by Heidi Norman
After his father told him about the diagnosis, Jeff went back to his life in the service and later enrolled in an army biology course. When he returned to civilian life, he completed an undergraduate degree in biology and began working towards a PhD in a lab studying Huntington’s. During this period he got married, and in the last year of his mother’s life he and his wife had twins.
By that stage Cindy Carroll’s body was so constantly overcome with the uncontrolled jerking and writhing, called chorea, that is typical of the disease that all her nursing home could do was place her on floor mats and hope she wouldn’t hurt herself. The night she died, Jeff brought his baby son to her, carefully placing him in the crook of his mother’s neck. It had been years since Cindy had shown any sign that she recognised her son, but when the baby nestled in to her, she was briefly still and seemed at peace. Her respite probably lasted only a minute, Jeff said, but to him it felt like hours.
After his mother’s death Carroll told a reporter that the worst thing about the disease was not the fact that it is fatal but that it ‘destroys your personality and turns you into an object of horror for your family’. Yet that is not the end of it. Huntington’s disease is hereditary, and when people talk about things like destiny and genetics and whether it is wise or not to know how you will die, Huntington’s is often what they have in mind. Cindy Carroll died in 2006, six years after her own mother, who was also a Huntington’s sufferer. When Cindy was first diagnosed, Jeff and his siblings learned that because of the way the Huntington’s mutation works, they had a 50 per cent chance of developing the disease themselves.
In 1993 researchers identified the genetic mutation that causes the disease. The discovery made an enormous difference to the likelihood that a cure would be found, and it led to the development of a test that can determine if someone will develop the disease. Before the test existed, the children of Huntington’s patients could only watch the suffering of their family members and wait anxiously to see if they developed symptoms, asking themselves whenever they dropped something if it was clumsiness or Huntington’s. Now the test brings grim certainty: if candidates have the mutation, they will develop the disease. Yet more than 80 per cent of the people who could take the test do not.
Jeff always knew he wanted to be tested, but it wasn’t until 2003 that he started the process. On July 31, 2003, he and his wife met with a physician to get the results. The physician told Carroll that he was positive for the mutation.
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Descriptions of a disease that sounds like Huntington’s can be found in writings that date from the Middle Ages. The uncontrolled twitches and swooping, circular, constant motion of the Huntington’s sufferer were first described as a dance in the 1500s. Later observers drew closer to understanding the condition and in the 19th century finally connected the affliction in one person to a similar condition in one of his parents. In 1872 the young physician George Huntington was the first person to clearly describe the illness as hereditary and degenerative, with an onset typically taking place in the afflicted in their thirties. ‘Those who pass their fortieth year without symptoms,’ he wrote, ‘are seldom attacked.’
Almost two hundred years later the science of Huntington’s was forever changed by Nancy Wexler, a then 33-year-old New York-based neuropsychologist whose mother was diagnosed with the disease in 1968. ‘It was as if some mad puppeteer was in control of her body,’ Wexler wrote. In 1979 Wexler travelled to a small town on Lake Maracaibo in Venezuela to visit the largest Huntington’s family in the world. Since the 1950s the people who dwelled in the town by the vast and ancient lake had been known in the medical literature for their extraordinary one-in-ten chance of developing Huntington’s, which they called el mal or ‘the bad’.
Wexler founded the US–Venezuela Collaborative Research Project and for several decades travelled to the region every year, studying pedigrees and sampling blood. She worked out that the villagers of Lake Maracaibo had seen more than 18 000 cases of Huntington’s in the span of ten generations. There are a few stories about when, and with whom, Huntington’s began in Lake Maracaibo. Some say the first cases were children of a woman called Maria Concepcion who lived in the early 1800s. Concepcion had ten children, and it’s thought that their father may have passed on the mutation. Genealogical work has traced tens of thousands of cases of Huntington’s to Concepcion’s pedigree. Another story, probably apocryphal, is attributed to a physician who diagnosed the villagers’ condition as Huntington’s in the 1950s and wrote that the locals told him that sometime between 1862 and 1877 a ship’s priest named Antonio Justo Doria left his ship and decided to live by the lake. He married and had children, and later in his life he was seen ‘walking with some strange movements, like dancing’. Currently 1000 locals have the disease, and around 5000 are known to carry the mutation for it. On a 2010 visit Wexler encountered a single large family in which both parents and ten of their 14 children had Huntington’s.
In 1983 Wexler’s team got close to the gene when they found a marker that was closely linked to it. In 1993 they finally identified the ‘huntingtin’ gene, as well as the mutation that caused the disease. Because the Huntington’s mutation is dominant, you only need one mutated copy from either parent to develop the disease. As categorical as the disease is – you either have it, or you do not – the genetic underpinnings of Huntington’s are oddly not so exact. Huntingtin contains a repeated sequence of the letters CAG. In normal copies of the gene, CAG is repeated around 17 times, and it can be repeated up to 26 times with no obvious consequence. However, if the CAG sequence is repeated more than 40 times, the carrier of that gene will develop the disease. When Carroll was tested, he found out that he had 42 CAG repeats.
While 40 repeats is a definitive threshold, the CAG repeats have an odd additive effect as well, which people in the community call the ‘gray area’: if you have between 35 and 39 CAG repeats, you will get the disease, but it won’t strike until your seventies or later.
If you have between 26 and 34 repeats, you will not develop Huntington’s yourself, but there’s a small chance that, if the gene you pass on mutates further, you may have a child who does. Even though Huntington’s is so strongly hereditary, Carroll explained that 10 per cent of the new cases every year occur in families where there is no history of it. Initially people suggested that such instances might be cases of adoption or illegitimacy, but that was shown not to be true.
Huntington’s usually appears in its sufferers between 30 and 50 years of age, but in rare cases children may also display symptoms of the disease. Often people with Huntington’s develop symptoms around the same time their parent did. But there’s a tendency too for it to appear a bit earlier if the mutation was inherited from the father. Wexler showed that the more repeats someone has, the earlier he will get the disease. The highest recorded number of CAG repeats on a huntingtin gene was near 100, a mutation carried by a boy whose symptoms began when he was two years old.
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Huntington’s may be the starkest model we have for reflecting on biology and fate. It’s a Mendelian disease, which means that the condition arises from a single gene.
Huntington’s also has deep resonance for how we think about all DNA. While so much knowledge has been steadily acquired in the realm of genetics over the last century and a half, and so much brilliance has blazed in the field in the last 20 years, there is still more dark matter in this particular universe than not. ‘We just learned the alphabet,’ observed Carroll, ‘and we were claiming we could write Shakespeare, and it’s a long way from here to there.’
The scientific and citizen community that has formed around Huntington’s disease is by now a highly educated one. The discovery of the gene had enormous consequences not only for Huntington’s disease but for all genetics. The genetic test for the mutation was the first offered for a genetic disease that appears in adulthood. Some of the techniques developed to identify huntingtin were later utilised to sequence the
human genome. Still, despite their intimacy with even the smallest molecules that affect the gene, there is a long list of incredibly basic questions to which scientists do not yet have the answer.
Scientists, for example, are baffled by what happens to someone who has two copies of the mutated huntingtin gene. It’s an extremely rare occurrence, but sometimes a man with Huntington’s and a woman with Huntington’s will have a child. That child will have a 75 per cent chance of inheriting one mutated copy of the gene and a 25 per cent chance of inheriting both. Yet despite the fact that more repeats on a single mutated copy means Huntington’s symptoms have an earlier onset, somehow people with two mutated copies of the gene do not develop a more severe set of symptoms than people with just one copy.
When Carroll gives a presentation about Huntington’s, he sometimes shows his audience a picture of slime mould, because slime mould has a huntingtin gene too. If a creature as simple as mould has a gene that humans also carry, then we can assume that a shared ancestor, an entity that lived millions and millions of years ago, had it as well – which means that all the creatures on the great evolutionary tree between mould and humans likely have it too. Any gene that is conserved in the genomes of many creatures is maintained because it has a very basic and very important function. The Hox genes, for example, are shared by all vertebrates and control their basic body plan, a central spine from which limbs project on both sides (in comparison to, for example, the blobby, spineless jellyfish). Yet scientists do not know what the function of huntingtin is in humans.
The significance of the huntingtin gene is demonstrated quite vividly by slime mould. When researchers turned off the gene in mould, it became sick. But remarkably, the huntingtin gene in mould and the huntingtin gene in humans are so similar that, when researchers put a healthy human huntingtin gene into the sick slime mould, it got better.
Not only is the huntingtin gene extraordinary for its spread across species, but its reach within the body is amazing too. Typically genes produce proteins in particular cells but not in others. It’s also generally true that genes produce proteins for a particular period of time but then stop doing so: they are turned on and off in the normal course of development. Huntingtin, by contrast, is one of the rare genes that is expressed in all tissues all the time. The protein the gene expresses is also called huntingtin, and it can be found in the cells of the heart and the lungs, in the blood and in the brain, and in the bones. Yet scientists still don’t know what the protein actually does. ‘It’s not super dynamic,’ explained Carroll. ‘It doesn’t seem to change its expression levels in response to signals, which a lot of other genes do. It’s like a housekeeping thing, it’s always there.’
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Carroll is a tall, clean-cut, strawberry blond who looks as if he still trains with the army. When he is introduced at conferences, presenters joke about how handsome he is. (In 2012 one colleague welcomed him to the stage by saying that during the Kosovo war, the women on both sides persuaded their husbands to lay down arms, just so they could look at Carroll.) He got his big break after his undergraduate degree with a job in the laboratory of prominent clinician and researcher Michael Hayden in Vancouver. Hayden’s team was trying to develop a drug that could silence the huntingtin mutation. ‘Gene silencing in Huntington’s is really attractive,’ Carroll explained, ‘because of the fact that it is a Mendelian disorder, so 99.9 per cent of people who have Huntington’s disease have the same mutation – variable length but the same place – and vastly all of them have one good copy and one bad copy of the gene.’ The drug in question would essentially be a ‘short piece of DNA or RNA’ that shuts down the bad copy.
Most research on gene silencing and Huntington’s has been focused on pan-huntingtin silencing, meaning that both the mutated copy and the non-mutated copy of the gene would be shut down. It’s easier to begin with this goal, Carroll explained, but it can take researchers only so far. Mice that have both versions of the huntingtin gene silenced in utero are nonviable; mice who have the gene silenced when they are older do better. But it’s still unclear how humans would fare with such a treatment.
The best way to silence the gene would be to target only the mutated copy, which was the focus of Carroll’s work. His team found that some of the letters of DNA in noncoding regions near the mutated gene were closely correlated with the mutation. By using those letters as a kind of address for the mutation, they were able to silence the bad copy in laboratory tests. In other tests that knocked out the mutant huntingtin in mice, one unexpected consequence was a rebound effect: the mice not only stopped deteriorating but actually got better. ‘Scientists are calling it a “Huntington holiday”,’ said Carroll. These drugs may not be able to stop the progression of Huntington’s forever, but they may give the brain ‘some space to compensate for some of the damage that it has experienced.’
Carroll put in long, hard hours on the drug, but once it reached the point of testing, he found he wasn’t motivated by the careful, plodding work of safety trials. ‘I got off my high horse,’ he told me. ‘You get humbled by therapeutic development, you realise you’re not that important. This is a team effort and I didn’t have to be the guy at the pointy end of the pipeline. I could decide what I wanted to do with my life.’
Carroll is now working on Huntington’s and metabolism because he became fascinated by ‘the remaining mysteries’. For example, even though the huntingtin gene is expressed everywhere, the places in the body where it is expressed more aren’t the ones that are most damaged in the course of disease. While most research examines the effect of huntingtin on the brain, because it so obviously and dramatically degenerates, Carroll is fascinated by changes in the liver and pancreas and other tissues caused by the mutant gene. ‘If you have cirrhosis of your liver, you get profound neurological symptoms.’ In some respects, neural imaging in these cases looks a lot like those of Huntington’s disease. ‘So you don’t have to just have brain degeneration that causes a brain disease; you can have peripheral dysfunction that causes brain dysfunction.’ He is also exploring the problem of Huntington’s and food. ‘It’s well known among caretakers and caregivers that Huntington patients eat a ton,’ Carroll said. Some Huntington’s sufferers consume as much as 5000 calories a day just to maintain weight. ‘They’re hyperphagic, and yet they lose weight,’ he said. Many of them die of starvation, but as Carroll explained, ‘Nobody knows why.’
Carroll also started a website called HDBuzz with a colleague, Huntington’s clinician Ed Wild. Both men were concerned about the amount of misinformation and hype about Huntington’s in the press, and they were struck too by the fact that while affected families desperately needed up-to-date information about research on the disease, Huntington’s also desperately needed affected families to help them with their studies. The site helps the two connect.
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When Carroll discovered he carried the huntingtin mutation, he decided he would never have children and risk passing the mutation on, but he changed his mind in the early 2000s when scientists came up with a method to ensure that the child of someone with a mutated huntingtin gene would never inherit that copy. In fact, two methods were developed. Doctors can test a fetus early in pregnancy and terminate it if it carries the mutation. They can also conduct a preimplantation genetic diagnosis. Using either a couple’s egg and sperm or a donor’s, doctors can create and test embryos for the mutated gene and then implant a noncarrier using in-vitro fertilisation. Jeff and his wife, Megan, were in the first generation of couples to use the second method, and after one try they conceived nonidentical twins who do not carry the huntingtin mutation. It used to be the case that most people started families before they knew they had the disease. Often they had children before they themselves began to display symptoms, and sometimes even before their own parents developed symptoms. There was also a great deal of secrecy about having the disease, a tendency to hide a diagnosis or not discuss it. In some cases the symptoms were thought
to be caused by something else, like alcoholism.
Despite the availability of testing, at least half of the population at risk for Huntington’s disease still has children without making use of the new technologies. Even some of the people who have prenatal testing for Huntington’s still have a profound reluctance to learn their own status. Couples who try preimplantation genetic diagnosis may even conceive a child and choose not to find out if the parent at risk has the mutation.
Deciding whether to find out one’s genetic status is a hugely divisive and painful issue within families and the Huntington’s community, but the desire to conceal information from oneself is a fraught position, especially when other people are affected by the same genes and the same knowledge. In one Huntington’s family a young woman was discouraged from taking the test by her mother, who did not want to know if she herself carried the mutation. The daughter eventually distanced herself from her mother, took the test, and discovered she was positive.
Silencing the mutation will put an end not just to the disease but to all the associated issues around disclosure. Until that happens, though, the issue remains extraordinarily stressful. Many adults who are at risk for Huntington’s and who have not taken the test worry that if they receive a positive result, employers may learn of their condition or, worse, insurers will. Although various organisations lobby to prevent genetic discrimination, it’s unclear how policy will progress, as the science changes so rapidly. Mostly, though, it seems to be the case that at-risk adults are traumatised and weary from looking after afflicted family members, and they feel terrible anxiety at the prospect of developing the disease themselves. The time just before people receive a formal diagnosis of Huntington’s is a critical period for suicide. Even those who are negative for the mutation may be haunted by survivor’s guilt. For most it is better to imagine that they do not have the mutation than to seek the knowledge that they don’t and risk finding out that they do.