Genes, ageing and metabolism

Kat - This month, researchers at the University of Oxford and the Wellcome Trust Sanger Institute published results from the biggest ever study looking at how genetic variation in people affects how they respond to malaria infection. To explain more about the study, and why it was urgently needed to push forward the frontiers in the battle against this killer disease, I spoke to project leader Professor Dominic Kwiatkowski, director of the Medical Research Council's Centre for Genomics and Global Health.

Dominic -  Well, it's been known for over half a century that human genetic factors influence the outcome of malaria and indeed that malaria has been a major source of evolutionary pressure on the human genome.  And there have being a very large number of papers, hundreds of papers, published on different genetic factors that seem to influence susceptibility to malaria and in particular, influence the likelihood that a child who's living in a malaria endemic region who is repeatedly infected with malaria, the chance that the child will die or suffer life threatening complications of that infection. 

Because one of the curious things is that in areas where malaria is endemic, whilst everyone has malaria for much over time, only a certain proportion of malaria attacks are fatal.  Although a lot of studies have been published on the genetic factors, they've tended to come from relatively small studies.  And so, when you look at the literature, you find lots of reported associations.  It's very difficult to know which of them whether when you differences, whether those differences are like true biological differences or alternatively, just due to small sample size or to various factors that cause noise or to differences in assay design.

Kat -  So, with this study, how many people did you manage to get into it and what did you find?

Dominic -  Well, we managed to recruit over 12,000 cases of severe malaria - life threatening forms of malaria - from about 10 or 11 countries, together with our 17,000 population controls.  So, the total size of the study was 30,000 individuals.  What we found when we tested about 50 known loci that had been reported to determine resistance from malaria, we found that some of them were undoubtedly authentic and gave very strong and consistent effects.  It was not any surprise at all that we found very strong effects - protective effects.

Kat -  Would this be things like the sickle cell gene that we know about?

Dominic -  Exactly.  Sickle, it wasn't at all a surprise that it gave a strong effect.  I think what did pleasantly surprise us was that that effect was very strong.  It gives about 90% protection.  It was very consistent across sites and also importantly, it was consistent protection against different sorts of severe malaria.  

So children can die of malaria for multiple reasons.  One is profound coma, a syndrome known as cerebral malaria.  Another is profound anaemia.  It turned out that sickle cell gave exactly the same protection against those different outcomes.  And that, I think tells us that sickle cell is not protecting against those outcomes per se, but it's doing something for that.  It's sort of helping to reduce the infection per se and that in turn is reducing risk of its complications.  

The take-home message would be three things.  Firstly, there was a bunch of things that we knew about that replicated, I mentioned sickle, also blood group O, also a calcium channel - a gene called ATP2B4 - another thing called G6PD.  But then a whole bunch of other things that have been reported before just didn't replicate in a multi-centre analysis.  And that really showed the power of doing large studies.  It allows you to sort the wheat from the chaff.  

The third thing we found which was really important was that some of the authentic loci gave very consistent effects, but others were undoubtedly authentic, but actually get quite heterogeneous effects.  Either heterogeneous between different locations, different geographical regions or heterogeneous in their effects on different forms of severe malaria.  And the most striking example that was this genetic factor called G6PD deficiency - that's a blood disorder - which gives protection against cerebral malaria.  That's to say, coma due to malaria.  But actually, makes individuals liable to profound anaemia.  So, that was a bit of a surprise to us.

Kat -  When you think about the battle between the human genome and the malaria genome, it is a bit of an evolutionary arms race.  That tells us that it's a complicated battle going on, doesn't it?

Dominic -  Well, it does and I think that this study gives us a foundation for looking at those issues because one of the most important outcomes of that evolutionary arms race that you're talking about is going on in real time.  It means that actually, things are changing a lot in real time and so, genetic effects that may operate today in one population may not be operating in a different population at a different time because the parasite population may have changed.  But what we have here as a result of this study is a framework that we can study those heterogeneous effects with some level of scientific certainty.  

But the problem is that when we just do patchy isolated small studies.  We never know whether those differences are due to true biological heterogeneity or whether they're just the sort of noise of doing small studies which aren't particularly well-standardised.  Now, we have a framework to study that heterogeneity in considerable detail, and that's an extraordinary advance for us and for the field, we believe.

Kat - That was Dominic Kwiatkowski, from the MRC Centre for Genomics and Global Health.

Bats are well-known carriers of human viruses, such as rabies and the headline-grabbing Ebola. But could they be harbouring other infections too? Researchers recently discovered flu virus-like genes in bats raising concerns that these nocturnal creatures might carry flu viruses, and could transmit them to people. Fortunately, a new study from US researchers published in the journal PloS Pathogens suggests that bats may be in the clear for now. Because they couldn't find any trace of live flu virus particles in the animals, the researchers looked at the flu-like genes in depth, to find out if they came from active, infectious viruses or were merely relics of defunct ancestors.

Next, they synthesised the entire DNA of one of the bat viruses, called Bat09, and put it into human cells growing in the lab. Surprisingly, the virus DNA led to the creation of flu-like virus particles, but these were unable to infect any other types of cells, including human, dog, monkey, pig or bats themselves. This is because the virus DNA doesn't encode crucial proteins in the virus coat that enables it to get into cells. And the scientists think that the bat viruses are unlikely to be able to pick up this ability by recombining with other flu viruses inside bats, due to genetic incompatibility. So for now we only have to worry about rabies and ebola...

Kat - We return to our age-old topic, with Dr Nazif Alic at the UCL Institute of Healthy Ageing. He's figuring out if tweaking some of the genes involved in metabolic signalling could help to prolong healthy lifespan - but could it help us live forever?

Nazif -  I don't think we'd really be able to live forever, but what we might be able to do is to have a lifespan that's free of chronic and debilitating diseases that occur with age.

Kat -  So obviously, this is the big problem in our society.  We all live longer.  We don't have as many infectious diseases, but there's a long period at the end of life when it's very debilitating.

Nazif -  The final outcome of the research that we are doing or we hope the final outcome would be, to actually reduce the severity or reduce the duration of that very unhealthy period that certain people have at the end of their life.

Kat -  So, this is about health span rather than lifespan.

Nazif -  Yes, hopefully it is about health span rather than lifespan.  But lifespan does keep on increasing in our society.  So, there's a certain fear when people talk about extending lifespan, but actually, most of the medical advances that we've seen recently as well as advances in hygiene and the way the society functions have resulted in an extension of human lifespan.  It's about making that lifespan better.

Kat -  So, tell me about the work that you're doing?  How are you trying to increase health span?

Nazif -  A big part of what I'm doing, or what I have been doing recently, is trying to understand how manipulation of a single signalling pathway can extend this healthy lifespan.

Kat -  These are the messages sent inside cells that tell them to do stuff.

Nazif -  So, this is the wiring that tells you how to respond to your environment.  These signalling pathways tend to be nutrient sensing signalling pathways and the one that we are working on is the insulin/IGF signalling pathway.  So basically, the pathway exists so that your body can adapt to changing environmental conditions and in particular, to changing nutritional conditions.

Kat -  So, you eat a meal, insulin helps you use the nutrients from that meal - the sugar.

Nazif -  Insulin tells our cells what to do with that.  The sugar is present and what to do with that sugar.  Essentially, it can dictate the metabolism of the whole animal.  What the community has recently found is that if you modulate that pathway - I mean if you slightly inhibit the insulin/IGF signalling pathway, in a number of animals, you can extend their healthy lifespan.

Kat -  So, you can kind of turn it down and they'll live longer, healthier.

Nazif -  Yeah.  So you turn it down, they will live longer, they will live healthier, and also, it seems to help with a lot of diseases.  When we look at model organisms and we try to mimic human diseases in model organism, reduction insulin signalling can ameliorate those diseases as well.

Kat -  You mention model organisms - what organisms are you looking at?

Nazif -  So, I'm basically working on the fruit fly, Drosophila melanogaster.

Kat -  That's not something I'd associate with being tremendously long-lived.

Nazif -  So, they're not very long-lived which helps us do the experiment so we can finish them quite quickly.  They do live for some hundred days.  We can get them to live 200 days or even longer.

Kat -  Presumably then you can actually find flies that do live at particularly longer or healthier lives even within that timescale?

Nazif -  Yes, so what's the biggest advantage of Drosophila is that its genetics have been studied for such a long time.  There are a lot of very neat tools that we can use to alter their genetic makeup or to alter signalling within these pathways in various specific moments in time during the adulthood of the fly and in very specific tissues.  So, we can try to understand in minute detail of what kind of manipulation we need to achieve a healthy long lifespan.

Kat -  How do you tell if a fruit fly is kind of feeling old.  "My back!  I forgot where I've put my car keys."  How do you actually look at these flies and work out how they're ageing?

Nazif -  So, one of the main outputs that we've been using is really just how long they live.  So simply, we can see when a fly is dead or alive.  But more recently, we've been trying to look at more detail about their lifespan.  So, we can for example look at how well they move.  So similar to humans, as flies get older, their movement becomes slower and they find it harder to move.  

Kat -  Little flies in a Zimmer frame kind of thing.

Nazif -  Yes, little flies not walking as fast as they could 20 days before.  So, that is a very simple measure of their health and one that we've been using a lot.

Kat -  So, you can find that manipulating this pathway, this IGF pathway affects their lifespan and their health span.  What now?  Where do you want to go with this work?

Nazif -  So, the most recent work that we've done is looking at the effector of these pathways.  So, we know in modern organisms again that the beneficial effects of this pathway require a transcription factor called FOXO.  And this transcription factor essentially rewires the way the genetic information is used, remodels the way the genetic information is used so that the animal lives longer.  And we've been trying to work out exactly what genes are controlled by FOXO in which tissues and how they can result in an extended period in life and extended lifespan.

Kat -  If I was to have a child, how long would it be before I could give them some kind of FOXO manipulating thing that might make them live a much, much longer life?

Nazif -  I don't think we really know how long it's going to be.  Hopefully, it might actually be within your lifetime, that you might be able to take something that will prevent dementia or that might prevent type 2 diabetes or any chronic condition that will increase in prevalence as you age.  But we don't know.  What's quite exciting about this field is now, we've come to the point where we do have drugs that can be administered to people.  So, they're FDA approved.  They're approved for use on humans.  And those drugs in model organisms can extend a healthy lifespan. 

Kat -  So, this seems to be much closer than perhaps we might think.

Nazif -  Possibly, yes.  I think the next step will be on one hand, people like me working on model organisms, we need to refine the approaches that can be used, and the other thing that needs to happen in parallel is, for people to find means to see if those manipulations actually do work in humans.

Kat -  How long would you like to live for?

Nazif -  I think the younger you are, the less you care, but I'm starting to care more and more.  I do know that I have a very good amount of risk for cardiovascular disease and I would really like to avoid having a stroke or a very debilitating heart attack.  So for me, it may not be that much about how long I live, but just the quality of life as I get older.

Kat - That was Nazif Alic from the UCL Institute of Healthy Ageing.