This is the 42nd year of the Frank Hastings lecture at the American Society for Artificial Internal Organs (ASAIO). It was a tremendous honor to deliver this talk and a highlight of my career. Dr. Egemen Tuzun contacted me well ahead of the event, and I took advantage of the time to reflect on past accomplishments and current challenges in artificial organ development. My thoughts ultimately focused on seminal achievements in the development of devices for circulatory support and the importance of integrity in research. Within this context, the current paper responds to the questions of what lessons we have learned to date and what directions we will take in the future.
FRANK HASTINGS, MD
Dr. Hastings (Figure 1) lived during an important transitional era in medicine. He was born in 1919 into a Quaker community. He graduated from Haverford College and then received his MD degree from Syracuse University College of Medicine (now State University of New York Upstate).1 Dr. Hastings was a work-study student for much of this time, but he fell short of funds to pay for his last year of medical school. The town of Chatom, Alabama, paid him a stipend with the understanding that he would practice there after an internship year at Charity Hospital in New Orleans (1950–1951).2,3 Following 5 years in general practice, Dr. Hastings left Chatom to begin work as a surgeon in hospitals supported by the mining industry (Miners Memorial Hospital Association facilities in Kentucky and Virginia).3,4 Hospitals started by Industry were common in the South during these years. In 1961, he became the Chief of the Surgical Service for the Miners Memorial Hospitals and somehow found time to begin development of a total artificial heart (TAH) with a grant from the National Institutes of Health (NIH).4 Where there is a will, there is a way.
In 1964, Dr. Hastings was appointed by the NIH to lead the newly created Artificial Heart Program,4 which was subsequently renamed the Medical Services Applications Program. During this time, Dr. Hastings’s team directly participated in the invention and testing of blood pumps.5 Dr. Hastings and the NIH also supported the work of other device developers through grants, contracts, and organization of investigator meetings.6 Dr. Hastings’s dedication to basic research and development in the spirit of helping patients with end-stage cardiac disease remains an example to those in the field today. Tragically, Dr. Hastings’s career was cut short by a stroke that took his life on March 15, 1971, at the age of 52 years. At his memorial service, eulogies from Dr. Hastings’s colleagues described him with the following words3:
“He stood true to his ethical code regarding rigorous testing of new medical devices before clinical trials.”
“He believed and daily demonstrated that the highest ethical conduct of his office was not only an official obligation but also a moral trust.”
“His departure from medical practice to research administration was based on the hope that by organized, systematic effort his talents and those of many others could be multiplied to provide meaningful extended life to untold numbers of cardiac patients.”
Dr. Hastings’s life as a physician and scientist was exemplary. It serves as a guide and inspiration to those that continue to work in the field.
SCIENTIFIC INQUIRY AND SEMINAL ADVANCES
A seminal advance is one that expresses important new ideas and influences subsequent developments. Seminal ideas are rare, primarily because they are novel. As such, only a minority of scientists can rightfully claim to have responsibility for a seminal event and even then must recognize the role of others in the achievement. Seminal advances are the result of three activities; they are as follows.
“Collaboration” is when investigators work together to create or achieve a shared goal. Seminal advances in circulatory support devices may be led by an individual, but the leader requires the cooperative work of numerous people with different skills to be successful.
“Concatenation” in the field of device development refers to events or ideas that are connected with an overarching scientific or medical theme. In his Presidential Address to the Southern Thoracic Surgical Association, Dr. Richard McElvein (University of Alabama, Birmingham (UAB) Cardiothoracic Surgery, retired) explained the importance of concatenation to seminal achievements in thoracic surgery.7 Examples are advances in the understanding of pulmonary anatomy and respiratory physiology, which provided a foundation for the development of endotracheal intubation, general anesthesia, and modern thoracic surgery.
“Competition” is defined as activity by multiple individuals or groups, each striving to perform or achieve at the highest level. An important aspect of competition relevant to device development is the desire to be first. Competition is a useful motivator but can tempt investigators to cut corners or engage in unethical behavior, especially when financial gain is involved. The consequence of such behavior is often failure of the therapy to perform as expected or unanticipated adverse events that can be devastating to a patient. When the reason for failure (i.e., fraudulent reporting or sloppy science) is uncovered, as it inevitably will be, the loss of public trust can be devastating to an entire field.
The personal characteristics of the successful innovator and leader are likewise important. They include integrity, altruism, courage, resilience, humility, and intelligence. However, an intelligent scientist or physician without the first five characteristics is unlikely to succeed. Leaders of research and development efforts should have the attitude of a servant to others and be capable of honestly judging themselves. It is easy to be enamored of your own work and be blinded to errors that become obvious when the hypothesis is tested by others or when a novel device is applied to patients. Overly confident leaders with ready answers to all questions are the most likely to be blindsided by reality. It is tragic when this occurs during a clinical trial, with an example given later in this paper.
CIRCULATORY SUPPORT: LESSONS FROM THE PAST
The development of circulatory support over the past 90 years is fascinating and inspiring. Shortly after the start of the twentieth century, physicians realized the potential for cardiopulmonary bypass to support patients during operations to treat congenital and acquired diseases. However, there were numerous challenges that had to be overcome to achieve this goal. By 1950, several groups had initiated the development of methods to temporarily replace cardiac and pulmonary function. The group led by Dr. John Gibbon was the most successful. Dr. Gibbon began work on the pump oxygenator with his wife Mary (Maly) at Massachusetts General Hospital. Gibbon subsequently moved the laboratory to Jefferson Medical College in Philadelphia. After years of research in canine models, Dr. Gibbon performed the first cardiac procedure in a child using his Model II pump oxygenator in February 1952. The child’s congenital defect was misdiagnosed (atrial septal defect incorrectly diagnosed rather than a patent ductus arteriosus), and the patient died. The second patient had a large atrial septal defect that was correctly diagnosed; the 18-year-old patient survived the repair that used cardiopulmonary bypass. The operation was performed on May 6, 1953. Dr. Gibbon operated on two additional patients, who unfortunately both died.8
Research on extracorporeal circulation continued at several centers around the world even in the face of the high associated mortality. Notably, the Mayo Clinic group headed by Dr. John Kirklin approached Dr. Gibbon through Dr. James Priestly, another Mayo Clinic surgeon, to seek collaboration in the clinical application of Gibbon’s device. Dr. Gibbon forwarded the pump oxygenator’s blueprints and instruction manuals to Dr. Kirklin’s team in 1953 for further development and translation to clinical use.8 The successful application of the Mayo-Gibbon pump in a canine model was reported in 19559,10 followed shortly thereafter by a collected case series of eight patients.11 The mortality in this group was 50%; however, the results were sufficiently encouraging that institutional and public support for cardiac surgery held fast. This was in part because of the forthright evaluation of the successes and failures as described by Kirklin’s group in their initial report.
Following the seminal advance of cardiopulmonary bypass, patients and physicians began to wonder whether longer periods of cardiopulmonary support were feasible. This quest stimulated a wide range of inquiry in areas such as blood–biomaterial interactions, adequacy of nonpulsatile circulation, oxygenator design, methods to quantify cardiac performance, cardiac pacemaker development, and diagnostic modalities for heart disease. Another outgrowth of this seminal achievement was extended cardiopulmonary support using extracorporeal membrane oxygenation (ECMO). The enthusiasm and persistence of early investigators in ECMO are notable. Despite many setbacks, ECMO is now an accepted therapy for cardiac and pulmonary failure. Details describing the early days of ECMO are beyond the scope of this paper. Readers are referred to the excellent Thoracic Surgery Residents Association (TSRA) podcasts by Robert Bartlett, MD,12 who is a past president of ASAIO and delivered the Hastings Lecture in 1990.
As mentioned at the start of this paper, Frank Hastings led the NIH research program for artificial heart development. The NIH collaborated with individual medical centers, university-based engineering groups, and corporate (industry) groups in the development and testing of blood pumps. The NIH supplied crucial funding and intellectual leadership through grants, contracts, and sponsorship of investigator meetings. Ultimately, pulsatile devices for ventricular assistance (ventricular assist devices [VADs]) and cardiac replacement (TAHs) were successfully commercialized. Rotary pump designs for VADs have supplanted pulsatile pumps and are now the most commonly implanted mechanical circulatory assist devices.13
Another type of circulatory support based on counterpulsation was conceived and developed during the timeframe of 1960–1970. Notable pioneers in developing a clinically successful device for counterpulsation (i.e., the intra-aortic balloon pump) include Arthur Kantrowitz (Hastings Lecture 1977), Adrian Kantrowitz (Hastings Lecture 1985), and Willem Kolff (Hastings Lecture 1986).14–16
The development of mechanical circulatory assist devices as described earlier is highly abbreviated. Readers are encouraged to study the original papers describing the seminal events that led us to where we are today. It is an instructive and inspiring tale.
CIRCULATORY SUPPORT: PLANNING FOR THE FUTURE
The first order of business in the future of circulatory support is solving the problems with existing mechanical devices. Interestingly, challenges identified during the early days of development persist today.17 They include device-related infection, bleeding, thrombosis, cost, and patient quality of life. Refinements in surgical and medical management have incrementally improved patient outcomes. More substantial improvements depend on seminal advances such as fully implanted blood pumps with transcutaneous energy transmission systems18 and TAHs that are based on rotary pump designs.19
Biologic therapies have tremendous potential to treat patients with end-stage heart disease. They have not yet entered clinical use, but I predict that biologic therapies will become available during the next two to three decades. This is within the professional lifetime of our ASAIO-fyi members.
Broadly speaking, there are two biologic approaches for treating end-stage heart disease; they are repair and replacement. Examples of repair include regenerative therapies to improve postinjury recovery (e.g., stem cell therapy for postinfarction healing),20 and gene modification or manipulation of gene expression in patients with familial cardiomyopathies. Options for cardiac replacement include xenotransplantation with hearts procured from genetically altered nonprimate donors (e.g., porcine hearts) and hearts stripped of native cells and then repopulated with cells genetically appropriate to the recipient.21
A NOTE OF CAUTION
Patients with end-stage heart disease are faced with a desperate situation and limited survival. Any hope for restoration of cardiac function is received with great enthusiasm, even to the point of clouding perception and diminishing healthy skepticism for unproven therapies.
In the era of 1990–2010, reports appeared describing growth factors (e.g., vascular endothelial growth factor and fibroblast growth factor) and stem cells that could resolve myocardial ischemia or even regenerate infarcted myocardium. Findings from mouse models of myocardial infarction22 launched numerous studies to identify biologic therapies with the goal of restoring normal cardiac function after infarction rather than just modifying postinfarction remodeling. The seminal advance leading to this notion was identification of cells with the capacity to engraft into the myocardium as contractile or vascular elements. The observation of native stem cell (myocardial or bone marrow origin) engraftment suggested that postinfarction healing could be amplified to produce functional heart tissue rather than noncontractile scar. The benefits of such therapy are obvious and substantial. Moreover, studies of postinfarction treatments using epicardial fibrin patches containing stem cells or intracoronary injections of stem cells suggested that the approach will work.
It took about a decade for investigative groups to publish studies casting doubt on the potential of stem cells (e.g., c-kit+ cells) to regenerate functional myocardium after infarction.23 Reports of fraudulent data manipulation then followed, shaking the foundations of public trust.24,25 Even more importantly, a human trial of stem cells as regenerative therapy for postischemic cardiomyopathy (CONCERT-HF Trial) was underway as the allegations of scientific fraud emerged. This multicenter study was halted on the recommendation of the study’s Data Safety Monitoring Board when the breach of integrity in the foundational research became known. The trial was only recently resumed to provide follow-up of the patients already entered in the study.26 The point of mentioning this incident is to exemplify how trust and integrity are essential for advances to occur in the field of circulatory support. Indeed, integrity is necessary for any scholarly or research activity. This was noted by historian John Hope Franklin who stated that, “You can’t have a high standard of scholarship without having a high standard of integrity, because the essence of scholarship is truth.”27
Medical research is a partnership that demands altruism and integrity from the investigators. These were personal characteristics of Dr. Frank Hastings as demonstrated by his contributions to the early development of artificial hearts. Today, it is incumbent upon us to follow his lead.
1. Obituary: Frank Hastings, in US research. New York Times Mar 16, 1971.
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3. Frank W. Hastings, outstanding artificial heart
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5. Four different booster heart systems-two implanted in calves-shown by AHP. The NIH Record 1969.21: 6
6. Contractors, scientists discuss progress and devices at artificial heart
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11. Kirklin JW, Dushane JW, Patrick RT, et al. Intracardiac surgery with the aid of a mechanical pump-oxygenator system (gibbon type): Report of eight cases. Proc Staff Meet Mayo Clin 1955.30: 201–206.
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15. Scheidt S, Wilner G, Mueller H, et al. Intra-aortic balloon counterpulsation in cardiogenic shock. Report of a co-operative clinical trial. N Engl J Med 1973.288: 979–984.
16. Moulopoulos SD, Topaz SR, Kolff WJ. Extracorporeal assistance to the circulation and intraaortic balloon pumping. Trans Am Soc Artif Intern Organs 1962.8: 85–89.
17. US Department of Health and Human Services: Artificial Heart
and Assist Devices: Directions, Needs, Costs, Societal and Ethical Issues. 1985.Bethesda, National Institutes of Health.
18. Waters BH, Park J, Bouwmeester JC, et al. Electrical power to run ventricular assist devices using the free-range resonant electrical energy delivery system. J Heart Lung Transplant 2018.37: 1467–1474.
19. Kleinheyer M, Timms DL, Greatrex NA, Masuzawa T, Frazier OH, Cohn WE. Pulsatile operation of the BiVACOR TAH - motor design, control and hemodynamics. Conf Proc IEEE Eng Med Biol Soc 2014.2014: 5659–5662.
20. Zhang J, Zhu W, Radisic M, Vunjak-Novakovic G. Can we engineer a human cardiac patch for therapy? Circ Res 2018.123: 244–265.
21. Taylor DA, Parikh RB, Sampaio LC. Bioengineering hearts: Simple yet complex. Curr Stem Cell Rep 2017.3: 35–44.
22. Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodelling. Nature 2002.415: 240–243.
23. van Berlo JH, Kanisicak O, Maillet M, et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 2014.509: 337–341.
24. Johnson CY. Scientists argue heart stem cell trial should be paused. Washington Post Oct 18, 2018.
25. Kolata G. He promised to restore damaged hearts. Harvard says his lab fabricated research. New York Times Oct 29, 2018.