Pink Floyd’s rock album The Wall tells the metaphorical story of a wall we build around ourselves so that we don’t expose our true passions. When society puts pressure on girls not to take an interest in science, it adds another brick in that wall. Neuroscientist Carla Shatz is acutely aware that this needs to change and she has led by example.
Shatz was the first female to get a PhD in neurobiology from Harvard and then the first female basic scientist to win a tenured position at Stanford Medical School – after being hired initially through an affirmative action policy to attract more women.1 She achieved a similar feat yet again when she became the first woman to head Harvard’s Department of Neurobiology. She loved Stanford and eventually moved back there but says of her Harvard job: ‘I couldn’t turn it down because I felt I was on a mission to represent women at the highest levels.’2 Many scientists champion a cause beyond their own research, because it takes a similar strength of character to drive change in social attitudes as it does to cut a new path in scientific knowledge – both require a healthy disregard for the status quo to break down its walls.
From her position of authority, Shatz has worked hard to help others attain a good work–life balance. Not one size fits all, she says: some people need access to good childcare while some need help in getting employment for their partner.3 She says that she knows all too well that juggling career and family is extremely challenging.4 Yet her challenge turned out to be in not having a family. She had always assumed that she’d have children at some point but, with her career going so well, she ended up waiting too long.5
Having broken the glass ceiling in her career, Shatz smashed through another invisible barrier: the prevailing scientific doctrine. At the time, proteins encoded by compatibility genes were well established as being critical in the immune system, but they were thought to have nothing to do with neurons. Through a series of experiments carried out during the late 1990s, Shatz and her team discovered these genes do, in fact, work in the brain. The immediate implication was that that the wiring of our brains involves key proteins from our immune system – and, once again, our compatibility genes appeared more powerful than we once imagined.
Basic processes such as how cells get their energy are pretty similar in all kinds of different cell types, so it is to be expected that many genes and proteins will be active in both neurons and immune cells. But compatibility genes – and the proteins they encode for – weren’t considered to participate in anything that cells do generally. They were considered to be especially adapted for a job in the immune system, so there was no reason to think they would be important in the brain. In fact, the textbook view of the time was that the brain was one of the privileged organs that are protected from immune reactions. So there was actually some reason to think that it was important that these proteins not be present in the brain.6 The thinking behind this was that the brain is such an essential organ that it would be too risky to have immune cells patrolling as usual. Damage to the brain that might be caused by an immune reaction – and the inevitable destruction of diseased tissue – is likely to be so devastating that the possibility is best avoided. In support of this idea, entry of immune cells into the brain is tightly regulated by the so-called blood–brain barrier. However, we now know that an immune response can occur in some situations – and a common view today is that the brain is protected from immune responses to some extent, but not entirely.7 In any case, Shatz’s work wasn’t revelatory for merely finding immune-system proteins in the brain – her research also indicated that these proteins were being used there for something that had nothing to do with fighting infection.
Shatz didn’t arrive at this point by setting out to study the immune system or compatibility genes. She wanted to understand how images received by the eye are interpreted by the brain. A neuroscientist by training, she worked for her doctorate from 1971 to 1976 at Harvard University under the guidance of Canadian-born David Hubel and Swede Tortsen Wiesel, who were at the time carrying out pioneering research which would later, in 1981, win them the Nobel Prize in Physiology or Medicine. Shatz joined their team, having been inspired by lectures she went to as an undergraduate student on the ‘Chemistry of Vision’ given by George Wald, famous for his research on understanding the retina (which won him a Nobel Prize in 1967). Shatz was fascinated by the question of ‘how we see’. It combined her love of art and science.8
Shatz’s PhD supervisors – Hubel and Wiesel – worked together for twenty-five years, from 1958 to 1983, to understand how our brain interprets what our eye ‘sees’. In the human brain, there are about 20 billion individual cells or neurons making a quadrillion – that is 1,000,000,000,000,000 – connections, or synapses, between each other.9 It is widely believed that the way in which contacts between neurons are configured underlies all emotion, thought and memory – somewhat similar to how the configuration of an electronic circuit determines what it does.
There was one crucial technical advance that allowed Hubel and Wiesel to probe which brain neurons fired when animals – usually cats – were shown different shapes projected onto a screen.10 Hubel – a technical whizz – had crafted a small wire, or electrode, fine enough so that it could be used to detect the activity of a single neuron. The electrode could be hooked up to an instrument that recorded – or made a sound – when one individual neuron was activated.
With this technical advance, they uncovered a spectacular array of information about how vision works. The first striking observation they made was when Hubel noticed that neurons in the brain wouldn’t do anything when he turned the lights on and off – but they would fire up when he waved his hand.11 This opened the door to the complexity of how animals ‘see’. Through a series of carefully planned experiments, the duo found, for example, that a particular neuron would react when the animal was shown a line of light orientated in a specific direction. That is, one particular brain cell would be activated when an animal was shown a line of light pointing to, say, the number two on a clock-face and not when it was rotated to point at numbers one or three. As well as this orientation-specific activation of neurons, they showed how movement of edges or borders was important in determining which brain cells fired. With this, Hubel and Wiesel could map out what they called the functional architecture of the visual cortex.
Before these discoveries, it had been assumed that what the eye saw was simply projected onto cells in the brain in some way – something like how an image is pixelated and displayed on a TV or computer screen. But Hubel and Wiesel found out that the visual field is processed and interpreted – so that, for example, a moving object is preferentially picked out from any non-changing background. It’s what you experience when you catch something moving out of the corner of your eye – like a bird flying out from a tree that you were barely aware of. Their research begun to establish how the visual world is dissected and analysed by our brain.12
It’s very rare that two scientists work so closely together over such a long period of time. Hubel said of their relationship that ‘had it not been for Torsten’s ability to keep his eye on the ball I might have squandered all my time playing with and designing equipment, rather than sticking to biology’.13 A multitude of colourful characters have made seminal contributions to science, but Hubel and Wiesel only offer an apology ‘for not having led more adventurous lives. Neither of us climbed Mount Everest, took part in the French Resistance, or sailed around the world.’14 Science was their big adventure.
Francis Crick, co-discoverer of the double-helix structure of DNA, realized that Hubel and Wiesel had opened a window into the impossible jungle of the brain.15 He had Hubel give a seminar to a small audience of ten leading molecular biologists at the Salk Institute, La Jolla, where Crick worked at the time. Scheduled for an hour but lasting for over three, the lecture ended with the select audience firing boundless questions at the speaker. The enthusiasm of such formidable scientists gave Hubel confidence and the feeling that his work was truly important or, in his own words, not so boring after all.16 Crick – turned on by neuroscience – wanted to recruit Hubel to the Salk Institute. But Hubel wouldn’t come without Wiesel, and Wiesel wouldn’t come without another colleague who in turn wouldn’t come without some of his co-workers. And negotiations evaporated. But Crick continued to meet Hubel fairly frequently and legend has it that Crick continued to edit his own final manuscript about the brain until the day he died in 2004.
Staying at Harvard, Hubel and Wiesel made many other important discoveries. They observed, for example, that different patches of cells towards the back of the brain responding to signals from the left or right eye. When they covered one eye, they found that a young animal’s brain could restructure these bands of cells and devote more neurons to signals from the open eye. This showed that a basic wiring of the visual part of the brain is present at birth but, importantly, it is not fixed for ever. Rather, the organization of this part of the brain develops during a critical early period in life, in response to what the eyes see. This research established that the cellular structure of the brain can change.
It was this activity-dependent restructuring of the brain that Shatz wanted to study. She wanted to understand exactly how it occurred, to identify which genes and proteins were switched on to develop the brain in response to signals from the eye.
For Shatz, this was a way into exploring the broad issue of how our brains change through learning and experience; a step towards understanding how the construction of the brain results from an entanglement of nature (genes) and nurture (cues from what the eye sees). Shatz sees this issue as being the key to figuring out what the brain is all about – because it’s this adaptability or plasticity that makes the brain so much more than just an ultra-powerful computer. In effect, by rearranging the connections between neurons, experience alters the hardware of a brain – something that doesn’t happen in man-made electronic circuitry.17
Shatz decided that the best way to attack the problem was to use drugs to block neural activity during development of the visual part of a cat’s brain – and determine which genes altered their activity as a result. This, in effect, gave her a list of genes activated when brain cells respond to cues from the retina. Unexpectedly, she found increased activity of compatibility genes correlated with neuronal activity, which indicated that these immune system genes could have a role in structuring this part of the brain.18
She submitted her discovery to be considered for publication in Nature. However, after a short time, an editor wrote back to her to say that he wouldn’t be able to publish the study or even send it out for in-depth peer review. He had bounced the paper off two experts in immunology and both had said there must be something wrong with the work because everybody already knows that neurons don’t use these genes; they’re only important in the immune system.19 This reaction from Nature made her realise that she was pitching a story that went against a powerfully guarded dogma – and she would need more evidence to convince people.
Pursuing the research in cats was difficult because feline genes had been relatively little studied. So Shatz switched to studying mice – where defined genetic variants are obtained easily. She realized that she could use mice which had already been bred to lack proteins encoded by compatibility genes; such mice had been used to establish the importance of these proteins for survival against infections. Shatz could examine what these mutations did to the structure of the mouse brain, something that nobody had ever thought to look at before, despite having the mice available for years.
Although these mice looked normal on the outside, upon dissection Shatz found abnormalities in the way the visual part of the brain was organized.20 She saw a higher number of connections between neurons than found in normal mice. Too many neuronal connections suggested that MHC proteins were important in pruning synapses that weren’t appropriate when this part of the brain developed. Her team also looked at another mutant mouse, which this time lacked a protein known to be important in white blood cells. She found the same alteration in brain structure, implying that other proteins used by immune cells are also important in the brain.
Her background – working with Hubel and Wiesel – led Shatz to focus on the visual part of the brain; but a question arising from her initial findings was whether or not it was only the visual part of the brain that gets affected in this way. To answer this, her team decided to look somewhere else in the brain: the hippocampus, the place where connections between neurons strengthen or weaken as memories form. In the mice that were defective in producing MHC proteins, stimulation of neurons in the hippocampus resulted in abnormally strong signals. This suggested that compatibility genes could have a role outside the visual part of the brain, affecting the area important for consolidating long-term memories.
Shatz concluded that neuronal connections in parts of the brain – even in the hippocampus – could be influenced by proteins previously thought to work in the immune system. And the reaction from other scientists? Most were cautious and sceptical, reminiscent of the reaction to Wedekind’s smelly T-shirt experiment a few years earlier. Suggesting that MHC proteins are important in structuring the brain felt like someone claiming they have a unicorn in their garden – it warranted close scrutiny.
It’s not that anybody would consider Shatz’s data as being deliberately falsified (fraud actually happens rarely in science, and only about 300 papers are formally retracted from around 1.4 million published annually),21 but rather that scientists know all too well that not everything that gets published turns out to be right – for any number of reasons. An experimenter might have been deceived by their own bias; reagents or chemicals might not have worked exactly as thought; experiments might have had inadequate controls; or, worst of all, scientists might have thought up some excuse to leave out part of the data that didn’t fit their story – ignoring the fact that at a high dose, for example, a particular drug did something that didn’t fit their hypothesis, and only publishing what happened when it was used at a low dose. It’s not always straightforward to tell right from wrong in published papers because scientists present their work as a ‘story’ based on a long series of complex experiments, and anything that doesn’t fit their ‘narrative’ often gets left out.
For Shatz’s work, the main source of contention was the lack of anyone having a detailed understanding about how the MHC proteins could influence organization of neuronal synapses in the brain. For any phenomenon that strays from what’s expected, biologists like a good explanation of how it works before taking the new idea as fact; as the mantra goes: show me how it works before I believe it’s true. Although sceptical, most scientists were intrigued, and if she was right then a burning issue was whether or not this reflected a trivial recycling of molecules to be used for a different task or whether, instead, this cracked open a fundamental link between our nervous and immune systems.
Given that compatibility genes – and the proteins they encode – vary so much, it might seem unlikely for the brain to co-opt such a complex system unless their variability was somehow important for their role in the brain. But this argument is flawed. Because it requires that we – and other living things – have evolved to end up working in an efficient or sensible way. In fact, there are many examples in nature where things work fine without being slick like an iPad. The way that we have been formed – through a process of evolution – means that everything must be built upon what went before, not constructed elegantly from scratch.
Take, for example, the path of a particular thin tube in men called the vas deferens, which transports sperm from the testicles to the urethra (it’s the connection that’s severed in a vasectomy). Instead of this tube taking a straight path, it follows a route far longer than it needs to by looping over another bit of tubing in the area, the ureter. There doesn’t seem to be any reason why it couldn’t follow a direct path; it just happened to evolve to go the long way round. This has been explained by suggesting that the position of the testicles changed as we evolved from our ancestors and as that move occurred, the vas deferens tube got caught over the ureter rather than going under it. So, things don’t evolve to a perfect design, and that’s why it can’t be taken for granted that the brain uses the same molecules as the immune system for any fundamental reason; it may have just happened to evolve that way. To claim that the connection between our immune and nervous systems is intimate – and not just a chance recycling of parts – there needs to be specific evidence.
We’ve discussed in detail how compatibility genes are linked to susceptibility or resistance to various types of infectious diseases, but also our variation in these genes has been linked to many neurological disorders, such as schizophrenia or bipolar disorder.22 This is consistent with an intimate connection between compatibility genes and our nervous system. But researchers studying schizophrenia, and other neurological diseases, differ in their view of how important these genes are. Although many tens of studies link compatibility genes to schizophrenia, dispute remains because each comes to a different conclusion about which versions of these genes are risk factors for the illness.23 This might reflect different diagnostic criteria used in studies: mental illnesses are notoriously difficult to categorize, and it is possible that different compatibility genes are important in particular versions of these multi-faceted diseases. There are at least three ways in which compatibility genes could, in principle, influence neurological illnesses.
An infection may underlie some mental illnesses; and then one way in which compatibility genes would be linked to neurological diseases is through their normal role in immune defence. In this scenario, the situation is identical to how these genes affect our susceptibility or resistance to other infectious diseases, such as AIDS. A second possibility is typified by the rare sleeping disorder narcolepsy, which has one of the strongest links of any disease to our HLA genes. About 1 in 2,000 people are affected so that their brain is unable to regulate the normal cycle of being awake and asleep.24 Sufferers can fall asleep at inappropriate times during the day and sleep poorly at night. The vast majority of people with narcolepsy have particular versions of class II compatibility genes.25 These versions of compatibility genes are found in almost all people with narcolepsy, but they are also common in those without the disease – so they are not sufficient to cause the illness and instead play some role in how it starts.
For some sufferers, there is evidence that narcolepsy is an autoimmune disease. That is, it arises because the immune system mistakenly attacks the body’s own healthy tissue. Symptoms could be caused by an immune reaction against the neurons that are important for regulating sleep and wakefulness. In support of this, a protein made by neurons triggers an immune reaction in narcolepsy patients.26 So HLA proteins could influence our susceptibility to narcolepsy according to the extent that they aid an immune attack on healthy neurons.
The third way in which these proteins could influence neurological disorders directly relates to Shatz’s discovery: that these proteins can influence the way in which neuronal connections or synapses are configured in the brain. One possibility of how this might relate to disease stems from the fact that, during any kind of immune reaction in the body, immune cells secrete proteins – called cytokines. Cytokines do many things to help the immune reaction, one of which is to increase the production of MHC proteins. So if cytokines were secreted from immune cells at a time when these MHC proteins are important in sculpting the developing brain, it is feasible that the change in their production could lead to abnormalities in the structure of the brain.27 But this is only an idea – nothing more than a feasible way in which compatibility genes link with neurological illness. Sadly, the causes of most mental illnesses remain baffling.
Aside from disease, Shatz’s discovery also begs the question of whether or not compatibility genes affect normal brain functions – perhaps in some way that’s more subtle than influencing the course of illness. Since her observations indicated that MHC proteins were important in how the brain changed in response to external stimuli – both in the visual cortex and then in the hippocampus – Shatz and her team decided to next investigate, in 2008, whether or not MHC proteins affect learning, a process that must involve changes to the brain.
It’s exceptionally difficult – perhaps impossible – to test whether or not immune system genes influence how well humans learn, but Shatz could more easily explore the idea in mice. First, Shatz clarified which types of compatibility genes were being used in the mouse brain. The genes that vary enormously among us – HLA-A, -B, -C and so on – are called classical compatibility genes. But there are also a number of other genes – in humans and animals alike – that encode similarly shaped proteins which don’t vary much between us. These are named the non-classical compatibility genes. Shatz’s earlier work didn’t distinguish between these different types of compatibility genes, but for their investigation into learning her team focused on the genes in mice that are equivalent to our HLA-A and -B genes – the classical compatibility genes that vary hugely in individual mice or people.
Mice genetically altered to lack these variable genes did indeed have defects in the cerebellum at the base of the brain. Specifically, synapses were not weakened in the right way, reminiscent of what she had discovered in other parts of the brain. The cerebellum is important for motor learning – how we learn skills by practising like riding a bike. Although we have little idea about how it works in any detail, it’s generally accepted that motor learning will somehow require a reconfiguration of the connections between neurons – some being strengthened while others weaken. So if compatibility genes can influence which synapses weaken in the cerebellum, Shatz reasoned, could they affect the ability of mice to actually learn a skill?
To test this directly, Shatz’s team used a simple apparatus called a Rotarod – a horizontal cylinder that rotates, on which mice can learn to balance so that they don’t fall off. It’s not harmful for the mice because the bar isn’t so high that it hurts when they fall. But timing how long an individual mouse can stay balanced on the bar is a way of measuring their ability. After some practice, normal mice were able to stay on the rotating rod for around a minute, but mice lacking the equivalent genes to our HLA-A and –B genes could learn to balance for nearly double that time.28 A lack of these genes isn’t something that occurs naturally, but, by deliberately testing what does happen if they are missing, this experiment revealed that compatibility genes can influence the ability of mice to learn.
Mice lacking these genes also remembered their skill for much longer because, after a four-month break from practising, they were still much better at balancing on the rod. How would our hero from Chapter 1, Peter Medawar, have reacted if a know-it-all alien had visited and whispered: Peter, the genes you’re studying – those that control the transplantation reaction – also work to fight infections, help organize the brain and influence learning? Still, stunning as these results are, there are at least two caveats – both of which Shatz acknowledges herself. First, it remains unknown whether or not humans (not just mice) use MHC proteins in this way in the brain; the problem is that it’s very hard to think up an ethically sound experiment to test these ideas on people. Second, Shatz’s experiments only show that the brain is affected in mice whose compatibility genes are completely incapacitated – an artificial situation just to test what happens if these proteins are removed. This doesn’t really tell us whether or not the brain could be influenced by the natural diversity in these genes. If there is an effect caused by differences in these genes it is surely going to be subtle, compared to when these genes are incapacitated.
Our understanding of compatibility genes in the brain has simply not yet benefited from the decades it took for everyone to agree, for example, the importance of Medawar and Burnet’s work. It is simply too soon for there to be unanimous agreement over the importance of Shatz’s observations (or pretty much anybody else’s discovery made within the last decade or so). Almost every statement in any scientific textbook is the outcome of many years’ hard work and debate; and MHC proteins working in the brain is beyond current textbook-level science. While many scientists would argue that a popular-level book like this one should also stick to established decades-old ideas, my view is that nothing can be more exciting than what’s happening at the edge of knowledge. And most questions about the brain are at the edge of our knowledge, but the field is ripe for breakthroughs in the twenty-first century.
More than 32,000 people attended a neuroscience congress held in Washington, DC, in 2011, for example, while the same meeting forty years earlier attracted just over 1,000 people.29 No other scientific discipline enjoys such stadium-sized lectures; Shatz says it feels like everyone’s becoming a neuroscientist. When she first presented her data indicating that compatibility genes are active in the brain, in 1998, it was as a lone mention of the subject, but the neuroscience congress in 2011 was chock-full of presentations about how immune-system genes influence the brain and nervous system.30 In fact, many components of our immune system are now known to influence our nervous system.
Receptors that immune cells use to detect bacteria, for example, can affect the extent of brain damage that occurs in a stroke.31 This, with several related discoveries, has established that stroke and many other neurological problems can be triggered or exacerbated by immune responses. The medical implication is that targeting immune-system components might help. Drugs that block secretions from immune cells (cytokines), for example, could alleviate the symptoms caused by neuronal injury in stroke or brain trauma.32 That Shatz helped establish connections between immune and nervous systems that soon might be medically useful must be gratifying, but when I put this to her in November 2011, she replied that, ‘like all discoveries, first everyone says it’s wrong, then everyone finds it out for themselves, and eventually everybody forgets that you made the discovery in the first place’.33
With hindsight, it maybe shouldn’t have been so surprising that molecules are shared between our immune and nervous systems. These systems must be intimately connected; we’ve all experienced feeling sad or sleepy when ill. Indeed, immune responses are connected to all kinds of physiological processes.34 In times of stress, for example, steroid hormones are released to alter energy use around the body and increase blood-sugar levels. These same hormones also dampen immune responses. They switch off excessive inflammation, which can damage tissues unnecessarily – this underlies the use of steroid hormones in preventer inhalers for asthma, to dampen immune responses in airways. A release of adrenaline triggered after an acute injury has the opposite effect; it stimulates or primes immune cells for action.
The interaction between our nervous and immune systems goes in both directions, as secretions from immune cells also affect the brain and central nervous system (and are the likely cause of us feeling sad and sleepy when ill). In fact, there is a vast web of neuro-immune circuitry that is critical to our well-being. Exercise, for example, affects the levels of various hormones and other proteins that circulate through blood, including adrenaline and cortisol levels, which in turn influence immune responses.35 Regular exercise can have an anti-inflammatory effect, for example, which can protect against diseases in which a chronic immune response is part of the problem – such as in type 2 diabetes.
More research in this area is important but in deciding what next to do – where to target funding – it’s useful to remember that Shatz’s discovery came from exploration into how vision works, not a specific attempt to study the intersection between the immune and nervous systems, nor a direct effort to tackle any specific disease. Sparks might emerge from fostering greater interaction between scientists working in silos for understanding either immune cells or neurons. Much can be learned by thinking about the differences and similarities between these two types of cell.
In 1994, immunologists Bill Paul and Bob Seder at the National Institute of Health in Bethesda wrote a speculative but hugely influential article suggesting that neurons and immune cells have some similarity in how they work.36 They reached this view because of an experiment that others performed in 1988 which showed that immune cells could secrete molecules in a specific direction, something that neurons had long been known to do.37 The importance of this was in showing that immune cells and neurons can affect another cell in contact, rather than all the cells in the vicinity. Soon after Paul and Seder’s article was published, Abraham ‘Avi’ Kupfer, working alongside his wife Hannah at the National Jewish Medical and Research Centre in Denver, performed experiments which directly showed a striking similarity in the way in which immune cells and neurons work.38
Kupfer’s discovery came through watching immune cells in action with a high-powered microscope. In 1995, he stood before an unsuspecting crowd of a few hundred immunologists gathered for one of the prestigious Keystone symposia – named after a US ski resort where the meetings are often held. He showed images of immune cells interacting with other cells which revealed that the contacts between them involved aggregates of proteins organized into bull’s-eye patterns.39 His images showed two cells in contact – like two balls squashed together – and across the flattened connection between the two cells a patch of one protein coloured red could be seen surrounded by a ring of another protein labelled green. Before that moment, nobody thought these proteins would arrange themselves into a pattern at the contact between cells – but it was reminiscent of the organization of molecules at neuronal synapses.
This led to the common use of the term ‘immune synapse’ to describe the contacts that immune cells make with other cells. Both types of synapse involve rings of proteins to promote adhesion between cells and patches of other proteins particular to the discussion between the cells. To the Keystone audience, Kupfer’s pictures were instantly accessible, and the immediate implication was that our thoughts and the detection of a virus both work through a complex choreography of molecules at the contacts between cells. One immunologist in the audience, Anton van der Merwe from Oxford University, remembers the event well:
I recall us looking at these beautiful images for the first time in stunned silence. Although his talk overshot the allotted time no one showed any sign of leaving. After he had finished there was prolonged applause followed by many questions. When the chairperson ended the question session many of us crowded around Avi to continue the discussion.40
Independently, Mike Dustin, then at Washington University School of Medicine, St Louis, and his collaborators were also imaging immune cells but with an interesting twist. Instead of imaging two cells interacting together, they replaced one of the cells with a surrogate membrane composed of the lipids or fat molecules from a real cell but laid out flat on a glass slide. As immune cells landed on this glass-slide-supported mimic of a cell surface, they could also see dramatic movements of proteins labelled with different-coloured dyes. This artificial system was easier to image because the microscope could rapidly capture pictures of the flat synapse laid out over the glass slide. Their approach revealed that the immune synapse is dynamic so that arrangements of proteins change when, for example, a T cell responds to the presence of non-self (peptide).41
My contribution to the story of compatibility genes comes here. While working with Jack Strominger at Harvard University, independently from Kupfer and Dustin, I also discovered a structured immune synapse – but this time, formed by human Natural Killer cells.42 I vividly recall looking at a computer screen, which relayed what was being detected down the microscope, to see patterns of differently coloured proteins at the contact between cells. Unsure of my ability to make an important discovery, I had to ask my girlfriend at the time (now my wife), who isn’t a biologist, to come into the lab and use the microscope herself – to be sure I wasn’t doing anything wrong. My research showed that synapses were important for different types of immune cell – and showed that different organizations of the synapse can switch immune cells on or off. The new science opened up by my research – together with Kupfer and Dustin – is that changing arrangements of molecules control immune-cell interactions, turning them on and off when needed, analogous to what happens at neuronal synapses.
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.