The history of liver transplantation

SPEAKER 1: If we begin way back before the 16th century, at the advent of medicine as we know it, the first evidence of something approaching a transplant was reported back as far as the 1100s, and concerns teeth. Here teeth, which had been knocked out, probably in a fight, we re-implanted. And this is revisited right up to the 1500s when noblemen and women allegedly would receive replacement teeth from their own servants. This was probably done quickly and without pain relief, although ether was available during this period, but was mostly used on animals at this time. Then in 1628, a great English scientist, William Harvey, described the circulation of the blood.

This is absolutely key to the field of transplantation as we begin to understand how the organs are actually connected to their blood supply. A little later in 1665, Robert Hooke used a microscope to describe the structure of cells as we would know them. And then a couple of years later in 1667, early blood transfusions were performed. These experiments were a little strange, as blood from animals was given to humans, and not very successfully as you might imagine.

The physical sciences advanced in the next few years with another great British scientist, Isaac Newton, first describing the laws of gravity and physical motion in 1667. And then later in 1751, a famous American, Benjamin Franklin, first realised that lightning was electricity. But we have to wait another 20 years until 1771 for our next transplantation advance, which again features teeth. Here, John Hunter, another British scientist amongst others, described the transplant of human teeth onto the comb of a rooster. Now I’m not sure how you would decide the success of this experiment, but unfortunately some of his other studies relating to human to human transplants had the benefit of revealing more information about how syphilis was transmitted.

And while we’re talking about syphilis and disease, there was another seminal discovery in 1796, when Jenner first described smallpox.

The 19th century begins on a much more positive note, with the discovery of morphine and its properties in about 1805. The beginning of the 19th century’s also characterised by the use of other drugs with similar properties, such as ether and chloroform, more commonly during surgical procedures. There was also an increasingly grizzly public interest in surgery and dissection, helped I’m sure, by the publication of Frankenstein by Mary Shelley in 1818. Her doctor sourced spare parts for his creature from the dissection room and slaughterhouse, which isn’t too far from the truth of what was going on at about this time to advance medical and anatomical knowledge. In the 1820s we begin to see early blood transfusions in the UK and America.

However, these were dogged by poor success due to clotting of the blood prior to transfer. Also in 1820s, two other famous characters appear between about 1827 and 1829 in Edinburgh, a centre for medical excellence. These two, called Burke and Hare, practised the kind of organ use hinted at in Frankenstein, and were responsible for 17 deaths in this period. The pursuit of anatomical knowledge and discovery was accelerating at this point, and the demand for bodies was rapidly outstripping supply. So medics such as Doctor Robert Knox began to pay for bodies to study, which started a trend for the illegal exhumation of dead bodies.

It’s likely that he had a relationship with Burke and Hare, which led them to start killing people to supply material. In 1846, William Moulton reported use of anaesthesia in surgery, followed by another example in 1849 describing the use of ether as pain relief in removing a tumour from the neck of a patient. Nitrous oxide is also being used about now, particularly in dentistry. And chloroform was also popular, particularly as a consequence of the fact that then Monarch, Queen Victoria, gave birth to her eighth child, Prince Leopold, in 1853 using chloroform as pain relief. A few years later in 1895, x-rays are described and understood for the first time.

And as the 20th century begins, we see a more widespread use of surgical procedures such as skin grafts and swapping of tissues from one patient to another, sometimes even from an animal to a human. This was often called grafting, probably as a nod to the kind of procedures that were performed by horticulturalists at this time. Transplantation as a term is present, but refers more exclusively to internal organs, such as the ovaries and kidneys. And these studies probably inspired HG Wells to write his novel The Island of Doctor Moreau, which features cross species transplantation in 1896. The same year, we also get our first real understanding of the concept of radioactivity here, as described by Henri Becquerel.

There’s a general environment of continued public interest in transplantation around this period, propagated by press reports of skin grafting experiments and other examples of animal transplants, which were not very successful. There are also cases where donors were being forced to donate organs against their will. Positive news appears at the beginning of the 20th century, when the science finally catches up with the science fiction. There’s a seminal early discovery in 1922 by Karl Landsteiner who realises that there are different types of blood. And this has a huge bearing on our use of blood in medicine. He got the Nobel Prize for this in 1930.

And his studies were followed by a surgical advance in France from Alexis Carrel, who described the procedure for joining blood vessels together. This is key for transplantation by enabling connection of the donor organ to the recipient blood supply. So at about the time that Albert Einstein was formulating his theories on relativity, we now understand blood types, and the connection of vessels. And during the war in 1918, blood transfusion really comes to the fore for becoming an established technology. This was aided by the fact that we now understand blood types and anticoagulation, and are also able to bank blood for use at a later date. The first renal transplants begin now in earnest, with the first kidney transplant attempted in 1936.

It wasn’t routine to use until the 1950s, though. In 1948, we see the inception of the National Health Service in the UK, so now doctors, nurses, and hospitals combine their services for free at the point of delivery. There’s also an important local discovery here in Birmingham in 1952, a group of scientists at the university, Billingham, Krone and Medawar a Nobel laureate immunologist, described the use of steroids. They use cortisol acetate during skin graft experiments in animal models to prolong the survival time of the graft. Thus paving the way for immunosuppressive drugs in humans. This was at the same time as Salk was describing and testing the first polio vaccine.

And in 1954, we see the first really successful renal transplant in Boston, between twins. Followed in 1959 by another advance in immunosuppression. Here, mercaptopurine a precursor to azathioprine which is a drug we still use today, was described by Schwartz and Damashek who showed that it suppressed immune responses also in skin grafting experiments in animals.

So now we’re in the 1960s, which is a key time in the context of liver transplantation. Lots of advances have been made in other disciplines, making it theoretically possible. And we also have some progress made in a practical sense. Thomas Starzl’s group in Boston have done experiments, primarily on dogs, to show that liver transplants are technically possible. Renal transplantation and the discovery of immunosuppressive drugs meant that liver transplant was more acceptable as a concept. But in the 1950s and ’60s in general, many doctors and the scientific community were not very optimistic about the survival and function of solid organ transplants between genetically different individuals.

In about 1961, for example, a future Nobel laureate, Frank McFarlane Burnett, said that he felt that the present outlook was unfavourable to success. Fortunately, many pioneers continued undaunted, post 1960. Now renal transplantation in particular advances and the immunosuppressive drugs begin to work well. The first UK renal transplant between twins occurred in Edinburgh in 1960. And in 1962, Thomas Starzl combined azathioprine with steroids for renal transplant patients with great success. This drug combination is still used today. Thomas does also performed the first human liver transplant in 1963 in Denver. But this wasn’t successful, and the patient didn’t survive, dying shortly afterwards from blood loss. However, Thomas learned a lot from this experience and did try again.

The next four patients all died before the 25 day time point. Autopsy reports suggested that the liver function of all of these patients was good. And that they’d actually died as a result of infection. However, the medical community were really sceptical now, so no more were performed until 1967, as the surgery was considered too difficult. From 1967 onwards, it did continue, but survival was poor, only about 25% in adults. The immunosuppressive drugs did mean that people were living for more than a year now, both in the USA and Europe. And the transplant landscape was very interesting at this time, with the first UK renal transplant from a non-heart beating donor taking place in 1965.

This potentially expanded the pool of available organs. And in 1967, as I said, we have the first successful liver transplant, and also the first human heart transplant in South Africa. A year later, we have the first heart transplant in Britain, and also the first UK liver transplant performed in Cambridge by Roy Calnes group. Interestingly, he too, like Starzl went on to discover more about immunosuppression, as they both realised that they needed to preserve the life of their grafts. So typically in the 1970s, about 15% of patients survived their liver transplants to a year, using a combination of steroids and azathioprine as immunosuppression.

New drugs come onto the horizon now to improve this. So in 1976 we see the first use of cyclosporine a, a T cell activation and proliferation inhibitor with the first paper describing its use, and importantly that it was specific and safe, appearing in the Lancet in 1978. And this changes the future of heart and liver transplants, particularly in the 1980s, when they become to be considered more routine, rather than as a research procedure, particularly when cyclosporine was combined with prednisone, although this can be associated with some side effects, such as renal toxicity.

So now we enter the 1980s. And there’s a big global increase in the number of transplant procedures with great improvement in surgical techniques. Thanks to many doctors learning in centres in the US where surgeons like Starzl are performing procedures, and also as a consequence of better immunosuppression. So for example, we move from about three transplant centres in the US in the mid-1970s to over 100 now. However, in the 1980s liver transplantation is still a long and complicated procedure, using upwards of 20 to 30 units of blood and other products like platelets. However, survival is improving.

So if you look between about 1979 and 1980, of the 12 transplants that Thomas Starzl performed in Colorado using cyclosporine, 11 patients to survive to one year. Thomas then moved to Pittsburgh and continues to teach others how to perform the operation. In the UK, too, transplantation is taking off. In 1980, we see the first transplant coordinators being appointed in UK to identify potential donors and match them to recipients, thereby facilitating the procedures. And in 1983, the FDA approves the use of cyclosporine meaning that they are happy with both its safety and efficacy. And in the same year, we establish a national transplant programme in the UK.

This means that there’s a national availability of shared organs between the nine specialist centres. There are also important changes to the law surrounding transplantation at this time. And in 1984, in America, the national organ transplant act is passed to forbid the sale of human tissue and to ensure that allocation is equitable and fair. I should also have said, actually, that in 1982 in Birmingham, we do our first liver transplant.

At this point in the early 1980s, it would typically take eight hours to collect donor liver. And the recipient operation can take up to 12 hours. So it’s still a relatively new field and quite a lengthy procedure. In 1984, two scientists, Bismuth and Hussein, pioneered the introduction of the split liver transplant, which was of particular significance for children waiting for livers. In 1986 and 1987, we see more advances in immunosuppression. In 1986, we see the first reports of an antibody, OKT3, a CD3 antibody which binds to immune cells and interferes with their function. And in 1987 a new drug called Tacrolimus, or FK506, was discovered. This was actually found in a product of soil bacteria isolated in Japan.

And it, too, blocks t cell function and signalling. It’s particularly good at protecting grafts that are already experiencing rejection. Later in the 1980s, in 1988, we see an advance in the field of liver preservation solution. We have the development of the UW, or university of Wisconsin, solution which was originally used for pancreas transplantation, but is now more widely used for all solid organ transplantation to preserve the tissue and extend its storage time. And this is far better than the previously used Collins solution, in terms of improving the quality of stored organs.

In the late ’80s and early 1990s, split liver and living donor transplantation become more common, particularly in countries like Japan and the Far East, where cadaveric transplantation is rarer. So in about 1990, depending on which report you read, you see the first living donor procedure, where a mum donated a portion of liver to her son. Then there are about 20 cases of this in the next few years with survival rates up in the order of about 85%.

In 1990, the Medicare health insurance system in the United States agrees that it will fund liver transplantation, which again accelerates the number of transplants performed. We also see some more unusual advances in the late ’90s, here involving Thomas Starzl again, and Xenotransplantation, with the first baboon to human liver transplant. Now obviously there are ethical issues associated with this procedure. But at its simplest, it would increase the number of donor organs available, if you could include organs from another species. In this case, a man presented at Thomas Starzl’s clinic in Pittsburgh who was Hep B and HIV positive and had been refused a transplant elsewhere. He was going into liver failure and needed a liver urgently.

And the group in Pittsburgh theorised that the baboon liver would not get re-infected with hepatitis B, so he was given a liver. And he did indeed survive for 70 days, after which he died, unfortunately, from a subarachnoid haemorrhage that was ascribed at the time to result from a fungal infection. When they looked at his liver, it was functioning properly and making albumin and doing all the things that a liver should. But there was evidence of biliary congestion that probably contributed to the failure of the liver. In 1994, we see our first living donor procedure here in the UK, and a rapid worldwide increase in transplant numbers.

So that by the end of the ’90s, a good surgeon could perform a transplant in around three hours. And finally, in 1997 in Scotland, we see the cloning of Dolly the sheep from an adult cell. And this is significant because similar cloning technology may mean that one day you might be able to clone and grow an entire human organ from a single adult cell.