The Compatibility Gene, page 3
In these few pages Medawar established a way to solve the problem of transplantation. That is, he found a way to transplant skin from one animal to another so that it would not be rejected – there would be no immune reaction at all – even if the animals were unrelated. The way in which he solved the problem built upon an observation made many years earlier. In science, in general, bolts from the blue can occur – like the discovery of radioactivity by Marie and Pierre Curie and Henri Becquerel in the late 1890s – but these are exceptionally rare. Even with radioactivity, understanding the initial observation certainly didn’t come in a flash of inspiration but required a long, hard slog. In Medawar’s case, the important foundation for his seminal three and a half pages in 1953 was a paper published eight years earlier by Ray Owen at Wisconsin University in the US.16 Owen’s work was initially ignored by most, and indeed Medawar was unaware of it until he read a paper published in 1949, by Australians Macfarlane Burnet and Frank Fenner, which quoted Owen’s research.
Owen discovered that the blood of non-identical cattle twins contained cells in common, presumably coming from the shared placenta. It would be easy to dismiss this as just vaguely interesting; an anecdote of anatomy. But in the context of transplantation, the observation was startling because it meant that each twin of a non-identical pair would not react adversely to cells from the other, even though they were genetically different. The importance of Owen’s finding was that this showed that it was at least possible for cells from one animal to exist in another without any reaction occurring: the holy grail for solving the transplantation problem. Inspired, Medawar set out to try to artificially recreate this natural situation in the lab, and this put him on the right track for solving the transplantation problem, and producing his three-and-a-half-page masterpiece.
Medawar worked on the project with his two research team-mates Rupert ‘Bill’ Billingham and Leslie Brent, who both moved with him from Birmingham to University College London in 1951. Billingham and Brent are far less renowned today than Medawar is; all three investigators played a pivotal role, but Medawar was their undisputed leader. Medawar arrived in London three months before Billingham and Brent to prepare the three large newly renovated laboratory rooms that they would move into.
Brent was the youngest of the three, aged twenty-six, and the research would form part of his PhD thesis. He had impressed Medawar while working with him as an undergraduate student. Brent’s story is one of amazing achievement after an early life of adversity. He was born Lothar Baruch in Köslin, Germany, in 1925 to Jewish parents who were not wealthy but comfortable. His mother wanted him to become a cantor, leading the synagogue congregation in prayer.17 However, by the time he was eleven, things had become intensely difficult.
Later in life, Brent vividly recalled hiding behind a curtain in his parents’ home as a march went past the house and hearing people singing: ‘And when Jewish blood spurts from the knife then all is really well.’18 The men who were marching belonged to the notorious Sturmabteilung, also known as brownshirts, after the paramilitary uniforms they wore, and it was an anti-Semitic lyric they frequently sang, years before the Holocaust.19 This was the Nazi group who, later in 1938, would be responsible for coordinated attacks on thousands of Jewish shops on Kristallnacht. One of Brent’s teachers at school was a member of the Sturmabteilung and sometimes taught in full uniform.20 It bothered him that the only Jew in the class was one of his best pupils. In one instance Brent was made to stand in front of his class while his teacher gave a Nazi diatribe.
Thankfully, Brent’s parents knew the director of a Jewish boys’ orphanage in Berlin, Kurt Crohn, who had left Köslin when young. One day, in the winter of 1936, Brent went by train to the orphanage, where it turned out that many Jewish boys – even those with parents – had been sent under similar circumstances.
However, the orphanage would offer only a temporary sanctuary. In 1938 it was ransacked by a mob while the thirteen-year-old Brent hid under the roof rafters with a friend. ‘There we stayed with beating hearts,’ he later recalled, ‘until everything became eerily quiet.’21 Shortly after, on 1 December 1938, a few weeks after Kristallnacht, his life was saved by being transported to England, in the Refugee Children’s Movement, or Kindertransport, programme. Crohn, the orphanage head, had nominated him to be one of the first to travel. Brent remembers how, when they reached Holland, en route to England, they finally ‘seemed to have been relieved of [their] role as scapegoats, villains and victims’.22 Many other boys in the orphanage were not so lucky: they were later rounded up and sent to concentration camps. Crohn himself was killed in Auschwitz in September 1944.
At Dovercourt Reception Camp in Essex – a Butlin’s seaside holiday camp used as temporary accommodation for refugee children in 1938–9 – Brent was introduced to English culture and, appearing on a BBC TV documentary aimed at encouraging British couples to take in these new immigrant children, he said he wanted to become a cook. Transferred to a boarding school, he spent his holidays with various families, and, when he was sixteen, a secretary of the Refugee Children’s Movement found him a job as a laboratory assistant at Birmingham University. Army service followed. He was in the British infantry from January 1944 to autumn 1947, and it was during this time that he chose his name to be Leslie Brent – Leslie after the actor Leslie Howard and Brent just chosen from telephone directory to have the same initials as the name his parents gave him. He was told that his real name sounded too Jewish/German, which could be fatal: if captured, he could be killed for being either a German traitor or Jewish. The army made him ‘confident, self-reliant and with a sense of belief in [himself]’.23 Because he entered a training programme to be an officer, he wasn’t sent to the front during the war but was stationed in Germany in 1946 and later served in Northern Ireland.
On VE day, 13 May 1945, he was at the celebrations in central London but couldn’t join in, feeling ‘horrendously oppressed’,24 not knowing the fate of his family. The following year he accessed official files in Berlin, which noted that his parents and sister had been ‘sent east’. He mistakenly took that to mean that they were killed in Auschwitz and he uncontrollably burst into tears visiting the concentration camp decades later in 1976. Eventually, he discovered their actual fate: in October 1942 they had been taken on a crowded three-day train journey from Berlin to Riga, the largest city in Latvia, led into the woods and shot.25
After the army, in 1947, Brent returned to Birmingham and, as an undergraduate student in zoology, began research with Medawar. Already in the lab, Billingham, four years older than Brent, had been Medawar’s first graduate student at Oxford after returning from active service in the navy. Impressed by the military rigour that Billingham brought to his planning and performing of experiments, Medawar obtained a position for him so that the two could move together from Oxford to Birmingham in 1947. Billingham came from a non-academic background – his father owned a fish and chip shop – and in general he was more down-to-earth, less of a philosopher, than Medawar. But Billingham’s role in the team is not to be underestimated; he was ingenious at getting experiments to work technically and, Brent recalls, he had a ‘single-minded dedication to his career’.26
In Birmingham, initially ignorant of Owen’s earlier research, Medawar and Billingham performed experiments to test whether or not skin grafts could have a practical use in determining whether cattle twins were identical or non-identical. They did this as a small side project to give some immediate relevance to their work, since such a test would have particular significance for farmers in identifying female calves (called freemartins) that had become masculinized and sterile by being exposed to hormones from a non-identical male twin. Medawar and Billingham’s test involved simply grafting skin from one animal to another and observing the outcome. They predicted that non-identical twins would reject grafts from each other, while identical twins would readily accept grafts. However, they were stunned to find out that cattle twins always accepted grafts from each other, no matter whether they were identical or not. The penny dropped when they eventually read Owen’s earlier research, which had demonstrated that even non-identical cattle twins shared blood cells, presumably through a shared placenta. Transplants could work between genetically different animals, and from their experiments and Owen’s earlier study, the trick seemed to be that, when animals shared tissue as a foetus, they could later in life still accept transplants from each other.
So the team of Billingham, Brent and Medawar – together in their new lab in London, 1951 – discussed a specific experimental plan that could test this idea. They decided that they could use inbred mice, which have defined genetic traits obtained by mating siblings many times. They injected cells from one inbred mouse strain directly into unborn foetal mice of another, non-identical, strain. They discovered that after birth, when tested as adults, the injected mice were able to accept skin from the unrelated mouse strain whose cells had been injected. These were startling, ground-breaking results – a solution to the ancient problem of transplantation. Jean dubbed the treated mice ‘super-mice’.
The super-mice had become tolerant to skin grafts from unrelated mice whose cells they had been exposed to when foetuses. This was not the bolt from the blue that radioactivity was, for example – the trio had planned and carried out a specific experiment to test a hypothesis – but, as with radioactivity, it cannot be over-emphasized how important their discovery was; as with radioactivity, nothing in our everyday experience hints at the fact they discovered.
Key to their success as a team, all three were trained in zoology, so they spoke the same scientific language and, perhaps most important of all, they were all dedicated workaholics. Although this might read as though the breakthrough happened smoothly and simply, in practice the team had to go back and forth with variations in the conditions of the experiment to get things to work out. And in the midst of it all there was, of course, no guarantee it was ever going to work out. Doing science is like playing snakes and ladders: you can be five squares from glory, but the die rolls to four, lands you on a snake and you’re back at square one. To win, the team worked long and hard.
They then went on to verify that the process was also true for other species – doing similar, but less extensive, experiments with chicken chicks. The transplantation problem had been solved, but in laboratory conditions, and using animals rather than humans. The team were acutely aware that this was not yet a practical medical advance: it would be impractical to inject cells into a human foetus. But their experiments had nevertheless revealed a solution to a problem previously thought insoluble. They had shown that it is, after all, possible to breach the natural barrier for transplantation between unrelated animals. In 2010 I met with Brent at his home in north London and asked what the trio’s reactions were to this astonishing discovery. I had anticipated an answer involving some tension-releasing euphoria, but he simply replied, ‘Well, we just worked harder.’ Medawar and his team, I assume, would have subscribed to the view that Noël Coward put in a nutshell: ‘Work is much more fun than fun.’
During these periods of intense research, Medawar didn’t even buy his wife Jean birthday or Christmas presents – that would have taken up time. He simply asked her to go and buy whatever she wanted. And they even joked about her writing the tag: ‘To my darling wife from her devoted husband’.27 Medawar later recalled, perhaps not entirely joking, that he was ‘an outstandingly rotten father and neglected [his four] children disgracefully . . . due to [his] total preoccupation with research.’28 Even within his team, Medawar was well aware of Brent’s background but, despite sharing a great deal of time together, they never discussed the Holocaust or religion, or any other sensitive issue.29
After the mice experiments, the trio of Billingham, Brent and Medawar became stars in the scientific world, known in the US as ‘the holy trinity’. In 1956 the trio published their magnum opus,30 expanding the initial three and a half pages published in 1953 into fifty-seven pages of incredibly detailed analysis accompanied by twenty photos of experiments involving mice, chickens and a duck.31 Then, in 1960, Medawar won the Nobel Prize, together with Burnet, the Australian scientist who, in parallel to Medawar’s experiments, developed a theory that the immune system could learn not to react to cells and tissues present at the foetus stage of life. Medawar openly wished that the prize – awarded collectively to a maximum of three people – could have been awarded to all of his team.32 And in a strong public statement of how important Billingham and Brent were, Medawar shared the prize money with them. In a personal letter to Brent’s wife, Joanne, Medawar wrote that ‘I wish to make it absolutely clear that it [a share of the prize money] is no way a present but comes to Leslie as of right.’33
Medawar was also generous to Ray Owen, who had made the early ground-breaking observation that blood cells can be transferred between non-identical cattle twins. Medawar wrote to Owen: ‘Of the five or six hundred letters I have had about the Nobel Prize, yours is the one I most wanted to receive. I think it is very wrong that you are not sharing in this prize . . . you started it all.’34
It is not simply winning a Nobel Prize that makes Medawar’s name endure, it is also the brilliance of his essays and books, which remain influential; the eminent biologist and writer Richard Dawkins takes inspiration from Medawar as the ‘wittiest scientist ever’.35 An example of Medawar’s incisive writing and clear thinking comes across well in his critique of a book, The Phenomenon of Man by French philosopher Pierre Teilhard de Chardin, published in 1955. The book, hugely influential at the time, used flowery language to present wild speculations about the process of evolution. ‘It is the style [of the book],’ Medawar wrote, ‘that creates the illusion of content . . . The greater part of it . . . is nonsense, tricked out with a variety of tedious metaphysical conceits, and its author can be excused of dishonesty only on the grounds that before deceiving others he has taken great pains to deceive himself.’36
A year after Medawar’s Nobel Prize came the death of another pioneering London-based transplantation scientist, Peter Gorer. Medawar wrote a memoir of him for the Royal Society. While Medawar’s research linked transplantation to the body’s immune response, Gorer’s research had earlier connected transplantation to our compatibility genes, and some felt that he should have won the Nobel Prize.37 But Gorer had not been a great communicator – he usually spoke with a cigarette hanging from his mouth – and probably the reception of his work suffered for it. He dressed carelessly, behaved eccentrically and regularly drank half a bottle of whisky in an evening.38 He was undervalued even in his own institute, the rigid medical environment of Guy’s Hospital in London, only being promoted to professor shortly before his death. While Medawar had given up smoking in light of Richard Doll’s landmark 1950 paper linking smoking to lung cancer, Gorer died of the disease, aged fifty-four, when he could have been enjoying widespread recognition of his achievements. Gorer’s research also probably came too early to be appreciated by the general public; his main discoveries were in the mid-1930s, and it was only later, during the Second World War, that surgery for the injured made plain the importance of research in transplantation.
Gorer had studied the length of time tumours survived in different breeds of mice. He injected tumour cells into mice and then observed whether the tumour would grow and kill the mouse or whether the tumour would be destroyed and the mouse survive. Publishing his key findings in 1936, aged just twenty-nine, he discovered that what happened to the tumour depended on whether the mouse in question had inherited a particular genetic component. If a recipient mouse had a different version of the genetic component, compared to the mouse from which the tumour was taken, the recipient mouse would be able to kill the transplanted tumour and survive. But if it had the same set of these genes as the mouse from which the tumour was originally taken, the transplanted tumour would grow and kill the mouse.
Then Gorer made an intellectual leap. This process, he suggested, was not particular to tumours. Although tumours are abnormal in their growth characteristics, they were behaving in these transplantation experiments just as any other tissue would. That is, the same rules for transplantation were obeyed both by tumours and by other tissues – so, Gorer postulated, his experiments had revealed the general rules for transplantation. In effect, he discovered a specific genetic component that determined whether or not cells transplanted from one mouse to another would be attacked or left alone. In time, it was found out that the genetic component identified by Gorer includes the mouse genes equivalent to our human compatibility genes; so Gorer’s transplantation experiments are arguably where our knowledge of compatibility genes really began.
The relationship between Medawar and Gorer was complex. Medawar would often make jokes at Gorer’s expense and they argued vigorously about several scientific issues. One long-running argument was over the nature of red blood cells in mice and humans – comparing experiments in these different species caused confusion because, as we now know, the protein encoded by compatibility genes is found in small amounts on mouse red blood cells but not at all on human ones – but they didn’t know this at the time. Nevertheless, they retained an appreciation of each other’s brilliance. Fellows of the Royal Society can submit a document to record the influences and inspiration for their achievements and Medawar was moved when he found out that Gorer had written of his ‘close friendship with P. B. Medawar’. Gorer wrote that ‘it is not easy to say how each [of us] influenced the other’s ideas, but the influence was none the less potent’.39
In 1962, a year after Gorer’s death, Medawar was appointed director at the National Institute of Medical Research in Mill Hill, London. Each day an institute chauffeur would collect him from his Hampstead home and take him to work; he was always there by 9 a.m., even following overnight flights back from the US. As this most celebrated period in Medawar’s research career – with Billingham and Brent – drew to a close, he and Jean visited Russia at the invitation of the Soviet Academy of Sciences. In 1950s England, Jean’s role as housewife was seen as perfectly normal; in Russia, however, she was commonly asked what her profession was. The question lingered in her mind, and when she returned to north London, Jean began to work in Islington’s family planning clinic. She went on to become the second chair of the Family Planning Association in 1967, at a time when the contraceptive pill was radically changing attitudes to sex. But soon after, Jean and Peter’s personal life changed dramatically and tragically.
