The Boy Who Wasn't Short

by Kirk, Edwin;

  A series of meetings in Canberra followed. There was support in principle within the health department for a pilot project, but nothing concrete was on the table. Unknown to us, however, we had a secret weapon: the Casellas. Michelle Farrar, Mackenzie’s neurologist, introduced me to Rachael and Jonny, and they arranged for us to be in the room when they met with Minister Hunt. The Casellas spoke about Mackenzie’s life and about their loss. They urged action on carrier screening. It was obvious that the minister was deeply moved by their story, as was everyone in the room. Hunt, already a strong supporter of research into genomic medicine, promised that he would take action, and he has been as good as his word. The government committed $20 million to a research project aimed at determining how best to introduce carrier screening to Australia, with the goal that screening should be available free of charge to any couples who wish to access it. The project was christened Mackenzie’s Mission by Hunt.

  I am co-leading the study with Nigel Laing and Martin Delatycki,21 an eminent geneticist from Victoria who is a long-time advocate for screening for genetic conditions. We plan to screen 10,000 couples over the course of the study, with research into every aspect of carrier screening. You might think there are few questions left to answer about such a simple concept, but it’s surprising how many details remain to be worked out about how best to deliver screening.

  [21 Working with Martin and Nigel, and with the many, many others involved in the project, has been a wonderful experience. It seems like nobody ever says no to helping with Mackenzie’s Mission.]

  A major task in the first year of the project was to work out what, exactly, we should be screening for. This might seem easy enough — it’s a matter of choosing severe genetic conditions and screening for those, right? But straightaway that introduces difficulties. What do you mean by ‘severe’? There are plenty of conditions for which this is easy. Uncombable hair is an autosomal recessive condition;22 few people would consider that severe enough to screen for. The information just wouldn’t be useful to most people — certainly it’s unlikely that many people would change their reproductive decisions on that basis. At the other end of the spectrum, a lethal condition like Tay-Sachs disease is also straightforward; almost everyone who thinks screening is a good idea would include that. But there are many conditions that sit in a grey zone, where some might think them sufficiently severe but others do not. Take deafness, for instance. Most if not all of the commercial screening tests include at least one form of deafness. But how severe a condition is it, really? Some think that it should not be considered a ‘condition’ at all — it has been argued that treating deafness is a form of cultural genocide, because it may eliminate the Deaf community and its languages.

  [22 While not affected by this condition, I am nonetheless undergoing the cure — like many men my age.]

  For Mackenzie’s Mission, we decided that we would include genes if the associated condition caused a medical problem that started in childhood, that was severe, disabling and/or life-shortening without effective treatment (or where treatment is very burdensome), and for which an average Australian couple would take steps to avoid having a child affected by that condition. After much debate, we concluded that deafness does not meet those criteria, and we have not included any genes for isolated deafness.23 However, we think the questions of what to include in a screening program and where the boundaries should be drawn deserve further work, and one of the questions we aim to answer during the course of the project is whether Australians as a group agree that we have this right.

  [23 In other words, deafness where that is the entirety of the condition. Deafness can be part of syndromes, too, in combination with a variety of other medical problems.]

  Our final gene list wound up being much longer than we had expected — 1,300 genes associated with more than 700 conditions. There are more genes than conditions because there are plenty of conditions that can be caused by variants in multiple different genes. Of course, many of these are very rare, and for the majority there will be no couples among the 10,000 we screen who are found to have a 1 in 4 chance of having an affected child.

  Other research questions we need to answer include some quite simple ones — for instance, how many of the 10,000 couples will be identified as carriers for one of the conditions? That one is simple, but important — if you want to plan a population-wide screening program, you need to know what resources will be needed, and this is a key piece of information. A similarly pragmatic question is: will screening be cost-effective? This may seem callous given the human impact of genetic conditions, but, if a government is going to pay for screening, it needs to know if it can afford it, so health economists are a key part of our team. Other questions are more complex: What are the ethical implications of doing this type of screening? How can we design a program that does the most good and the least harm? How do we translate the research evidence we generate into medical practice as efficiently and effectively as possible?24 And so on.

  [24 This is a whole field of academic effort, called implementation science.]

  There’s no such thing as a perfect screening program. There will always be gaps in our knowledge and limits to our ability to identify those who are affected by, or carriers for, genetic conditions. I’m hopeful, though. I hope that within a few years, we will be able to offer the option to be screened to all who wish it. I hope that many will choose to be screened, and that, while most will receive reassuring information, for those who are found to have a high chance of having an affected child, the information will be helpful.

  Most of all, I hope that, over time, I will need to have fewer meetings with young couples to give them bad news about their children.

  There is a great deal to be optimistic and excited about in genetics. This book has been about the past and present of genetics, and how it affects peoples’ lives. But what about the future?

  12

  Where to from here?

  To complain of the age we live in, to murmur at the present possessors of power, to lament the past, to conceive extravagant hopes of the future, are the common dispositions of the greatest part of mankind.

  EDMUND BURKE (1770)

  In a room right next to my office in the lab, there sits an extraordinary machine. It is the NovaSeq 6000, which is capable of sequencing the genomes of 6,000 human beings per year. Its manufacturers, Illumina, used to make sequencers that looked like they would fit just fine as props in a science fiction movie. With the NovaSeq, however, they seem to have given up on industrial design, and the device looks uncannily like a large washing machine. The message is clear enough — when you have this much power, you don’t need to look impressive.

  Six thousand genomes per year. One machine, and it is one machine among many — there are three others in New South Wales alone, and likely hundreds or even thousands worldwide. When I started my career, we hadn’t even sequenced a single human genome. Back then, the idea that I might be sitting at a desk just a couple of metres away from a device that could do so much would have seemed wildly implausible.

  This suggests that any forecasts I make about the next 20 years, or even the next five, should be viewed as somewhat suspect. But there are some pretty safe bets.

  The first safe bet relates to technology. It will keep getting better, cheaper, and faster. Ten years from now, the NovaSeq 6000 will be a sadly outdated piece of equipment, and few labs will still be using them. At some point in the coming years, the costs for whole genome sequencing will come down so much that there won’t be any point in doing exome sequencing any more. Already, as we saw in chapter 10, we sometimes sequence all 23,000 genes in order to get information about just one or two, and it’s quite likely that genome sequencing will replace many tests we currently do that are targeted at particular changes. It’s not impossible that, one day, if we want to find out information about a single base of someone’s DNA, we will read all three billion and
just look at that one position we are interested in, ignoring everything else.

  The next safe bet is that genetic testing will become more and more commonplace. Exome sequencing has already gone from being an exotic, very expensive test ordered only by clinical geneticists to being a routine test ordered by many different specialists. Within a couple of years, attitudes among my colleagues have gone from ‘wow, my patient is going to have her exome sequenced’ to ‘why is this exome result taking so long to come back?’ We will be doing more and more complex testing, and it will be done earlier. There’s a term used to describe the often years-long process by which people used to reach a diagnosis for a rare genetic condition (if a diagnosis was ever made): the diagnostic odyssey. Many different tests, many appointments with specialists, years of frustration and uncertainty … often, now, we can avoid that altogether by doing exome sequencing as soon as it is apparent that there is a severe problem. The diagnostic odyssey should quickly become a thing of the past.

  Along with improving access to better, faster testing, the situations in which it is used will broaden. Already, there are large research projects involving sequencing the genomes of cancers to look for genetic changes that might respond to specific treatments. The term ‘precision medicine’ is used to describe the use of genetic testing — be it for cancer or other conditions — in order to tailor a treatment to a patient’s individual genetic make-up. The term itself is something of a meaningless buzzword, because it ignores so much that has gone before. I would argue that identifying a child with PKU using newborn screening, then giving that child a precisely targeted treatment that lets her avoid the devastating effects of the condition, deserves the name ‘precision medicine’, if anything does. If you have a bacterial infection and the lab tests the bacterium that ails you to work out exactly which antibiotic it is sensitive to … that seems precise, too. So I prefer the term ‘medicine’ to describe the new advances. Medicine is going to get better, and more genetic. Perhaps we will even get to the point where general practitioners will order whole genome sequencing before referring patients to a specialist.

  But that leads to a problem that doesn’t have an obvious end in sight: the problem of interpretation. Already, the hardest part about exome sequencing isn’t generating the data — it’s understanding what it means. No doubt we will improve with time, but, just because your doctor may be able to send your blood to have your genome sequenced, it doesn’t mean she will necessarily be able to understand the results in a way that will help with your medical care. As we’ve seen, most human disease is genetic in some way, but mostly this means complex disease, with genetics that are very difficult to interpret meaningfully for an individual. Even when we’re looking at variants in a single gene that are known to be linked to a specific genetic condition, it can be a challenge to be sure if the changes you find are the cause of the problem or not. Be wary of the company that offers to sequence your whole genome and interpret the results in a way that will guide you in making decisions about your health: they may be promising more than they can deliver.

  Having said that, treatments for genetic conditions are going to become more and more common, and more and more effective. Some will be cures. Most will continue to be eye-wateringly expensive.

  Regardless of the changes in technology; regardless of the treatments that may or may not be around the corner; no matter how fast we accumulate knowledge, and turn uncertainty to confidence — the fundamental nature of my field will not change. It always has been, and always will be, human genetics. The story of the future of human genetics will be like the story of its past, and its present — it will be the story of people, people like those you’ve read about in these pages. The scientist, on fire with a new insight. The doctor, working patiently to gather knowledge about a rare condition. The child with a syndrome, growing and living in a way that is defined — even more so than the rest of us — by her genes. The parents of that child: loving, grieving, learning, hoping. It is always, and only, about people.

  Here’s my final and favourite prediction: there will be things that happen in genetics in the next few years that will be a complete surprise. I have no idea what they will look like, but I can’t wait to find out what’s next.

  Glossary

  Amniocentesis: A type of prenatal diagnostic test. Performed under ultrasound guidance, typically at around 15–16 weeks, although it can be a little earlier or a lot later in pregnancy. A long needle is passed through the woman’s abdomen, and a sample of amniotic fluid is taken. Amniotic fluid is the liquid in which the baby floats. It contains cells that come from the baby. Nowadays, most testing on amniotic fluid is DNA-based and involves directly extracting DNA from these cells or growing (culturing) them in the lab, then extracting the DNA. They can then be used to test for chromosomal abnormalities or other genetic conditions. Old-school chromosome analysis can also be done on the cells (looking at the chromosomes under the microscope), as can other types of testing. For instance, biochemical testing can be done on the cells, or on the fluid itself. These are becoming much less common, however.

  Autosomal dominant: A form of inheritance in which there is a change in a gene on one of the autosomes, i.e. chromosomes 1–22, and this is sufficient to cause a genetic condition. You can think of this as the faulty copy of the gene ‘dominating’ over the other, ‘normal’ copy. A person who has an autosomal dominant condition has a 1 in 2 chance of passing this on to each of his or her children. Dominant conditions generally affect males and females equally, although there are some that mainly affect one or the other sex. For example, familial breast and ovarian cancer due to variants in the genes BRCA1 or BRCA2 is a condition that does increase the risk of some cancers (including breast cancer) in men, but mainly affects women. Dominant conditions tend to vary a great deal between affected people, even people in the same family who share the same variant in the relevant gene.

  Autosomal recessive: A form of inheritance in which there is a change in both copies of a gene on one of the autosomes, i.e. chromosomes 1–22. If a person is affected by an autosomal recessive condition, it is nearly certain that both of his or her parents is a carrier for the condition — i.e. they have one faulty and one ‘normal’ copy of the gene. There are some very rare circumstances in which one (or, in theory, even both) parents is not a carrier but a child is still affected. For example, there could be a new change in the copy of the gene passed on by the parent who is not a carrier. This is something that happens very rarely for most genes, but there are exceptions; spinal muscular atrophy is one condition in which — although it’s far from common — we do sometimes see affected children who have only one parent who is identified as a carrier. Virtually everyone is a carrier for one to several autosomal recessive conditions. This is almost never an issue for the carrier’s health, although again there are rare exceptions.

  Autosome: Any of the chromosomes other than the X and Y. Chromosomes 1–22 are all autosomes.

  Centromere: Part of a chromosome. Visible in pictures of chromosomes as the ‘waist’ of some chromosomes, although the centromere can be at one end of the chromosome as well (this is called an acrocentric chromosome, because the centromere is at the peak (‘acro’) of the chromosome. The centromere has an important role in cell division.

  Channel: The cell membrane is carpeted with proteins, or complexes of multiple proteins, which function as channels. These allow specific substances, such as potassium ions, to pass across the cell membrane. Sometimes this is a passive process and sometimes an active pumping. Normal functioning of these channels is important for maintaining the right mixture of salts inside and outside cells and for regulating the electrical activity on the surface of cells.

  Chorionic villus sampling (CVS): A type of prenatal diagnostic test in which a sample of the placenta is collected — specifically, the chorionic villi. Typically done at around 11–12 weeks of pregnancy. Under ultrasound guidance, a needle is
passed through the woman’s abdomen, or sometimes a flexible tube is passed through the placenta, and suction is used to collect the sample. The idea behind the test is that, early in embryonic development, there is a split between the cells that go on to form the fetus, and ultimately the baby, and those that form the placenta, but they start from the same point and share their initial genetic make-up. Genetic test results from the placenta are usually an accurate representation of the fetus, but sometimes there can be changes (especially chromosomal abnormalities) that occur after the split. This usually shows up as apparent chromosomal mosaicism at CVS. If there is mosaicism that is only in the placenta, it’s called confined placental mosaicism. Usually, this is harmless, although occasionally it can affect the function of the placenta. This means that, if we find a mosaic chromosomal abnormality at CVS, we often have to follow up with an amniocentesis to work out the significance of the result.

  Chromosome: Chromosomes are structures found in the nucleus of the cell. They are made of very long strands of DNA, wrapped around proteins called histones. The human genome is arranged into 23 pairs of chromosomes (in most people); you inherit one of each pair from each of your parents. The chromosomes are numbered from 1–22 (the autosomes) plus the X and Y chromosomes (the sex chromosomes). If you have missing or extra chromosome material, that means you have missing or extra copies of genes, which can cause chromosomal disorders.

  Coding: DNA that is coding is translated into proteins; non-coding DNA is not. Within a gene, the coding parts are the exons, whereas the non-coding parts are the introns as well as regulatory sequences before and after the exons (the 5’, pronounced ‘five prime’, and 3’ untranslated regions). Non-coding DNA may still be transcribed, i.e. copied to RNA. The resulting RNA molecules may have a variety of functions, including signalling and regulating the action of genes.