by Kirk, Edwin;
If you think of television’s version of the brilliant diagnostician on television, who comes to mind? House, perhaps. The irascible Perry Cox from Scrubs, maybe, or George Clooney’s Dr Ross in ER. By and large, the character is assertive, often eccentric, and (apart perhaps from some of the characters in Grey’s Anatomy) has almost always been male. Kathy — a softly spoken, calm, kindly woman — could hardly be farther from this stereotype. But brilliant she undoubtedly is.
In 2012, two Dutch groups, both working with doctors from around the world who had seen people with Cantú syndrome, independently discovered a link between a gene called ABCC9 and Cantú syndrome.18 Dianne was one of the patients who helped with that discovery (her third appearance in a medical journal). What, exactly, had they found?
[18 This kind of thing happens remarkably often in science. It’s not at all unusual for a journal to publish two papers in the same issue, with different groups reporting the same discovery. Sometimes, the simultaneous publication is no coincidence — each has become aware of the others’ work, and they have coordinated their submissions in order not to scoop each other. Nonetheless, for there to be any such agreement, the starting point had to be that both had made the discovery at the same time.]
The body’s cells are surrounded by a fatty membrane. When you see drawings of a cell, this membrane typically looks like a smooth, unbroken surface. Really, it is absolutely carpeted with proteins, which do many different jobs. Some of them are like radio receivers, listening out for messages from elsewhere in the body. Some of them join one cell to the next (without them, you’d disintegrate in a gooey mess). And others regulate the levels of various substances on either side of the membrane — also vital to your survival. Much of what happens inside cells needs the levels of salts and acids to be tightly controlled in order to work. Your nerves and your muscles, including your heart, can’t function without the flow of calcium, sodium, and potassium across the cell’s membranes being just right. Stop this flow from happening altogether and you’d be dead in seconds. Mess up just one of the many, many different channels, and the effects vary from nothing at all, through to problems like sudden death or severe childhood-onset epilepsy.
One particular type of that last group of proteins is a channel in the cell membrane that helps to control the flow of potassium ions across the membrane. That channel can be open — letting the potassium flow — or closed, depending on the needs of the cell. In people with Cantú syndrome, the channel is jammed into the open position, allowing a constant, uncontrolled flow of potassium across the membrane.19 We don’t fully understand how this links to all the various features of Cantú syndrome — for example, we have only guesses about why this should cause hair to grow excessively.
[19 In turn, this likely suppresses the electrical signals that would normally be happening in affected tissues. Genetics is simple, but cell biology and physiology — the way the body’s systems work together — can be complex!]
It turns out that minoxidil works by jamming this exact channel open, closely mimicking the situation in Cantú syndrome. Kathy Grange was spectacularly right.
A diagnosis is a powerful thing. It gives answers, and it helps with the future — with prognosis and with treatment, and in allowing couples to make informed choices about future pregnancies. Although the dysmorphologist’s role has been changed by the new sequencing technology, that human element remains important — for choosing the best tests, and especially when there is uncertainty about the meaning of the results. No matter how cheap, fast, and easy to access genomic testing becomes, we will still need people with the skills of a Rani Sachdev or a Kathy Grange, and there will still be times when our best chance of getting answers is by taking the question to the Dysmorphology Club.
8
How to make a baby
All you need is love
JOHN LENNON
There’s a slogan popular among those opposed to same-sex marriage: ‘God made Adam and Eve, not Adam and Steve’. Increasingly, around the world, Adam and Steve can get married. They can even have children — but only with the help of someone to provide an egg, and someone to carry the baby. We’re nowhere close to developing an artificial womb, but could Adam and Steve dispense with the egg donor, and have children to whom both are biological parents? Equally, could Anna and Eve skip the sperm donor?
The answer to that question may soon be yes.
The question might also be posed this way: could Adam make an egg? Could Eve make a sperm?
Which leads to the question: what are eggs and sperm, anyway? And could we make them without the aid of ovaries and testicles? Surprisingly, the answer lies in part with a little boy, hovering on the edge of death.
James was just three when, one day, all of his muscle cells fell apart.
He had been a happy, healthy boy, always on the go, an explorer. Like any small child, he had had his share of colds and other minor illnesses, but nothing out of the ordinary. Then he ran into a virus that stressed his body just slightly more than the others had — and uncovered a vulnerability that had always been there, but had never before revealed itself. James woke one morning cranky and irritable, complaining of pains in his legs. Then he collapsed. His mother called an ambulance, which only just got him to the hospital in time.
Your muscles contain an enzyme called creatine kinase, shortened to CK. It’s an important enzyme, but for this story it doesn’t really matter what it does — just that muscle cells contain a lot of it, and, when they die, CK is released into the bloodstream. Muscle cells wear out and are replaced all the time, so there’s always a little bit of CK in your blood. Normally, that would amount to less than 200 units of enzyme per litre — more if you’ve just run a marathon, but not usually a lot more. The first time I heard about James was from the intensive care specialist who was looking after him. He was marvelling at James’s CK. ‘500,000! It must be a world record!’ And he thought the problem must surely be genetic, which was why I was there.
Record or not, it was bad news for James.
The problem did turn out to be genetic — James had two faulty copies of a gene called LPIN1, which is important for keeping the lining of muscle cells stable and strong. In its absence, his muscle cells were fragile, needing only a small push — for example, from what would otherwise be a mild viral infection — to make them break down completely. The same virus that might have given you a runny nose and some aches and pains was potentially a deadly threat to James.
When cells die, other substances pour into the blood. Sometimes, the effects of this can be fatal; cells are rich in potassium, but too much of it in the bloodstream can stop your heart. James had escaped that fate, but he was still in terrible trouble. His muscles felt hard to the touch, like wood wrapped in rubber. We worried that he might have a problem called compartment syndrome, in which swollen muscles are trapped inside their sheaths and the resulting rise in pressure blocks off their own blood supply, so that the muscle dies completely. The surgeons decided to do an operation to check for this, and if necessary release the pressure in his leg muscles. After a single cut, they closed him up again, sure there was nothing to be done. The muscle looked ghastly — pale, bloodless, and seemingly beyond hope.
Without muscles, you can’t walk or use your arms and hands, and you can’t breathe. James was totally paralysed, and most of us thought he was going to stay that way. Only one of the team looking after James was optimistic about his chances. His neurologist, a man of long experience in the field, told us, and his parents, that he thought there was every reason to be optimistic, and that James could make a full recovery. I found it hard to believe, and felt cross with my senior colleague for giving the parents false reassurance.
Six months later, James walked into my consulting room looking as though he had never been sick.
How was this possible? Although many cells in each of his muscles had perished, some had s
urvived. And among the survivors were some that were special.
They were stem cells.
Sperm are relatively simple critters. They are little guided missiles, carrying only the bare essentials needed to get to their targets. In the head of a sperm is the payload — half of the man’s genome (he’s only potentially ‘the father’ at this point). There’s a mid-section full of mitochondria — that’s the power plant. And there’s the tail, a thrashing motor driven by that power plant. A sperm has one job, and one job only: get the payload to its target. When a man ejaculates, there are generally hundreds of millions of sperm released. Most of the time, there is no egg waiting for them, and they die, unmourned and unfulfilled. But even if there is an egg, only one of all those millions can fertilise it. A man might produce 500 billion sperm in his lifetime, with only one or two fulfilling its destiny. If you were naturally conceived, the sperm that makes up half your DNA was the winner of a contest against incredible odds. The same goes for each of your parents, and their parents, and so on. If you ever find yourself lying awake at night wondering if there is anything special about you, consider this — you are the culmination of a long, long line of outstandingly lucky sperm, stretching back over many millions of years. They were all great swimmers, to be sure — but mostly they were freakishly fortunate. There are many, many ways for a sperm to fail to reach or fertilise an egg. The odds against your existence are genuinely astronomical. You are, without a shadow of a doubt, something special.
Once that magical, one-in-hundreds-of-billions of sperm hits its mark, its job is done. It is swallowed up by the egg, which gathers up the DNA in the head of the sperm and hunts down and kills the DNA in the sperm’s mitochondria — and then the real work can begin.
To understand how remarkable an egg is, you first need to know the difference between a muscle cell and a liver cell. Why is one of them good at contracting powerfully, while the other would never dream of doing such a thing, but excels at cleaning toxins from your bloodstream, and manufacturing the proteins your blood needs so it can clot when you’re bleeding? Both cells have exactly the same DNA — but they use it in different ways.
You can think of the genome as a box full of electrical components, all wired to a single giant circuit board. There’s everything you need to make a television, everything you need to make a hairdryer, everything you need to make a microwave oven, and so on. It’s said that there are over 200 types of cell in the human body. There’s reason to think there might be considerably more than that — there may be important differences between a skin cell on your elbow and one on the tip of your nose, for example. But let’s say there are only 200. This means that the box of components in the cell nucleus has everything needed to make any one of 200 different electrical items. There are some things that almost every type of electrical equipment needs — a way of getting electricity from the outlet, for instance — and there’s only one of those in the box. Similarly, there are some components that every cell needs, such as the toolkit that is used for disposing of damaged proteins. On the other hand, only your fridge needs a compressor, just as only a particular set of cells in your pancreas needs to make insulin.
Let’s say our electrical box is set up so there are switches that select whether any one component is used or not, and let’s pretend it doesn’t matter in what order they are joined up. This means that, by choosing which of the components in the box to switch on, you can make it behave very differently. The same box could function as a computer, or a printer, or an electric mixer, or a bandsaw. That’s pretty much what happens in a cell, too. Each cell has exactly the same set of 23,000 genes, but in each type of cell only a particular set of those genes is switched on — the rest are silenced, more or less permanently. There’s a set of genes that are switched on in every cell, known as housekeeping genes; there are genes that are needed by multiple cell types, but not all; and there are some genes, like the insulin gene, that are specific to just one type of cell.
The special thing about the egg is its potential. A fertilised egg can — and must — give rise to every other type of cell, including the eventual eggs or sperm that will become the next generation. I like to imagine this first cell as vibrating with energy, bursting with potential. That first cell, and all of its daughter cells for the first few cell divisions, are the ultimate stem cells. They are totipotent — literally, ‘wholly powerful’ — meaning that each of those cells is uncommitted, and can become any of the hundreds, or perhaps thousands, of cell types needed to make a person — and also the placenta, needed to support and nourish the baby until it is ready to be born. One step down are the pluripotent stem cells, which are ‘severally powerful’ — although the only thing they can’t make is a placenta. Identical twins are evidence of the power of pluripotent stem cells — if something causes an early embryo to split, you get two babies for the price of one.
As the embryo develops, however, cells start to set off down particular paths, gradually becoming more and more committed until most of them have reached their final form (a bit like an evolving Pokémon). Once a liver cell is a liver cell, that’s all it will ever be. The molecular switches that choose the particular set of genes needed by that cell type are welded into place. The television will only ever be a television; the blender will never download an ebook.
Except … except for the cells that don’t go all the way down that path. In every part of your body, there are cells that didn’t quite commit all the way. Most of them sit around waiting to repair damage — these are the ones that saved James, by regrowing his muscles.1 Some are very active, like the ones that live in your bone marrow making new blood cells, or the ones that replenish the cells in your gut, which are always being worn away by the contents of your bowel. Others seem to sit around for a very long time, ready for when they are needed.
[1 The stem cells in muscle are called satellite cells. When muscle is damaged, they divide; some of the daughter cells remain as satellite cells, ready if they are needed in the future. The rest merge with the damaged mature muscle cells and repair them.]
Stem cells can be more or less specialised, too. A haemocytoblast can become any type of blood cell. Once it commits to becoming a megakaryoblast, it’s still a stem cell, but all it can ever make is megakaryocytes. These, in turn, are the weird cells that make platelets, the little cellular scraps that circulate in your blood, waiting for the chance to help make a clot. Megakaryocytes — unlike the tiny platelets that they make — are huge, and have an enormous nucleus, with extra sets of chromosomes. While they are forming, they double and redouble their chromosomes, and they can have as many as 32 times as many chromosomes as a cell usually does. We have no idea why they do this, by the way.
So — stem cells are just cells that have the flexibility to become other types of cell. Unfortunately, the power of stem cells is limited. Often, damage to tissue leads to a scar, rather than replenishment by stem cells. Still, there is a lot of interest in using stem cells as medical treatments, getting them to repair damaged tissue — such as after a heart attack — with healthy new cells. For our purposes, though, what matters is that stem cells have this flexibility, and that the fertilised egg is the ultimate stem cell, ready and able to become every other type of cell.
For Adam and Steve’s purposes, we don’t need Adam to make a fertilised egg — we can get sperm from Steve, after all. But we do need to be able to persuade a cell that has gone down one path in life to change its mind and mature first into the precursors of an egg and then into an actual egg. Making an egg is a complex process, but, if we could persuade any cell type to become another cell type, there’s no reason the second cell type couldn’t be an egg.
Can we do that persuading? In principle, there’s no reason why not.
Professor Richard Harvey, who was my PhD supervisor, is an eminent biologist who studies the way the heart develops. Richard’s lab uses a variety of different methods to try to understand t
he complex processes that lead to the formation of the heart and all its structures. Once, I was visiting the lab and Richard beckoned me over to a microscope and asked if I wanted to see something cool. There’s only one answer to that question … and he delivered, in spades. Looking through the microscope, I saw a glass slide with clumps of cells growing on it. The cells were pulsating rhythmically. These were cardiac organoids: clumps of cells that had been persuaded that they were actually a heart, and were behaving as though this were true, pumping away faithfully. They had been made by treating stem cells with cellular messages that said: you will be part of a heart.
Even cooler, Richard’s lab had started out by making the stem cells from mature skin cells. In other words, it is already possible to make stem cells by starting with mature, fully committed adult cells and hitting reset. What you get are known as induced pluripotent stem cells — iPSCs. That sounds like a mouthful, but all it means is cells that have been chemically persuaded to roll back the clock, to the time when they were cells that could become any other type of cell.
Could you use the same method to transform a skin cell into an egg? There’s no reason why not, in theory at least. In fact, quite a lot of progress has been made towards producing sperm (which are easier) from stem cells. The reason given for attempting this has been as a possible treatment for infertility, but, once it’s possible to use skin cells from a man to make sperm, it might not be too hard to use cells from a woman to achieve the same thing. Eventually, the skin-to-egg method is likely to be possible as well, although making an egg is a much harder task. Anna and Eve might get first crack at this technology, it seems. Still, the technical challenges are just that — challenges, which can undoubtedly be overcome.
However, it’s likely that there will be objections raised to actually making sperm from a woman’s cells or eggs from a man’s. From a practical perspective, it would be very hard to be sure that this could be done safely. Would an embryo formed from such a manufactured egg or sperm grow into a healthy baby? Who knows? There’s no way of testing it without trying, and no guarantee that if this works in animals it will be safe in humans. On the other hand, the history of this type of technology has been that if it is possible then someone, somewhere will give it a go.