The Compatibility Gene, page 21
One important difference between neuronal and immune synapses is that nerve cells sustain connections for very long periods of time – often years – while immune cells are specialized in making relatively brief contacts with other cells. An immune cell must assess the state of health of another cell very quickly and move on. An immune cell can kill a single tumour cell or virus-infected cell as fast as in five to ten minutes before moving on to check the next cell.
As well as forming synapses, another thing that nerve cells specialize in is using long protrusions or axons to connect with other cells that are far away. The textbook view of immune cells is that they don’t do this; axons are something special for neurons. But again, the textbooks probably don’t have the whole story, and immune cells may actually physically connect with other cells over long distances – albeit in a more transient fashion. My research team and others have observed that long tubes made of cell membrane do readily form between immune cells and other cells.43 I called these connections ‘membrane nanotubes’, and they could constitute a new mechanism for communication between cells that are far apart. A cost of having these connections is that viruses such as HIV may use these connections to efficiently spread between cells.44 Dangerous proteins that can cause mad cow disease, called prions, can also move between cells along nanotubes.45 But these nanotubes are hard to detect – because they are so thin – and it remains an open question as to when and where they occur in the body; this is at another edge of our knowledge.46
Whether or not this particular detail about immune cells turns out to be important, it is already clear that our immune and nervous systems intersect at many levels. They must work in unison – because many molecular components and cell structures are shared. And this is a theme that emerges from much contemporary research in human biology. As we seek to understand how the billion proteins in an average cell allow them to move, multiply, create a brain or defend us against viruses and bacteria, we are beginning to discover how so many aspects of our bodies are intimately connected. The Human Genome Project revealed that we each have around 25,000 genes, which was a far smaller number than most scientists had predicted before the project began. And now we see why: because genes multi-task, making it inevitable that disparate aspects of us are interconnected.
The link between our immune and nervous systems through our compatibility genes is especially intriguing, because these genes vary so much between us. We know that these differences matter in our immune system and there’s the possibility that something of our brains could be affected as well. However, there’s simply no escaping the fact that we haven’t got this all worked out; knowledge always ends somewhere, and that’s never satisfying. To know more, you have three options: 1. sit back and wait patiently; 2. put on a lab coat and try to dig deeper yourself; or 3. encourage children to wonder, and maybe they’ll figure it out. Perhaps we should have known from the beginning that any chapter about the brain would have to end too soon; everyone knows that there are more questions than answers in brain science. As Hubel said,
We breathe, cough, sneeze, vomit, mate, swallow, and urinate; we add and subtract, speak, and even argue, write, sing, and compose quartets, poems, novels, and plays; we play baseball and musical instruments. We perceive and think. How could the organ responsible for doing all that not be complex?47
Little in human biology is as miraculous as the brain. But birth must at least come close. And guess what: our compatibility genes turn up there too.
10
Compatibility for Successful Pregnancy
The idea behind this chapter doesn’t really need words that are poetic, personal, colourful or clever because it is explosive enough said plain and simple: our variable immune system genes influence whether or not pregnancy is successful. Couples having certain combinations of immune-system genes are more likely to miscarry or have other problems in pregnancy. This extends the reach of compatibility genes into a whole other realm of human biology and links two of the most powerful natural forces that control human existence – survival from disease and successful reproduction.
Pregnancy has long been recognized as a problem for the immune system. Peter Medawar is often credited with bringing the issue into focus in an influential article published in 1953.1 From his experiments – and the theories of his contemporary Burnet – he knew that detection of non-self can trigger an immune reaction, and this is what causes transplant rejection. Medawar realized that a foetus has half its genes from its father – so why doesn’t the mother’s immune system attack the foetus for being different, just like in a transplant? Every baby in every mother’s womb must survive against the normal rules for successful transplantation. And so – Medawar reasoned – pregnancy presents a paradox, because a mother must nourish, not reject, tissue that is genetically different from her own.
Medawar considered that the most likely solution to this paradox is an anatomical separation of the foetus from its mother, but he never made much headway into exploring any details.2 He was right that there is no direct contact between an embryo and its mother: a baby develops within an amniotic sac, and its blood circulation is kept separate from the mother’s. The place where genetically different cells derived from the foetus could meet the mother’s immune system is in the placenta, the organ which grows for nine months to connect the developing baby and the mother through the umbilical cord. The placenta is where an immune reaction must be prevented – and where the answer to Medawar’s paradox must lie.
The human placenta lies on one side of the mother’s uterus (or womb) and its main job is to allow nutrients and gases to pass between the mother and baby. The structure of the placenta – and birth in general – varies a lot between animals. While this is a great source of wonder for anyone fascinated by the diversity of life on earth, these differences are a source of frustration for scientists trying to work out basic principles of pregnancy. This is one area of human biology for which studies in animals are of limited use.3 But, unlike most other human organs, it’s relatively easy to obtain a human placenta, and so we know a great deal about the cells that go to make the placenta and its overall anatomy.
In the human placenta, maternal blood flows over a tree of finger-like projections, or villi, made from cells derived from the foetus. These villi contain foetal blood – to collect gases and nutrients – and are coated on the outside with cells that are called trophoblast cells. These trophoblast cells are, in effect, foetal cells that are in direct contact with the mother. A second type of cell from the foetus also contacts the mother’s tissue – they are called extra-villous trophoblast cells. These foetal cells directly invade the mother’s uterus and affect the walls of her arteries to help make sure that there is blood flow sufficient enough for nutrients to be absorbed by the foetus.4 Where these trophoblast and extra-villous trophoblast cells from the embryo contact the mother, two individuals are connected in the most intimate way possible.
From this, the answer to Medawar’s paradox is reduced to understanding trophoblast cells. A solution to the problem would be if trophoblast cells come into contact with the mother’s blood but not her immune cells. That is, if the mother’s immune cells are prevented from entering the uterus during pregnancy, making the uterus a privileged site in the body like the eye and the testis – special places where immune responses are prevented from occurring. Rupert Billingham – from Medawar’s holy trinity – was one prominent scientist who explored this idea during the 1960s. But he found out, as did others, that immune cells can reach the uterus during pregnancy and infections can be fought there.5 This isn’t the answer.
Part of the true solution to Medawar’s paradox is that trophoblast cells derived from the foetus are different from almost all other types of cell in that they are not able to trigger a strong immune response. Specifically, trophoblast cells don’t make the proteins HLA-A and HLA-B, while almost all other types of cell in the body do. Trophoblast cells still make the HLA-C protein,6 but by lacking HLA-A or HLA-B, there’s not much for the mother’s T cells to look at on trophoblast cells. In this way, they can avoid switching on the mother’s T cells.
The situation is reminiscent of how some viruses infect cells and interfere with HLA proteins so that T cells can’t detect that anything’s wrong. But when that happens, another arm of your immune system spots the problem. Recall how Natural Killer (NK) cells can be activated by detecting ‘missing self’; a loss of HLA proteins at the surface of cells can itself be taken as a sign of trouble. So if trophoblast cells inherently lack HLA proteins to avoid an immune reaction from the mother’s T cells, why wouldn’t they instead activate the mother’s NK cells?
One solution to this conundrum would be if a mother’s NK cells don’t enter her uterus during pregnancy, even if other immune cells do. And so this begs the question of which kinds of immune cells there are in the uterus. Three pioneering British women answered this question independently in the late 1980s. One was Ashley Moffett, working at the time with Malaysian-born Yung Wai (Charlie) Loke at the University of Cambridge.7 Loke was already in his fifties while Moffett was not yet an established scientist, having focused her career instead on clinical medicine. Loke and Moffett’s story – a long partnership which began with Moffett’s observations about which type of immune cells are present in the uterus – leads us to the unexpected link between the immune system and pregnancy.
Born in 1934, Loke had taught medicine in Malaysia before being recruited to Cambridge in 1967, where he had earlier been a student and where he then stayed thirty-five years, until retiring in 2002. His reputation was established in 1986, by being the first to isolate trophoblast cells from a human placenta so that they could be studied in detail. Moffett says that Loke is just as happy ‘in a sarong, a tweed jacket or his scarlet academic gown’.8
Loke had had a distant relationship with his parents and was looked after by nannies during his early childhood. From age thirteen, he went to boarding school in the UK. He had wanted to be a marine biologist but ended up in medicine because he was taught at boarding school that medicine – unlike marine biology – was a proper career. Also at boarding school, he was given his name – Charlie – because nobody could pronounce Yung Wai. He has always remained an outsider. Even though he spent so long in Cambridge, he would often feel excluded when a conversation centred on an aspect of society he didn’t know much about, sometimes bringing on a deep loneliness in the company of friends and colleagues.9
Before being sent to boarding school in the UK, Loke and his family fled from Malaysia to Singapore when it was captured by the Japanese in 1941. He moved again and lived under Japanese occupation in Kuala Lumpur with scarce resources and a diet of brown rice.10 Memories of people being moved against their will influenced him ever after. He would always refrain from joining organized sightseeing tours often arranged during a scientific congress because he didn’t like the idea of being shepherded about in a large group against one’s free will.11 His passion for freedom included making sure that his thinking was never trapped in paradigm.12
In fact, Loke was about as free as any scientist could be. He came from an exceptionally wealthy family, his grandfather having founded the tin and rubber industries in Malaysia. So, if he didn’t get a particular research project funded through the normal peer-review system, he could just fund the work himself.13
At the time they began to work together, Moffett had only recently returned to work after a five-year career break during which time she had three children.14 She had first met Loke while she was an undergraduate student; Moffett being one of about twenty women studying medicine with nearly 250 men.15 Moffett had trained as a neurologist but took a job as the pathologist in a Cambridge maternity hospital, simply because it was all that was available. Quickly, she realized that a maternity hospital is a hectic environment to work in: babies are born round the clock without any consideration for sociable working hours. Her duty was to diagnose problems in pregnancy from biopsies and medical notes, but when Moffett queried how the biopsies actually related to the underlying causes of problems in pregnancy, nobody seemed to know; nobody had time to think about it. Biopsies could provide tell-tale signatures of particular problems in pregnancy, but nobody knew what caused such characteristics.
Moffett was often half asleep – with babies on her mind at work and at home – but she wanted to understand what happens when pregnancies didn’t work out, and pre-eclampsia was one problem she came across frequently. It is a condition caused by abnormalities in implantation, resulting in poor blood flow in the placenta and high blood pressure in the mother. Left unchecked, it can lead to eclampsia, with symptoms that include seizures and coma – and which can be fatal. Looking through the biopsies, Moffett couldn’t help but wonder why some women have this problem and others don’t. And it felt unfair to her that other medical problems were studied so much more intensely. She felt that there was a gravitas given to, say, research in cancer – even relatively rare cancers – that just didn’t seem to apply to studying pre-eclampsia, even though it affects 6–8 per cent of pregnancies. Pre-eclampsia can often be resolved with speedy delivery of the baby by caesarean section or induction of birth, but occasionally an abortion is necessary. The intervention saves lives, but premature birth of babies can sometimes lead to other problems – and the root cause of the problem is left unchecked. Moffett felt that if pre-eclampsia was a male problem, it wouldn’t have been so under-studied.16
Each time she brought her microscope into focus, she didn’t just seek a diagnosis, she looked for clues as to what caused pre-eclampsia. One thing she noticed over the slides she examined was that immune cells in the uterus were often particularly speckled or granular. Other scientists had already found immune cells present where foetal trophoblast cells invade a mother’s uterus, but their identity was unclear. Moffett had read that an unusually speckled appearance was characteristic of NK cells – recall that this was the trait used to identify human NK cells in the first place. In 1987, she decided to go and see Loke, the renowned local expert in the placenta – to tell him that she had discovered a lot of NK cells present in the uterus during pregnancy. She expected the old master to be flabbergasted – but his response was simply: what are NK cells?17
Loke wasn’t ignorant. Rather it was a time when NK cells were relatively little known. Kärre’s idea for the way in which NK cells detect diseased cells – the ‘missing self’ hypothesis – was only beginning to be debated. Loke got up to speed on NK cells and he invited Moffett to leave her hospital work and take up research full time in his laboratory. He mentioned that, if she really proved that NK cells are abundant in the uterus, she would probably never return to patient care. Moffett agreed to take a short sabbatical in 1987 and Loke’s prediction proved right; she never did return to clinical medicine.
In Loke’s lab, Moffett examined the uterine immune cells by systematically comparing stains for different kinds of cell and confirmed that a huge fraction of them were NK cells. They published their observations in a relatively obscure specialist journal.18 Neither Loke nor Moffett was ambitious in a career-focused way and they never thought it important to seek a higher-profile place to publish.19 The two others who discovered the presence of NK cells in the mother’s uterus around the same time as Moffett were Judith Bulmer at Newcastle University and Phyllis Starkey at the University of Oxford.20 Bulmer works as a clinical consultant for placental pathology, while Starkey left science to pursue a career in politics, becoming a Labour Member of Parliament in 1997 – it gave her ‘a chance to change people’s lives for the better’.21 It probably helped her in politics that she had training in science like it helps in science to be good at politics.
It isn’t just coincidence that much of the research described earlier in this book was male-dominated, while here women take the lead. In the six decades over which this story has unravelled, the role of women in science has improved considerably – a trend likely to continue as the stereotype of the male scientist becomes outdated and ignored. All three women, however, published their discovery about the placenta in specialist journals which weren’t read by the mainstream NK-cell research community. The first time NK-cell researchers heard of this discovery was when Moffett presented her data in a poster at the NK-cell congress held in St Petersburg, Florida, in 1992. Discussion at that meeting centred on how NK cells detect diseased cells – and Kärre’s idea of NK cells looking for ‘missing self’ was beginning to be accepted. All research on human NK cells at that time was done using cells isolated from blood. Moffett’s suggestion that NK cells were also abundant in the uterus was met with bemusement. At that time, these meetings were male-dominated, and by far the most common question asked about her discovery was simply: ‘What is a uterus?’22
Nowadays, the presence of so many NK cells is known to be a characteristic change to the uterus caused by the hormone progesterone. NK cells accumulate as part of the monthly cyclical changes that occur in the uterus and they die off a couple of days before menstruation, or stay if pregnancy occurs. Rather than ‘What is a uterus?’, the important question to be asked is ‘What are all these NK cells doing there?’ NK cells specialize in detecting a loss of compatibility protein from cells, which is exactly the case for trophoblast cells – so what stops these NK cells from attacking these cells in the placenta?
