The secret body, p.13
The Secret Body, page 13
Deisseroth’s team next developed what has become an important feature of many optogenetics experiments: rather than targeting neurons according to their location, scientists can now choose them according to where they reach. This is achieved by delivering the light-switchable protein to one area of the brain, and the light itself to somewhere else in the brain. This way, only neurons which span the two areas became activated. Using this, Deisseroth’s team showed that each particular feature of anxiety – including increased respiration, risk-avoidance and apprehension in the absence of any actual risk – involves neurons connected to different brain regions.81 Another team of researchers showed that the neurons involved in anxiety also link to parts of the brain involved in motivation.82 In other words, separate brain modules are involved in different aspects of anxiety.
There’s no escaping the vital caveat that all this work is done with mice, not humans, and carried out in unnatural settings. And what it tells us about the causes or nature of anxiety is very hard to say. But if any comfort could be drawn for anyone with an anxiety disorder, it’s perhaps that these behaviours in mice could be dialled up or down instantaneously. It’s not that optogenetics could easily do this in people, but that these discoveries tell us which brain neurons might be best targeted for investigation. Most importantly, they point to new therapeutic ideas – and to change being possible.
One area where this already looks especially promising is in treating addiction. In 2001, a team led by Antonello Bonci, then at the University of California San Francisco, found that mice given a single dose of cocaine showed a change in brain activity.83 Circuitry normally involved in reinforcing learning was affected for several days. A broad implication was that a vulnerability to addiction might be opened up by just a single dose of cocaine. Then, in 2013, Bonci and their many collaborators showed that, at least in rats, optogenetics could be used to alter brain activity to stop cocaine addiction.84
For eight weeks, rats were given access to cocaine by pressing a lever. Then the set-up was changed so that each time a rat pressed the lever to obtain cocaine, there was a chance it would also receive a mild electric shock to its feet. This was enough to stop some rats from continuing to take cocaine. But others would self-administer the drug even when doing so had this clear negative consequence. In those rats, the team found a particularly low level of activity in their prefrontal cortex, a region of the brain implicated in all sorts of behaviours. Astonishingly, optogenetic stimulation of that region rescued the rats from their addiction.
Needless to say, human and rat brains are very different. Human brains are much larger, for example, and are especially well developed for language, while rat brains are more adept at dealing with smell. But perhaps surprisingly, there is a lot of commonality too. The broad set-up of the brain is similar and many basic pathways seem to be shared. Something as primal as the feeling of pleasure leading to wanting to repeat an activity again – the so-called reward pathway – is so essential for survival in us and other animals that at least something of its structure is preserved across species. This is the pathway hijacked by addiction. So it’s at least feasible that what helps stop an addiction in rats could help people too.
Optogenetics can’t be used directly on humans, not least because it would require genetic modification to a person’s brain. But the activity of a human brain can be influenced instead by transcranial magnetic stimulation (TMS). Here, a small device that produces a rapidly changing magnetic field is placed against the head, inducing local electrical activity in the brain. The device is sometimes used to treat depression where drugs or psychotherapies have failed. In 2016, a group of cocaine addicts were treated with TMS, targeting the part of their brain analogous to the area in rats’ which had been targeted by optogenetics.85 The effect was clear: stimulating this part of the brain suppressed their urge to want cocaine.
As striking as this is, there isn’t yet consensus as to whether or not this technique can play a role in medical care. In this study, patients knew they were being treated and so could have also benefited from a placebo effect. More work is also needed to standardise the procedure.86 But even so, it’s clear that discoveries made by optogenetics are important.87 Probing the brain in this way is almost certainly going to help us better categorise mental health issues. And eventually, this seems likely to lead to new treatments that specifically target the right brain circuitry, replacing the current gamut of broad-brush pharmaceuticals.
Most people would be happy with optogenetics, and other technologies, leading us to new medicines to treat clear problems. But in-depth understanding of the brain is likely to also lead us to far more controversial issues. Intelligence is something of a taboo topic in contemporary science. It’s hard, if not impossible, to define it, let alone measure it. Supposed tests of intelligence only report how good someone is at that type of test. Still, there is plenty of evidence to show that people are interested in boosting their own cognition. One in five respondents to a survey in the journal Nature in 2008 said that they had used drugs to stimulate focus or improve concentration.88 People are already self-medicating to boost their cognition, despite so little clear information about what does or doesn’t work, or even what the aim is.
It’s hard to say whether or not we will understand what ‘riding a bike’ looks like in a brain anytime soon. But there can be no question that technology will continue to develop and, as our knowledge deepens, new ways of manipulating the brain are going to be more powerful and more precise.
The global endeavour to map the detailed structure of a brain is well under way, and already a mouse can be instructed to move by remote control. The aim of all this is to solve problems like depression or anxiety disorders. But mission creep is inevitable. For now, our vulnerabilities, our vanity and our capacity for love and hate, remain hidden inside our brains. There is a door which hasn’t yet been found, a code still to be cracked and a threshold which hasn’t yet been breached, but it’s only a matter of time.
A conversation, book, song or movie – any number of things affect you. But for good and bad, hacks into the brain – in the form of virtual reality headsets, manipulative advertising and repetitive games on a touch screen – are becoming much more direct. All of which is nothing compared to what’s coming. In twenty, fifty or a thousand years from now, our understanding of the human brain will be at a whole other level. We are at the moment before a jump scare. Something big is about to happen. We’re fumbling in the dark, the tension is building, we know it’s coming, but it’s hard to say when – or what it will be.
5 The Others Within
My teeth are kept usually very clean, yet when I view them in a magnifying glass, I find growing between them a little white matter … [and] to my great surprise perceived that the aforementioned matter contained very many small living animals.
Anthony Leeuwenhoek, letter to the Royal Society, 17 September 1683
In the 1970s, it was thought that about 300 different species of bacteria might be found in the human body. With this in mind, scientists at the time set out to identify a core set of bacteria found in healthy people, thinking that if any of these were missing, it would indicate disease, or perhaps even be an underlying cause of disease. Now we know that this idea was far too simplistic. In fact, the human body hosts an ecosystem of micro-organisms of unimaginable diversity. There are about as many individual bacteria in you as there are human cells. They comprise around 10,000 different species of bacteria, some of which are not known to exist anywhere else on Earth. Altogether, these bacteria carry about 1,000 times as many genes as your own human genome. As well as this, there are untold numbers of viruses and fungi in, and on, our bodies, about which we know far less than we do the bacteria. In total, this – the human microbiome – amounts to something akin to an organ weighing about the same as a human brain. The reason it’s not easy to relate the contents of a person’s microbiome to disease is that this vast universe of life within our bodies is enormously diverse and – unlike any other human organ – it varies considerably from person to person, and changes during the course of our lives, as we go through puberty, pregnancy or even when we move house.
In the last decade or so, our understanding of the microbiome has exploded, thanks to the development of two types of technology which together identify microbes genetically. First, laboratory hardware can be used to rapidly sequence large amounts of genetic material.1 Secondly, we have developed computer hardware and software that allow us to sort out all the different microbial gene sequences, seek patterns in the data and correlate results with other factors, such as a person’s diet or state of health. The endeavour to understand the human microbiome has become a flagship enterprise for big-data science.
Even though the full extent of the symbiosis of humans and microbes is yet to be realised, there is no doubt that our health and wellness vitally depend on their alliance. And like any long-term relationship, the bond is complicated. Different parts of the body are colonised with different microbes, for example. Those that live on our teeth are different from those on our skin or in our gut. Even in a person’s gut, there is exquisite diversity in the types of bacteria that live along its length. Separate environments, like islands hosting different animals, are created by folds in the intestinal wall and local variations in acidity, mucus and oxygen.
It is these, our gut bacteria, which have been studied the most, mainly by analysing faeces.2 As long ago as the 1680s, when the Dutch scientist Leeuwenhoek first used a primitive microscope to discover bacteria, he looked at them in his own faeces. This must have been a shocking observation; intuition does not tell us that 25–50 per cent of our stool is comprised of living and dead bacteria. In 1909, the US bacteriologist Arthur Kendall suggested that the types of microbes in a person’s gut could vary in accordance with their diet.3 He had been testing the idea by feeding monkeys different foods and then trying to culture the bacteria in their faeces. From the decades of research that followed, the gist of what gut bacteria do for us – or at least one aspect of the function they provide – is now widely known: the gut provides a home for bacteria in return for their help in digesting food and producing nutrients. For example, gut bacteria produce B vitamins which we otherwise might lack.4 But recently, our advancing knowledge has thrown up other revelatory details, far beyond anything Kendall might have imagined. From them, various claims have been made for microbiome-based therapies or treatments. Many are over-hyped, but not all; genuinely transformative ideas are on the horizon relating to everything from nutrition and diet to our ability to fight disease and even our mental health.
You might think that the shape of your body is a product of your genes, the food you eat and the frequency with which you exercise. But evidence has accumulated which shows that something else is also a major factor: gut bacteria. The journey towards this scientific revelation began in 2004 at Washington University, where a postdoc researcher in the lab of biologist Jeffrey Gordon observed something unexpected and important.
While working for his PhD in Sweden, Fredrik Bäckhed had become fascinated by the fact that the exact same bacteria which live happily in our gut can cause disease if they infect another part of the body, such as the urinary tract. He reasoned that there had to be something different about the way the gut senses and controls bacteria compared to other places in the body. He knew Gordon by reputation, and knew he was interested in studying gut microbes, so emailed him to ask if he could join his lab once his PhD was complete.5 Bäckhed was full of ideas for research – such as looking at the effects of microbes on the nervous system – but together they settled on a plan to look at how microbes could affect an animal’s metabolism. Gordon suggested they look at something very simple at first: whether the amount of body fat an animal has might be affected by the absence of any bacteria in its gut.
Normally, all mice have plenty of bacteria in their gut, just as we do. But in labs, mice can be kept in a sterile environment so that they never contact microbes at all. These mice are born and raised in a sealed-off plastic enclosure and fed food which has been irradiated. They have an unusually straightforward scientific name: ‘germ-free mice’. What Bäckhed observed in 2004 was that germ-free mice were much thinner than microbeladen mice raised in a normal lab environment. More importantly, when he deliberately exposed germ-free mice to bacteria, they began to put on weight.6 It’s not that they started eating more – in fact, they ate a little less – they just got fatter.
On the face of it, these results implied that microbes directly affect an animal’s body weight. But as germ-free mice are not found naturally, any number of strange things might have been going on in these animals, with their fluctuations in weight being mere side-effects. Evidence of a different kind was needed to establish a direct causal link, and this came from another postdoctoral researcher in Gordon’s team, Ruth Ley. In her experiment, instead of germ-free mice she used mice with a specific genetic mutation that causes obesity. Specifically, these mice had a non-working version of the gene responsible for the production of a hormone called leptin, which helps the animal match its energy intake to its energy use. A deficiency in this hormone causes the mouse to uptake more energy from its food than it needs. By studying the microbiome of mice with this genetic mutation and comparing it to those of mice without it, Ley found that the obese mice harboured a distinct mix of bacteria in their gut.7 Even among littermates given the exact-same food and living in the exact-same environment, those mice that inherited this genetic mutation had a different microbiome from their siblings.
It could be that the changes in their microbiome and in their body weight were both caused by this genetic mutation independently, but it seemed more likely that the two were connected: that it was the mutation that caused mice to become obese, which in turn changed their microbiome, or that the mutation affected the microbiome, which then caused the mice to gain weight. The next experiments in Gordon’s lab gave the answer.
Working with Ley and others in Gordon’s lab, PhD student Peter Turnbaugh transferred bacteria from overweight or lean mice into germ-free mice.8 Amazingly, mice which received microbes from overweight mice put on far more weight than those given microbes from lean mice. Two weeks after being colonised with bacteria from overweight mice, their body fat increased by an average of 47 per cent. Those given microbes from lean animals also increased their body fat, but to a much lesser extent. These results implied that gut microbes could directly influence the size of mice. This happened more or less irrespective of how much food they ate. If anything, mice given the microbiome of an obese mouse ate slightly less. As Gordon later recalled, ‘It was an ‘Oh my God’ moment.’9
By analysing the microbes in detail, the team found that a high proportion of bacteria from obese mice included enzymes that break down sugars that are otherwise indigestible. This suggested that microbes from obese mice equip the animal with an ability to harvest more energy from food. Amazingly, these same types of bacteria – those rich in enzymes which break down sugars – were then also found to be more abundant in obese people.10 Later, leading her own lab, Ley showed that microbes from obese humans also cause germ-free mice to gain far more weight than if they received microbes from lean people.11 Altogether, this led to a revolutionary idea: that the composition of a person’s gut microbes can affect how much energy is extracted from food, which can in turn impact a person’s body weight. This ground-breaking discovery hinted at new possibilities for healthcare, but a further step would be needed before they could be realised.
Eran Elinav, based at the Weizmann Institute of Science in Israel, sees it as his life’s mission to understand the molecular language by which the human body talks with microbes.12 He trained to be a medical doctor, his childhood dream, but ‘clinical routine got to be a little bit boring’.13 So he switched to focus his career on research, and earned a PhD in immunology. He became interested in the microbiome in the mid-2000s, just as research in the subject was taking off. Leading his own lab since 2012, he set out to understand the relationship between diet, obesity and the microbiome.
As Elinav learnt from countless scientific papers about nutrition, many diets originate in a system for rating foods according to their effect on our blood sugar level: the glycaemic index. This way of characterising food came from research led by David Jenkins at the University of Toronto in 1981. Jenkins had small groups of people fast overnight, eat a particular food, and then measured their blood sugar levels over the following two hours.14 Each type of food was given a score according to how much it raised those levels per unit of carboydrate, with sugar as the benchmark with a score of 100. Honey scored 87, sweet-corn scored 59, tomato soup 38, and so on. The reason this was an important advance was that it rated food not by what it’s made of, as such, but by how it affects the human body. Today, every conceivable edible thing has been analysed this way and – very generally speaking – those seeking to lose weight are advised to avoid foods with a high glycaemic index, which cause short-lived spikes in energy that may soon leave us craving more, and to tend toward foods with a low glycaemic index, which release their energy more slowly, helping us feel fuller for longer.
