Retinas revived after donor's death open door to new science

Host: Benjamin Thompson

Welcome back to the Nature Podcast. This week, reviving retinas after death.

Host: Shamini Bundell

And the likelihood that life originated as RNA. I’m Shamini Bundell.

Host: Benjamin Thompson

And I’m Benjamin Thompson.

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Host: Benjamin Thompson

First up on the show, reporter Nick Petrić Howe has been finding out how scientists are reviving human retinas after death to give us new ways to study diseases of the eye.

Interviewer: Nick Petrić Howe

When a person dies, the central nervous system shuts down. The signalling and talk that goes on between neurons goes irreversibly quiet, or at least so it has been thought. But in recent years, research has begun to challenge that seemingly obvious idea.

Interviewee: Frans Vinberg

A paper published in Nature in 2019 actually questioned this irreversibility of loss of neuronal signalling, and they were able to revive function of individual neurons in the pig brains up to five hours after death.

Interviewer: Nick Petrić Howe

That’s Frans Vinberg, a neuroscientist who specialises in eyes. That paper, which I covered on the podcast back when it was published, showed that neuronal functions could be restored by hooking pig brains up to a machine that pumped a blood-like substance into tissues and had chemicals in it that would help revive the brains. And this paper motivated Frans to investigate whether it would be possible to do a similar thing in his own field – with eyes. Specifically, Frans was thinking about the retina, which contains neurons that fire in response to light and communicate with each other. These neurons are part of the central nervous system so, like the pig brains, this opens up the possibility that they could be revived after death. And Frans wasn’t the only one interested in this. Here’s Anne Hanneken, a clinician who tries to understand the causes of visual loss.

Interviewee: Anne Hanneken

People have been trying to study human vision for 100 years, but there's so many unanswered questions that we couldn't answer with the typical models that we use, which rely on animals. But the human eye is very different than the eye of an animal, and you can't really study a human disease with a model that doesn't represent a human disease.

Interviewer: Nick Petrić Howe

When the two met at a conference five years ago, they joined forces to try and make this goal of reviving retinas a reality. To start, they had to figure out what causes the thought-to-be irreversible damage after death. And, well, is it actually irreversible? So, they got some donated human retinas and bathed them in a solution that mimicked the conditions of being inside a living person.

Interviewee: Frans Vinberg

Initially, we were able to revive these photoreceptor responses even from the eyes that were collected up to five hours after death, but then as we couldn’t make the cells to communicate to each other, then we actually went to mice and tried to understand why we lose this communication.

Interviewer: Nick Petrić Howe

So, the team were able to get the human retinal cells to respond to light, but not to talk with one another – something which is definitely required for a functioning retina. To get this communication nailed, Frans and Anne looked to mice and some of the key factors that occur after death.

Interviewee: Frans Vinberg

We know that after death, there are several factors that happen to the tissues, and two major things are lack of oxygen – hypoxia – and then second thing is acidification, and we tested these two factors. What we found from those experiments was that both acidification alone or hypoxia alone actually led to very quick loss of light signal communication from photoreceptors to the next neurons.

Interviewer: Nick Petrić Howe

But one of these factors was slightly more key than the other because the team could reverse the damage done by the acidic conditions, even several hours after death.

Interviewee: Frans Vinberg

So, the acidification was not a reason for this irreversible loss of cell communication, but then it was different with hypoxia.

Interviewer: Nick Petrić Howe

After death, hypoxia sets in very quickly. In fact, through their experiments, Frans and Anne were able to determine that human retinas would be irreversibly damaged 60 minutes after death, so trying to restore their function meant trying to avoid this damaging process as much as possible. Here’s Anne to explain.

Interviewee: Anne Hanneken

We realised that we probably needed a different system, and human autopsy eyes weren't ever going to be available fast enough for us to be able to restore that communication. So, what we did was we set up a very close collaboration with the Organ Donor Society and collected human eyes from organ donors after cardiac death in a very rapid manner. So, instead of waiting up to five hours after death, we were able to collect these eyes within an hour after death. And in fact, if we could get the eyes at 30 minutes after death, we were then able to restore the communication between the nerves.

Interviewer: Nick Petrić Howe

To ensure there was as little exposure to hypoxia as possible, they even developed a special transportation system where they could immediately get the eyes into oxygen. And with all that, the retinas would function much like they would in a healthy person. I should mention that the retinas were not connected to anything, so there’s no real way that they could ‘see’. But the functions of the cells were restored, meaning that they could sense light and fire signals to one another. Anne and Frans say that that although these retinas are essentially functional in a dish, it would take many years of research before these revived retinas could be used for things like transplantation. However, in the short term, they say that this work could help researchers to ask questions about vision and answer them in pretty much the closest thing you can get to actual human eyes.

Interviewee: Anne Hanneken

So, now that we have this method, we can take human retinas from people who have problems with their vision, we can look at the retinas from people who've passed away, and we can try to work out the mechanisms that are causing these changes in visual chemistry. That's really key because now we'll be able to do this in a human eye, we’ll be able to understand what these mechanisms are, and develop treatments that can overcome and restore the visual chemistry back to normal levels.

Host: Benjamin Thompson

That was Anne Hanneken at the Scripps Research Institute in the US. You also heard from Frans Vinberg from the University of Utah, also in the US. For more on this story, check out the show notes for a link to the paper.

Host: Shamini Bundell

Coming up: the researchers figuring out whether life on Earth was ever composed of just RNA. Right now, though, it's time for the Research Highlights, read by Dan Fox.

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Dan Fox

A new technique for making chocolate has been found to also yield a product with a fruitier and more floral flavour. To produce the distinctive taste of chocolate, fresh cocoa beans are fermented immediately after harvest. But in a new technique called moist incubation, unfermented, dried and crushed cocoa beans can be stored and transported before being rehydrated with an acidic solution and kept warm for three days. The researchers who developed the new method wanted to understand how it affected the finished chocolate’s flavour. Trained tasters were enlisted by the team who described the chocolate made with the newer process as fruitier, sweeter, more floral and less astringent than fermented chocolate. The team also analysed the bouquet of compounds in each chocolate type and identified those responsible for the different flavours, finding higher amounts of multi-tasting compounds in the chocolate produced with the new method. The researchers concluded that the pleasant flavour and aroma of the new bars means moist incubation could be a viable alternative to traditional production methods. If that has whet your appetite, you can read the research in full in the Journal of Agricultural and Food Chemistry.

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Dan Fox

3D imaging has uncovered some of the largest known Native American cave art, revealing figures spanning more than 2 metres in a cavern in Alabama in the United States. A team of researchers identified the images in a cave system known for the engravings on its mud walls. The ‘mud glyphs’ were inscribed on the ceiling of a cramped chamber whose height is rarely more than 125 centimetres – and often much less. Radiocarbon dating suggests that humans inhabited the cave well over 1,000 years ago. To visualise the scope of the wall art, the team used a technique called photogrammetry, which builds a 3D model from thousands of photographs. This model allowed the mud glyphs to be viewed from a much wider vantage point than was possible in the tight confines of the cave, revealing giant images of human and animal-like figures and other forms that were not apparent to the naked eye. Photogrammetry is often used to document cave art, but the researchers say that the technique could also help archaeologists to uncover hidden evidence of human creativity. Uncover the rest of that research in Antiquity.

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Host: Shamini Bundell

Next up on the show, reporter Adam Levy has been looking into the first dance of life. From the primordial soup, how did we get from just molecules to ultimately you and me. One key question scientists have been trying to answer to get a clearer picture of this is, ‘Before DNA, even before proteins, was there ever a world where life was just composed of RNA?’ Here's Adam with the story.

Interviewer: Adam Levy

For better or worse, I'm a physicist, and I'm used to people reacting to that by saying things like, ‘Oh my god, physics is so complicated.’ But here's the thing. Every time I learned about the fundamentals of biology, I realise just how much more complex life is. Even at its most fundamental, you have a delicate dance between information storage on molecules like DNA and RNA and jobs being done by proteins, which raises the key question, ‘How did these dancers take their first steps?’

Interviewee: Thomas Carell

I mean, life could have never started with such a complicated system from the beginning on.

Interviewer: Adam Levy

This is Thomas Carrell, who has a paper out this week which is trying to pin down how the dance of life began. It's a statistical impossibility that such a complex dance began directly out of a disordered mixture of molecules. So, if things didn't start with this complicated system, how did life emerge from a mixture of molecules? Here’s Nature biology editor Bryden Le Bailly.

Interviewee: Bryden Le Bailly

We need to understand how we went from some sort of primordial soup to life as we know it today, over the course of however many billions of years.

Interviewer: Adam Levy

One proposal is the ‘RNA world’ – a phrase coined in 1986. This suggests that before RNA and proteins danced together, RNA was playing the role of both lead and follow, coding for information and doing the jobs of a catalyst. This is a particularly intriguing possibility, because, in life as we know it today, RNA does indeed perform both roles to some extent, carrying information and occasionally performing tasks. For example, in the ribosome, where it teams up with proteins. But this idea has plenty of roadblocks. In particular, there aren't many examples of RNA getting complex catalytic jobs done by itself, where it would increase the rate of reactions. It's also unclear how a world of just RNA evolved into a world of RNA and proteins. But conversely, it's also hard to imagine a world starting with just proteins.

Interviewee: Bryden Le Bailly

So, RNA is very good at information storage, but it's not a good catalyst in terms of being able to form anything or do much beyond making and breaking its own bonds. And proteins are very good at making and breaking lots of different kinds of bonds, but they can't self-replicate.

Interviewer: Adam Levy

So, we're somewhat stuck with a chicken and egg riddle here. Which came first, the RNA or the proteins?

Interviewee: Bryden Le Bailly

It's very hard to ever nail down an answer in a field when you're talking about something that happened 4 billion years ago. So, there's always going to be intense debate in this kind of field about what might have happened, what actually happened, because we're never going to get a definitive answer.

Interviewer: Adam Levy

Ask any archaeologists how to study the past and they'll tell you, you need to dig up some relics. And that's exactly what Thomas and his collaborators did in their study. They looked at some weird RNA that exists across many different organisms today, suggesting that it dates back to our common ancestor. RNA is typically made up of four particular building blocks, but the building blocks of this ancient RNA are different. In fact, these building blocks are found in modern organisms bound to amino acids – amino acids being the building blocks of proteins. These RNA-amino acid structures play a key role in protein production, so the researchers were curious how these hybrid building blocks might behave outside a cell. And lo and behold, this molecule constructed a chain of amino acids – a peptide.

Interviewee: Thomas Carell

And they form longer and longer peptides. I mean, we were absolutely excited when we saw RNA in our culture tubes that decorated itself with peptides. So, it's really a new world.

Interviewer: Adam Levy

This new world isn't the RNA world, it's an RNA-peptide world. Here, the idea would be that the very first molecules were mashups – not chicken or egg, but chicken and egg.

Interviewee: Thomas Carell

So, we believe at the moment that an RNA world constructed exclusively out of RNA may have never existed, but that from the beginning on, what was present was RNA and amino acids, basically hand in hand, connected to each other.

Interviewer: Adam Levy

So, with such a profound possibility, is that all done and dusted? Is Thomas ready to hang up the lab coat?

Interviewee: Thomas Carell

No, I would certainly not hang up the lab coat. So, the next steps are clearly defined. I mean, the absolute dream would be to find an RNA-peptide hybrid structure where the RNA can self-replicate. This would be then a molecule that is able to get a son or a daughter, to get offspring. So, this would be the big next breakthrough.

Interviewer: Adam Levy

So, there's plenty of work to be getting on with, and not just for Thomas and his team, but many researchers may now be curious to investigate what an RNA-peptide world could have looked like. What's clear is that there are still plenty of questions that need answering about life's very first dance. Here's Bryden again.

Interviewee: Bryden Le Bailly

This solves a lot of those problems by the two working together to make a peptide. There are so many questions you can think about to answer now, and this is why, to me, this is a classic kind of Nature paper is that it opens a lot of avenues for research. Whether it kills the RNA world hypothesis I think is still up for debate.

Host: Shamini Bundell

That was Bryden Le Bailly, a senior editor at Nature. You also heard from Thomas Carell from Ludwig Maximilian University of Munich in Germany. To find out more about the first molecular dances, check out the show notes.

Host: Benjamin Thompson

Finally, on the show, it's time for the Briefing chat, where we discuss a couple of articles that are featured in the Nature Briefing. And you know what, Shamini, I'm going to go first this week, and I've got a story that I read about in Nature, and it's based on a paper in the Astrophysical Journal, and it asked the question, ‘When is a galaxy not a galaxy?’ And the answer is when it's actually a star.

Host: Shamini Bundell

Now, I'm not an astrophysicist, but you’d have thought that a star and a galaxy would look quite different. What was confusing about this particular observation?

Host: Benjamin Thompson

So, this star is a pulsar. Now, these are highly magnetised spinning neutron stars, right. And as they spin, they give off streams of radio waves from their poles. These are called pulses, hence the name, I guess, and these can be detected by astronomers. Now, typically, the pulse from a pulsar is faint and it flickers periodically. But this one, this star, its pulse has been described as wide and bright on the radio spectrum. In fact, so bright, ten times brighter than any other pulsar detected outside of the Milky Way. And so, this didn't fit the typical profile of a pulsar, and so scientists just went, ‘Ah, it’s probably a galaxy, right?’

Host: Shamini Bundell

And how did they then figure out that what they were looking at was, in fact, this unusual pulsar?

Host: Benjamin Thompson

Well, it seems that what's happened here is they've kind of used the astronomical equivalent of a pair of polarised sunglasses, okay. And when we think about polarisation, I guess we often think about light. And light waves can oscillate in a bunch of different directions, right, but these sunglasses, they filter out some of those directions and only let one oscillation through, maybe up and down, for example, right. Now, the emissions from pulsars are also often highly polarised, but some of them oscillates in a circular way, right. So, these signals kind of spiral along, and very few objects in space do this, and so they stand out, and this is what's been key for identifying this star as a star.

Host: Shamini Bundell

So, it's really that they've sort of seen this thing that they thought was a galaxy, taken another look and seen this rotation.

Host: Benjamin Thompson

Yeah, well, that's part of it. In this work, researchers suspected that this object could be a pulsar, thanks to data collected by a telescope array in Australia. And then what's happened is, this is where the sunglasses analogy comes in, right? So, they've used a computer programme to block out everything that's not circularly polarised, and it reveals as clear as day that this is, in fact, what it is, this star which is called PSR J0523−7125, which I think you'll agree is a very, very catchy name. And it's 160,000-odd light years away in what's known as the Large Magellanic Cloud, which is a satellite galaxy of the Milky Way. And in fact, it is potentially the brightest extragalactic pulsar ever seen – ten times brighter than other ones that have been detected.

Host: Shamini Bundell

Wow, and they're hiding there in plain sight. And presumably, it's because this star is so unusual that the scientists are now quite excited to have spotted it.

Host: Benjamin Thompson

Yeah, I think hiding in plain sight is exactly it. So, yeah, it was always there, right? If you look at the article in Nature, you can kind of see a before sunglasses and after sunglasses, and it is there. But then suddenly, everything else is gone and it's just this star. We'll put a link to that in the show notes. And I think, in future, this technique could be used to find even more of these kinds of rare pulsars outside of our galaxy.

Host: Shamini Bundell

Ah, brilliant. So, we've got a cool star and we've got a method for finding other cool pulsars and other stars.

Host: Benjamin Thompson

Yeah, well, I hope so, Shamini. But that’s my story this week. What have you brought to this week’s Briefing chat?

Host: Shamini Bundell

So, I've got a bit more of a biology story for you this time. This is an article in Nature about a paper out in Science, and it's about one of the things that is sort of killing and hurting coral. You may have heard that coral reefs aren't doing great at the moment.

Host: Benjamin Thompson

Oh, 100%, and what is this thing then that’s potentially damaging them?

Host: Shamini Bundell

So, aside from issues of sort of global warming and the temperature changes in the sea, which is a big one, there's also been this issue of a particular chemical in sunscreen that people thought was contributing to coral bleaching and damaging the coral. And this paper actually goes and looks into how this particular chemical might be turning toxic in the water.

Host: Benjamin Thompson

So, as someone who is quite pale-skinned, I'm obviously a big fan of sunscreen. But it turns out then that maybe going into the water with sunscreen on is damaging the coral. What did researchers do to try and figure it out?

Host: Shamini Bundell

Well, it does depend on whether it contains this particular chemical called oxybenzone, which is in quite a lot suncreams, right? So, it's there to absorb the UV rays and prevent damage. But what these researchers have found is that it looks like some organisms could be taking this oxybenzone molecule and, in an attempt to sort of detoxify it, they change it in a way that's actually making it toxic. And ironically, the reason that it's damaging is that now instead of blocking UV light, it's actually activated by light to produce free radicals that are then damaging things like the corals.

Host: Benjamin Thompson

So, it's acting then as almost a reverse sunscreen then?

Host: Shamini Bundell

Yes, and it highlights the issue that it's not just a matter of working out what chemicals are in your product and might be going into the sea, but what then happens to those chemicals. So, these researchers actually looked at what was going on in sea anemones to find this sort of particular issue. And sea anemones are sort of closely related to coral and also have a similar symbiotic relationship with algae, so photosynthetic algae, for example, that live inside the bigger creatures. And they also found when these anemones are missing their algae, they actually die even quicker when exposed to this oxybenzone, and also sunlight because it needs the UV light to actually do some damage. So, that kind of implies that perhaps in corals, where corals have already been bleached – so corals being bleached means they've kind of expelled their symbiotic algae – this molecule could be causing even more harm to already bleached corals.

Host: Benjamin Thompson

And you said at the start there, there's a lot of other things that are damaging coral, and bleaching can happen because of sea-temperature rise, for example. Where does this maybe stack up in importance? I mean, it seems like stopping climate change is probably one of the biggest ways we can protect coral moving forwards.

Host: Shamini Bundell

Yeah, absolutely. So, this research is important because if you're trying to design a sunscreen that isn't going to hurt sea creatures, this is the kind of thing that's going to contribute to the chemistry of what goes into it. But ultimately, individuals changing their sunscreen is going to have a lot less of effect than the massive impacts of climate change. And there's a quote from a marine biologist in this article who says it's ironic that people will change their sunscreens and fly from New York to Miami to go to the beach. ‘Most tourists are happy to use a different brand of sunscreen, but not to fly less and reduce carbon emissions.’

Host: Benjamin Thompson

Well, a strong message from that researcher there, Shamini. Thank you for bringing that story to this week's Briefing chat. Let's leave it there then. And listeners, if you'd like to learn more about these stories, we'll put links to them in the show notes, as always, alongside a link on where you can sign up for the Nature Briefing to get even more stories from the wide world of science delivered directly to your inbox.

Host: Shamini Bundell

And that's all for the show this week. We'll be back again next week but, in the meantime, feel free to reach out to us. We've got an email – it's [email protected]. Or you can tweet at us – @NaturePodcast. I'm Shamini Bundell.

Host: Benjamin Thompson

And I’m Benjamin Thompson. Thanks for listening.