Three Decades of Outstanding Scientific Achievement

Richard Weisel

"Dear Richard, As the eighth recipient of the American Association for Thoracic Surgery Scientific Achievement Award, you will be joining Drs. John Kirklin, Norman Shumway, Michael DeBakey, Denton Cooley, Alain Carpentier, Gerald Buckberg and Andrew Wechsler as a recipient of the highest recognition this Association can bestow upon a member. The Association recognizes your pioneering work in myocyte culture and transplantation, your ability to elucidate the molecular events of myocardial ischemiareperfusion injury and your efforts to embrace and bring molecular biology into clinical cardiac surgery practice. In addition to these and your other scientific contributions to our specialty, you have trained and nurtured two generations of young surgical scientists, teaching them the importance of good questions, rigorous science and data analysis."

So begins the letter to Richard Weisel from Alec Patterson, President of the AATS. Alec will present this award at the annual meeting of this distinguished international organization to be held in Toronto, May 1-5, 2010. The award celebrates three decades of diligent application of the scientific method to advance the practice of cardiothoracic surgery. Coincidentally, in the Canadian Institute for Health Research's (CIHR) legacy review of the impact of its grants, a 1983 grant to Alec Patterson and Richard Weisel on heart and lung preservation was selected for a look back at what has happened to the field in 26 years.

The story begins with Steve Fremes and Shaf Keshavjee, when they were residents working in the lab on techniques to preserve hearts and lungs for transplantation. Both groups developed new preservation solutions which have been employed clinically.

In addition, perfusion techniques were evaluated to preserve the heart and lung block. The early clinical applications of the perfusion techniques were not as successful. The heart and lungs were perfused in a modified fish tank and on one occasion, the tank developed a leak and the transport plane was forced to stop to find a fish store to fix the tank. On another occasion, one of the transplant surgeons had to donate their own blood to maintain the blood perfusion during transport. After these inauspicious beginnings, perfusion techniques were abandoned for many years. Recently, both heart and lung resuscitation has become popular with new perfusion equipment.

However, the concept of perfusing the heart continuously with warm blood persisted; it was evaluated initially in the laboratory, and then an important clinical trial was led by Steve Fremes and David Naylor. A series of clinical trials of blood cardioplegia led to the conclusion that the perfusate should be "neither too cold, nor too warm, but just right" and that the critical components for safe preservation during blood perfusion were potassium and magnesium.

The preservation solutions were evaluated in human cell cultures by resident John Ikonomidis. The cell culture technology had been developed by the laboratory director

Renke Li who one day asked the outrageous question: "Why not inject the cells into the heart?" The problem following a myocardial infarction is cell loss, and once the cells are gone, half of the patients develop congestive heart failure following the infarction and half of those die by two years. The cellular injection has gone a long way in the past 13 years since it was presented at the STS. Extensive clinical trials have suggested that stem cell injections can improve cardiac function. However, the results achieved in the laboratory were considerably better than the results in the initial clinical trials, probably because the stem cells in young animals were very active, but the stem cells in old patients following a myocardial infarction were dysfunctional. Stem cells in old patients can be rejuvenated toward "younger cells using gene therapy". Surgical resident Shafie Fazel demonstrated that restoration of marrow stem cells could restore heart function after a myocardial infarction, but would not restore the cardiomyocytes which were lost. A new development which could provide new beating cardiomyocytes for cardiac repair is the induced pluripotent stem cells (iPS) which are the subject of intense and enthusiastic experimentation. Shinya Yamanaka developed the technique in Kyoto. In Toronto Gordon Keller, Janet Rossant, and others have improved the process of cellular production and differentiation to cardiomyocytes. The important upshot of this work is that cells from human embryos may not be necessary to restore the cardiomyocytes lost after a myocardial infarction, relieving investigators and clinicians of a troubling ethical quandary.

As Alec Patterson's letter clearly states, two generations of academic surgeons have been "grown in the culture of Richard Weisel's incubator." Terry Yau, Vivek Rao, Gideon Cohen and Subodh Verma have joined Dick in our Division of Cardiac Surgery, while others have dispersed to important academic posts ranging from Charleston, South Carolina to Leipzig, Germany. Residents trained in this mode have received their PhD and developed skills comparable to those of their basic science mentors in the process. Following formal laboratory training, they maintained their link to the laboratory and to clinical investigations, publishing more after their laboratory years through collaboration and continued application of the scientific method to their work. Many cardiac surgical residents continue to perform laboratory research, but others are pursuing a PhD degree in clinical research. Anusha Jega is currently the Kirklin Fellow working with Chris Caldarone, Bill Williams and Eugene Blackstone to develop her skills in clinical epidemiology.

The next generation of trainees will probably follow a somewhat different pathway. Cardiac residents are learning percutaneous skills to insert valves and endovascular stents, helping to catalyze the change. Adoption of the modular approach undergoing preliminary testing in the Division of Orthopaedic Surgery will help with the time-management of training in cardiac and other subspecialties of surgery.

Richard continues his illustrious career as director of the Toronto General Research Institute. Under his leadership the Regenerative Medicine and Guided Therapeutics Programs have received over $18 million from the Canadian Innovation Fund and additional funding has been received from Research Hospital Fund. A future feature article will describe the facilities, techniques and projects developing under Richard's remarkable, internationally recognized leadership.

M.M.