC platform can be used to (i) elucidate disease mechanism, (ii) implement personalized regenerative medicine, and (iii) accelerate drug discovery. First, we are now able to generate unlimited quantity of patient’s own heart cells, which will allow us to understand the molecular and cellular mechanisms of inherited cardiomyopathies, and channelopathies, as well as to model acquired heart diseases (e.g., chemotherapy-induced cardiomyopathy, radiation-induced cardiomyopathy, and viral-induced cardiomoyapthy). Second, these heart cells may be used for regenerative medicine applications following myocardial infarction. Although additional studies are needed to test their safety and efficacy, it is remarkable to note that Dr. Yamanaka and his colleagues in Japan are already planning on using autologous iPSC-derived retinal pigment cells for treatment of macular degeneration. Third, we are all cognizant that the pharmaceutical industry faces numerous challenges in the development of novel drug compounds. For example, the average new drug requires more than $1.8 billion and 12 years from the time of discovery to commercial launch. Even after approval, ~4% of drugs released to market are subsequently withdrawn due to safety issues, and cardiac toxicity is the leading cause of drug attrition (accounting for ~40%). Hence, the development of a library of patient-specific and disease-specific iPSC-CMs can be used to better predict drug toxicity, accelerate drug discovery, and lead to the transformative concept of “clinical trial in a dish” in the 21st century.
Can you reflect on what you feel was one of the most important experiences or defining moments in your education, career, or life that has contributed to your success? How do you think this has this affected your work and/or career?
This is a difficult question because many experiences, people, and opportunities have contributed to my career development. To name a few, I would say the UCLA STAR PhD program was instrumental because it provided me with a protected 4-year time frame for research training. I would say my PhD advisor Dr. Sam Gambhir, and still a mentor today, is instrumental because I learned how to conduct research, write manuscripts, and apply grants from him. I would say having a supportive spouse who understands the demands and sacrifice of academic medicine is essential.
How easy/difficult do you find it to keep abreast of new techniques and literature in the field?
There are so many cutting-edge publications being published on daily or weekly basis that it is very difficult to keep abreast of all new techniques and literature in the field. I think you’ll find most investigators struggling to do the same.
What do you feel is the most challenging aspect of your job?
I would say coming up with innovative research ideas and figuring out how to test these hypotheses.
What has been the greatest personal challenge that you have worked to improve upon, that has helped you in your career?
There are only 24 hours in a day. So learning how to balance work life and home life is a challenge, and learning how to prioritize to get things done effectively and efficiently.
How important is a collaborative approach in your research and how multidisciplinary has this been/is this becoming, in your experience?
I am a strong believer that science is a team effort. It is very difficult for an independent lab to do everything by itself. Collaboration is both more efficient and can foster more creative projects. We work with scientists from different disciplines both within and outside of Stanford. Some of my most innovative research ideas have come from talking with investigators who are neither cardiovascular-centric nor stem cell-centric.
What would your words of advice be to early stage researchers, currently trying to establish an independent career in the highly competitive field of stem cell research?
I tell all my postdoctoral fellows that they have to “work hard, work together, and work smart”. There is no substitute for working hard. Thomas Edison once said that “genius is 1% inspiration and 99% perspiration”. As mentioned above, science is a collaborative effort and so the early stage researchers should learn how to work together because if they don’t learn that philosophy early on, it’ll be difficult for them to adapt later on. Lastly, I would encourage them to think outside the box and give them much freedom to pursue non-conventional projects.
What do you think are the main barriers to the applicability of iPSCs for in vitro disease modelling and the treatment of human disease?
For cardiac pluripotent stem cell biology, I think we have made significant stride in improving the efficiency of cardiac differentiation. Back in 2004 when I started my lab, we were happy to see a few human ESC-derived heart cells twitch here and there, with <5% differentiation efficiency. These days, we routinely achieve >90% cardiac differentiation. In the next 5-10 years, however, we will need to focus on how to make iPSC-heart cells more mature (which is a challenging problem that also troubles investigators in other fields trying to make iPSC-neuronal, iPSC-hepatic, or iPSC-vascular cells more mature). Another challenge is to make cardiac lineage-specific cells such as iPSC-ventricular, iPSC-nodal, and iPSC-atrial cells. This has significant implication in terms of improving disease modelling and drug screening.
Which are the most important fundamental cardiovascular or stem cell biology questions that still remain to be answered, in your opinion?
For cardiovascular medicine, my lab is very much interested in using iPSC-heart cells as a platform for drug discovery and for “clinical trial in a dish”. The most important fundamental questions needed to get there include cellular maturation and lineage specification as I mentioned above. But I believe that the entire field is moving at a rapid pace now because more investigators (both at senior and early stages) are getting into it. The collaborative effort among investigators with complementary skillsets will help us get there.
There has been a huge shift in public thinking about the use of stem cells in research and to ameliorate human disease, and clinical safety trials are already underway. In your opinion, what are the greatest barriers that remain prior to the broad clinical translation of human embryonic stem cells and induced pluripotent stem cells (hESC, hiPSC) for restorative therapies? How do you foresee these being overcome?
In our lab, we are currently working on several of the critical issues related to clinical translation of ESC- or iPSC-derivatives for regenerative medicine. For tumorigenicity, we need to make sure that the transplanted cells has no chance of becoming a teratoma (see review by Lee AS et al, Nat Med 2013;19(8):998-1004). One such adverse event in a patient will set the field of pluripotent stem cell-based therapies back for years. For immunogenicity, we are interested in developing novel immunosuppressive protocols that will allow both ESC- and iPSC-derivatives alike be used as allogeneic cell therapies (see review by Pearl JI et al, Sci Transl Med 2012;4:164ps25). We also need to find out what are the advantages and disadvantages of using iPSC or ESC-derivatives versus existing adult stem cells, not only from safety & efficacy perspectives but also from practical commercialization feasibility. In my lab, these endeavours are being funded by a California Institute of Regenerative Medicine (CIRM) Disease Team Grant with the goal of obtaining an Investigational New Drug (IND) for transplantation of ESC-heart cells in patients with heart failure.
Great advances are being made all of the time, and we are moving ever closer to generating complex functional tissues from stem cells. How closely do you think that we can truly model human disease in a dish in the lab using pluripotent stem cells, in order to generate clinically useful results?
In the next few years, I think you will see many different platforms using pluripotent stem cells to model human diseases (e.g., 2-D monolayer, 3-D tissue engineering, whole organ system, or in silico model). I don’t think there will be an “one size fits all” solution. I think investigators will need to understand what the problems are and to discover what approach can be used to answer them based on the pros and cons of each technology.
In your opinion, what do you consider to be the most important advance in stem cell research over the past 5 years?
In my opinion, the most important advance over the past 5 years is the collective effort of many investigators working on genome editing using ZFN, TALEN, and CRISPR. These techniques are not perfect yet, but will
surely improve over time. The genome editing of stem cells allows us the opportunity to study complex human diseases without the need to recruit patients or to "cross" patients for multiple mutations like we do with
genetically modified mice. Just like how transgenic mice have revolutionized biomedical research since the 1980s, the genome editing approach will have similar impact for decades to come.
What are your greatest hopes for the future of stem cell research and clinical translation in your specialist area?
I am really hopeful that in the near future, instead of asking a patient to take a drug (and making the patient a de facto guinea pig), we can test the drug on the patient’s own iPSC-derived cells first to see if the drug actually works or not, before giving it to the patient. This is the essence of “personalized medicine”, which is something that physicians have been dreaming about for a long time, but we haven’t had a feasible strategy for realizing this vision until recently. I think successful translation of stem cell research will play a crucial role in making this possible, hopefully within the next decade or two.
Can you recall a fond memory or funny moment from your clinical or research experience that you would be willing to share with us?
During my PhD, I acquired one of the very first images of cardiac gene expression in a living animal. I was very excited and showed the lab notebook to my wife and trying to explain what the individual steps needed were to get to that heart image. Her reply was “so what?” Luckily, she’s been fully supportive of what I do. These days, I go to work and interact with my clinical and research colleagues. They range from clinicians to scientists to postdoctoral fellows to graduate students. They range from having decades of experience to those starting out who possess some of the most creative and wildest ideas for problem solving. I am fortunate to have the opportunity to interact and learn with them on a daily basis. The experience has been quite humbling and exhilarating, and I wouldn’t trade my job with any others.
More information about the Wu research team can be obtained from the lab website.
Shushing T cells promotes acceptance of stem cell therapies, say Stanford researchers – Stanford Medicine Scope
New treatment helps stem cell transplants evade rejection – The Stanford Daily