HIV case cured by umbilical cord stem cells
How doctors in the US have “cured” a woman with HIV, does Venus have volcanoes? Reexamining 30 year old probe footage has got scientists wondering, and signs that an artificial sweetener can affect the immune system...
In this episode
00:53 - Umbilical cord blood stem cells cure HIV case
Umbilical cord blood stem cells cure HIV case
Ravi Gupta, University of Cambridge
A woman in America has become the fourth person to be potentially cured of HIV when she underwent an immune cell transplant procedure to treat a blood cancer that she’d also developed. Speaking at a press conference as the results were unveiled, UCLA infectious diseases specialist Yvonne Bryson, who led the team treating the patient, was cautiously optimistic about the results…
Yvonne - We have not been able to detect virus in the blood and also her cells are resistant now. She's clinically healthy, free of both cancer and HIV, and we are calling this a possible cure waiting on a longer period of follow up.
Three male patients have previously also been cured of HIV in a similar way. One of them, Adam Castillejo, dubbed “The London Patient”, was on this programme 2 years ago alongside Cambridge infectious diseases doctor, Ravi Gupta, one of the team who helped to effect his cure. Ravi’s back with us today to explain a bit more about this announcement from the US. But before we get into what they did, why HIV is so hard to cure in the first place?
Ravi - So one of the hallmarks of HIV is that it actually, as part of its life cycle, integrates itself or becomes part of your genetic material in the immune cells which it's infecting. And that makes it really hard to remove it. The only way that the viruses code can be removed is by the cell dying. And so that's why the virus is really, really hard to cure. It can be controlled, but it is really hard to remove genetic material from all of your cells.
Chris - And when you cured Adam, how did you do that?
Ravi - Well, Adam was living with HIV and his immune system had suffered quite badly. And as a result, he developed a cancer that needed a transplant in order to cure it, what we call an unrelated stem cell transplant, where the cells from another person are used to replace Adam's own blood cells. But to do that, you've got to remove Adam's own immune system and blood cells using chemotherapy, which can be quite dangerous. So the interesting thing that was achieved was, which is that we found a donor who had a special mutation in one of the target proteins for HIV and that mutation allows you to become resistant to HIV. And we replaced Adam's cells with these new cells that not only cured his cancer but also made him resistant to HIV.
Chris - Is that mutation naturally present in the population then, there are people out there who are naturally resistant to HIV?
Ravi - Yes. So, in particular Europeans have this mutation called the Delta 32 mutation. Around 1% of Caucasians will have both of their copies mutated. And so that's one in a hundred, which across millions of people, uh, amounts to a fair number of potential donors.
Chris - And they're uninfectable?
Ravi - That's right. They're uninfectable with the strain of HIV that commonly circulates. There are variations of HIV that will get around that mutation but they're less common than the standard variant.
Chris - And so in Adam's case, by giving him cells that make it bone marrow and cells that therefore make an immune system that have or carry those changes, he ends up with a new immune system that cannot be infected with HIV.
Ravi - That's right. So we believe the cancer chemotherapy also helps to kill the HIV infected cells. And actually then the new cells that come in cannot be infected. And so you end up with a situation where the infected cells have died and there are no new possibilities for infection of fresh cells.
Chris - The paper that's been published in the journal cell with Yvonne Bryson, who we heard at the beginning there, describing how they've cured their patient, this woman, the first woman to affect a cure, they're saying they've done it slightly differently than your approach. They're using what they call umbilical cord blood stem cells. So what's the difference?
Ravi - The stem cells that we were using were from adult donors. The paper that we are discussing here involved umbilical cord cells. So these are cells from babies or neonates, and they are taken for future use potentially, for either themselves or other individuals for the purpose of curing various diseases including cancers. So the difference there is that you're taking similar cells, but from much younger humans.
Chris - But apparently they're much more comfortable grafting their way into a person who's a less close match. I think that's the attraction, isn't it, of using those cord blood cells?
Ravi - Yes, apparently. That's right. So, you can get away with a poorer match if you use those types of cells.
Chris - So what are the implications of this? Now, this is patient potentially number four.
Ravi - The main implications are, first of all, it shows that you can achieve a cure in different ways. Secondly, it shows that the CCR5 gene target is a really important one. Because we've now had four examples. And then I think there's an interesting sort of racial slant to this, which is that with this new approach I'm quite pleased to see that actually you can expand the numbers. The sort of people who could benefit from a cure or a curative approach. And that really, I think is really important in this day and age where the vast burden, the vast majority of people living with HIV are not in Europe anymore. So I think that's important for us.
Chris - There's some 38 million people currently infected with the disease and we've cured four of them. Do you think this is a realistic prospect as a way forward? Or is this just an academic interest and great news for the people for whom it works, but it's really beyond the reach of those 38 million?
Ravi - Most treatments start out being tested in small numbers, in what we call pilot studies. And, so you might sort of see this as a pilot study of a test of principle. And of course what we really want to do is to be able to take cells, mutate them to make them resistant to HIV and then give them to a person living with HIV, but without giving them strong chemotherapy that can weaken their immune system and make them vulnerable to quite dangerous infections. So the immune suppression side of this is really where, where the next kind of frontier is going to be.
Chris - Well, I was gonna ask you that because surely doesn't this now say, well the next step would be to get stem cells from a person, their own stem cells, that we can prove they haven't got HIV in them and then just, just do gene editing? I say just, making it sound really easy, but we've got the tools now to genetically engineer the sort of changes into a person's cells to make it as though they were naturally a carrier of this CCR five, delta 32 mutation that gives you the resistance to HIV.
Ravi - That's an excellent point. So that's been the focus of intensive research over the last decade or more where people have tried different gene editing, editing strategies to do the thing you're saying, which is to make the mutation. The difficulty has been the efficiency of that editing has been one of the frontiers. So if you take a hundred cells, maybe only 80 of them would get edited, and so you'd still have 20 that were normal. And what would happen is if you put those back into a person, that those 20 potentially could take over in the patient and then therefore that patient would still be susceptible to HIV. So it's about getting from 80%, um, editing efficiency to 99.999.
Chris - So there's somewhere to go. But it's exciting all the same, isn't it?
Ravi - Absolutely, very exciting for me.
08:12 - New evidence of volcanic activity on Venus
New evidence of volcanic activity on Venus
David Rothery, Open University
Despite Venus being as close to us as Mars, much less is known about its surface and inner workings. That’s because Venus is a very hostile environment. The atmosphere is 100 times thicker than Earth’s, which makes peering through the gloom and studying the surface with satellites very difficult, and the high temperatures - hot enough to melt lead on the surface - also mean that most probes cook: the longest any man-made structure has lasted on Venus is two hours! But now, by revisiting 30 year old images of the surface of Venus, scientists from Alaska Fairbanks University have discovered two photos taken 8 months apart that show an apparent lava flow coming out from one of Venus’ volcanoes. So how much light does this shed on how Venus operates? Will Tingle asked Open University planetary geologist David Rothery to take a look at the findings for him…
David - I've lost track of how many times active volcanism has been "discovered" on Venus. And this was just another attempt to see if anything had changed in an eight month period that was possible by the repeated imagery. Venus' surface is clearly young. There are plenty of places where lots of lava flows and volcanoes and it's not been blasted to smithereens by impact craters coming in. It's clearly a young surface, but how young? This has been a debate and if it's all relatively young, surely some of it should still be erupting today.? After all, the Earth, same size, mass and density as Venus, has got plenty of active volcanoes.
Will -Purely for the listeners at home, not me at all, do volcanoes work the same way on Venus as they do on Earth?
David - Well, Venus is Earth-like in terms of its gravity, size, mass and density, so you're melting the same kind of stuff. It's got a much denser atmosphere, 90 times denser than ours, and also a much hotter surface, about 400 Celsius all the time. So if molten rocks rise to the surface and start to spread out like a lava flow, they'll cool down slower than they will on the Earth. If the rocks erupt explosively, which is hard to do because there's a denser atmosphere confining the volcanic gases, but if they do erupt explosively, you can get a sustained eruption column with convection going on, but it won't reach as high as it would on the Earth. But you can get convecting eruption columns like you get on volcanoes in Indonesia lately, for example, where there have been eruption columns on volcanoes. So, many of the processes, volcanologically, on Venus are very similar to Earth and more similar to Earth than on an atmosphere-less body like Mercury, or a body with very little atmosphere like Mars. So Venus is going to be the best analogue elsewhere in our solar system for finding volcanic processes that in all stages look very similar to Earth's.
Will - What does this apparent volcanic activity signify about the planet?
David - Well Venus, although it's the same size mass and density as the Earth, is behaving perplexingly differently. Earth gets most of its heat out through plate tectonics, warm stuff rises at mid-ocean, cools down, forms an oceanic plate, which then disappears below the continents at the subduction zone like the ring of fire around the Pacific. And those volcanoes are an indirect manifestation of plate tectonics. It doesn't work that way on Venus. We don't have young plates forming and cold plates descending. As far as we can see, all the heat is either getting out through just conduction or through hotspots where the volcanoes are operating. Finding out the balance of how this is happening and whether it goes on at a steady state on Venus, or whether it's episodic. There was a theory, a decade or so ago, that Venus had some rigid lid which kept all the heat in and then every few hundred million years it overturned in a vast orgy of global resurfacing that would be very catastrophic and that's gone out of fashion now and people are saying no, it probably erupts here and it erupts there and we have to use a special pleading to understand why they can't see particularly young regions and particularly old regions manifested by the number of impact craters they can count. So it's not well understood. So there are some very important differences between the global heat transport outwards on Venus and the global heat transport outwards on the earth. And it's understanding why these two planets, which should be the same but aren't, are so different and yet so similar. That's the fascination of doing volcanology on Venus.
Will - So by better understanding what's going on in terms of the volcanic activity, we might be able to get a better look at what's going on under the hood as it were?
David - Absolutely looking under Venus' hood. That's a good strapline for a talk. I might try and nick that one
Will - It's all yours. So what's next then? As you say, there's a few more flights going past Venus. Are they hoping to shed a bit more light?
David - There are two NASA missions to go to Venus. There's Da Vinci and there's Veritas. There's a European one - Envision. So after many decades of nothing concentrated on Venice's surface, we now have a fleet of spacecraft going there which will peer through the clouds, one will send a descender on a balloon to go through the clouds and see the surface for a while before it cooks and we'll have better radar mapping of the surface. So we're going to understand Venus much better and these exciting hints that have been building up over the past 30 years that there is ongoing volcanic activity, we'll be able to really test those and if in eight years time we don't know for sure whether or not there's volcanic activity on Venus, I'll be very surprised. I think these missions are going to cleans it for us.
Will - Very exciting. Set our watches for eight years time, then?
David - Something like that, yeah.
14:23 - Artificial sweetener suppresses immunity
Artificial sweetener suppresses immunity
Karen Vousden & Fabio Zani, Crick Institute
High doses of the artificial sweetener sucralose, which is 600 times sweeter than sugar but yields zero calories when consumed, reduce immune responses in mice. Karen Vousden and Fabio Zani have found that the agent seems to affect the signals produced by immune T cells when they activate themselves to fight infections. They haven't looked in humans yet to see if the same thing could be happening, but if it is, it might be possible to use sucralose to control certain autoimmune diseases where the immune response inappropriately turns on the body itself…
Karen - Our lab's been interested in the impact of diet on disease for quite a while now, and we've been looking at how different components of our diet might be modulated for therapy. And as you know, across the globe, the consumption of sweetners is increasing rapidly and careful studies by many regulatory agencies have shown them to be safe at the normal levels of consumption. Now our study doesn't contradict these findings, however, in recent years there have been reports that sweeteners may have more effects than previously thought. So we carried out a study to look at the effects of some of these sweeteners in mice.
Chris - And how did you do it, Fabio?
Fabio - We looked at the effect of giving sucralose to mice at very high doses, doses much higher than what a normal person would see by just consuming food and drinks containing sucralose as a part of a normal diet. We measured many physiological responses such as weight gain and other metabolic parameters, including the composition of the gut microbiome. And we didn't see any major effect in any of these physiological parameters until we tested a possible effect of sucralose on T-cells that are part of our immune system.
Chris - And just to be clear, were you comparing mice with sweetener and mice without sweetener or rival sweeteners or sweeteners that are natural sugars? I mean, what was the comparison group here?
Karen - So all of those things, we fed our mice with just water and we also fed our mice with water containing different sweeteners. What we found was that feeding mice with sucralose- but not the other sweeteners we tested -somewhat decreased their ability to properly activate T-cells. So T-cells are a major component of the immune response. So what in effect we saw is there was a dampening of the immune response. So as Fabio's just said, there was no effect of sucralose on any of the other physiological responses that we tested. Also, when we tested mice with these high doses of sucralose, we didn't see any alteration of the immune system under normal unstressed conditions. However, when we used models that would trigger an immune response that involves those T-cells in mice, we did notice that the activation of the T-cells was less effective. And importantly, all of those effects are reversible. So when we take away the sucralose, the immune response goes back to normal. Then we actually went onto test where the sucralose could have any therapeutic effect, and we looked again in mice of T-cell mediated autoimmunity. So that means autoimmunity caused by overactivation of T-cells. And so we looked in two models, a type one diabetes model and a colitis model. And we found that these very high doses of sucralose dampen the T-cell responses and reduced inflammation, which in the end was beneficial for the mouse.
Chris - Now obviously we're not advocating, Karen, that someone with those diseases should take extremely high doses of sucralose to try to control their disease. But what it might highlight, if you can work out how it's having that effect, is a novel avenue therapeutically presumably, isn't it? So do you know how the sucralose is affecting the T-cells in the way that it is?
Karen - We spent a long time trying to answer that question. It was quite difficult to answer. So in our cell culture systems, we found that, in fact, exposing T-cells to sucralose prevented them from properly activating the signals that are required to mount a proper immune response. The way that that seemed to be happening is that the sucralose seemed to be affecting the membrane dynamics of those cells. So preventing the normal clustering of the receptors that these cells have allows them to signal downstream to properly activate the T-cell and thus activate the T-cell immune response.
Chris - So Fabio, do you think that this is clinically relevant? It's very interesting academically and at the doses you gave it - very, very high doses in the mice you saw this effect, but does this have impacts for clinical medicine and also the consumption of these sorts of sweeteners for people more broadly?
Fabio - So we don't know whether we would see the same effect in humans, and we are now hoping to test whether high doses of sucralose could have a similar effect in people. We really want to emphasise that our study did not support the idea that normal sucralose consumption is immunosuppressive. We need very high doses indeed. In our study we use two different doses of sucralose and both these doses are very, very high. And the lowest of the two doses already shows some decreased ability in modulating T-cell responses. That prompted us to think that it's unlikely the normal sucralose consumption could have any effect. However, we hope that we can exploit this discovery to design new therapeutical strategies and we think that high doses of sucralose could potentially be useful into some dependent autoimmune disease. Maybe by adding sucralose to existing treatment, we can achieve a better therapeutical effect.
20:34 - Endangered mussels squirt out offspring
Endangered mussels squirt out offspring
David Aldridge, University of Cambridge
You’ve heard of throwing the baby out with the bathwater, but researchers at Cambridge University have really pushed the boat out with the discovery that a rare mussel species squirts its young across a river so that fish mistake them for food and temporarily snap them up, and but then end up nurturing them for the next few months. David Aldridge tells the story of unio crassus, the thick shelled river mussel…
David - We've stumbled on something absolutely incredible and really very surprising. A freshwater mussel known to be endangered, which during the springtime, the females of this species move to the margins of the rivers in which they live and start squirting jets of water, about a meter long, back into the river. And we've found that these jets of water carry the tiny little larva of this freshwater muscle back into the river.
Chris - When you say they moved to the margins, these animals are almost beaching themselves. They're actually coming out of the water to send these jets through the air and then back into the water, aren't they? Because I've looked at the footage that you've published of them doing this. It's quite extraordinary.
David - Yes. These mussels are sort of exposed. They're just on the edge of the water and they suck up the water inside their shells and then they squeeze the shell together that squirts these jets and these beautiful loops back into the river. And what's happening is that the larvae of freshwater mussels have this amazing life history where the larvae are like miniature castanets. They're about a third of a millimeter long and they have little hooks and spines on them and they have to attach to the gills or the fins of a host fish in order to complete their life cycle. And so what we found is that each of these jets carries about 50 or so larvae. And when those jets of water land in the river, they are perceived as food by the fish, which are the best hosts for these mussels. And instead of getting food, they actually get parasitized by the larvae. And this is a really neat system for the mussel because by using fish as a host, it allows them to travel around a river system. And obviously mussels are very immobile. They sort of sit in the mud at the bottom of the river. But fish can particularly help to transport these larvae upstream.
Chris - How long are they in the fish for then?
David - Well, they can stay on the fish for about two or three weeks in some species. And over a year in other species in this particular mussel, it's probably, they're probably on fish for a month or so before they drop off.
Chris - And then it's down to the riverbed to spend the rest of their life maturing, becoming adults. And then they're doing this behavior later.
David - That's right. What we found with this muscle is that unlike most European muscles, this particular species, the thick shell river mussel, has a very narrow range of fish that it uses. That's probably one of the reasons why we've got this peculiar behavior that the mussel wants to make sure it gets its larvae on the right fish and not on the wrong fish because otherwise it would waste a lot of its larvae. And by having this close association with a particular range of fish species, those fish share the same habitat as this particular mussel. So there's a greater chance of the juvenile mussels leaving the fish in suitable habitat. So we've got this very close sort of coevolution going on.
Chris - There's a million questions going through my mind because it is such an extraordinary story. First is how does a shellfish that doesn't have a brain know it's at the riverbank, get itself partly emerged from the water and do that at the right time of year?
David - <laugh>, I think your guess is as good as mine. It's totally mind blowing that yes, as you say, this is an organism without a head or a brain that knows to do this really by specialized behavior. My hunch is that they are responding to the sound of the water on the margins of the riverbed. So that's sort of acting as a cue for them to move to the margins. But we really don't know. I mean, there's some opportunities for great experiments to try and try and sort of really work out what's going on.
Chris - Tell us then, how did you spot it? Were you just sitting on a riverbank counting mussels and you spotted one squirting and then that made you wonder?
David - <laugh> Like many of the greatest pieces of scientific research, this emerged from a conversation over some beers at a conference. These mussels were living in a river in Poland, and my colleague mentioned that he'd observed this peculiar behavior. And so a group of us said, let's go and spend a week in the Carpathian mountains in Poland and see what's going on. But I don't think anything really prepared us for what we were going to see. It was remarkable. Just all these mussels all the way along the riverbed squirting away.
25:39 - Gorillas enjoy getting dizzy
Gorillas enjoy getting dizzy
Marcus Perlman, University of Birmingham
Dizziness is a sensory paradox. As we grow older, it’s usually associated with feeling out of sorts or unwell, but while we’re young, it’s a state of mind many children seem to actively strive to achieve, whether that be through playground equipment or theme park rides. Well, it turns out that reaching this altered state of mind is not unique to us humans, as researchers at the Universities of Warwick and Birmingham have been finding out. They’ve been observing the thrill-seeking tendencies of gorillas by trawling through online videos and noting how many rotations and for how long our fellow primates are spinning. James Tytko asked Marcus Perlman what gave him the idea that apes engaging in such behaviours might be significant…
Marcus - I guess, it was about a decade ago, even more than that. There was a viral video of a gorilla named Zola who did some impressive spinning. And then Zola appeared again more recently, maybe about five years ago. And another viral video spinning behavior has been documented as a gesture that apes use. But in the case of Zola, it looked like he was spinning around as part of a creative display. And it looked like he was having a lot of fun. So that video made me start to wonder, and then my co-author, Adriano Lameira, made us start to wonder how widespread this behaviour is. What is the range of variability in this kind of spinning behavior? And so we started searching YouTube and found lots of videos of spinning apes.
James - When I'm watching animal videos on YouTube, I'm told it's procrastinating. But when you are doing it's research apparently. How's that fair? What did you infer then? I've seen the video you're referencing and as you say, it's undeniable that Zola's having a lot of fun.
Marcus - Yeah. It seems like from what we've observed, they specifically engage in rope spitting, maybe because it's fun and stimulating, but certainly as a consequence they get dizzy very often. They will spin around for a minute or so, kind of let go of the rope, stumble around, fall, and then jump up and do it again and repeat. It's not clear whether the spinning is stimulating and fun, and then the dizziness is a consequence of that, or whether the dizziness is part of the stimulation and the fun.
James - And it does raise the psychological, perhaps even philosophical, questions as to why apes and by extension us, why we feel the urge to engage in these mind altering behaviors because it's something almost universal across humanity and reaching a different sort of consciousness.
Marcus - Yeah, I mean, the way I sort of think of it is that by spinning around and altering your perceptual experience and causing them subsequently, the world continues to spin around. I think that sort of highlights the subjectivity of our experience. And maybe that insight allows us to kind of break free out of the blinders that we normally have in our daily experience.
James - And is it significant then that these altered states of mind might be something that our evolutionary ancestors have passed down to us? I suppose the question is whether this is been observed in other animals other than observed in primates.
Marcus - I was searching around last night with my partner and we were looking at videos of animals. 'Doing research'. And we found a grizzly bear on its side rolling down the hill. And it looked like it was having fun, whether, you can infer that it was probably getting dizzy. We also found a panda bear rolling, but sort of somersaulting headfirst and rolling down the hill. So I think the behavior probably extends to other mammals, at least now the rope spinning in particular, I think is probably something that is more special to primates. Really gives the animal the leverage to spin fast and to spin for repeated rotations in a way that gets you dizzy, I think in a way that it's harder to do without, without the use of a rope.