Should we screen for more genetic diseases at birth?

Let’s look again at a couple of the genetics studies currently making waves, and what might be some of the deeper questions being asked by geneticists. It’s time to venture back down into Cambridge and link up with my genetics gurus, Shivani Shukla and Aylwyn Scally.

Will - First of all, thank you both for allowing me back <laugh>. You weren't scared off in the first instance too much. It's lovely to be back and talking about genetics with you. Let's talk about, first up, an article published in The Lancet has called for a potential reassessment of the UK's newborn screening program, a service which takes a blood sample of a newborn to test for genetic diseases, to determine if it should be updated to test for more genetic diseases. Shivani, I touched on it just then, but can you talk us through what the current screening program involves and what it looks like?

Shivani - The current screening program involves pricking the heel of a newborn baby, ideally five days old, and then testing that for nine different genetic diseases. And I thought it'd be interesting for listeners to know which genetic diseases they are. So those nine diseases are sickle cell anaemia, cystic fibrosis, congenital hypothyroidism, and six different metabolic diseases.

Will - We've got nine at the moment. Do we know how many they're proposing we go up to?

Shivani - Yes. So the estimates are between 200 to 400 different diseases and the US is currently at 63. So it'll be interesting to see what different countries do with this information. And it might completely change.

Will - By testing for these and knowing that they may appear earlier, you can start to treat them earlier. Is that the idea?

Shivani - In a way, yes, because for things like cystic fibrosis, sickle cell anaemia, they're very well studied diseases and there's quite a clear course of kind of prognosis. This is what a lifespan can look like. This is what doctors here in the UK can do for you. So it's useful to know earlier on. So you can manage the disease better. But for things like the more niche genetic diseases where maybe there's only a couple of children in the UK who are affected by it, I guess that it's useful to know, but then is it useful to include that in a massive screening program. And does every parent need to know? I don't know. That's where the debate comes in. And then it comes down to screening in lots of ways. Like if you have a relative who has Huntington's, some people would question, should I be screened for Huntington's? And if I do, what do I do with that information? So it's all the sort of question that we are asking with genetic screening and testing becoming more readily available.

Will - This is becoming an increasingly, almost ethical side of genetics in that would you want to know? And if you are performing this test on a newborn, they may grow up and decide that they wouldn't have wanted to know. And where do you draw the line ethically, there is that kind of the balance you need to strike with this sort of study.

Shivani - There's so many ethics when it comes to it, and what do you do with all that data? And newborns can't consent, they can't refuse. So yeah, there's a lot to think about. I think about the implications of this study.

Will - If we are going from 9 to maybe 400, that's just so many more, from a human side of things, many more things to worry about almost.

Shivani - That's very true. And also you have to consider how accurate whole genome sequencing is. And actually the rate of false negatives is higher in whole genome sequencing because you're picking up a lot of variations. But as we discussed in the last episode, an association is not a causal relationship. So it's complicated.

Will - Could this lead to an increasing clinical pressure with people being far more aware that they might have diseases. More coming in, more staff are needed to treat these sorts of things?

Shivani - Definitely. Without a doubt, because the follow up from this, if it becomes a national screening program, would be immense. And I can just think of the number of appointments with worried parents who want to know what's been picked up on this test. What are the implications for my child? What can I do? Which is understandable, but then it comes back to the question of what can the healthcare service even do about certain diseases? So one needs to think about can the NHS handle that basically?

Will - It'll be very interesting to see what this study concludes, I think.

Aylwyn - The other context to this is that there's a lot of potential money to be made around the world from providing these services. So there's a huge sort of health economic aspect to this too. So one has to bear that in mind as one of the reasons certain companies are keen to get involved in this. I think of a disease like dementia with other examples as well as Huntington's disease, as they later in life effect increasing numbers of people as they get older. And that's also something that we can't really do very much about. I mean, for me, that's the real distinction between a lot of these diseases that if it's a disease that we currently can't treat, that's when people say, well, maybe I'd rather not know. But there are some diseases where actually early diagnosis means there are preventative treatments that can be changed. And I think that was the original reason for the heel prick test was it was a set of dietary changes that could be made. And things like that. Then I think there's a non ambiguous that good that comes from doing it.

Will - It seems extraordinary to me that you could be presented with a list of 400 potential genetic diseases and maybe there are 20 of them that you have markers for and you worry about that your whole life and then you end up being hit by a car. And it was all meaningless.

Aylwyn - Absolutely <laugh>.

Will - So on that note, we shall move then from the beginning of life to the end of life. We come to a study from the University of Michigan published in Science Advances, which concluded that genetic mutations that promote reproduction tend to shorten human lifespan. Do we know which mutations promote reproduction when they talk about this?

Aylwyn - Like with any trait or characteristic of people, we can go and look for genetic factors, differences in the genome, in people's genomes that are correlated with an increase or decrease in a particular trait. And reproductive success is an example of such a trait. So you can look at a large number of people, hundreds of thousands for example, where they looked at reproductive success as measured by the number of children that someone had over the course of their lifetime, and looked at correlations between that and genetic differences. The actual causes and how those variants might specifically cause you to have more children or influence you, the number of children that you have, that's much harder to get.

Will - It's one thing to be able to say these genotypes may cause a shortened lifespan, but it must be a complete other kettle of fish to turn that into a phenotype that we could observe.

Aylwyn - I mean, the context of this actually is quite interesting because you might assume that ageing, for example, is something that we understand and you might even in fact assume that it's something that's inevitable. Certainly it's true that everybody dies, but it's not clear that ageing is inevitable. And by ageing, I mean degradation and falling apart. That happens to us all in the way our bodies breakdown. That may not be necessary. It's possible that we could kind of live like the elves in Lord of the Rings. We could be immortal <laugh> Until, you know, we have a car accident or somebody kills us. First of all, some people seem to age more slowly than others. So there is some variation even within humans. And then some animals live much, much longer than others. Some live hundreds of years. And if you think from an evolutionary perspective, it doesn't really make sense. Like, the longer you live the more chance you have to have children, more chance your genes have to reproduce. Surely there's a strong evolutionary pressure to just keep going and to and to not die by accident.

Will - To my layman brain, I read this, as callous as it sounds to ignore a human's thoughts, feelings, and ambitions. But if you reproduce early, that's kind of you done in terms of passing on your genetics and kind of serving your purpose.

Aylwyn - Well, you can keep reproducing. I mean that's really the difference that if you reproduce early and reproduce often, like voting some people say, then you will ultimately have more success than someone who reproduces late or just who stops reproducing has fewer children. There is nevertheless a greater sort of fitness advantage from starting early and from reproducing early. And that relative difference means there's a sort of an increased selection of genes that give you increased reproduction earlier in your life and relatively less for reproducing later in your life. And natural selection is ruthlessly efficient and anything that's slightly less favourable than another thing will essentially be kind of wiped out as a trait.

Will - You could have offspring as late as you like, but if you're not fit enough to keep them alive, then is that kind of an evolutionary disadvantage.

Aylwyn - If you have offspring later in life, the chances of being able to do that are just going to be a little bit less because there is always the chance that you might accidentally die. I mean, if you think about it, the world is a dangerous place and so death is going to be a thing no matter how long we live. And even if we supposedly were immortal. Once you sort of relax the kind of strength of selection on a particular trait and, for example, old age or reproduction, then what happens is that natural selection allows things to kind of come in like mutations that basically mess up the mechanisms and you just accumulate mutations which give rise to diseases later in life. So things like Huntington's disease for example.

Shivani - Can I just add, it's quite interesting in terms of Huntington's, there's a phenomenon called anticipation, which is that, if someone gets Huntington's because it's in their genes at a certain age, the amount of repeats, because it's a trinucleotide repeat, kind of accumulate through generations, which means as every generation passes, people will be getting the Huntington's earlier and earlier, which is obviously detrimental and quite bad. But because I suppose it doesn't affect their reproductive success earlier in life, it keeps being selected.

Will - And I was going to ask, complete blue sky thinking here. I suspect the answer to this is no, but if we know this information, if we know that certain genes kind of shorten our lifespan if they're based on reproduction, is there a gross sounding money-man looking at this, rubbing their hands going, that there could be some kind of gene therapy that we look at this and we could potentially allow people to live longer?

Aylwyn - There are people conducting research into sort of extending lifespan and delaying senescence. Another approach we could do which would be if we weren't so worried about our own personal life, since we just wanted to let natural selection do its thing, we could just extend reproductive life and just make the world a bit safer for ourselves so that we're less likely to die due to car accidents and other problems. Those processes eventually will then tip the balance in favour of longer life reproduction rather than getting your kids out as quickly as possible before something bad happens, which is currently what natural selection is aiming to do, it seems.

Will - That's your take home message. We all really need to improve our road infrastructure in order to live longer, more than anything else here.

Aylwyn - I'm glad that is the message. <laugh>.