The Boy Who Wasn't Short

by Kirk, Edwin;

  Let’s leave Adam and Steve now, and consider a heterosexual couple who are planning a baby. John and Jane have dreams for their yet-to-be-conceived child. They want him or her to be healthy, of course, but perhaps they hope for more than that. Jane, sporty herself, hopes for a child who might become an Olympic athlete. John, raised in a difficult home environment, wishes for a child who will be compassionate and kind. They know that being smart and attractive gives people an advantage in life, so of course they want those things for little Oscar or Sophie as well.

  Can they choose? Should they be able to, if they can?

  The diagnosis of genetic disease is unique in that it can be done not only before a person is born — prenatal diagnosis — but before an embryo is even implanted in the mother’s womb. Pre-implantation genetic testing (PGT) isn’t just for mitochondrial conditions; we can test a bundle of cells too small to even see without a microscope, and say, ‘If this embryo grows into a person, one day he or she will have Huntington disease’ (or any of thousands of other conditions).

  For PGT, in-vitro fertilisation is used to make as many embryos as possible (which is also the usual goal when IVF is done to treat infertility). The embryos are allowed to grow for a few days until they form a little ball of cells. In the most delicate of medical procedures, a few cells are sucked out, and DNA from those cells is tested for a specific genetic condition. Then, an embryo that is known not to be affected by the condition is implanted. This way, the parents can be sure from the beginning that their child will not be affected.

  We can do PGT for single-gene conditions only if the exact genetic cause of a condition in a family is known. Even so, it’s pretty common for the idea of ‘designer babies’ to be raised when PGT is discussed. This is obvious nonsense in relation to the way the testing is actually used in most countries, but it’s easy to understand where the idea comes from. If you can choose to avoid a bad outcome such as a fatal genetic disease, could you select in favour of something you think is desirable in your child, such as intelligence, height, beauty, or sporting ability?

  The closest this gets to a ‘yes’ is using the technology to choose to have a boy or a girl. In some countries, boys are favoured over girls, to the extent that those who can afford it sometimes use PGT to choose to have a boy. It seems likely this has been widely done across the world. In some countries, the practice is banned — even those, like Australia, where there has not been any particular bias towards one sex or the other among parents who seek selection. Using PGT for ‘family balancing’ is frowned on, and even banned, for reasons I have never understood. If you have two boys and would like your third child to be a girl, there would be no obvious harm to that girl or to her brothers, and no apparent damage to society at large from that decision. Would she be a ‘designer baby’? Only by the very broadest of definitions. As we shall see in chapter 9, the way that characteristics like height and intelligence are inherited makes it unlikely that we will be able to pick the ‘best’ embryo from those that are available. Even if we could, we wouldn’t have ‘designed’ the baby, we would just have selected one who could have been naturally conceived anyway.

  So — if you can’t choose your preferred embryo in any meaningful way, can you manufacture an embryo to suit? The answer is, a very qualified, yes. The genie is out of the bottle, but this genie is not necessarily to be trusted.

  Genie: Okay, Dave, you get one wish. Use it wisely!

  Dave: I wish I was rich.

  Genie: You got it! Enjoy!

  Rich: Hey, wait a minute …

  It has long been possible to modify the genes of a living creature. We talk about ‘making a mouse’ or ‘making a fly’ (or a fish, or a worm) in order to study what happens when the function of a particular gene is altered. This can include knocking a gene out, so it doesn’t work at all, or adding a specific mutation to a gene, or just putting in extra copies. You can put genes from one creature into another — a famous example is putting the gene that makes some types of jellyfish fluorescent into other animals, so that you get a rabbit that glows green when you shine the right sort of light onto it. There are practical applications to the jellyfish protein, it’s not just a genetic engineering party trick. For instance, if you want to work out if a specific protein is needed in a particular developing tissue, you can splice in the jellyfish protein next to the gene you’re interested in, and then see which bits of an embryo glow green. The green glow marks out very precisely where the protein you’re interested in can be found.

  Genetically modified organisms are already economically important — mainly in crops, of which there are many, but there are also a number of animals that have been modified and will probably find their way to your plate soon, if they haven’t yet. Could you modify humans? Of course you could — what works for one mammal works for another. But what type of genetically modified human (GMH) would you make?

  One option might be to create a GMH with big muscles. There’s a gene for a protein called myostatin, which acts as an off-switch to muscle growth. Some people aspire to look like Arnold Schwarzenegger in the 1970s, but, from an evolutionary perspective, there’s an advantage to keeping the growth of muscles in check. Making muscles takes nutrients, and then once you have them, you need extra food to keep them going. Limiting muscle growth is all about resource management: efficiency demands that we have enough muscle, but not too much. But if resources are no obstacle … well, there’s a breed of cow called the Belgian Blue that has enormous muscles because it has faulty myostatin. That’s an advantage (although not to the cow) if your plan is to eat that muscle. Would it be helpful otherwise?

  There’s at least one human being reported who lacks myostatin. When last described, 14 years ago, he was an extraordinarily heavily muscled and strong four-year-old. Presumably, he is now an extraordinarily heavily muscled and strong young man. So, you might say — what’s the problem? Let’s get cracking and create an army of Olympic weightlifters!

  There are two problems, and both relate to safety. When you modify an organism’s genes, there’s a chance that things might go wrong. In the process of knocking out myostatin, you might inadvertently take out something else you would rather have left alone. You could wind up a with a child who is very muscular, but who has a high risk of developing bowel cancer at a young age, or who is born with severe epilepsy. The second problem is that even if everything goes perfectly, we don’t know what the long-term effects might be for people with no myostatin. Perhaps they will remain healthy all their lives. But one healthy four-year-old gives you no grounds for confidence about that. Belgian Blue cattle are somewhat fragile — they struggle in harsh climates, they have difficulty giving birth, and their fertility is lower than that of other breeds. It may be that some of those problems are separate from their enhanced muscles, but there is no way of knowing if a GMH lacking in myostatin might also have long-term health problems.

  Or maybe you are after basketballers. Growth hormone, as its name implies, makes you grow. So how about a GMH who has extra growth hormone? Well, we already know how this one turns out. It would indeed produce people who are tall — very tall — but they would very definitely have other health problems as a result. We know this because there is a naturally occurring version of this GMH as well. André Roussimoff, known as André the Giant (who so superbly played Fezzik in The Princess Bride) had this condition: acromegaly. His over-production of growth hormone was caused by a tumour, rather than by any genetic difference, but the effect would be the same either way. Indeed, Roussimoff was tall (224 cm/7 ft 4 in.), and strong, a professional wrestler. But with his size and strength came overgrowth of his facial features and a host of health problems, leading to his death aged just 46.

  In late 2018, it was announced that a Chinese scientist called He Jiankui had used the CRISPR technology, a powerful tool for editing genetic material, to change the genetic make-up of two babies in an attempt to make them res
istant to infection by HIV. Later, it was revealed that a third baby had also been born. Dr He’s stated goal was to introduce a specific change in the gene CCR5. This gene codes for a protein that sits on the surface of some white blood cells, and is exploited by HIV to get into and infect those cells. The particular change Dr He was trying to introduce is fairly common in Europeans but absent from Asians; people with two copies of the changed protein (about 1 per cent of Europeans) are resistant to HIV infection.

  The couples recruited for He’s research were chosen because, in each case, the father had HIV. On the face of it, this makes He’s intentions seem like they might be justified: he wanted to make babies who would not be affected by their father’s HIV; a purely medical motivation. Except that this would have been medical nonsense: there are already sperm-washing techniques that mean that it’s possible for an HIV-positive man to father a child with an extremely low risk of being born infected by the virus. There’s no medical justification for changing such a child’s DNA to further reduce that small risk. Dr He himself, interviewed in November 2018, stated that his goal was to protect the babies against HIV infection later in life. So what was the point of recruiting HIV-positive fathers? Your guess is as good as mine. He doesn’t seem to have offered any coherent explanation.

  Later, it emerged that although He did succeed in modifying the CCR5 gene in the babies, he didn’t manage to introduce the specific change found in Europeans, meaning that there’s no way of knowing for sure whether those will be resistant to HIV — particularly because it seems that the changes only affected some of the babies’ cells, i.e. they are mosaic. There are potential downsides to having CCR5 that doesn’t work normally, with vulnerability to some other viruses being part of the price paid for HIV resistance. It’s not at all clear whether these three babies have been helped or harmed, and that’s assuming that the gene that was targeted is the only gene that was changed in the process.

  Sound ethically dubious to you? It did to the Chinese authorities, too, and an investigation revealed that He had acted without proper ethical approvals in place. In 2019, he was jailed for three years and heavily fined for his actions.

  This is not to say that there are no conceivable medical reasons why you might edit an embryo’s DNA. Almost always, when there is a specific genetic condition in a family, it’s possible to use PGT to select embryos that are not affected by that condition. Sometimes, though, there are circumstances in which this may not be an option. Suppose, for example, that both parents are affected by the same autosomal recessive condition (perhaps they met in the waiting area for a specialised clinic). Both parents have two faulty copies of the gene in question; neither has a normal copy. This means that every embryo they conceive will also be affected, so there would be no unaffected embryos for PGT to choose. At present, if they want to have a child who is not affected by the same condition, they would have to consider adoption, or the use of donor eggs or donor sperm. Gene editing could open the door for them to have healthy children who are biologically their own. Would that be such a bad thing? It seems possible that with careful preparatory work, likely to take years, this may one day become a standard medical procedure.

  Having said that, many would think that safety concerns are not the only objections that should be raised to deliberately changing the genetic make-up of a human being, particularly in a way that can be passed on to that person’s own children. Some would argue that this is playing God, against nature, or otherwise an ethical minefield. Whether you accept that or not, there can be no doubt that deliberately modifying an embryo to create an ‘improved’ human raises extra questions about safety, not only from the procedure but from the changes that you are aiming to make, that seem impossible to answer. Only someone completely unscrupulous would attempt such a thing.

  Which means, of course, that, by now, someone, somewhere, has done it already. There is surely a genetically modified superbaby out there in the world. For her sake, and for the sake of her future cousins, I hope my concerns about safety are wrong.

  9

  Complexity

  At the dawn of the twentieth century, it was already clear that, chemically speaking, you and I are not much different from cans of soup. And yet we can do many complex and even fun things we do not usually see cans of soup doing.

  PHILIP NELSON

  Speaking of safety … thalidomide is a remarkably useful drug. By suppressing the growth of blood vessels, it effectively treats a common and serious complication of leprosy, and it is active against a type of cancer called multiple myeloma, as well as against certain inflammatory conditions. Unfortunately — as it turns out — it’s also a really good treatment for nausea, and works as a sleeping pill without causing addiction. The latter was a powerful claim when the drug was introduced, because it was a time when barbiturates were widely used and were known to cause death from accidental overdose,1 as well as being highly addictive. Unlike barbiturates, you can swallow a handful of thalidomide tablets and survive the experience without any immediate harm — a handy angle for marketing purposes.

  [1 Also deliberate overdose — Marilyn Monroe was only one of many who died this way.]

  Advertising for the drug highlighted its safety: an advertisement in the British Medical Journal in 1961 proclaimed the drug ‘highly effective … and outstandingly safe’. One advertisement showed a toddler holding an open medicine bottle, with the message being that, if the bottle had contained barbiturates, the toddler would be in mortal danger. Luckily, the bottle was instead full of nice, safe thalidomide.2

  [2 The modern childproof lid for medicine bottles was invented in 1967 by Mr Peter Hedgewick, following efforts over a five-year period to encourage development of such a lid by a Canadian paediatrician, Dr Henri J. Breault. Breault was sick of treating children who had accidentally overdosed and was determined that such overdoses should be prevented. The idea caught on quickly in Ontario, but, despite the obvious benefits of the invention, it took some years for its use to become widespread elsewhere.]

  In fact, the drug had hardly been tested for safety at all. A few years after its introduction, it emerged that thalidomide could cause damage to nerves, resulting in chronic limb pain. Then, in late 1961, the first reports of damage to unborn babies started to trickle in. The drug was withdrawn from sale almost immediately in most countries.

  Sadly, this was too late to prevent an unprecedented medical catastrophe. Thalidomide’s anti-nausea effects had led to it being marketed as a treatment for morning sickness during pregnancy, starting in the late 1950s. As a result, thousands of children were born with physical malformations. The most striking of these were severe limb deficiencies — being born with missing hands or arms, or with all four limbs reduced to small remnants or being entirely absent. Other problems, such as congenital heart disease and kidney malformations, were also common. Many affected babies did not survive infancy, and many pregnancies were miscarried due to the effects of the drug.

  Among developed nations, the United States stood apart in being almost completely spared the ravages of thalidomide. This was thanks to the brilliance of a doctor who was working for the Food and Drug Administration (FDA) at the time of the drug’s introduction elsewhere in the world. Dr Frances Kelsey reviewed the safety information provided by the drug’s manufacturer. She found the evidence unconvincing. Six times applications were brought to the FDA, and six times Dr Kelsey rejected them — saving unknown thousands of children.

  Kelsey was a remarkable woman. Born in Canada3 in 1914, she trained in pharmacology at McGill University, receiving her Master of Science degree in 1935. She applied to the newly established pharmacology department at the University of Chicago for a research-assistant position, which came with a scholarship that would allow her to study towards a PhD. She was delighted to receive a letter of offer, but concerned that it came addressed to Mr Kelsey; it appears her name had been confused with ‘Francis’. She ask
ed her professor at McGill if she should send a telegram explaining the point. He told her that would be ridiculous, and advised her to reply accepting the position, but writing (Miss) after her name. Interviewed by the FDA Consumer magazine in 2001,4 Kelsey said, ‘To this day, I do not know if my name had been Elizabeth or Mary Jane, whether I would have had that first big step up. And to his dying day, Professor Geiling [her supervisor in Chicago] would never admit one way or the other.’

  [3 Canadians seem to have made a disproportionate contribution to the cause of drug safety.]

  [4 Like you, I always keep a stack of these on my bedside table.]

  Kelsey’s first big impact on medicine came while she was studying with Geiling. He was asked by the FDA to investigate a series of deaths in people treated with a new antibiotic, sulphanilamide. Kelsey helped to discover that the method used to prepare a syrup version of the drug (which had an unpleasant taste in pill form) involved the use of a poisonous but sweet-tasting solvent, diethylene glycol.5 The syrup tasted good, cured infections, sold very fast … and, because it had not been tested for safety, also killed 107 people, many of them children. This disaster seems to have left a deep impression on Kelsey, and doubtless shaped her thinking in relation to drug testing. As you might expect, it had a similar effect on the country as a whole, and led to legislation, the Federal Food, Drug, and Cosmetic Act of 1938. This law has had a profound and long-lasting impact on the way that the safety of medications is managed. The Act required drug companies to show evidence that medications were safe before they could be marketed, and to provide warnings of potential hazards. This seems an obvious idea now, but it was a major shift from the free-for-all that had prevailed beforehand, and, because of the importance of the US as a centre for drug development and as a market, has had a major and lasting effect on the management of drug safety in the rest of the world as well.