Tracing the origins of COVID19

A new “bionic eye” system has been successfully implanted in a patient in the UK. The recipient was a woman with a condition called age-related macular degeneration, which progressively robs victims of their central vision, greatly reducing their quality of life. Julia Ravey spoke to eye surgeon Mahi Muqet, who performed the implant surgery, to find out more…

Mahi - At Moorefields last week there was a patient who I had implanted an electronic chip into in December and her eye had settled from the operation. She has a condition called dry age related macular degeneration, where she's missing the very centre of the eye in a particularly large area. There isn't any treatment for this, so our clinical trial is looking to implant a device that essentially replaces the light sensitive cells in that part of the eye. The good news was that the electronic chip was working one hundred percent and she actually was very quick to pick up how to use the system.

Julia - How does this bionic eye implant work?

Mahi - It's a pair of glasses that the patient wears. There is a small video camera and it captures about a 50 to 40 degrees field of view. That is then passed from the glasses down to a small pocket computer that sits on the patient's waist, that can be tuned and that then sends a much cleaner image to the glasses. The signals are then beamed using near infrared light inside the eye, directly over the electronic chip. It's about the thinness of a human hair, so it's very, very tiny, and we have these specialised technicians that will help her to use the device and start to scan her visual world.

Julia - Why is it electrical signals that get sent to this chip?

Mahi - It's a bit like solar panels. Out in the desert you may see these cells called photovoltaic cells, that's the technical term, but they're essentially small electrodes; little cells. So, the electronic chip has 300. I think 78 of these small electrodes are called pixels. The near infrared light from the glasses is beamed onto the chip that then charges up these small electrodes to start working. You then have little currents that run through the chip and then the tissue surrounding the chip inside her retina starts to pick up these signals. They start to work and then the network kicks off and all the human function inside the eye helps to take these signals, process them, and they go down the optic nerve to the brain. Imagine you're looking at something, like a letter box, you see it upright, you see it in the right direction - that's to do with all the processing inside the eye. If you didn't have that, it might be lying on its side or upside down. So, what we found in a previous trial is, with the chip, patients are able to see everything in the right orientation -  that's due to the processing. That's the chip working with the cells of the eye.

Julia - Amazing. So, for the cells that I'm missing, it's plugging that gap and allowing you to still patch in the signal to the brain.

Mahi - Exactly, yeah.

Julia - How clear is the vision that you get from it? If I was looking at an eye chart, what line would I be able to read if I had this chip in place?

Mahi - From seeing just shadows, they were able to recognise individual letters and they were also able to scan words. So, if you imagine a patient that has no vision in the centre, is completely dark, they're starting to pick up words and letters. We anticipate that perhaps they could pick up about two lines on the charts, but it's such a small study that now the European study will look at lots of different people in lots of different countries, and then you put all the results together and that will give you a much better and more accurate result from the trial.

Julia - You mentioned that there are trials going on now for using this chip. What more needs to be done before the technology is more widely rolled out?

Mahi - So the first one was what's called 'the first in humans' -  you put the device into patients to actually see if it works. And then once, you know it's safe, you run them over a much larger group of patients and then you follow them up during the study and it's a three year study. The results usually come out towards the end of the study period and, at that point, people are then preparing the next steps. Once we see the results, the next step is being planned.

Julia - It really does sound like life changing technology. How do you think devices like this will change the field of sight restoration?

Mahi - Well, I think for this particular condition, where as you are probably aware, there is no treatment available, if you can restore some form of vision for a patient that's essentially blind in that eye, it can give a significant improvement in the quality of life.

Scientists in Cambridge announced this week the discovery in Uganda of a new species of insect that belongs to a group so rare that its closest known relative was last seen in 1969! The new species is a leafhopper; these animals drink sap from plants and in turn are food for birds, beetles and spiders. Alvin Helden, from Anglia Ruskin University, was doing fieldwork when he made what some have dubbed a “once in a lifetime discovery”...

Chris - Alvin. Tell us what the leafhopper looks like.

Alvin - Right? Well you know what a cicada is, it's like a miniature cicada and this particular one looks a little bit odd for a leafhopper. In addition it's a little bit humpbacked, they're generally not that humpbacked. It's quite dark in colour, most are quite lighter. And it's got a sort of metallicy sheen, particularly in its wings, which is really quite unusual too.

Chris - How did you stumble across this one?

Alvin - Okay. I had a little project going, trying to find out the number of kinds of species that existed at a national park in Uganda called Kibale. I was sampling for leafhoppers and I was using a sweet net through some bushy vegetation and I came across this one. I thought it looked unusual, but I didn't know for certain what it was. It was only when I got it back to the UK and I was able to look through various identification guides. I came across a drawing, looking very similar to this and I thought, 'Ah. That's it.' And so I followed that up and then discovered it was very rare indeed.

Chris - How do you notice a new species though?

Alvin - You have to kind of do some research into the literature. See if anybody's found anything before and assume somebody found something really quite similar in the same, very close group. But then you have to actually look at the detailed structures. Particularly in leafhoppers, you really have to look at male genital structures, so really you're talking about the penis and the associated structures. You have to look at that and compare it with other specimens of other species. When I did that, I found that this one was unique and it was different from the very close relative that had been found before.

Chris - Now, the fact that you've discovered something so rare, does that mean that you are the world's luckiest scientist or does this mean actually, they were rare once, but in fact, perhaps conservation efforts or other are sorts of bio remediation efforts to restore environments are working, and in fact, they're now becoming more common than they were?

Alvin - We really don't know. Only three individuals of this particular small group of leafhoppers have ever been found. We don't know why they are so rarely found. Is it because they are really rare and they're just so few of them, or is it, we are just not looking in the right places? Maybe it's just that we don't find them because we don't look in the right places, but we don't know what those places are. We know very, very little about these particular insects and why it might be rare. We can't really say anything about how successful the conservation is. Where it's found is in a national park called Cali national park, which is well protected and it's treated very well by the local people in terms of respecting the boundaries of the national park pretty well. It's in a fairly safe place, but of course, surrounding that national park has been really badly deforested in many ways.

Now it's hard to believe that it's been almost two years since a pandemic was declared for a new virus that could cause serious respiratory disease. Although the virus has changed and caused several waves of infections since early 2020, the debate around where the original virus came from continues to rage on…

Julia - While the initial focus of these investigations honed in on trying to find the animal intermediates from which the virus jumped through to get to humans. More recently, talks of a lab leak have started to surface. So, which theory is right? Well, we have to start back at the beginning

News Readers - COVID19 News montage

Julia - Throughout history, we have faced constant threat from disease outbreaks. Tiny pathogens, invisible to the naked eye, can hijack our systems, use our cells as breeding grounds to increase their numbers, and leave devastation in their wake.

Chris - Each one of these outbreaks from a global pandemic to a few cases in a community, leaves a trail though, a clue as to where it's come from. And that is its genetic material. And for the SARS-CoV-2 virus, which causes COVID 19, this code has been at the centre of trying to crack how and where this virus originated.

David - SARS-Cov-2 is a kind of virus known as an RNA virus

Julia - That is David Matthews, a professor of virology at the university of Bristol, who specialises in the study of coronaviruses.

David - We were working on coronaviruses before the pandemic started. So we immediately made requests to see if we get a hold of SARS-Cov-2 and start to chip in our expertise.

Chris - Like a recipe book, genetic material encodes the instructions for life. From humans, to dogs, to mice, plants, bacteria, and viruses. SARS-Cov-2 is generated from a 30,000 letter long set of instructions that are written using a form of genetic material that's a chemical relative of DNA that's called RNA.

Julia - And just as the human genome project has helped to reveal how our cells work, the coronavirus RNA code can tell us about the properties of SARS-Cov-2. But reading the viral genetic code is not as simple as opening that recipe book at a certain page and scanning through. It requires specialist equipment and experts like David to translate its meaning.

Chris - As well as using genetic material as a blueprint to predict how a virus might act, it can also be used to trace where it came from. Like humans, a virus has a family tree, a line from which it was descended. And if you look at your parents or siblings or cousins or grandparents, your genetic code will be more similar to those members of your family than it would be to say a stranger in the street.

Julia - Although we are all human and our genetic instructions contain the same recipes, small spelling mistakes - a changed letter here and there - generates different outcomes when these instructions are followed.

Chris - Those spelling mistakes or mutations are more similar between family members than strangers. Meaning we can trace our lineage by comparing our genetics and viruses are just the same.

David - What happened at the beginning of course is, they extracted the RNA from the early patients and sequenced it. And what you do then is you compare the sequence of the genome that you've got with all the other genomes of all other known viruses.

Chris - David Matthews. And that is how you track down the closest relatives of a new virus to find out where it may have come from and how it emerged. Aris Katzourakis from the University of Oxford works on how this trail of genetic breadcrumbs can be used to lead us back up the evolutionary tree to find the ancestors and therefore, the sources of diseases like COVID19

Aris - Evolution leaves imprints that can be deciphered when we read the genome of a virus. By comparing sequence data from different species, we can try and work out where different viruses may have come from, what kind of species they may have crossed from. Let's say you see a virus in a human, and it's incredibly similar in terms of sequence data to a virus in a mouse, you may conclude that there has been some source of transmission between those two species in recent history,

Julia - The more similar a virus' code the more closely related they are. And if we find the parent, we can crack the mystery of where this virus SARS-Cov-2, which caused one of the most significant pandemics in our history, originated.

In the absence of an obvious animal on which to pin the origin of the COVID19 virus, we return to what the genetic code of the virus can tell us. Is this virus, for instance, from the same source as its four bears, the original SARS or MERS viruses. That genetic code says not…

Julia - These viruses are very different. When comparing SARS-Cov-2 to the original SARS virus, their genetic codes are 79.4% similar. While that sounds like a pretty high number, in genetic terms that is about as similar as a human is to a cow. And when compared to MERS, this similarity drops to around 50%. So in order to find a closer relative, the genetic sequence of SARS-Cov-2 was compared to other documented coronaviruses already discovered in the wild.

Chris - Jesse Bloom studies viral evolution at the Fred Hutchinson Cancer Research Centre.

Jesse - The two closest known relatives of SARS-Cov-2 are two different coronaviruses that were isolated from bats. So one of these viruses, the first one that was known is called RATg13, and that was a virus that was sequenced at the Wuhan Institute of Virology and they had collected it from a bat cave in Yunnan province. More recently, another virus similarly close to SARS-Cov-2 was discovered in Laos. These viruses are both about 96 to 97% identical to SARS-Cov-2.

Chris - 96% the same is a lot closer. But how far apart in evolutionary terms is that missing 4%? In other words, given the rate at which coronaviruses evolve, how long would it take to fill that genetic gap? The answer is still a very long time.

Jesse - That corresponds at sort of the evolutionary timescale of a number of decades, say 30 to 50 years of time from which they diverged. It's also really important to emphasise that something like RATg13 is not the ancestor of SARS-Cov-2. The relationship between SARS-Cov-2 and these bat viruses is like the relationship between, let's say you and your cousin. Neither you or your cousin are descended from each other, but you have a common ancestor.

Chris - I was just going to say, it's a bit like we know chimpanzees and humans share a very high fraction of our genetic material. It's not that we have descended from them. It's just that we have descended from a common ancestor. We both shared an ancestor back in history. So that argues, then there must be some kind of virus back in history that gave rise to SARS-Cov-2 and to these viruses you've just mentioned. So where is it then?

Jesse - It's not known. These two closest known relatives to SARS-Cov-2 were from bats that were in Laos or Yunnan province, both of which are actually fairly far away from Wuhan. So it's believed that the ancestor of SARS-Cov-2 is probably a bat coronavirus that existed somewhere in this geographic area. But how that bat coronavirus got to Wuhan is what remains unclear.

As the search continues for the ancestors of SARS CoV-2 in the wild, another hypothesis has circulated -  the virus leaked from a lab. When first proposed, many dismissed the idea out of hand on the grounds there already seemed to be a reasonable explanation for how the virus emerged. But, the possibility that SARS CoV-2 is an escaped laboratory experiment has gone back up the agenda with the discovery in recent months of new evidence of the kinds of experiments that were being conducted, or at least proposed, at the Wuhan Institute of Virology…

Julia - This kind of work is vital to understand the pandemic potential of some infectious diseases, but, as David Matthews who studies MERS at his Bristol lab explains, this kind of work needs to be conducted very carefully.

David - We have a high containment facility here: containment level three. It's airtight, it's sealed, it has an air handling system that sterilizes the air inside the room Only sterile air leaves the room, so nothing escapes, and then within that room we have another cabinet which is called a "class three cabinet", which is the sort of thing you see in Hollywood movies where you've got a sealed box with giant rubber gloves that you stick in and there's airlocks and techniques for passing things in and out. Anything that leaves that contained box has to be sprayed down with a bleach solution and left for 15 minutes and, even before we do all that, we have to do a series of experiments to prove that our techniques for sterilizing things actually do kill viruses. It's a series of layered defense between yourself and the dangerous virus.

Chris - But where there are humans, there are, of course, potential or real errors. Lab leaks have happened before as in the case, for example, of foot and mouth. Alina Chan, who's a scientific advisor at the Broad Institute of MIT and Harvard, and co-author with Matt Ridley of 'Viral, the search for the origin of COVID 19', explains -

Alina - We know that lab leaks occur quite frequently, and accidents happen to even the most highly trained people; as long as there's human error, there's a chance for a virus to escape from a lab. This was demonstrated in the recent lab leak of SARS CoV-2 in Taiwan in late 2021. That was a researcher in her twenties, she was fully vaccinated with Moderna, but she had been bitten by a mouse at least twice in that lab. She was diagnosed on December 9th, 2021 and Taiwan immediately launched an investigation into the lab, as well as all of her contacts. Within 12 days, they had already publicly announced that they had concluded the investigation into the lab. They said it was definitely from the lab. They went into that bio safety level three lab where the animal work had been done. They found contamination all over the place and then also identified several flaws in protocol where there were human error. So, we know that it can happen.

Julia - Wuhan house is one of the leading laboratories in the world for studying SARS like viruses, which is important to take into account.

Alina - With SARS CoV-2, the virus that causes COVID 19, we know that it occurred on the doorstep of a lab in Wuhan city that had a long history of collecting SARS like viruses. So, the question is, did it come from the laboratory in that city?

Chris - Are there any other explanations, though, because one must be cautious about the difference between cause and association: if one asks "do fire engines cause fires because I always see fire engines where I see fires", I could draw the wrong conclusion. Are there other possibilities?

Alina - COVID 19 was detected in the city where they had the world's best expertise at tracking SARS like viruses. They had spent the last decade, at least, searching through south China and Southeast Asia where these viruses were known to be found. The spillover zone for SARS-like viruses is down South, like thousands of kilometres South, so it's not impossible that an animal was infected and was somehow transported all the way up, thousands of kilometres up into Wuhan, and only caused an outbreak there, but I'd say that the odds are pretty low.

Chris - Were the agents, meaning the samples, the possible viruses? Were they similar enough to what we see now causing COVID 19, the SARS CoV-2 virus, for that to be a reasonable prospect? Or were they studying viruses that were so different that the chances of what they were collecting turning into the causative agent behind COVID 19 so remote as to be impossibly likely?

Alina - We now know, based on the work of independent analysts and scientists, that when COVID 19 was detected in Wuhan had in their hands at least nine of the closest relatives to SARS CoV-2 at that time. So, there is a lot of circumstantial evidence, I would say, that warrants a deep investigation into the origin of COVID 19.

Chris - In terms of the research they were then doing on these viruses to further study them, what were they actually doing?

Alina - Their purpose was to predict future outbreaks. To do so, their aim was to collect and study as many viruses from the wild as possible. After they collect these samples, tens of thousands of samples, they are sent back to Wuhan city and in the lab they take these samples and they sequence it. They're trying to see what viruses are in here and, if possible, they try to grow them so as to extract the virus out of the sample.

Julia - Speculation has circulated around the exact work which was going on to grow these viruses. Certain viruses are notoriously hard to culture in a lab. By altering the genetic sequence, this can then enhance its ability to grow, making it easier to study. One theory was that SARS CoV-2 emerged as a hybrid of other coronaviruses being grown. But, Jesse bloom suggests this is unlikely -

Jesse - I don't think that's possible because if SARS CoV-2 looked like two known viruses, where part of it looked like one, and part of it looked like the other, then we could imagine the scenario you're positing. But compared to the closest known viruses, SARS CoV-2 has the mutations scattered across the whole genome, so this combinational mixing - I can't explain it. Whatever SARS CoV-2 is directly descended from is a virus for which we don't yet know the sequence.

Chris - Another point of contention when trying to deduce if SARS CoV-2 arose naturally or was synthetically manipulated comes from certain sequences inside its genetic material. Specifically, SARS CoV-2 contains a structure called a furin cleavage site. This is a bit like a pin in a grenade -  when this furin pin is pulled, the virus is primed to infect. Some coronaviruses naturally have these, and they do boost infectivity enormously, but, critically, none of the closest relatives of SARS CoV-2 that we have found have them. And this is what initially made people very suspicious. Alina Chan, again -

Alina - Without this furin cleavage site, the virus could have never caused a pandemic, and we know that now from studying the virus -  if you take out this cleavage site, it's completely attenuated - it can barely cause disease and is barely transmissible. So, the question is, how did it appear in SARS CoV-2? The reason why some people find the furin cleavage site very suspicious is that, if you look at all SARS-like viruses that have arisen to date, only SARS CoV-2 has this furin cleavage site. So, the question is, was it natural? Was it just a freak accident in nature? Or was it put there in a lab?

Chris - Now, as furin cleavage sites are found in the wider coronavirus family, they do naturally occur in these viruses, it's not beyond the realms of possibility that this powerful genetic infectivity boost could have cropped up in the COVID 19 virus by chance. But, a leaked grant proposal that surfaced only recently and which involved The Wuhan Institute of Virology and collaborators in the US, is very grave cause for concern.

Jesse - In late 2021, a grant proposal called the DARPA diffuse proposal was released, which showed that a group of scientists were proposing to introduce furin cleavage sites into SARS related coronaviruses. That particular proposal was not funded, and it's unknown if that work ever happened, but I think at this point we certainly know that furin cleavage sites can arise in coronaviruses and that there are scientists out there who are interested in engineering them into coronaviruses.

Chris - Now we don't know if this kind of work was actually being carried out on SARS-like coronaviruses, which is why Alina Chan points out investigation is urgently warranted -

Alina - This group of researchers say that they're gonna put horns on horses and, about two years later, a unicorn strolls up in their city. So, based on that striking coincidence, there's a need to investigate.