Luck of the gene
Can we fix small DNA errors which are causing serious diseases? (10 minute read)
From an early age, I understood that people sometimes see what they expect to see, whether or not it is there. It’s commonplace for people to comment on the resemblance of children to their parents, and it seemed that this happened with me as often as it happened with my brother. Sometimes, people thought I looked like my mother. Sometimes, they thought I looked more like my father. But what they saw was either a coincidence, or an illusion created by their belief that all children resemble their parents.
As it happens, I do strongly resemble my mother, just not that mother. I have two, a biological mother and an adoptive mother. There’s no particular resemblance between me and my adoptive parents. But with my biological family, the resemblance is unmistakable. It goes beyond appearance too. Although I never met any of them until I was 21, I have mannerisms, personality traits and interests which resemble them as well.
I learned about genes and inheritance at school, but I didn’t give much thought to how it might apply to me. The experience of meeting biological relatives, though, showed me how influential our genes can be on our lives. We are all subject to a genetic lottery, with genes from our mother and genes from our father, just as they were subject to the same lottery before us. Like any lottery, some do better and some do worse, although I can’t think of anyone who has won a jackpot on genes alone.
On the other hand, for some people this lottery is viciously cruel. A tiny error in a single gene can have catastrophic impacts on their lives. It's almost incomprehensible how much harm can be caused by such a small variation. But such variations can affect people in ways that are hard to imagine.
One example is an error in the gene which makes an enzyme known as PAH. This is not the worst example of the damage a single faulty gene can do, but it’s still serious. The PAH enzyme has one job: to convert one particular amino acid to another. We can still get the second amino acid from protein in our diet, so that’s not a problem for people without the PAH enzyme. The problem is that the first amino acid builds up in the body, and too much of it is toxic, especially to the brain.
Although there’s no sign of the disorder, known as phenylketonuria or PKU, in newborn babies, the amino acid begins building up as soon as they begin feeding. Both breast milk and infant formula contain plenty of protein, including the toxic amino acid. By the time a baby is a few months old, they are already showing a developmental delay. Untreated, it damages the coating which separates nerve cells from one another. The result is a severe intellectual disability, along with tremors, other involuntary movements, muscle control problems and epilepsy.
Babies are routinely tested at a few days old to see if they have the disorder, because it’s fairly common. For example one person in just over 4000 in Ireland and Italy is affected, and one in 16,000 in New Zealand. It can also be managed if detected and treated early – before damage has been done to the brain, which means within a few weeks, or perhaps months, of birth. But it’s not easy. While there are some medications which might help, the only reliable treatment is by eating a diet low in protein, to limit the amount of the toxic amino acid. Fortunately, the levels of the toxic amino acid are low enough in breast milk to allow breastfeeding, but if breastfeeding isn’t possible, then a special formula is required.
To get an idea of how difficult this disorder is to manage, I checked a dietary guide from a British charity which supports people with it. Even at a time when there’s high awareness of allergies and conditions such as coeliac disease, the diet for PKU is difficult. Foods that must be completely avoided include all meat, fish, cheese, nuts, eggs, grains and flour-based foods, and soy products. Some foods can be eaten in limited amounts, but the amount which can be eaten must be calculated according to a formula. These foods are needed to allow the body to get enough protein and include potatoes, milk, cream, figs, passionfruit, corn, broccoli and a number of other vegetables. Finally, there are foods which don’t have to be weighed and can be eaten without restriction. But there’s not much left – fruit, some vegetables, sugar, fats, arrowroot, cassava flour, tapioca and sago. I saw the diet described by one sources as “complicated and unpalatable”, and I think that’s an understatement.
This diet needs to be life-long. Although it was once thought that the restricted diet wasn’t necessary after childhood, the evidence now suggests that a normal diet is harmful at any age. Even if people follow the diet strictly, they still struggle to keep their amino acid levels below a safe level. The buildup of the amino acid affects thinking, concentration and mood in those with PKU.
There are many other disorders caused by tiny changes in single genes, many much worse or less treatable than PKU. One of the more horrific examples is Lesch-Nyhan Syndrome, mercifully rare but profoundly disabling. It is caused by mutations which affect an important enzyme, resulting in difficulties with muscle control, involuntary movements, kidney problems and painful, swollen joints. The most distressing symptom, though, is that the involuntary movements include self-mutilation, such as biting lips, fingers and the tongue. Severe combined immunodeficiency is a group of disorders which affect the immune system – those affected have very little ability to fight infection. They can suffer life-threatening illness as a result of microbes which never cause harm to those with healthy immune systems. Huntingdon’s disease only begins to affect people between the ages of 30-50. Then, it causes brain cells to die, resulting in involuntary movements, difficulties with attention, judgement and balance, and behaviour changes.
The most common among the diseases causes by small DNA changes is cystic fibrosis. Again, it’s only a single molecule which is affected – one which is responsible for making a protein which moves chloride around cells. Chloride is one half of sodium chloride – table salt – and it affects the water levels in cells. As a result, mucus in the lungs and digestive tract becomes thick and sticky instead of thin and slippery. It can clog up the lungs and block the flow of enzymes needed for digestion. Although people who are affected can now often lead healthy lives into adulthood, it’s still a debilitating disease.
If all these diseases are so harmful, why do they still occur? This is where the genetic lottery comes in. All of them, apart from Huntington’s disease, are caused by genes known as recessive genes. This means that if a person has one working copy of the gene, this takes over and does the job. The cells simply ignore the faulty gene. While this is fine for the person carrying one copy of the faulty gene, it also means they often don’t know that they are carrying it. If two people carrying one copy each of the faulty gene have a child, this child has a 25% chance of receiving two copies of the faulty gene. Then, the disease shows up, because they don’t have a working version of the gene.
Huntington’s disease is different, because it’s caused by a dominant gene. This means that if someone has one copy of the faulty gene, the disease shows up. The cruelty of Huntington’s disease is that the symptoms often don’t show up until after the patient has had children. If one parent has Huntington’s disease then any children have a 50% chance of receiving the faulty gene and therefore developing the disease.
Although there have been advances in the treatment of many of these diseases, it’s easy to understand why scientists have been wondering if there isn’t some way of curing them by using gene technology. If a small error in the DNA has caused the diseases, could a small tweak of the DNA cure them?
I think that the vast majority of us are disturbed, at the very least, by the possibility of genetically modifying people. However, gene therapy for diseases such as cystic fibrosis or Huntington’s disease is very different from a dystopian vision of someone producing designer babies – or even preventing babies from being born with these diseases.
We have the technology now to gene-edit human embryos. A scientist in China claims to have done so, and his claim is not disputed, especially since he was jailed for doing so. However, it’s widely recognised that there are many ethical issues with doing this, many people are opposed and many countries prohibit it. The question here is not could we, but should we?
However, most gene therapy aims to cure people who are affected by a disease. This turns out to be much more difficult technically, but simpler ethically. Even though all of our cells have the same set of genes, in each cell only a subset of genes are switched on. In skin cells, for example, the gene which makes the faulty PAH enzyme leading to a toxic amino acid buildup in the brain is never switched on. If we fixed the faulty gene in the skin cells, it would make no difference. The cells which make the PAH enzyme are in the liver, so the working gene somehow needs to reach the liver.
Our liver cells and skin cells are not passed on to the next generation. None of our normal body cells are – the only ones passed on are eggs and sperm. This means that someone treated with gene therapy couldn’t pass along their altered genes, so such approaches don’t create the same ethical issues. Of course, people will have different views about what is acceptable, but the conversation is different. To me, the important issues are about safety, what treatments people with a particular disease are comfortable with, and what rights those who aren’t affected have to argue against someone receiving life-saving treatment.
Unfortunately, though, curing people with a disease caused by their genes seems to be harder than it first appears. To fix the gene making the faulty PAH enzyme, scientists have tried using a virus to carry the healthy gene to liver cells. When they tested this with mice, they found the treatment worked for two weeks, and then the immune systems of the mice recognised there was something different about the modified cells and killed them. Even if they can get the healthy gene into the liver cells and the immune system doesn’t destroy them, liver cells are constantly being renewed and the new cells don’t end up with the corrected genes.
There has been more success with the treatment of severe combined immunodeficiency. Gene therapy for this disease has used viruses to carry the healthy genes to the bone marrow, and clinical trials have had some success. A small number of people affected were effectively cured by the treatment, however, around a third went on to develop leukemia as a result of the virus used to deliver the healthy gene. Safety remains a significant concern with gene therapy of this kind – at least one early attempt resulted in fatal side effects for the patient. Those making the decision to take these experimental treatments are showing real courage.
Treatment of cystic fibrosis has suffered from problems similar to the treatment of PKU, in particular the constant replacement of treated cells by new cells which still have the faulty gene. In 2021, there was a clinical trial in progress, but only one. Likewise, there is work towards treatments for Huntingdon’s disease and Lesch-Nyhan Syndrome, but no cure yet.
A search of the literature for gene therapy of genetic disorders suggests that we are on the edge of some great achievements, but that these treatments are far from becoming routine. So far, there are a small number of treatments available and many more clinical trials, but also substantial barriers. As well as the scientific challenges, and issues with safety, there’s the vexed question of cost. These treatments aren’t cheap to develop or administer. We have been getting better and better at treating people with some debilitating illnesses, but we aren’t getting better at supporting scientific research or our health systems – not here in New Zealand, nor in the USA. Unless we get these right, the promise of gene therapy for alleviating suffering may turn out to be an illusion.
