From the publication of Mary Shelley’s Frankenstein in 1818, the prospect of using the organs of another human being to help prolong or improve the life of a fellow person has long fascinated both the medical community and the general public.
It took a while before the real world caught up with fiction, however, with the idea of transplantation from a donor to living subject only beginning to take shape in the late 19th century.
Such small but important innovations included the first reported use of a skin graft from a recently deceased person to a burned man in 1881, while the idea of replacing a person’s bone marrow to treat leukaemia began to form in the 1890s, although early attempts involved patients taking bone marrow orally following a meal.
Arguably, the first modern transplant was conducted in 1883 by Theodor Kocher, who pioneered treatment of thyroid conditions by implanting human thyroid tissue into living people in an attempt to correct the loss of postulated thyroid functions.
This was followed in the early 20th century by the first successful cornea transplant conducted by Dr Eduard Zirm, who was able to give sight back to a man blinded by caustic lime.
The early to mid 20th century saw further developments in transplantation, including the first human-to-human kidney transplant in Russia in 1936, the first successful lung transplant in 1963, the first successful liver transplant in 1967 and the first successful heart transplant also in 1967.
With these internal organ transplants came the problem of organ rejection by the host body, with the immune system rejecting this alien appendage.
There had been some developments into immunosuppressant compounds at this stage, including the steroid hormone cortisone, the purine analogue azathioprine and radiotherapy, but severe side effects for each ensured that transplantation remained a limited choice for many with organ problems.
The breakthrough began in the 1970s with the discovery of the immunosuppressant effects of cyclosporin – the first of a new generation of immunosuppressive drugs called calcineurine inhibitors that could prevent organ rejection without the harmful toxicity of available products.
Cyclosporin was first discovered in Norway in 1969 by Sandoz biologist Dr Hans Peter Frey from a soil sample collected in a plastic bag by a Sandoz employee on a trip (the company encouraged employees to collect such samples on business trips and holidays to search for new antibiotic drugs from fungal metabolites).
Although initially investigated as an anti-fungal antibiotic, fellow Sandoz researcher Dr Jean Borel discovered the compound’s immunosuppressant potential in its ability to suppress T cells in the immune system.
A pure form cyclosporine was synthesised in 1973, with further investigation by Dr Borel and his colleagues, including Dr Borel testing the compound on himself to discover its potential for use in injection.
Other researchers then took on the task of investigating cyclosporine’s potential in preventing organ rejection, including Cambridge University’s Sir Roy Yorke Calne, who demonstrated promising results for the drug’s use in animals, as well as early efforts in humans.
These early human studies produced some troubling results, however, including high incidence of lymphoma and high patient mortality, due in part to overdosing of cyclosporine.
One of the major advancements came in March 1980 when 12 liver transplant patients began taking the drug in a more careful dose in combination with the steroid prednisone as part of a study led by Dr Thomas Starzl.
Of these 12 patients, 11 lived for one year or longer, while the study’s paper published in the New England Journal of Medicine remarked that there was a “striking improvement in the early results after liver replacement”.
This trial helped boost interest in cyclosporine’s potential as an immunosuppressant, and further research from Dr Thomas Starzl helped support the US FDA’s decision to approve cyclosporine in 1983, with Sandoz launching the drug under the brand name Sandimmune.
The increased use of cyclosporine in combination with steroids meant transplantation became more realistic prospect for many patients, with Dr Starzl describing in an essay for Nature Medicine how a Consensus Development Conference for liver transplantation held by the US National Institutes of Health decided to update liver transplantation from an ‘experimental procedure’ to a ‘clinical service’.
“The resulting worldwide stampede to develop liver-transplant centres was even more dramatic than that of kidney transplantation two decades earlier,” said Dr Starzl.
It was an effect also seen in other forms of organ transplant, including bone marrow, heart and kidney, initiating the modern era of organ transplantation as a routine healthcare procedure, with tens of thousands of transplants performed each year across the world.
Of course, the procedure is still a major operation, and chronic rejection – involving long term treatment with high doses of immunosuppressives – can be a burden for many patients.
Nevertheless, cyclosporine enabled a huge leap forward in medical science and helped the fantastical become reality.
