A 'functional' cure for HIV?

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Welcome to Inside Science on the BBC World Service. I'm Tom Whipple, and today we are talking about a possible functional cure for HIV.

What does it do? How promising is it? And the really crucial question, what does functional mean?

From one terrible pandemic to the most terrible pandemic of all, did the Black Death start because of a volcano thousands of miles away and some enterprising Venetian merchants?

And our global science watcher Roland Pease has been peering into deep Homo sapiens history, courtesy of some caves in southern Africa.

And joining me to review the big journal stories of the week is Caroline Steele. Caroline, give us a teaser.
So I'm going to talk about why photobombing is an issue in space. Excellent.

I look forward to the aliens getting in shot.

This is not a cure. Almost 40 years ago, those were among the first words said about the first treatment approved for HIV.
Amid a terrifying pandemic, Robert Wyndham from the U.S.

Department of Health and Human Services told reporters that they had a treatment, a drug called AZT, that attacked the virus, but he did not want to over-promise.

Four decades on, scientists are still wary of the C word, but patients have a very different experience. Once, those infected took daily pills with marginal results and awful side effects.

Today, they can live near normal lives. And this week, the word cure was used again, albeit preceded by the word functional.

In In trials, an antibody treatment seemed to enable some patients to control the virus apparently indefinitely. What is it doing and what does functional mean?

I'm joined by Kate Bishop, principal group leader at the Francis Crick Institute. She studies antiretrovirals and their role in treating HIV.
Afternoon Kate.

First of all, can you just describe these antibody treatments for us? Yes, people were given antibodies that recognised a range of different HIV variants.

So these are called broadly neutralizing antibodies. And I guess we need to go back a step really and just describe what an antibody to HIV is.

Like all viruses, HIV has proteins on its surface that it uses to get into target cells to infect them. And these are the things that the antibodies recognize.

And basically antibodies will bind to the virus. And some of them, if they're called neutralizing antibodies, will stop that virus being able to infect a new cell.

And how effective was this in the trials? Because it worked for some people, didn't work for others and was in between for most.

Yes, I have to say I think this is one of the most promising trials that have come out, but you're right, it didn't work for everybody.

One of the things to recognize about HIV is that within one patient, it's not just one virus,

there's hundreds of different kinds of virus. So we're used to maybe hearing about variants from things like SARS-CoV-2 and COVID.

Well, there's more variation within one person for HIV than there is in the whole world for something like SARS-CoV-2 or flu. But the people for whom it worked, and let's get to this word functional.

So they took this and then months later they were still controlling, I'm using the word controlling the virus. Can you explain to me why this isn't a cure?

So for that, we have to understand how HIV replicates. So one of the key things about HIV that's different from most viruses is that it it inserts its genetic material into the host genome.

That cell then has permanent copy of the viral genes in it and for all intents and purposes it looks like any other gene in your body.

So it's extremely difficult to get rid of and in fact the only way we can get rid of it is to kill that cell that's infected. Because of that we would have to kill every infected cell in the body.

And the other problem is that HIV then, once it's infected cells, it becomes dormant. So these cells, although they are harboring harboring the viral genes, they don't actually make any virus.

So then it's extremely difficult to recognize these cells and work out which cells have actually got copies of the virus in them.

So in some ways it's a little bit like cancer and that's why we sort of we don't use this word cure like in cancer they use remission.

And so it's similar that we know that there are HIV infected cells in the body, but we don't necessarily know where they are and we can't really recognize them.

And so the word functional cure comes in. We want to be able to have people that don't have to take drugs every day.

And where this research was exciting is that these people were given broadly neutralizing antibodies.

And then even after the antibodies disappeared and they couldn't detect the antibodies in the patients anymore, they were still able to control the virus.

When the virus turned up, when it emerged from these cells, they were attacking it and preventing it from doing anything. Yes.

So if there was virus around, the antibodies would bind it and prevent it infecting any more cells.

But there seemed to be an extra thing going on where potentially these antibodies were activating the immune system to try and sort of recognise infected cells and destroy them as well.

We're all now familiar, as you say, with COVID, of talking about antibody treatments and all of these sort of viral things.

I think people listening to this will wonder why 40 years on are we giving people

what feels like the obvious thing, an antibody treatment that attacks it. What is it about HIV that actually means that this is is so much harder?

There's multiple reasons why it's difficult to make antibodies against HIV.

First of all, they're coated in sugars, which are made from the body, so they actually look much more like part of you and they're not recognised as foreign, which is what we make antibodies against things that are foreign to us and not ourselves in general.

But importantly, HIV mutates all the time. And so every time we make antibodies against HIV, the virus moves on and changes and those antibodies don't work.

These broadly neutralizing antibodies are so important, but they're really difficult to make. Not everybody makes them.

So it's taken years, as you say, to isolate these and to characterize them, actually to make them.

And then the other thing that they did for this study is they've also stabilized these antibodies so they make them last longer in the blood.

So it's been a sort of gradual process of making these things better and trying to understand them before they can even get to the point of using them. What does the future look like for HIV?

Is there a situation where people are still thinking there might be a cure, there might be a magic bullet, might it even be this thing?

Or more pragmatically, are we looking at lots and lots of stuff together? I think it's going to be a combination.

So one thing about this broadly neutralising antibody treatment is it's very expensive.

Also the antibodies are proteins, they need to be kept cold, they need to be in a fridge and they need to be delivered by injection.

And none of those things are particularly amenable in the field in Africa.

The other thing would be these long-acting antiretroviral therapies where instead of having to take daily medication, you could just have sort of one injection a year, which would also make it a lot easier for people to take their medication.

Adherence is one of the main problems. So I think that there will be a combination of different things.
Prevention is really important. We still have over a million new infections every year.

We really need to stop that. And we do have at the moment, I think we have the means to do things like that.

So actually, although we haven't got the means to cure, I think we have got the means to stop transmission. Obviously, most of these things require money, so that's always the issue.

But we do have the tools. Thank you very much.
That's Kate Bishop from the Francis Crick Institute. Now, at Inside Science, we are always at the cutting edge.

So we begin the next section with a 14th century chronicler.

In the year 1346, on the Feast of the Martyrs, the great famine began everywhere, where a sester of wheat both old and new was worth 100 souls.

The famine lasted until Our Lady of August.

In the year 1348, in the month of March, the mortality began in Bezier and lasted until the month of August. The mortality was such that out of every 25 people, barely two or three remained.

First, in 1345, the sky had darkened. There were reports of eclipses.
Then the summer didn't come. Crops failed and famine followed.

Finally, grain ships came from the east, bringing food and salvation. Or, the residents of Italy thought they did.
But with the grain they so desperately needed came something else.

Rats, fleas, and a little bacterium called Yosinia pestis. Is this how the Black Death began? With me is Ulf Buntgun from the University of Cambridge.

He has uncovered a chain of events that began with the eruption of a volcano thousands of miles away in the tropics and ended, he thinks, with a third of Europe dead.

Ulf, let's start with the volcanoes. What happened in the early 1340s and how do we know about it? We honestly don't know really a lot about the volcanic activity up to 800 years ago.

There are ice core records both in Greenland and Antarctica and these record sulfur depositions that can be released from large eruptions.

If we find the sulfur signals in the ice cores from Greenland, we would assume that the eruption took place on the northern hemisphere extra-tropics, if it's in Antarctica, southern hemisphere.

And if we find temporally synchronized spikes, so evidence in the same year of sulfur in ice cores from both hemispheres, we would assume it's a tropical one, which was the case in the mid-1340s.

And then you've traced this cluster of eruptions to some bad summers. How did you do that? In fact, we did it the other way around.

We looked into the tree rings from different sites, hundreds and thousands of trees that are growing in different mountain systems in Europe and Scandinavia and also northern Africa.

And they indicated a sequence of up to three consecutive cold summers. And that gave us indication that there might have been volcanic forcings.

During the growing seasons of 1345-46, trees were not able to lignify their secondary cell walls and really form a proper ring.

So temperatures must have been dropped under a certain threshold that do not allow trees to lignify.

And this is where, I guess, we move on from your area of geography into you've co-authored a paper with a historian.

Tell me how this then translates to what people were writing and what this chain of events set off. So there is this link.

We want to understand climate variability pre-industrial, so in the past, but then on the other side of the chain reaction, we also want to know what might have been societal consequences.

And then I'm usually reaching out to historians. And in this case, I did that with Martin Bauer, who is a medieval historian, climatologist.

And then he could corroborate these climatic downturns or anomalies. Talk me through the documentary evidence.
What are people saying in the mid-1340s in Europe?

One important thing here is that we can really nail it down to the year and even the season. And that is very, very important.
The tree rings are absolutely dated and the historical sources as well.

So Martin would look into these and then we see, yes, there is a lot of indication about bad harvest, harvest failures, large-scale famine.

And if we see that these sources report reductions in grain productivity, harvest failures at larger scales, so what Martin would call supra-regional or pan-Mediterranean, then we know directly the source or the reason for these harvest declines must have been a climatic one and can't be explained with local factors.

And this is where I guess your paper goes maybe into slightly another discipline. You've got a bit of economics in there.
So what happens?

We've got harvest failure, you've got accounts of people eating nettles, eating herbs, there's clearly people dying from famine. What happens next?

Italian city-states like Venice, Padua, Pisa, they had established a Mediterranean-wide network of grain supply for the very rare cases that these supra-regional harvest failures occur.

And they did it in this case.

They put everything to water that could float to import large-scale grain from the northern Black Sea regions via Constantinople and then into Venice and the other ports in the Mediterranean.

So the safety net functioned and they could prevent starvation, but ironically, they also imported something no one could know at that time.

And one can then very nicely see how Iassinia pesticider was spread over. Isn't it wonderful that you can look at something happening in a tree

and

expand it out into all of these other findings? I think it is.

I mean, the trees are not telling us these things, but they contribute to a more comprehensive picture and they provide an environmental and climatological context of what have happened in the past.

And we have to be careful to not be deterministic, but these are factors that contribute to decision-making and understanding plague and infectious disease and how climate and society have been interwoven in the past.

And even today,

I think that requires collaboration between different disciplines, and the tree wings are just one of them. So we should should remember the lessons of the 1300s.

A reminder, you're listening to Inside Science on the BBC World Service.

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Now, it's time to peer even further back in the story of us with our global science correspondent Roland Pease.

And I'm going back to the beginning of our species, Homo sapiens, with new DNA results from remains from South Africa dating back as far as 10,000 years ago.

As you'll know, getting DNA from old bones has transformed our understanding of human evolution, particularly the realization that European ancestors picked up genes from Neanderthals tens of thousands of years ago and early Atians from another cousin species, the Denisovans but our origins predate all that in Africa where the genetics are much richer although the DNA samples just reported from South Africa come from long after the earliest humans they are old enough Karina Schlibus of Uppsala University told me to carry the signatures of older genomes without being overprinted and confused by later population movements what is interesting in ancient DNA if you go back into the history and take ancient DNA samples of people that lived before, say, the last two to five thousand years, you go back into really the hunter-gatherer history of Africa.

So, before the movements of populations that were expanding because of farming, so all over the world, in the last two to seven thousand years, people were expanding because they adopted farming practices and populations grew and they moved into new areas.

So, the same happened in southern Africa. Before 2,000 years ago, there were just hunter-gatherers living in Southern Africa.
But then after that, a lot of other groups migrated into Southern Africa.

East Africans bringing herding practices and West Africans bringing agricultural practices.

But before that, there were only hunter-gatherers living in Southern Africa, and they were the ancestors of the Khoisan of today.

And those hunter-gatherers living in Southern Africa represent the first split in the tree of all humans.

In a previous paper, you made, I think, some pretty striking claim that Homo sapiens sort of is established by about 300,000 years ago, which is 100,000 years earlier, I think, than previous descriptions of fossils, for example, from East Africa.

This one, you seem to have the same picture that Homo sapiens establishes sometime around then, then it divides into groups in different parts of Africa, including this southern migration.

Yeah, it's all kind of a growing story, what is emerging for Africa. But more and more, we see that Africa has a very deep structure that goes back many hundreds of thousands of years ago.

So the debate is where humans come from, how did we emerge from our archaic ancestors, like for instance, Someractus and so on.

But more and more, it seems that there were different parts of Africa where archaic humans transitioned into modern human forms. But some parts of Africa were a bit more isolated from other parts.

So we had these different evolving groups of humans in different parts of Africa. And it seems that southern Africa for some reason was quite isolated.

So the ancestors of the Khwesan didn't mix as much with the other populations. And therefore they are the most isolated and they their population split around 300,000 years ago from other populations.

And what does that tell us about the pattern of evolution of humans overall?

I mean it's it seems to to me that the the the big story always with Africa is that the genetic diversity is so much larger there than it is in basically the rest of the world.

And that's basically because of the rest of the world is a subset of the variation 60,000 years ago in North East Africa.

So it's just a very small subset of the variation in Africa because then the rest of the populations in Africa represents much deeper history.

They started to diverge in different population groups way before that.

So the first population divergence that we see is then the square sign population that diverged from other populations in Africa around 300,000 years ago.

The differences, are they just sort of genetic spellings which are different or are there

do they affect actually the physiology of people in the different parts? Yes, it seems so.

It is very interesting to look at parts of the genome that evolved differently between the different groups that lived in Africa, but we can also compare the whole human species then for instance to Neanderthals to see how we are different from Neanderthals but to look for these variants it's really important then to include the most diverse human groups and we compared all human groups including Khoisan for instance to Neanderthal and there we saw that on the human lineage there has been an enrichment of genes that govern kidney development and we think it might have something to do with with water retention because humans are quite different from our closest ancestors, the great apes, the other great apes, in terms of our ability to have more water retention.

And we think it has to do with heat regulation and maybe long-distance running that the human lineage is quite well known for. That we're very good with that.
That's really strange.

So, by looking at this subset of genomes,

you're actually revealing something quite interesting about, I guess,

Yeah. I mean, we don't know.
We are making this hypothesis. We don't know at all.
We see kidney. There is a lot of selection in kidney-related genes.

It might have to do with water retention, but it is quite interesting. And is there more that you can learn? I don't know.
I imagine that for you this is only a footstep along the path.

Yes, there's many more interesting questions.

So basically the same questions that were asked for the out-of-Africa expansion where humans expanded and replaced or mixed with Neanderthals, these same types of questions are also there for Africa.

What happened in Africa? Was it a single origin?

Was it a single origin with migration and mixture with other archaic forms, or was there multiple places where humans turned from archaic humans into modern human forms?

Because we know there are archaic human forms also living together with our ancestors. For instance, Homo Naledi and human remains from Cabwe,

we know it's relatively young, it's around 200,000 years old, and these very archaic populations were living alongside our ancestors.

And then the question is whether our ancestors had mixed with these populations or not.

So, to be clear, in a sense, what you're saying is a story that we've seen with genes being introduced from Todisovans and Neanderthals in European and Asian populations.

You're saying that there may be some kind of similar tributaries, as it were, of genes in the southern African population. But you haven't been able to find it yet.

Yes.

So the question of archaic admixture in Africa is a very current question, and many people are trying to address this, whether these archaic forms of humans that we know existed in Africa, because we have fossil remains from them.

So we know they were morphologically archaic looking, so very different from our ancestors. They look quite different morphologically, but we don't know whether we mix with them or not.

Karina Schlabush, who is herself originally from South Africa and whose study just appeared in Nature This Week. Thanks, Roland.

Caroline Steele is here for our review of the rest of the week's science. Caroline, what else is there? So I want to start by talking about a photo bomber.

So I'm going to show you a photo and then could you describe it? And I want you to guess what or who is photobombing. Okay, you ready? I'm going to turn my laptop around.

I'm having a look at that's definitely space. Correct.
There's lots of spacey things. Yeah.
There is a big line across the top left-hand corner obscuring a beautiful, I'm going to say nebula.

But I know that space doesn't have big straight lines. Ah, is it a satellite in a time-lapse photography? Perfect.
10 points.

That is a satellite sort of obscuring an image from a space-based telescope.

So, according to a paper published in Nature this week, 96% of images from space-based telescopes could be spoilt by satellites in the next decade, which is a huge problem because it makes these images much less useful to scientists.

And telescopes in space are really important because, unlike telescopes on the ground, they don't sort of get influenced by Earth's atmosphere. So they're incredibly valuable to scientists.

But they share a sort of world with satellites because they both orbit Earth.

which means that when satellites get in the way and reflect light that sort of interferes with the image, the images spoil.

And that's a big problem because, so in 2019, there were only 2,000 satellites in orbit. Now we have 15,000.

And scientists in this study looked at a database of planned launches and found that we're likely to see as many as 560,000 satellites launched in the near future.

And that would contaminate 40% of NASA's Hubble Space Telescope's images. This is essentially intractable, though, isn't it?

I mean, there's a massive commercial imperative to put these up, and that's going to win out over the astronomers.

Some companies are looking to fix this so SpaceX and other companies have tested some solutions like covering up satellites with a thin dark film so they reflect less light but actually it didn't work very well and some of the satellites just heated up and were damaged so that's not really a solution.

If we could somehow make it happen you could move satellites lower in Earth's orbit but then you've got the issue of satellites interfering with Earth's ozone layer.

I personally think the kind of only realistic solution is to just launch fewer satellites and actually clean up after ourselves because, you know, at the moment we have millions of pieces of space junk orbiting Earth and some of that is retired satellites which are just orbiting Earth and not actually doing anything.

So we should be getting them back down. Okay, now final story.
Okay, final story. Plastic can be programmed to have a lifespan of days, months or years rather than taking centuries to break down.

This is according to a paper published in Nature Chemistry recently, which is very exciting because obviously we have vast amount of plastic to deal with.

And depressingly at the moment, only about 14% of plastic is recycled. Now a little bit of chemistry.
So plastic is a polymer, which basically means it's a molecule made up of repeating smaller units.

And scientists at the State University of New Jersey wondered why natural polymers like DNA break down quite easily, whereas synthetic ones like plastic just don't.

And the reason is natural polymers like DNA have these structures in them called neighboring groups that basically help break down the polymer at the end of its life.

So scientists, I think this is pretty impressive, basically created their own artificial neighbouring groups, added them to the plastic, and it worked. The plastic now breaks down.

And you can alter the neighbouring group to change. Does it break down in 10 days? Does it break down in 10 months? Does it break down in 10 years? So you can kind of time itself.

It still has the thing that makes plastic good, which is... durability.
Exactly. Which is, yeah, really cool, but hopefully it won't last for centuries.

Of course, there are some shortcomings, so it's better for not structural things. And there's a couple of problems to solve before it can be used commercially.

Like when the plastic's broken down, it forms a kind of liquid. We need to check we can release that into the environment or use it to make new plastics.

And also, this sort of destruction of the plastic needs sunlight, so if stuff ends up in landfill, it won't work.

But this is sort of the thing that's excited me most in the world of plastic for a very long time.

Well, look, exciting plastic is a wonderful place to end, but it's not only plastic that has a built-in end of life, so does every episode of Inside Science, and ours has come to an end now.

That's it. It's goodbye from me, and it is goodbye from Caroline.
Goodbye.

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