The secret body, p.4
The Secret Body, page 4
Super-resolution images obtained in my lab have led to a new idea for treating patients with a rare genetic disease called Chediak-Higashi syndrome. Children with this syndrome are unable to fight infections that would normally be dealt with easily, and often die young. In normal circumstances, immune cells kill aberrant cells – including cancer cells or virus-infected cells – by secreting toxic enzymes into them. These enzymes are stored inside immune cells within small droplets of liquid, called lytic granules, each enclosed by a thin layer of fat molecules. When an immune cell encounters a diseased cell, such as a cancer cell or a virus-infected cell, receptor proteins protruding from the surface of the immune cell will detect molecules on the outer coating of the diseased cell that identify it as a threat. The immune cell will then flatten up against the diseased cell, establishing a tight surface contact. Once the cell is in position, the lytic granules – containing the toxic enzymes – take about a minute to gather together at the edge of the immune cell, next to the diseased cell, and there they pause momentarily. Then, in a process that still isn’t entirely understood, some of these lytic granules fuse with the outer edge of the immune cell (the coating of the lytic granules and the surface of the whole cell are made up of similar fat molecules), so that their contents – the deadly enzymes – are expelled from the immune cell onto the diseased cell. In a few minutes or so, the diseased cell visibly bulges and bubbles. Less easy to see directly, the diseased cells’ proteins and genetic material are chopped up and degraded. Remnants of the dead cell are then engulfed by another type of immune cell, where they will be broken down further and their chemical components re-used, in the same way that when we are buried, our molecular parts may be re-used by organisms in the earth.
But in children with Chediak-Higashi syndrome this process doesn’t work. Working with Polish scientist Konrad Krzewski at the US National Institute of Allergy and Infectious Disease in Bethesda, therefore, we deliberately mutated a gene known to cause Chediak-Higashi syndrome in immune cells in a lab dish, and examined them with a super-resolution microscope. We hoped to understand how this genetic mutation changed immune cells, to help explain why children with this syndrome are especially susceptible to certain types of infection.
We found that these genetically altered immune cells had larger-than-usual bags of toxic enzymes inside – about twice as big as normal. We discovered that they were simply too big to pass through the structural meshwork – a bit like the strings of a tennis racquet – that underlies the cell surface and gives the cell its shape, and would therefore be unable to launch an attack on diseased cells.67 This could indeed be part of the reason why children with this syndrome can’t deal with some types of infection very well, because their immune cells can’t easily launch an appropriate attack.
This in turn led us to think that finding a way to open up the meshwork – increase the size of the holes between the racquet strings – might restore the affected immune cell’s ability to kill diseased cells.68 I knew about a drug that can do precisely this, used to treat patients with certain types of cancer, because it kept my own father alive. It is also responsible for one of the world’s worst ever medical tragedies.
The use of thalidomide to help pregnant women with morning sickness led to many thousands of babies being born without fully developed limbs and with a host of other deformities. Roughly half of them subsequently died young. Nobody knows how many miscarriages were caused by the drug. Compassionate and conscientious doctors had to care for ‘thalidomide children’, as they became known, aware that they themselves had suggested their mothers use the drug, thinking it would help.69 However, thalidomide was also observed to have some positive effects on various diseases, including leprosy and cancer. The US pharma company Celgene created a safer derivative of thalidomide, sold as Revlimid, by switching one oxygen atom for a nitrogen atom in its chemical structure. My father, afflicted with multiple myeloma, took this drug for many years. It’s not entirely understood how it works – thalidomide and its derivatives have many effects in the body – but one thing it does do, as we found out in my own lab, is boost the opening up of an immune cell’s structural mesh, making it easier for them to kill cancer cells.70
Krzewski and I first got chatting about Chediak-Higashi syndrome at the hotel bar during a scientific meeting in Heidelberg, Germany, in September 2013: the most valuable encounters at scientific meetings are usually the informal ones. He was studying the illness directly and my lab had expertise in using super-resolution microscopy to watch immune cells kill. Although we didn’t have any clear plan at first, it seemed like we should join forces. I had a Polish researcher in my lab at the time, Ania Oszmiana, who was also at that meeting. That she and Krzewski shared a language and culture probably helped get things going – rapport between scientists is at least as important as a good idea. Eventually, this led us to test whether the drug my father was taking to treat his cancer might also help children with Chediak-Higashi syndrome. By the time we arrived at a clear set of experiments to do, Ania Oszmiana had achieved her doctorate, largely based on other work using super-resolution microscopy, and she had left my lab to work in Australia. These experiments were done by an Ethiopian student in my team, Mezida Saeed.71
Giving children with the syndrome the drug directly was not an option, and, besides, we couldn’t then have given them a deliberate viral infection to see how they fared. Instead, we isolated immune cells from their blood and tested whether adding the thalidomide derivative would rescue their ability to kill diseased cells in a lab dish. The answer turned out to be yes, to some extent. This is not a medical breakthrough, because we didn’t try any experiments on animals or humans, and the drug could, for example, have unwanted side-effects. But scientifically, it was a useful advance – understanding a disease and what sort of approach might work as a treatment – and all brought about by super-resolution microscopy.
In my view, there are two ways to use a super-resolution microscope. Most commonly, it is used in the way I have just described: to investigate a process we already know to be important – in this case, how toxic proteins emerge from an immune cell to kill a diseased cell – revealing crucial new detail. But the other way to use a super-resolution microscope is more akin to the way Hooke used a microscope in 1665: to explore nature, without setting out to see anything in particular. By using a super-resolution microscope simply to watch cells or combinations of cells, something entirely new might be revealed. Perhaps a new part of a cell will be discovered, or an unexpected way in which two cells interact will be witnessed. Both approaches – digging into the details of known mechanisms and open-ended exploration – are vital. But it’s the second approach that leads to the most magical feeling of discovery.
Jennifer Lippincott-Schwartz and her lab team were the first cell biologists to use Betzig and Hess’s microscope after they relocated it from Hess’s living room to her lab. She has spent her whole career using new technology to understand cells, and is very familiar with what often happens when you see something unexpected for the first time: others don’t believe you. Having earned a degree in philosophy and psychology, she has given a great deal of thought to why people react in this way – what it takes to change someone’s view of the world and the sociology of science. Understanding that it takes time for a scientific community to come to agreement about anything new is what has given her strength to persevere in the face of criticism.72
At a prestigious scientific meeting in 1998, before super-resolution microscopes had been built, Lippincott-Schwartz presented a movie, itself a novelty at the time, made up of a series of microscope images captured at intervals of a couple of seconds, revealing how protein molecules move from one particular place to another within a cell.73 Previously it was thought, based on indirect evidence, that small bags or droplets known as vesicles carried these proteins, shuttling them from place to place, but her movies revealed direct evidence of something else: tubular structures were ferrying the proteins, with no small vesicles to be seen. Rather than take her movies at face value, though, someone in the audience asked: where are the small vesicles? Someone else in the audience suggested that they were invisible because her microscope simply couldn’t detect them. Needless to say, Lippincott-Schwartz was proved right – there were no invisible vesicles, as lots of methods eventually showed – but it took some time for the community to shift its thinking. When asked about the drive it takes to persevere with ground-breaking research, she says, ‘I don’t like doing things which are not significant.’74
In 2016, Lippincott-Schwartz’s team used a super-resolution microscope to look at the elaborate structure inside cells where proteins are manufactured and processed, called the endoplasmic reticulum, or ER.75 It was thought that this structure, which fills a large part of the cell, was made up of sheets and tubes of membrane. But it turns out that this view, found in high school textbooks, wasn’t really right either. Lippincott-Schwartz’s team revealed that the supposed sheets of membrane were in fact tubular structures, too, so densely packed that when viewed under a normal microscope they looked like flat sheets of membrane. There had been nothing to suggest that this would be the case. It was an entirely unexpected discovery. Super-resolution microscopy has set us a new challenge: understanding what this means. A dense tubular structure might increase flexibility, which could be important when the cell moves. Or it could provide greater surface area, the better to store or facilitate reactions. As yet, we do not know.
In a similar way, another new structure has been discovered inside axons, the long, slender projections that connect our nerve cells to other cells. Zhuang, who had developed super-resolution microscopy around the same time as Betzig, used the new technology to discover a series of protein rings lining the surface of axons.76 The rings are so close together that they can’t be seen when viewed through a normal microscope, which is why they hadn’t been detected before.77 This structure, named the membrane-associated periodic skeleton, has now been seen in axons protruding from every type of neuron that has since been examined, including neurons from a wide range of animals.78 Once again, nobody predicted its existence, and we now need to understand what it’s for. Perhaps it gives axons strength that is essential for their survival throughout a person’s life. Or it might play a role in the transmission of electrical impulses along the axon’s length in some way that we don’t yet understand.79
Exploring cells with these new microscopes is akin to the moment you put on a new pair of prescription glasses. Details are revealed which you had no idea were there. The technology is still so new that a tremendous amount is still being discovered. One of the most tantalising discoveries – with evidence accumulating from new microscopes as well as other technologies – is that cells send out small bags of genetic material and proteins as a means of communication with other cells. As far back as 1983, it was shown that membrane-enclosed vesicles were jettisoned from cells.80 But at first, most scientists thought that these were small bags of trash, carrying away biological components that the cell no longer needed. In 1996, however, it was discovered that vesicles had the ability to alert immune cells to the presence of a problem, such as a virus infection.81 Then, in 2007, a team based at the University of Gothenburg, Sweden, showed that vesicles also carry genetic material.82 The implication is that cells can send out exquisitely complex messages – in the form of bundles of protein and genetic material – to other cells. Tools and information can be shared perhaps to help establish integrated communities of cells in our organs and tissues.83 Philosophically, such complex integration between cells can be considered a challenge to the central doctrine of what a cell is. The individuality of one cell versus another is less clear if any number of their components can be physically shared.
Leaving aside this debate, for which there’s no easy answer, we now know that there are at least two types of vesicles that cells can emit. One type, micro-vesicles, form like buds at a cell’s surface, while another type, exosomes, are assembled inside the cell. These are only broad descriptors, however. In the same way that we refer to immune cells and nerve cells when in fact there are many different types of immune cell and nerve cell in the body, there are no doubt many different varieties of vesicles within these two categories. The menagerie of small vesicles released from cells – and what they do in the body – is still being explored. Some are likely to be long-lived and circulate in the blood to impact distant organs or tissues, while others probably break down and release their contents locally. In at least one situation, vesicles may even move between people.
Astonishingly, human breast milk contains vesicles that encapsulate nearly 2,000 different proteins.84 Some of these proteins have been studied in other situations and found to regulate cell growth and influence the immune system. This leads to the idea that vesicles in breast milk might aid the development of a baby’s gut and immune system. But before this affects anyone’s decision about breastfeeding or using formula milk, it is crucial to note that this is only an idea, and one that is extremely hard to test directly; we are at the cutting edge of knowledge here and much is unknown.
Vesicles may also play a role in disease. There is evidence, for example, that vesicles can contribute to a build-up of fatty deposits (called plaque) in arteries, which can in turn cause life-threatening problems such as heart attack or stroke.85 Other types of vesicles might be crucial to how cancer spreads in the body. Vesicles from a primary tumour, in a person’s breast for example, can enter the bloodstream and land somewhere else in the body, such as a person’s lung or liver, where they then unload their cargo, preparing this new location for the arrival of the cancer.86 It’s conceivable, then, that new medicines could work by blocking the genesis, movement or activity of vesicles. In the short-term, however, vesicles are most likely to prove useful in diagnosing disease. The contents of a person’s vesicles isolated from a blood sample, for example, might be used to indicate the state of a person’s health, assess the type of cancer a patient has, and so on. Eventually, vesicles might also be exploited directly as a drug-delivery system. Vesicles might, for example, be constructed to deliver gene-editing tools into cells – a subject we will return to.
Cells are often said to be life’s basic building blocks. But this conjures up an image of cells being like Lego bricks. Thanks to super-resolution microscopes, and other technologies, we are discovering that if a cell is like a Lego brick, it’s one that can change its size and shape, that has the ability to move, multiply and kill off other, damaged Lego bricks, and can send out small packets of information that change the nature of Lego bricks far away. It’s fair to say that Lego – or anything else manufactured by us – has nothing on life.
In the same way that Samuel Pepys stayed up until 2 a.m. reading Hooke’s Micrographia, I relish the new views of cells described in this chapter. They reveal an intricacy to what we are, far beyond anything we might have imagined without the development of super-resolution microscopes and other tools. These details are magical and humbling. But also, personally, I find it existentially unsettling to realise how much is going on within my body without my awareness. The discoveries described in this chapter elevate that feeling to a whole new level.
This new world – the nanoscale anatomy of the human body – was opened up not by large corporations or a government strategy, but by a few rebels with a big vision, built upon by thousands of scientists around the globe, leading to new instruments that let us see ourselves more clearly than ever before. The technology continues to improve. Other new microscopes are being built right now, allowing us to see more and see better. New wonders will be found that will impact our lives, not least in creating whole new categories of medicine. The rebels planted trees that will bear fruit for decades to come.
2 The Start of Us
My birth had caused a worldwide sensation and thrown up all kinds of moral and religious arguments.
Louise Brown, My Life as the World’s First Test-Tube Baby
In 2006, Magdalena Zernicka-Goetz had a genetic test which indicated her unborn baby might carry a serious abnormality: an extra copy of chromosome 2. This chromosome holds around 8 per cent of the human genome. An additional copy of so many genes can have any number of effects on a baby’s health and development, including an increased chance of miscarriage late in pregnancy. Crucially, the test indicated that not all of the baby’s cells were likely to have this extra copy of chromosome 2; about a quarter of the cells taken from the placenta, which is derived from the foetus, showed the abnormality. ‘As a woman, I wanted to believe there was hope,’ she recalls. ‘As a scientist, my instincts from my work in this field told me that there could be.’1
Born and raised in Warsaw, Poland, Zernicka-Goetz had once dreamed of following in her father’s footsteps to become a neuro-scientist. But at age nineteen, she attended a lecture by one of Poland’s most celebrated scientists, Andrzej Tarkowski, which changed her life.2 He ‘was sitting in front of the room, no slides, and he was just telling the story of how you manipulate embryos … [and it was] magical’.3 From then on, she made it her ambition to understand how embryos develop. Few biological systems can be as important and relevant to us as the genesis of human beings. And scientifically, a special elegance of studying embryos is this: when looking at any other living tissue, it’s hard to know about its history – the journey each cell has taken to reach its present condition, how its complexity has been arrived at – but when you study an embryo, you’re starting from the very beginning.
