As this project shows, the 1960s has many legacies. And none so illustrious as the progress in organ transplantation surgery. During our era, all the knowledge and strivings of previous times finally saw success, the pace of innovation and practice accelerated, and to this day has never stopped.
The general purpose of this column is to connect the period 1960-75 to events today and to show our project’s relevance. For this reason, we turn to a very relevant pig this month, as he is the hero of our story.
On January 7, surgeons at the University of Maryland gave a man suffering from terminal heart disease a pig heart for the first time in the history of medicine. Deemed a success and a “breakthrough,” the whole world cheered Mr. David Bennett, 57, who received a new lease on life, spent precious time with his family he never thought he’d have, even watch the Super Bowl on television. On March 8, however, Bennett died from complications and causes not immediately known – perhaps only obliquely related to the transplant.
To those who know the 1960s, this is a familiar human and medical story: patient with organ failure has little hope of survival except as a candidate for a new organ, whether lung, liver, kidney, or heart. The 1960s saw all of these. But the most well-known were attempts at heart transplantation, when surgeons with names like Bernard, Cooley, Shumway and Zudhi became rock stars in the field between 1964 and 1970. Nazih Zudhi alone connects the 1960s to Mr. Bennett today not only as a heart surgeon but through his pioneering the first use of pig heart valves to replace worn-out human ones.
What also connects Bennett’s ordeal to the 1960s is the outcome of his journey. His death after only two months was typical, indeed expected, in the early days of transplantation. Today, such an operation is risky and likely unsuccessful depending on the organ. Patients lived for only days or weeks, and survival for the space of months was very good.
In the second decade of the 21st century, medicine and surgery are grappling with procedures that are still, in the scheme of things quite quite new. Only in the 1950s, after all, did researchers begin to understand the mechanisms of “grafts” – that is, what would attach to what without rejection; and that the phenomenon of a rejection was an immunological event.
Armed with this knowledge, drugs in the 1960s and 1970s like Imuron and cyclosporine appeared that enabled doctors to begin to manage the thorny problem of getting a body to accept something foreign, something from the outside, an organ from someone else. These were a good start, but imperfect, since the behavior of white blood cells (leukocytes) – the markers of infection often accompanying transplant operations – was not understood until well into the 1980s. Added to all this were the dosages and the reactions of patients to these powerful anti-rejection potions, so that immunosuppressive therapies themselves became a risk factor complication, and even a cause of post-operative patient death.
BUT WAIT!!
All these problems are multiplied by another connection of the 1960s to Mr. Bennett and surgeons in 2022: Our hero, the pig.
The famous heart transplant surgery legacy of the 1960s is rightly deserved but these began with constant experiments with so-called “xenografts” and xenotransplantation – animal-to-human operations – just like Mr. Bennett’s doctors were trying to do. Surgeons used chimpanzees for dry runs in the middle 1960s for human hearts, and were never successful. Almost always, this was the stuff of “last resort” procedures, usually to solve the problem of cadaveric human organ shortages, or for use on a “last resort” emergency basis with terminal cases – usually from the 1960s onward for kidney patients, but later, most commonly for liver transplants using baboons and chimps. See a bare sketch of transplantation highlights history below for context:
SOME TRANSPLANT MILESTONES
(see “Surgery Achievement Timeline” under SCIENCES)
https://www.the1960sproject.com/sciences/1960s-surgery-achievement-timeline/
1954
Joseph Murray overcame the barrier of organ rejection through identical twins; performs the first successful kidney transplant.
1960
Oxford zoologist Peter Medewar and virologist Macfarlane Burnet wins the Nobel Prize in Physiology and Medicine “for discovery of acquired immunological tolerance” (the idea of immune system unresponsiveness to certain molecules, based on the non-presence of chimerism), a breakthrough to the acceptance of successful tissue grafts, and clearing the way for organ transplantation; first genetically non-related kidney transplants; Paul Janssen synthesizes fentanyl which became an almost miracle anesthetic in long transplant operations in the early 1970s.
1963
Thomas Starzl describes the addition of corticosteroids (prednisone) to the accepted anti-rejection protocol of azathioprine (Imuran) dramatically reduces rejection outcomes, particularly kidneys at the time; Starzl performs first human lung transplant, patient lives 18 days; Claude Hitchcock (UMinnesota) uses rhesus monkey for source of renal transplant.
1964
James Hardy transplant a chimp heart into a man at the University of Mississippi, organ rejected; Starzl carries out baboon kidney transplants in six patients with graft survival of 19-60 days.
1966
Starzl performs two liver xenografts from chimps, patients live 1 and 9 days respectively.
1967
Christiaan Barnard performs first human-to-human heart transplant, Cape Town, South Africa; patient lives 18 days; W.D. Kelly and R.C. Lillehei perform first successful pancreatic transplant; Starzl tries liver transplant again, patient lives a year, considered a success.
1968
Barnard repeats heart transplant, patient lives 19 months; Norman Shumway at Stanford performs first heart transplant in North America; F.H. Bach executes successful bone-marrow transplant.
1969
Denton Cooley implants first temporary artificial heart at St. Luke’s Hospital in Houston; Starzl performs a chimpanzee liver xenograft, patient lives 2 days.
1970
Nazih Zuhdi performs first pig aortic value transplant in North America, Baptist Hospital in Oklahoma City.
1971
The immunosuppressive wonder drug, cyclosporine, discovered; cleared for clinical use in 1983; F. Derom et al. have ten-month patient post-op survival after lung transplant.
1974
Starzl attempts final chimpanzee liver xenograft; patient lives two weeks.
1984
Baby Fae transplanted with a baboon’s heart, lives 21 days
1989
Starzl et al. transplant multiple abdominal viscera; introduces tacrolimus as immunosuppressive agent.
1992
O. Goulet et al. execute infant small bowel transplantation; Starzl performs baboon liver xenograft, patient lives 70 days; another in 1993, patient lives 26 days.
2022
Bentley Griffith leads a team at the UMMC to transplant a genetically-modified pig heart into Mr. David Bennett; patient lives two months.
I have cited Thomas Starzl above as one of the most pioneering and talented surgeons of the 1960s to the present day and could name others. For our purposes, Starzl was representative of a diligent attempter of xenotransplantation, but early on in his 1964 book Experiences in Renal Transplantation, Starzl had strong views as to the limitations of animal-man operations.
“The use of any form of heterotransplantation must be considered as the purest form of investigative effort . . . There is, at present, no place for unplanned or casual procedures of this type. What must emerge from a minimal number of cases is a clean body of unassailable factual data upon which to build future progress. There is no other justification for such a surgical experiment.” (pp. 262-282)
The 1960s from which Starzl and the transplant pioneers come to fame was a time of empirical, repetitive methods, and the drugs that kept organ rejections at bay were advances in their day. Xenotransplantation – including pigs – remains a main method to learn the surgical craft and to meet emergency needs in seriously ill patients, like Mr. Bennett whose risk of death through surgery is at least as great as doing nothing.
Dr. Thomas Starzl (1926-2017) supervising a liver transplant in 1989
But it appears that Starzl’s admonition about “factual data upon which to build future progress” is alive and well, and practiced by Bentley Griffith and the team of the University of Maryland. They likely knew that mortality risk was high with Bentley and the pig. It is always high at the start of a new procedure. The 1960s and subsequent decades tell us so. But each procedure gains the practitioner more knowledge and skill. And more.
This is a new era in transplantation since the pig heart was helped in its acceptance not only by anti-rejection medications, as in the 1970s. The pig and patient were were also “genetically modified.” Antibodies produced by people, for example, recognize sugars on pig cells as foreign. The pig heart was modified to not produce these sugars. In addition, human genes went to Mr Bennett: two anti-inflammatory genes, two genes that promote blood coagulation/prevent blood vessel damage, and two regulatory proteins needed to tamp down antibody responses.
The result was that the pig heart worked for about a month without incident, considered an achievement. Beyond the month, this writer does not have information. But he knows that if the past – the period of our project – is prologue, more genetically-modified xenotransplantation will come, and more, and more. Each a little different, and tweaked, by the firepower of “precision medicine” with genetics at the core. And each procedure will present more “factual data” and chance of success.
Starzl, Bernard, Cooley, and Co. would recognize this as the pattern of tinkering toward a successful outcome. It started in the 1960s as far as transplantation is concerned. It continues today with a genetic component, but Mr. Bennett’s life and death moves us closer to extending life by transplant means.
Man’s best friend may indeed be the dog. But it appears the noble pig has a place all his own.
Until next month,
PEA
peterevansaustin@gmail.com
March 16, 2022