You were born in Innsbruck, grew up in Natters, a small village in Austria's Tyrolian Alps, and attended Medical School in Innsbruck. What motivated you to do a Research Fellowship with Doris Taylor at the University of Minnesota?
Dr HARALD C OTT: Through my clinical work as a cardiac surgery resident in Innsbruck, I developed an interest in regenerative medicine and to rebuild lost cardiac function. With the support of Dr Laufer, the chair of cardiac surgery in Innsbruck, I visited Dr Taylor who was at the time still at Duke. My goal was to learn more about “cellular cardiomyoplasty”—injecting revitalizing muscle cells into the damaged heart to regain cardiac function. Back in Innsbruck, I had the opportunity to learn basic science techniques under the mentorship of Drs Laufer, Hering, and Podesser, and I completed several small animal trials examining the fate of various cell types injected into the heart. When Dr Taylor moved to the University of Minnesota, she was so kind to give me an opportunity to join her team as a research fellow and I joined her lab in 2004. I felt that dedicating 1 to 2 years of my training to full-time research would help me to deepen my knowledge in regenerative medicine and to build the necessary foundation for an academic surgical career.
After your research fellowship, you moved to Massachusetts General Hospital in Boston for a residency in Surgery and clinical fellowship in Cardiothoracic Surgery. What motivated you to stay in the US?
HCO: During my research time at the University of Minnesota, I met several surgeons, who recommended, I continue with my surgical training in the US. I was impressed with the structured approach to surgical training, the dedication to education in- and outside the operating room, the intensity of the training experience, and was delighted to see early independence as a stated priority. I therefore decided to enter the match program and was lucky to receive a categorical residency spot at Massachusetts General Hospital. At the time, I felt that taking this opportunity would bring me to the academic epicenters in regenerative medicine and tissue engineering and help me build a solid clinical foundation.
You managed to run a laboratory as a principal investigator in parallel to a very busy residency and fellowship. What was your secret in balancing clinical and research commitments?
HCO: The 3 factors that enabled me to bridge clinical training and basic research were the right mentors, the right team, and a strong home base. At MGH, mentors like Drs Mathisen, Vacanti, Madsen, and Warshaw understood my drive to continue basic research during my clinical training. Mentors from other disciplines like Drs Kotton and Scadden helped me focusing my interests, build a research group, and to compete successfully for National Institutes of Health funding. Once benches and funding were in place, building and running an organ engineering laboratory during training was only possible because of a team of highly motivated, passionate, intelligent, and hardworking scientists and students pushing forward, rain or shine. Nocturnal lab meetings, and holiday experiments were the norm, we made it work, and believed in the idea of creating living tissues and organs.
As a young and pioneering researcher in regenerative medicine, you may have benefitted from great mentors. At the same time, you are mentoring your own group now. What is your mentoring secret? How would you advice young clinician-scientist starting an independent research career?
HCO: Finding the right mentors and sponsors is essential in building a career in academic surgery. Without support by colleagues, leadership, and the institution, it is impossible to establish an independent research group. However, I believe that a career in science should not be built on strategic considerations but on a passion, an area of interest, and exciting ideas. Success in obtaining support for a given project depends on the ability to convince others of its importance and on the ability to obtain buy-in from team members, peers, and leadership. In life science, we are dedicated to improve patient’s lives—nothing is as contagious as a good idea or a novel approach to solve a clinical problem. In terms of building a team as a young clinician-scientist, I believe in organic growth and that most great projects and programs started small. My advice would be to focus on a well-defined topic, identifying the necessary resources, and beginning to obtain independent funding as soon as possible. Never be discouraged if grants are not supported or manuscripts not accepted: rejections are the daily reality of any successful author or grant writer!
You have pioneered and refined a cellularization/reseeding method to engineer bioartificial organs. What source as an extracellular matrix do you see having the most relevant clinical application?
HCO: Native extracellular matrix is a unique resource and a very attractive platform for the development of several types of tissues and organs. At the same time, bioengineering techniques utilizing techniques such as three-dimensional printing have come a long way and may provide valuable manmade alternatives. In my view, the application should dictate the type of material and manufacturing technique used. While in some instances (ie, lung or liver engineering), native extracellular matrix might be ideal, other applications such as blood vessels or airway may call for more simple or different matrix constructs.
What do you consider the most relevant hurdles that will need to be addressed prior to a clinical application?
HCO: One key hurdle to developing a successful clinical solution is to understand what exactly patients desire. Designing a product that functions at a very sophisticated level but does not improve quality of life is futile. For end-stage renal failure patients, for example, not being tethered to a device and not being stuck with needles may represent the most important features of a possible treatment modality. Portable dialysis requires both, while kidney transplantation (ie, an implantable renal replacement device) does not require either. Another hurdle is the challenge in improving safety and efficacy of human biologic devices. Finding the right animal model that predicts long-term function and lack of complications of human tissue proves to be challenging. Transplantation in large animal models across a xeno barrier may not allow us to fully understand and appreciate the effect of the human immune system on human stem cell–derived devices. The use of animal-derived implants as an alternative may not be fully representative of human devices especially as clinical implants become more complex. Finally, an important hurdle will be related to device costs. While the concept of patient-derived devices built on personalized stem cells may be attractive from an immunologic perspective, good manufacturing practice–compliant production of such devices is prohibitively expensive. Alternative strategies such as universal donor cells or matched donor lines are in development, but have not reached maturity yet.
Will ECM components still have an antigenic capacity and how do you expect to address this immunological challenge?
HCO: The extracellular matrix does elicit an immune response leading to graft remodeling and possibly loss of high-level function (eg, through fibrosis and loss of gas exchange capacity in lung grafts). Controlling the immune response to engineered tissue and organ grafts will be key, once we have reached a stage of sufficient and longer-term function. I would not be surprised if patients undergoing implantation of artificial tissue and organ grafts will require some degree of immunosuppressive treatment. Other strategies may include the incorporation of immune barriers or immunomodulating substances in our devices that help keep the host immune response at bay.
You have contributed greatly with a refinement of the decellularization technique for several organs. What are some of the organ-specific challenges you have encountered, and what organ do you see being closest to clinical application?
HCO: While perfusion/decellularization of most organs is achievable, repopulation of different areas within these organs with specific cell types can be a limiting challenge. For example, epithelial cells along the nephron are highly specialized and enable filtration and reabsorption as part of a larger 3-dimensional structure. Achieving targeted seeding of cell types into their respective niches will be necessary to rebuild the nephron’s function and therefore poses a specific challenge to the engineering of functional kidney tissue based on native ECM scaffolds. Another challenge we have encountered is the difficulty to repopulate the relatively dense native heart matrix with muscle cells to form a sufficient cardiac function at a human scale. Independent of the organ we try to rebuild, we must understand which biologic process we are trying to mimic to enable the formation of functional tissue. In some instances, we may be able to take advantage of repair pathways (eg, regeneration of respiratory epithelium from basal cells and conducting airways), while other applications may require true reiteration of morphogenic steps (eg, myocardial compaction of induced pluripotent stem cell–derived cardiomyocytes).
Pediatric transplantation is another area with a desperate need of organ supply. What are specific challenges of applying the decellularization/reseeding technique in children? Will decellularized/reseeded organs have the potential to grow?
HCO: Theoretically, tissue and organ grafts derived from human pluripotent stem cells could have the potential to adapt to the physiologic demands of a growing host. However, aside from vascular and airway conduits, to the best of my knowledge, these experiments have not been done using engineered solid organs.
Work/life balance is not only a buzz word but a real challenge. How do you balance a busy clinical research schedule with the demands and wonderful opportunities of a young family?
HCO: I am extremely grateful for the joyful experiences I have had and continue to have as part of my family, my clinical team, and my research group. It is an incredible privilege to treat patients one day, to work on tomorrow’s therapies on another, and at times to escape to a world of unicorns. I think there is no magic formula. I try to listen carefully and to maintain the flexibility to shift priorities with changing demands from all sides. Most importantly, none of this would be possible without the support of my wonderful wife, herself an anesthesiologist, a loving mother to my children and the true North of our family.