You were born in San Francisco, spent time as a child in Germany and then moved back to Mississippi where you spent most of your time growing up. What motivated you to be a scientist?
DAT: My upbringing absolutely motivated me to become a scientist. Growing up in different locations gave me the opportunity early on to see people who were changing the world. I wanted to do that. At the same time, growing up in a family where my father had died of cancer and where I had a brother who had cerebral palsy also impacted my decision. My brother struggled and was not treated fairly in school; that had a strong influence on me and made me realize that I wanted everyone in the world to have a fair chance. Science and medicine combined seemed like the perfect way to do that. My goal since that time has been to build new solutions for people with disease so that no one would ever have to feel or experience what I did as a child.
Regenerative Medicine was in a different place when you started work in the field. What has and continues to fascinate you about Regenerative Medicine?
DAT: Regenerative medicine is an attempt to treat an underlying injury or disease, not merely treating the symptoms of the disease or to get the remaining healthy organs and tissues to compensate for the disease. Put simply, our goal is to cure diseases approaching the problem at its roots. Regenerative medicine captures our body's ability to do that, which I find fascinating.
If you think about it, for most of our lives our body repairs itself. We don't have chronic injuries when we are born, at least most of us don't. As children, falling and scraping our knee, cutting ourselves or breaking a limb, our bodies heal and regenerate rather than repair. As we age, we lose that capacity because our body loses the tools for endogenous repair. Regenerative medicine is about harnessing or resupplying many of those tools, whatever you believe they may be.
Taking that approach, I was fortunate to be the first person to transplant cells experimentally into hearts showing that we could regenerate cardiac function. Based in part on those data, clinical studies began in 2000. At the same time, I also pioneered and implemented preclinical comparative studies with different types of cells to show the effects on cardiac function. Those were such exciting discoveries that the field moved forward with clinical trials after only 18 months. While the hope was that those discoveries would be the panacea, it ultimately wasn't, in part because our knowledge of cell-types, timing and recipients was limited. Nevertheless, our data provided the basis to a number of different discoveries that have made it possible for us to extend the health-span rather than simply the lifespan of an individual. I believe that we have made huge strides in medicine and regenerative medicine has contributed largely to this progress. The opportunity to continue to learn and advance the field along with my colleagues is one of the most fascinating and exciting parts of my job.
You and your team published a landmark study in Nature Medicine (2008) showing the potential of using decellularized organs as scaffolds to create bioartificial hearts. What have been responses that you received following this publication?
DAT: That publication was very much like our 1998 cell therapy paper in Nature Medicine a decade earlier. It opened a door to entirely novel opportunities. In this case, we opened the door to autologous solid organ transplant—or to building biologic organs in the laboratory. Building these new in the laboratory and the potential of providing a solution to the organ shortage crisis is incredibly humbling, motivating, and exciting.
There are times in a scientific career, when one feels able to change the world. For me, our data published in 2008 were a game changer and provided such an opportunity in the field of solid organ transplant. I had been working on cell therapies for over a decade, and this was a natural extension of my previous work. In recognizing that we were probably never going to be able to use cells to totally move a thin, leathery scarred region of heart back to a healthy region, we said, “wouldn't it be cool if we could take out the sick cells and replace them with healthy cells?” We tried and have been very fortunate to succeed. Since the publication of this work in Nature Medicine, the technology I pioneered—decellularization—is used in laboratories worldwide to generate scaffolds for organs, tissues, and research tools. The responses have been amazing, and it's been exciting to watch the results from our study influence and shape research efforts in so many ways.
But what I am perhaps most proud of, is that a decade later, this manuscript remains one of the most highly cited papers in several of my former students' and fellows' CVs. By building an inclusive group of people that brought their unique expertise and perspectives to the table, we made a discovery that has and continues to impact the field of transplantation for the long term. And it has positively impacted the careers and future goals of the entire team. I am extraordinarily proud of that.
The decline of stem cells is considered a hallmark of aging. Is the aging process of Extracellular Matrix (ECM, as the structure of bioartificial organs) comparable to that of cells that repopulate a scaffold?
DAT: The truth is that ECM gets stiffer as we age. Some of the proteins get damaged or crosslinked. Moreover, the ECM changes with injury and use, which has biologic consequence. Both cells and ECM engage in a cross-talk allowing them to respond in a dynamic way to the situation. At the same time, the ECM can be damaged with accumulating hits much as cells can. Clearly, the matrix in a scar is not the same as the matrix in a healthy organ or tissue. In fact, we have recently suggested that not considering the extracellular environment sufficiently may deleteriously affect the success of cell therapy.
Envisioning the clinical application of regenerative medicine, all cellular transplants, recellularized organ scaffolds, or organ patches appear feasible applications. What modality do you see clinically most relevant and applicable?
DAT: Organ matrices, either as a hydrogel or as matrix itself, are already approved clinical products that are being used to repair organs and tissues. Less complex organs, such as bladder (a balloon) and trachea (a tube), have been constructed in the laboratory. Whole organ scaffolds are more complex. There is a vascular tree, complex parenchymal structure and it's organized in a multifaceted way. Nevertheless, progress in bringing whole organ scaffolds to clinical application is happening in laboratories around the world and in manufacturing groups and in consortia that recognize this approach as part of the future of regenerative medicine. Certainly, there is a lot more work to do!
I think transplanting cells and providing the ‘right’ environment in which they will function and perform best remains a challenge of regenerative medicine. But cell therapies are being considered more and more relevant in many fields. Understanding the cross-talk between cells and environment will be critical not only for matrix- or cell-based tissue-engineered patches, but also for lobes of organs and tissues as well as whole organs—liver, lung, kidney, pancreas, heart.
You have not only been a pioneer in regenerative medicine but also in showing sex-specific aspects of stem cells. Are hormonal effects the driving force behind sex-specific aspects of stem cells?
DAT: Sex-specific aspects of biology show numerous differences that are not immediately obvious. I believe it's much more than hormonal effects that are the driving force behind sex-specific differences. The immune system, the stiffness of the extracellular matrix, hormones are only few examples. For example, our studies show that the composition of bone marrow and cells in the peripheral blood of male and female animals differ, and this has held true in humans. These distinctions likely contribute to the biologic differences we see in stem cells between men and women. There is still so much for us to learn, and not enough research and resources are dedicated to understanding sex-specific differences between stem cells.
Female organs do not only have a sex-specific physiology but also a specific capacity to respond to injury and repair. Can we utilize those effects to increase the functional capacity of male organs?
DAT: There are many clinical examples for sex-specific disease processes. Men are more likely to develop pulmonary fibrosis, women hypertension. Men develop Coronary Artery Disease (CAD) earlier but the rate plateaus later in life. Women develop the condition late, but CAD progresses faster in women until they catch up and pass men. All these clinical examples can teach about the basic mechanistic pathways of endogenous repair processes. Truly, regenerative medicine offers a potential for personalized medicine.
You have mentored researchers who have started very successful clinical and research careers themselves; you are ‘mentored’ by some of the pioneers in Cardiology and Cardiac Surgery at Texas Heart Institute. What do you consider your secrets in mentoring and what do you appreciate the most in receiving mentorship?
DAT: I feel very privileged to have had excellent students and fellows in my group over the years who have gone on to have very successful clinical and research careers. Here at Texas Heart Institute, I enjoy interacting daily with pioneers in cardiology and cardiac surgery. That places me in a unique position where I can see the best and I've taught some of the best.
In terms of secrets, honestly, I've had to learn how to be a mentor which has been both challenging and rewarding. None of us (at least I don't think most of us) would say we started out in science or medicine because we wanted to be a role model for someone else. But as you move ahead in your career, you find that is one of the most rewarding ways you grow as a professional in the field. What I've learned so far is that people are successful when they have others advocating for them, giving them the space they need to prosper, and providing support for growth at the right time. Synchronizing support and timing seem critically important aspects of a successful mentorship.
I remember one of my colleagues saying to me, “You always want to be under the radar, except when an opportunity arises.” Good mentors embrace that and try to create that environment for their mentees. Giving people room to express their passion, be who they are, achieve their best, and then advocating for them when opportunities arise. I have tried that approach and many in my group have utilized the support and the expertise in the laboratory for their own, independent career.
The capacity of stem cells is impacted by various aspects including red wine. Is that link the answer to the French paradox?
DAT: If only I knew! I certainly think red wine is an answer to a long week in the lab and a celebratory beating heart. But I also think, all kidding aside, everything that we eat, drink, and metabolize has many effects and we understand only a few! That was what one of my earliest pharmacology professors taught me. The reality is that we don't yet understand biology, much less complex physiology. We have partial insights but with every new discovery, we appreciate the complexity of the human biology a little bit more.
Part of what makes science a career and so interesting is that it's ever evolving. As we learn answers, we can apply our knowledge to things we thought we already understood. Someday, we may find that red wine is the manna, or power, for stem cells. Today, what I know is that endogenous repair remains to be fully understood, and pondering it over a glass of wine, resveratrol and all, is ok by me.
Revitalizing organs with stem cells is certainly exciting. Revitalizing your thoughts to move the field forward is relevant as well. What do you do to distract yourself in the free time that is left?
DAT: I love reading, teaching, riding a bike and swimming, and I must admit, that being with people I love and care about is probably what drives me the most. It's about regenerating the heart at every level. If I don't get to talk to my family near and far every day, I'm not as good as I could be. Laughing and trying to change the world both personally, as well as professionally, is what I aim for, everyday.