Store, write, edit
As scientists announce that they have used CRISPR technology to fix a faulty gene in a human embryo - not for the first time, but more accurately than ever before - we take a look at storing, writing and editing in DNA. Plus, our gene of the month is all ears. This is the Naked Genetics podcast for August 2017 with Dr Kat Arney, brought to you in association with The Genetics Society.
In this episode
01:06 - Editing human embryos
Editing human embryos
with Yalda Jamshidi, St George's University of London
At the beginning of August we saw headlines loudly proclaiming that scientists have managed to use precision gene editing technology known as CRISPR-Cas9 (or usually just CRISPR) to fix a faulty gene in early stage human embryos. In fact, this wasn’t the first time that researchers have used CRISPR on human embryos, but it was certainly the most successful attempt to date.
The research team, made up of scientists in the US, South Korea and China, successfully fixed a faulty version of a gene called MYBPC3, which is responsible for the serious heart defect hypertrophic cardiomyopathy, which affects one in 500 people and can be fatal. Although the fix wasn’t perfect, it was more efficient than previous attempts, marking an important step forward for the technology.
To find out more about what’s different this time, Kat Arney spoke with Yalda Jamshidi, who specialises in the genetics of heart disease at St George’s, University of London.
Yalda - So, there's actually been three attempts that have been published in the medical literature before that were all out of China. And in all three cases, they had similar problems. One of them was that they couldn’t get enough of the healthy copies into the embryos so that the correction wasn’t very efficient. And also, they found that there was a mixture of modified and unmodified cells so whilst some cells there was a correction, there wasn’t in others. And they didn’t have very high efficiency rates. So, I think in the first study that was published, out of 68 embryos, they could only correct four of them.
And so the difference between that study and the current published study is that they had tried to edit this after the sperm and the egg fertilized. So it’s a much later stage in development. It was still in the embryo but certainly not as early as the current one which literally was at the time of fertilization, they would put in the CRISPR or the gene editing machinery at the same time.
Kat - Now, I used to study very early development and I know that that time when the sperm goes into the egg, there’s also sorts of unpacking, repacking, rearranging going on. Do you think that might have contributed to the success of the process?
Yalda - Yes. I think actually that probably isn’t too unexpected, because at that time in development the embryo is already trying to deal with a lot of mutations or correcting lots of changes that it finds. And so, perhaps this process already happens to some extent at that early stage and having just an extra mutation to correct wasn’t so difficult for the embryo.
Kat - So this is just one condition. Was there a particular reason why this condition was tried? Could it work with other diseases or even traits, for example like intelligence?
Yalda - So I think that’s an interesting question. Perhaps one of the reasons they focused on this cardiomyopathy is because it’s fairly common - so 1 in 500 adults actually suffer from hypertrophic cardiomyopathy.
It’s also quite severe, so there’s no treatment at present. Anything that they do take is really to try and alleviate symptoms, but there’s no cure. And because it’s highly associated with sudden cardiac arrest, so you might hear about it when you see these athletics who are running around and suddenly suffer cardiac arrest on the pitch, it’s actually quite a shocking condition.
So I think maybe part of the reason was that it is a very severe life threatening condition, so that would be one reason to target it. Whether or not they would apply this to other genes, and other mutations in diseases, we’ll have to wait and see.
But I think when it comes to traits like intelligence or height or eye colour, you hear about all these designer babies and whether we’re going to do that, I think that’s a much more complicated situation because it’s not one gene and one mutation that causes those. It’s actually lots, hundreds and thousands working together. So whether we’re ever going to be able to gene edit 100 at one go is probably fairly unlikely.
And also, the genes we know contribute to many conditions and many traits, so you might target something that is going to affect height but actually end up affecting something else unwanted, so you might end up affecting weight by editing that gene. So I think that’s not going to happen anytime soon.
Kat - In terms of the technical side of this, what actually happened to the embryos? These didn’t grown into babies, did they?
Yalda - No. So like much research that’s carried out on embryos, there’s a limit to how long you can keep them in culture. That’s usually 5 to 7 days maximum. So at that point they would have been destroyed. There was certainly no intention by the researchers to implant these embryos at the end of it.
Kat - Given the kind of techniques we have at the moment for screening for serious genetic diseases at the pre-implantation stage in the IVF process, is this really necessary? How would it work? How would it fit into that?
Yalda - So at that moment, if a couple would opt for preimplantation genetic diagnosis, the laboratory that would deal with it would take the sperm and the egg, and they would be screened for mutations.
And if a parent has a mutation such as the one for the hypertrophic cardiomyopathy, half of the embryos will have a mutation, therefore, half of them would need to be discarded. So, in ethical terms perhaps, if we didn’t need to discard those 50 per cent of embryos and we could correct them and improve the efficiency then I think there might be a place for this kind of treatment.
Kat - So the idea is that if this correcting procedure works when you put the sperm into the egg, you would just correct all of them whether they were faulty or not and then expect that you would have a much higher percentage of fixed embryos that you could choose from.
Yalda: Yes, that’s correct. So, if you could make the efficiency high enough then you wouldn’t need to worry about discarding any unhealthy copies.
Kat - Now we’ve obviously know that probably we can, should we do this?
Yalda - So, it was much more efficient than previous studies. I think it was just over 70 per cent efficient. But what they we're actually doing was enhancing what we already carry out, which is preimplantation genetic diagnosis for families like this.
So whether or not we would want to bolster the current chance of those embryos being healthy by an extra 20 per cent, 25 per cent, is probably not quite there yet. It would need to become much more efficient and much closer to 90 per cent efficiency. Because ideally, you want to have a situation where all of your embryos are corrected and healthy, and able to implant them. So I think there’s still some way to go with efficiency.
The intention wasn’t necessarily to use this to treat. It was more about learning how the process works, and we don’t know lots about how gene editing affects embryos over time. And there would need to be much more research time to study that, probably on non-human primates before anyone started thinking about doing clinical trials and getting this into clinics. So I think we’re quite some way off in that sense.
Whether we should do it or not, I think that’s a highly contentious question and certainly, a lot of the papers and the people are asking that question. And in my own opinion, I would say that, hopefully if we could make the procedure much more efficient, much more safe and there was plenty of evidence that it would work and it would be fine, then in some cases, where there really is no other alternative, no other medical treatment or possibility, then it should be something that could be considered. But only once the public and the scientific community and the legal community have come to a kind of a consensus about what we are going to do with these sorts of techniques and how safe they are, and we really are okay with it happening.
Kat - How would you like to see the discussion about these techniques, about this technology, changing in the media?
Yalda - I think it would be great if there could be more of a balance with what is being reported and less focus on designer babies and the use of genome editing to try and produce these designer babies. Because much of the research and the researchers who are looking at it, they’re really not looking to and up with the designer baby that they can then go and help a couple improve the child’s intelligence. It’s actually more about trying to help patients who have serious life-threatening conditions now, and they want to alleviate their symptoms where there isn’t a medical cure at present.
Kat - And hopefully, more education and understanding about what this technology actually is and how it works and how genetic works.
Yalda - Definitely. I think genetics is getting even more and more exciting at the moment and it’s definitely starting to get into the media a little bit more. But there’s plenty of room for education and for helping people understand what we mean by all these science fiction-type words and techniques, so that people will understand a little bit better what we are trying to do and why we are trying to do it.
Kat - Yalda Jamshidi from St George’s University of London.
10:51 - Getting gene therapy into cells
Getting gene therapy into cells
with Michael Linden, Pfizer
Gene editing is an exciting technique that opens the door to new approaches for gene therapy - manipulating genes in the body to treat disease, either by fixing a defective gene or by adding in a functional copy of a broken gene. To find out more about the latest progress in gene therapy, Kat Arney spoke with Michael Linden, a former professor of virology who left academic research to become vice president of gene therapy at the pharmaceutical company Pfizer.
Michael - There are many rare diseases out there - six to eight thousand rare diseases - some of which have been very well characterized and the characteristic of many of these diseases is single gene defects. What that means is that the gene has a wrong instruction, in essence making a product that is either wrong or not making a product that a cell needs and therefore, we get sick. And what gene therapy is trying to do is to replace that function.
Kat - So we know that our genes are made of DNA. That’s the instruction our cells use. But you can’t just like stick DNA in people or feed DNA to people. How do you get these fixed or these ‘well genes’ into people and into the right places in people?
Michael - So, what we do here is we really look back into nature and we looked there, what we find is a concept that does exactly that. And the concept is called viruses. So viruses don’t do anything but deliver their genetic material to their respective hosts for example to us and then replicate there.
What we’re now doing is we’re taking these viruses and changing them. We’re changing them, we’re taking out the ability that they can amplify themselves and hurt us, for example. And we’re replacing the genetic material that the virus otherwise would have brought to our tissues by therapeutic DNA.
Kat - And what sort of viruses are these, because there are lots and lots of viruses that infect humans? There's everything from HIV through to herpes viruses, and all sorts of things. What were the viruses that gene therapists like to use?
Michael - Yeah, what you’ve just done is you’ve described pretty much the early stages of gene therapy development, because every single virus that we had some idea about was explored for the possibility of delivering genes to humans. Currently, the front runners in gene delivery of viruses for example, adeno-associated virus which clearly is a human virus and a non-pathogenic human virus. What that means is even the wild type virus doesn’t make us sick.
Kat - So we just catch it and nothing happens.
Michael - We just catch it and nothing happens until we’re infected by a nastier virus for example, herpes or adenovirus. And then AAV, adeno-associated virus, starts replicating and killing these cells. So for us potentially it’s even a protective virus. So, we’re taking that virus and we changed the genome to contain whatever therapeutic treatment we need and then manufacture these recombinant viruses ultimately as a drug product.
Kat - I guess the big challenge is, you’ve got this virus, it’s loaded with the gene you want someone’s cells to make. What are the big challenges there? I guess it’s kind of hard if you want to manipulate every cell in someone’s body. How do you get enough of the virus into the right place?
Michael - Yeah. So, that’s a very good question because that’s one of the challenges that gene therapy faces. That’s really the result of many years of research which have shown us that for example, adeno-associated virus can be modified and can be modified to infect particular cells or particular organs more efficiently.
What that does in essence, it gives us a panel of viral vectors based on this one system that has preferential targeting efficiencies so we can generate viruses that are very well at infecting the CNS, the Central Nervous System, or viruses that are good at infecting the liver for example. We have now a choice of many where we can really use the behaviour of these recombinant viruses and design our approach around those.
Kat - Where are the kind of the best or the most interesting approaches for really making this work in practice?
Michael - Yeah, I think you know my pragmatic view of this is that we really have to start with simple concepts and one of the example is, for example, Hemophilia B where Pfizer has an involvement. And really, what that is, it’s a single protein that’s not functioning well, that’s not functioning at all, in fact, which leads to the bleeding deficiency of these hemophilia patients.
Now, what a simple gene therapy does in this case is the Factor IX gene that’s defecient in the hemophilia B is being put into an AAV vector and systemically delivered to the liver. What that then does is it makes the liver become a protein-factory. It reads the DNA. The DNA instructions, it generates the protein - the Factor IX protein and secretes it back into the blood circulation which then allows the patients to have normal clotting behaviour which in essence means the disease can be cured.
Kat - My two really big questions about these are, a.) Is it safe? And then b.) how much will it cost? We’ll take this one at a time because I do remember from some time ago, there was a very famous case of a gene therapy that was tried and the person undergoing the therapy actually died and it did raise a lot of questions about, is this safe? Should we be doing this? So, let’s tackle that first. What has come on since then to make these therapies safer?
Michael - Yes. So, Jesse Gelsinger died in 1999 as a result of an immune response to the viral vector that was used at that point which was based on adenovirus. Adenovirus is actually a very immunogenic virus.
Kat - It’s kind of nasty stuff.
Michael - Yes, exactly. And also, it causes a strong immune response which really wasn’t or hadn't been recognized at that point. But what I have to say that in the past almost 20 years since that, we’ve learned an awful lot.
A lot of work has been done around the safety of these vectors. We now have parameters where we can measure what the response to the delivery vehicle will be and anticipate setting the stage for a really safe trial. As you know, a large part of the clinical trials are driven by one concern and one concern only, and that is safety.
Kat - And then there’s the cost. And I know that some clinical trials have happened to test things like gene therapy in the eyes, trying to restore sight. You’re talking about the clinical trials in hemophilia, there are trials ongoing in cystic fibrosis, and we hear about things like there's basically a gene-based medicine for muscular dystrophy. And these things seem to cost so much money. Is this really a viable approach for the future?
Michael - So you’re talking to a scientist and I think it would be really unwise for you to ask me about costing of this, which is very complex issue. All I can tell you is that I know that gifted people are currently considering exactly what impact costing has, and so on and so forth.
All I know is really the science behind it, and what I can tell you is that I think what we’re trying to do is more complex than just a cost for one drug. What we’re trying to do is a novel approach which in essence can, for a long time or ultimately maybe forever, modify a disease. And if it’s forever, you can ‘cure’ a disease, and these are concepts that are novel which is why a lot of government agency, pharmaceutical companies, and so on are really now sitting down and trying to figure this out.
What is the medical, what is the health consequence for this type of treatments and they can be vast in fact, because many of the disease that we’re looking at, they’re not treatable by other methods. And you know, at some point, somebody will really figure out what is the reasonable cost of this really novel space.
Kat - That’s Michael Linden, speaking to me at the British Science Festival in Swansea last year.
19:32 - Storing secrets in DNA
Storing secrets in DNA
with Nick Goldman, European Bioinformatics Institute
Last month scientists used CRISPR technology to sneak a strand of DNA into bacteria encoding a string of genetic information that could be decoded, once the bug’s DNA was sequenced, and read back into digital information encoding a short movie - a famous early film of a galloping horse.
And just last week, a team of researchers announced they had managed to encode a piece of malicious malware code into DNA. When this DNA was fed into a sequencing machine, it hacked into the computer programme responsible for analysing the DNA coming from the sequencer.
Nick Goldman at the European Bioinformatics Institute was one of the first people to have the idea of storing digital information in the form of DNA, around five years ago. Kat Arney asked him where did it come from and how do they do it?
Nick - The idea came from meetings where we were talking about the problems of storing all the information in cellular DNA that we now, as scientists, are learning to read and interpret to understand about molecular biology and health, and all the different aspects of genome research. But our work at the institute here includes storing all that information, making it available for the scientific community and that means we need large data centres and we have trouble managing those.
At the end of a long day of meetings we were having a joke in the bar about wasn’t there some other way of storing information, and DNA itself is a way of storing information and that inspired us to hatch this plan of doing an experiment to show that you could store any information in DNA just as you can store any information in your computer or on your phone or any digital device with a memory.
Kat - Because the information that’s in my phone or in my computer that’s in binary – it’s ones and zeros - and the DNA code is four. You’ve got A,C,T and G in nature, that’s the code you’re using.
Nick - In nature, there’s a very specific code in which the As, Cs, Gs and Ts hold the information of how a protein should be made and a number of many other genomic functions as well, controlling what goes on in cells. So that code is no use to us. That code doesn’t store zeros and ones which we use to make MP3 files or PDFs or whatever it is.
So one of the things we had to do was invent our own code where the input would be the 0s and 1s from a file on the computer. And the output would be a series of As, Cs, Gs and Ts which, combined with the code we had just invented, would allow us to store that zero and one information - the binary information - and later on to recover it again.
Kat - So then to de-encrypt it, so you take any string of DNA and it will spit out this binary computer code at the other end.
Nick - Not any string of DNA. We put in all sorts of special constraints that would help with error correction and would reduce some of the problems we knew would occur as a consequence of the techniques in molecular biology we would use. So in fact, not any string of DNA would decode to meaningful series of zeros and ones, but essentially any one that was holding information in our code could be converted back.
In a sense, it’s very straightforward. If everything worked with no errors, it would be very, very easy and very fast to do that. And of course, the devil is in the detail and what we actually spent all our effort doing was devising a system that would be robust to the various errors we knew would happen along the way.
Kat - And how robust is it? What your sort of error rate and how does that compare with say, other systems where you really don’t want errors?
Nick - We mostly did a proof of principal experiment so far. And I'm proud to say our error rate is 0, but we were very conservative with the way we device the code. We didn’t make a code in the way you would for a mass production system. It’s not like in a mobile phones where they know there will be a certain amount of loss and we’re kind of used to that.
We didn’t want to do a demonstration which had a bit of lost information and showed that it was kind of possible. So we were really very, very careful with how robust we made our code to errors, with the intention of getting it entirely right. In the real world for mobile phones, we tolerate a certain amount of distortion and we can live with that. But computer data centres talk about 99.99999 per cent accuracy.
And so, what we’re working towards will be codes that will try and achieve about that level. I mean, 100 percent accuracy is not realistic but we try and get in the future for large amounts of information. The idea will be to get exceedingly low error rates. And we’re optismistic that should be possible.
Kat - The thing about this is like you know, you’ve got 0s and 1s binary code, and we’re talking about letters. We’re talking about As, Cs, Ts, and Gs of DNA. But these are molecules. These are chemicals – adenine, thymine, cytosine and guanine - and DNA is a molecule. How do you turn that binary information into a molecule? So, we’re literally talking like a string of DNA that has this sequence. How do you make that?
Nick - Well, there are companies who do exactly that and it’s a difficult process. Humans are not as good at doing that as the cells of living organisms are, but we’re getting there. Roughly speaking now, the state of the art is machines that can make molecules that are about 200 letters long. One of the problems we had to overcome was that one of those is not nearly enough information to encode an MP3 or PDF.
And so, we had to device a system which would use many fragments of DNA which in combination held all the information we needed. And this introduced yet another problem which is that when you read them back, they don’t come in any specific order so we have to add a kind of indexing procedure to it. So that when we did read each piece back, before we decoded the information in that piece, we first read the bit that said, “I belong in file no. 23 and I belong – the information is at position 797 in that file.”
Kat - And how do you then read it back out again?
Nick - So reading it is actually slightly easier. Humans got better at that. And that’s all been driven by genome sequencing projects because there’s a huge demand to read the genomes of living organisms particularly humans, but any living organism has a genome for us to read. And there’s been a number of changes in the technology over the last few years on how we do that and there’s more changes in the pipeline that we know are coming in the next year or so.
But the aim is always the same, that given pieces of DNA we can read those and read back the sequence of letters. Normally, we’re doing that to understand our genomes, look at the differences between one human and the other, to understand the causes of genetic diseases, and so on. But for our purposes, exactly the same technology gives us back the series of letters which is what we need to decode to recover information.
Kat - And it sounds wonderful but not quite as simple as the read, write of a computer’s hard drive.
Nick - It’s not quite as simple, but bear in mind there’s a lot of stuff going on in your computer and in the disk drive that they don’t tell you about because no one wants to know. No one wants to know that there’s constantly errors on their hard disk drive and that there’s a very complex machine in there, moving components around and whizzing things around in circles, and reading them. You don’t need to think about that when you use a hard disk drive because they are now very reliable and so on.
So partly, it is more complicated but a lot of that is simply, we’re learning as humans, as scientists to manipulate DNA and write it and read it. But we’re still not as good at that as we’re going to be in the future. Of course, one of our aims on this project is to make DNA information storing devices which we can use much more like a hard disk drive or USB stick, or something like that.
Kat - So here, you’ve got a huge data centre. I’ve seen it – it’s enormous boxes with blinking lights and all these kinds of things. What would a future DNA storage centre look like? It would just be loads of little tubes?
Nick - Probably or even smaller than that if you could – in the future, we may be thinking you’d be able to read these on something more like a computer chip, so perhaps it would be a small device, maybe like a bank of hundreds or thousands of USB stick type devices. But inside each one, as well as electronic components, there’d be amounts of DNA and there’d be some microfluidics going on inside there that would move the samples to the region where the reader would be.
Perhaps if you needed to recover the information, you’d go on in there and pick one off the shelf or may be a robot would do it like in a tape archive centre. It’s mostly robots that go and select the tape. We’d have a robot that would select the little USB stick type device and plug it into a machine that would take a tiny sample out, read the DNA, and use a computer to process that information.
Kat - So one day, all this information that we’re getting about genomes from around the world – humans, animals, pathogens – all that information about DNA, from DNA, could be stored in DNA.
Nick - Yes, strangely and of course, all the other information in the world that we’re storing. All of Facebook’s archives of everything anyone has ever posted, any large data application you can think of. And we’ve had a lot of interest in this technology because the storage of the information has a much smaller energy requirement so it could save money in the long term.
And also, a much smaller amount of space is needed. DNA is incredibly dense information storage medium and so, the amount of information you store in something the size of your finger is thousands of times as much as you can store in an equivalent amount of hard disk.
Kat - Nick Goldman from the European Bioinformatics Institute.
29:58 - How to Code a Human
How to Code a Human
Naked Scientist Kat Arney has a new book out! How to Code a Human is a kind of field guide to genetics, packed with useful diagrams and pictures, explaining how our genes make us who we are. Here’s the introduction:
"It is obvious from looking at any family that people who are closely related tend to appear similar. None of us is a perfect clone of a mother or father, though, and there are even differences between identical twins. Scientists have puzzled over this for thousands of years, devising all kinds of explanations for how traits and characteristics are inherited from our parents. However, it is only in the last century that we have discovered how this information passes down the generations in the form of genes, written in our DNA. It has also become clear that the path from genes to person – or from genotype (genes responsible for a particular characteristic) to phenotype (the physical manifestation of inherited traits) – is not a straightforward one.
To elaborate further, an adult body consists of millions upon millions of tiny cells – nearly 40 trillion according to some estimates – forming organs and tissues with distinct characteristics, shapes and functions. There are hundreds of different cell types, ranging from lung, liver and lymph nodes to bowel, bladder and brain. Yet they all come from one single cell, which is created when a sperm fertilises an egg. This cell divides in half, creating two cells. These grow and divide again to make for cells that, in turn, divide again and again. Over time, cells in different parts of the growing embryo begin to specialise, eventually creating all the various types of cells needed to make a baby. However, this process does not stop there. As the human body develops further, cells continue to divide constantly, replacing damaged and worn out cells and preparing wounds.
We now know that genes control all these processes and also respond to the environment around them – nature and nurture of therefore both very important. Scientists are only just beginning to find the answers to some really big questions such as:
- How does a fertilised egg divide and specialise to make all the tissues of the body?
- Why does a liver cells stay in the liver and a brain cell remain in the brain?
- How do genes make you the person you are?
- How are traits, characteristics and diseases inherited?
During the 1960s, scientist started to piece together the concept of the molecular gene, discovering that genes are stretches of DNA encoding specific instructions telling cells to do something (usually to make a specific molecule, such as protein). Around the same time, computers were becoming more sophisticated, so it was easy to make comparisons between the strings of chemical “letters” that make up DNA and the logical string of digits or commands within computer code. Following on from this was the idea that if we could just crack the code and read all our genes, then we would understand exactly how our cells and bodies work.
Over the past few decades, it has become clear that this view is far too simplistic. Instead of being a computer code, with tidy electric circuits, genes are more like recipes. They are living entities, full of constantly shifting molecules and with many options for flexibility, depending on the range of things a cell needs to manufacture. Somehow, in the midst of all this biological hurly-burly, genes need to be switched on and off at the right time and in the right place to ensure that cells continue to function properly.
It is also important to note that there is no such thing as a gene "for" a trait, such as height or intelligence, or "for" a disease, like cancer. Genes are recipes for making molecules, and it’s how all these molecules work together in our cells, body and brain – along with the environment around us – that make us who we are and determines our risk of all kinds of illnesses.
We will look closely at the human genome, discovering how genes work and the way in which the twisted double helix of DNA encodes the instructions for life. We will track the journey made by our genetic ancestors out of Africa and around the planet and see what traces of them remain in our genes. We will find out how our DNA makes us who we are, right from the very beginning when the egg and sperm meet, and how cells remember what they are supposed to be doing. We will uncover the genes that shape our bodies and build our brains, and discover what happens when things fail to work as they should. Finally, we will look at what the future might hold, for both our genes and the entire human species.”
Kat's first book, Herding Hemingway’s Cats: Understanding how our genes work is also available in paperback, audiobook and Kindle versions from all retailers - it’s a more in-depth look at the latest ideas in genetics, with personal interviews with experts on the cutting-edge of the field.
Gene of the Month: Spock
Named after the pointy-eared first officer of the USS Enterprise in Star Trek, Spock is one of a number of genetic mutations that affect hearing in zebrafish. And yes, it does give them little pointy ears.
It may seem strange, but these little fish do have ears and an auditory system. Spock is just one of a number of zebrafish mutations involved in ear development that were identified in a large screen run by German researcher Janni Nusslein-Volhard - who’s known in genetics circles for her large-scale discovery of faulty fruit fly genes.
By searching through thousands of embryos created by mating male fish that had been exposed to DNA-damaging chemicals, the team found nearly 60 mutations giving them faulty ears. As well as Spock - an obvious name for the fish with pointed ears - many of the other gene faults affecting the shape of the fishes’ ears have appropriate names, including boxed ears, earache, dog-eared, big ears, earplugs and headphones. There’s even a Van Gogh mutation, after the painter who famously cut off his ear. Regular listeners might remember that there’s also a fruit fly gene called Van Gogh - but that’s a different gene, involved in bristle patterning.