Over the next several weeks, Distillations will be talking to people who have special insight into the coronavirus crisis—biomedical researchers, physicians, public health experts, and historians.
In this episode, our producer Rigoberto Hernandez talks with Katrine Bosley, who has worked in the biotech industry for more than 30 years. Until recently, she was the CEO of Editas Medicine, a company that focuses on a gene-editing technology known as CRISPR. She’s now on the board of the Massachusetts Eye and Ear Hospital and is advising the facility on its quest to create a COVID-19 vaccine. She tells us how CRISPR can be used to make faster diagnostic tests and how the hospital in Boston is creating a vaccine using a gene therapy method.
Lisa: Hello and welcome to Distillations. I’m one of your hosts, Lisa Berry Drago.
In response to the coronavirus pandemic we’ve launched a brand-new series focused entirely on COVID-19. Over the next several weeks we’ll be bringing you interviews with people working at the heart of the crisis: including biomedical researchers, physicians, and public health experts.
In this episode our producer Rigoberto Hernandez talks with Katrine Bosley who has been in the biotech industry for more than 30 years. Up until recently she was the CEO of Editas, a company that focuses on a gene-editing technology known as CRISPR. She’s now on the board of the Massachusetts Eye and Ear Hospital and is advising them on their quest for a COVID-19 vaccine. She tells us how CRISPR can be used to make faster diagnostic tests and how the hospital in Boston is creating the vaccine using a gene therapy method that works in treating certain forms of blindness.
Rigo: You’ve been in the biotech industry, as you mentioned, for a long time. And I’m wondering, from your background, how has that informed your perspective on this pandemic?
Katrine Bosley: It’s interesting because in many respects the whole world is seeing the scientific process in real time. You know, you learn something about the virus and your first data are kind of incomplete.
They suggest some things, you need to follow up, you need to do more experiments. They give you ideas of what’s going on. You need to develop a hypothesis and figure out how to test it. And it’s iterative, and not every idea is right. But that process of being iterative—testing, thinking again, rethinking, testing—that is the scientific process, and it’s happening both as we understand what the virus does to a person to make them sick. Why do some people get really sick, and why do people, other people not have such a severe course? How is our immune system responding? How do we make the best tests to detect?
There’s a whole lot of science around the detection tests, and on and on. So many different aspects about this virus that scientists in many different biological disciplines are working to understand. And there’s been spectacular progress in a quite short time but obviously a lot we don’t yet know.
Rigo: I’m wondering, in that same vein, what are some of the things that you have seen in this pandemic that impress you about science’s response and some things that have you wishing for more?
Katrine Bosley: Well, first and foremost, everybody that I’ve seen has had absolutely the same orientation of sharing their data, learning from each other, supporting and helping each other. So spectacular levels of collaboration and trust. I think that’s the thing that strikes me most, both in academia and industry and combinations thereof. And that is, I think everybody’s being fully aligned on how can I help be part of the solution here? What expertise do I have? What things do I know? What resources, what tools do I have? How can I put them to work?
So that leads me to the second thing, which is tremendous creativity. I think that there’s a lot of examples of people taking an area that they know well and saying, how can I apply this to be helpful with regard to this pandemic?
And so, for example, one of the projects I’m involved with is where we’re working on a different approach for a vaccine. There are a lot of really good vaccine approaches out there, leveraging vaccine types of technologies that have been around for a little while. But there’s a gene therapy researcher at Mass Eye and Ear, Dr. Luk Vandenberghe. He works on gene therapy medicines, and he saw an opportunity to say, hey, I could adapt this a bit and apply it to potentially making a vaccine for SARS-CoV-2. And you know, that kind of creativity of seeing, every scientist seeing their own technology in a new light is fascinating.
WCVB: It’s called the AAV COVID vaccine program, AAV short for adeno-associated virus. What makes it different from other vaccines currently being developed is that this is a genetic vaccine.
Rigo: So going a little bit into the Massachusetts Eye and Ear Hospital, that was the write-up in the New York Timesthat I saw in which they talked about using that method. And I was hoping you can kind of walk us through a little bit of this method that’s being developed.
Katrine Bosley: So let’s maybe just take as a first step, let’s just remind ourselves what is a vaccine, and then what is this particular technology and why do we think it could potentially be a really compelling vaccine? So a vaccine is, you give a person in some form a little part of a virus so that your body’s immune system can see it, recognize it, and build up its capability to react or to respond so that if in future you get exposed to the whole actual virus, your immune system is already prepared and able to quickly mount a defense and prevent you from getting the disease.
That’s the basic concept. Now that little piece of the virus that you give to a person in a vaccine, we refer to that as the antigen. It’s essentially the substance that your immune system responds to. And there are a lot of different ways you can give somebody that antigen. So you can give, you know, in the old-fashioned but still quite effective versions of vaccines, you actually give, you know, a little piece of the actual virus. That’s one physical way you can do it. Another way is you could synthesize a little piece of the virus. So instead of just taking it from the virus in nature, you can construct it, synthesize it.
A third way that is a newer set of vaccine technologies are what are called genetic vaccines or gene transfer vaccines. There are a few different names that you might read, but essentially what you’re doing is instead of giving it a little bit of protein as the antigen, you’re giving either a piece of RNA or DNA, essentially the instructions, because RNA and DNA are instructions to the body, instructions for how to make that little piece of the virus, instructions for how to make that viral antigen. So if you look at some of these approaches that you may read about, for example, Moderna’s approach and bioNTtech’s approach, they’re using RNA.
So they deliver a piece of RNA that codes for, that’s the instruction code for a little piece of the Sars-CoV-2 virus. In this case, you might also hear about what’s called the spike protein. And if you see, if you think about those images of the coronavirus, you see it’s like a ball with these—they’re usually colored red. They’re not really that color in nature, but I think that’s the image everybody has seen. So you think of those little red spikes coming off of that viral ball, those spikes are proteins. And those spike proteins, which is what they’re called, they recognize a receptor on our human cells and that’s how the virus gets inside your cells.
That spike protein is like the lock into the key, and the key is one of our own receptors called ACE-2. So that spike protein, if you could somehow teach your immune system to recognize that spike protein, to recognize that viral key, then that’s the strategy to create immunity against this coronavirus. But another way to think about making a genetic vaccine is what if you could deliver a piece of DNA? So you could deliver RNA or DNA to make that spike protein.
Then the question becomes, how do you deliver it? And this is one of the technology challenges of these genetic vaccines, and there are different approaches. So each of them has a lot of technical detail about how it works, but the concept is quite similar. And with the work at Mass Eye and Ear and Luk’s work, the work he’s done in gene therapy, he’s been working on the question, hey, how do you deliver a gene to help a person who has a genetic mutation?
And you essentially need to kind of replace the gene that they’re missing or replace the gene that’s faulty. And the way that you can deliver those genes, the way that you can introduce them into the body for a person who has some genetic disease in the work that Luk has done is using something called AAV.
Now like a lot of science, it’s an acronym and it sounds kind of jargony, but not so complicated really. So AAV stands for adeno-associated virus. Like a lot of stuff in science the name comes from when it was first observed; people name it based on what they were observing. And usually after the fact, you kind of think, wow, that name, it’s kind of historical, but we think of it differently now. So that’s the case here, because you hear adeno-associated virus. It’s because it was discovered in conjunction with a different virus called adenovirus. So even though they’re totally different and they’re not related to one another and all that, it’s totally easy to confuse them because adenovirus, adeno-associated virus, they sound like they’re almost the same thing.
But AAV turns out to be a really good way to deliver genes for gene therapy. And it’s been engineered, right? So it’s not, it’s a harmless virus. It’s not going to do anything bad to you. It’s just like a little carrier, basically.And inside is a piece of DNA. And the thing is, what it’s all been engineered to be able to do, is you can put whatever piece of DNA you want inside.
So if you’re making gene therapy, you put inside the gene that’s going to help the person with the genetic disease. If you want to make a vaccine, you put inside a piece of DNA that codes for that spike protein antigen, what we were talking about earlier, right? So this is, it’s a way that’s different from all the other approaches. It’s a way of delivering that spike protein antigen so that you can then essentially teach your immune system how to recognize it so that if you get exposed to the actual virus, your immune system already knows what to do.
Rigo: Right. So it’s like a, this is a different vehicle that takes you to the same place.
Katrine Bosley: Exactly. One of the things that’s important for all of us competing against this virus is to have a lot of technologically different strategies to try to make a vaccine.
Because what we don’t know yet is which one is going to be best at stimulating the immune system in the right way because each one, you know, they’re a little different. Each has good logic to it, but there may be differences that will be important. And the only way we can find that out is to move them each forward, which is what’s happening. I think it’s really good that we have so many different approaches.
Rigo: So what—this kind of goes back to the idea of that creativity being used right now is the fact that this adeno-adjacent virus method is already one that they use for treating other diseases. So it’s kind of like piggybacking on that technology.
Katrine Bosley: Yeah, no, that’s an excellent point, and piggybacking is exactly right. One of the reasons, I mean, obviously it has to be scientifically compelling, first and foremost. In addition probably people are reading a lot about things like manufacturing of vaccines and how do you scale it up and get to the literally billions of doses that need to be made?
Vaccines are indeed very complicated and challenging to make, and a lot of effort and a lot of resources are pouring into that problem. And that will, we’ll solve that problem. Ultimately it’s an engineering problem. I’m confident it will get solved.
However, when you’re working with a technology where people have been working with it for a while, you just have collectively more experience. You know, there is a lot of experience, I should say. How do you make AAVs? How do you check the quality? What are all those analyses that you need to do? What kinds of tests and assays do you need to run to say, yup, this is good quality. We’ve made it right, and it’s safe and all that. So those sorts of, those are sorts of the supporting technologies that get developed over years, literally, that help you in manufacturing something. So all that work that’s been done in the field of gene therapy with other kinds of AAV therapies is very helpful and relevant as we think about making an AAV-based vaccine.
Rigo: Right. And so when I hear you say, like some of this stuff sounds like it’s going to take time. So are there some things that can be done to address the timeline issue?
Katrine Bosley: There’s a balance. And I think that’s what a lot of the conversations are around the balance of how much risk to take and what kinds of risks, right? So it’s one thing to take a risk of, okay, we don’t know if this vaccine works yet, but we are going to start investing money in scaling up the manufacturing before we know if it works, so that if it works, we’re ready to go.
If it doesn’t work, then we’re taking the risk that we’ve wasted that money. Okay. That’s a monetary risk. That’s not such a complicated risk to decide about. And that’s happening everywhere. There’s lots of scale-up investment being done at risk so that it’s, you know, it’s ready if something works. And that I think is frankly a relatively straightforward decision.
A much more complicated decision is, we talk about risks with regard to safety. And the typical development path for a new vaccine or a new medicine, it’s pretty stepwise and pretty sequential. You know, you test in a laboratory, then you test in animals for safety, which is a really, really important step because that’s one of the only ways we can get a better understanding before asking human beings to agree to be part of an experiment. I mean, that’s when you think about the ethical implications of clinical research, right? You’re asking a human being to be part of an experiment. And so clinical, usually animal safety work, that’s quite extensive before you go anywhere near a human being.
And then you’re stepwise within the clinical trials and people, right? So smaller at first and then you gradually expand the number of people, but you also start usually in people who are healthier. And then you expand it to people who are more vulnerable, right? So for example, with SARS-CoV-2 too, clearly some of the people who are at highest risk are the elderly or people with other kinds of comorbidities, or diseases that, whether it’s obesity or diabetes or heart disease, those increase your risk.
Well, if you want to test a new vaccine, on the one hand, you want to protect the most vulnerable first, but there’s a big ethical question. How quickly are you comfortable asking a more vulnerable person to be exposed to an experimental vaccine as compared to a healthy person? So those sorts of risks are much more complicated to consider.
And so I think there are a lot of active conversations about how to manage that. It still needs to be data driven, right? We still need to have data to justify moving forward, informed consent. All those things still very much apply. But certainly things are moving much more quickly than they would if this were not a pandemic.
Rigo: So that talks about the vaccine. I want to talk a little bit about the diagnostics part of this, which is getting tests, to be able to test everyone in order for us to get back to a normal—testing is very important, is what I’m trying to say. And so you actually also are something of an expert on CRISPR. And it’s a very buzzy gene-editing technology, and it’s been brought up as a way to—do you see CRISPR, what function do you see it having here?
Katrine Bosley: Well, CRISPR is actually an incredibly versatile basic research tool. So I’m sure I can’t even begin to enumerate all the ways people are using it in supporting their research for different aspects of this. But there is actually specifically an approach that Feng Zhang has taken. Feng is one of the real pioneers of CRISPR overall and really made some of the most fundamental important discoveries that have led it to spread like wildfire, in a good way, through all of the biology labs in the world.
So he’s based at the Broad Institute here in Cambridge [Massachusetts], and you know, like many scientists, as soon as this popped up, I think he’s turning his mind to, what can I do to help? And among the things that have come out of his lab, I was recently reading about how they’ve used CRISPR in a diagnostic approach with the goal of—his idea is how do we get to rapid tests that could potentially be done at home or in a setting that doesn’t require a very professional, complicated laboratory to run the test?
Rigo: Right. Because one of the issues is the fact that these tests that we do have approved, that are available, take four to six days and have to be taken to a lab.
Katrine Bosley: Or longer sometimes. Yeah, exactly. And so what Feng has been trying to do is create a test that can be, you know, rapid and simple and at home and things like that. But he’s specifically posting the procedures and such on his lab’s website so that other scientists can look at them.
And he basically is like, hey, can you make it better? Can you pressure-test it and see if it works for you too? Can you repeat it? And it’s that collaborative aspect of, you know, they figured out something, and they’re, he has a very good lab, and I’m sure it’s pretty interesting. But it’s going to move faster by inviting more people into helping solve the problem, which is exactly what he’s doing.
And I do think too, there’s one other aspect of testing that’s worth just touching on because, you know, we’ve all been reading a lot about testing for the last, I don’t know, it’s hard to keep track of the weeks, frankly, but let’s just say lots of weeks. And there’s really two big categories of tests for folks to think about.
The first is the test that asks the question, do you have the disease right now? Is the virus in your body right now? That’s question one. So do you have the virus right now is number one. Question two. Did you ever have it? You know, maybe you’re healthy now. Did you have it in the past? Are you immune to it? Do you have antibodies to it? These are two very different questions. They have different technologies to ask and answer the question, and there are different scientific certainties and uncertainties that we’re still working out, particularly on that second question.
So the first question, do you have a virus right now? That’s where the first thrust of testing has been and where there’s, you know, are we doing enough testing? Getting that ramped up so that we can test a lot and rapidly and get answers rapidly, as you said, so that we’re not having to wait many days before knowing the answer. There’s still a lot of work to do. It’s getting better every day, but there’s just still a lot of work to do there to do enough tests, because we’ll have to keep testing. Right? It’s not about you get tested once and you’re good. You know, if you get tested and you’re clear, and then you get exposed, you know, maybe the next day you’re not clear anymore.
So that whole side of testing: do you have it? There’s a lot of different technologies for that. That’s the, when you talked about CRISPR, that’s the problem that Feng and his lab are working on, many others are working on. You hear about the PCR-based tests, the big diagnostic companies are working on this. There are lots and lots of people in labs and companies tackling that problem.
The second problem—you’ll hear words like antibody tests or serological tests or things like that. Do you have, have you been exposed in the past? And has your immune system already developed antibodies? So people are working on those tests too.
There are scientific questions there that we are still figuring out. If you’ve been exposed before, can you get infected a second time or not? What kind of antibodies are doing the best job of protection? Do we understand that?
So to these sorts of questions of, it’s one thing to say there are antibodies, but are they the right antibodies? What does that even mean? What are the right antibodies? Those are really active questions right now that people are working on actively so that we can understand what kind of test result will be the answer to, yes, you’re okay. You are protected because your immune system has the right tools. Work in progress: that’s science happening in real time to answer those kinds of questions.
Rigo: I’m going to touch on CRISPR a little bit more. It is because, I was really fascinated to learn that CRISPR itself, like the way that the bacteria developed it over millions of years. It’s like a, it was a way to fight off viruses.
Katrine Bosley: Totally. It is a fascinating scientific story, I have to say. And for folks who haven’t read about it, I’ll just give a real, a little brief vignette. So talking about names again, right. CRISPR stands for, and this is a mouthful—and actually to give it context—this was first observed in bacteria, right? So there were scientists in Spain who were studying the genetic sequences of bacteria, and they saw this really weird pattern of these short, interspaced palindromic repeats. And they’re like, what? That’s just weird. Like what is that? It makes no sense. And literally, the name just describes these regularly interspaced palindromic repeats, short palindromic repeats.
It just describes the pattern. That’s just the name of the pattern in the DNA that they saw. Over many years they figured out what was going on with these patterns. And what was going on was the bacteria, the thing that can attack a bacteria is a virus. The bacteria, when they would see a virus that would attack them, they would snip out a little piece of the viral DNA, insert that little piece of the viral DNA into their own bacterial DNA as a way to keep a record book, kind of like a mug shot of the virus they had seen. And then when they saw the virus again, they had that mug shot, and they’re like, oh wait, I know that one. And then they would attack it.
So the tools in the bacterial system—to do that recognition, to do the cutting and snipping, to paste it into its own DNA—there’s a bunch of different molecules that were part of this system that ended up being called CRISPR. And so there are a lot of different molecules that are part of that system, right?
There’s stuff to cut and paste and snip, so that the system is actually quite a complicated system within the bacterial world. There’s one of, or a couple of molecules from that whole big complex system that turn out to be exceptionally useful in a much more general sense. And this is work that came out in—2012 and 2013 were really the key publications where it was figured out that you could use CRISPR Cas-9—so one particular version of a CRISPR molecule. And instead of just using it for bacteria cutting and pasting its own DNA, you could actually use it to cut and paste any DNA. It’s a generalizable tool. It’s not just this cool, weird, interesting thing happening in bacteria. It’s a tool you can use in a very broad-based way in biology.
And that is what then set the world on fire with regard to CRISPR, because you had, you know, something that had before been really a complicated thing to do, you know, cutting and pasting DNA in a precise way. Now you had this tool, frankly, the high school students can use it, right? And one of the things about CRISPR is that first and foremost, it works.
You know, there’s lots of complicated, fancy scientific tools that are also kind of delicate, and it’s just hard to get them to work. But CRISPR is very robust. And so a lot of scientists, I’ve had them say to me, “I tried it and my firstexperiment worked.” For anybody who’s done experiments, usually your first experiment doesn’t work. Your first experiment tells you you didn’t get it all set up right. It’s like a lot of us are doing a lot more baking these days, and we all know that the first time we bake something, it doesn’t really quite turn out like it did on the Great British Baking Show. So practice makes perfect. And same thing with sciences, with anything else. So having something, having an experiment work the first time you try it, that’s not so common, but tends to be the case with CRISPR.
But further, it works in a lot of different contexts. By that I mean with so many different species, right? Obviously it works in bacteria, but it works in yeast. It works in fruit flies, it works in mice, it works in humans.
It works in all these different species. So you go from this weird pattern observed in bacterial genomes, this pattern of clustered, regularly interspaced, short palindromic repeats—CRISPR—to this incredibly powerful, robust, and flexible tool that can be used in all kinds of different aspects of biological inquiry and therapy.
Rigo: So the reason why I brought that up is because—I don’t know if this is the right word—but it’s kind of like maybe poetic. The fact that the origin story of CRISPR could potentially be used for now, for a virus.
Katrine Bosley: I’m so glad you used that word because I completely agree with you. I mean the bacteria use it to fight off viruses, and maybe we’re going to be able to do the same thing.
Rigo: And just to clarify a little bit about these diagnostic tests, basically it works like, the way that it’s been described, there are actually two of them. One in Mammoth labs [Mammoth Biosciences] in the Bay Area and the other one by MIT lab, which is the one that you’re describing. And these two tests, as I understand, they would kind of highlight the certain proteins of the virus so that they’re very visible to see.
Katrine Bosley: Essentially, yes. I mean, what they’re able to do is, because if you think about it, if you take a sample from a person, right? Let’s say it’s from the nose or the back of the throat or something like that, some kind of biological sample. So you take a sample from a person, a little bit of fluid, essentially.
And what you’re trying to figure out is in that little bit of fluid, is there any evidence of the presence of the virus? Now, obviously you don’t have a lot of fluid, and the virus, you know, how many particles of the virus do you have? So what you’re trying to figure out is, you’re looking for a bit of a needle in a haystack in that little sample.
So what you need to do is, one, is have a tool that can see if it’s there. And then two, how does that tool give you the signal back to say yes, it’s positive, or not? So that’s the amplification you’re talking about. And you know, with the first laboratory tests we have, you may have heard the acronym PCR. So the way that they do that amplification is through PCR, which is a very well-established technology. It stands for polymerase chain reaction. But that’s a way of finding a really small amount of something and increasing the amounts. In that case, you’re kind of copying or replicating that first little bit that you find, and then by increasing the amounts you can detect it.
With the CRISPR-based approaches the molecule that they’ve created, the CRISPR-based molecule they created, can find it. And instead of copying that little bit of virus that they find, they’re actually amplifying it by showing a signal. So they have a way of essentially sending up a signal flare, is essentially what they’re doing.
So it’s a different way of sort of amplifying the signal, but in each case you’re using a technology to very accurately detect the presence of a teeny tiny amount of something, and then you have to somehow send up that signal flare. Either make a lot of copies of it so you can see it, or with the CRISPR send up a signal flare.
Rigo: Those are all the questions I had. Is there something that I didn’t ask you about that you want to add or contribute?
Katrine Bosley: You know, if somebody is listening to this podcast, they’re probably already pretty interested in science, which is great. But understanding the science and the data, I think, can help in that you can see why decisions are being made and the way they’re being made. And I do think that, you know, there are social questions to balance here as well as scientific ones.
But, you know, learning about the science, I think it can help. And obviously I kind of live in that world, and I enjoy it as well as think it’s important. But I just, you know, when we were, all of us were little kids, we used to love anything science, right? It’s just cool stuff, and it is cool stuff.
It’s still cool stuff. So I think there’s an opportunity for folks to really find that inner childhood joy of science being interesting. Maybe that’s a tiny little silver lining of what otherwise is a really dark cloud, for sure. But I’m all about looking for silver linings.
Rigo: Well, thank you so much for talking to me. I really appreciate you taking the time.
Katrine Bosley: My pleasure. My pleasure. It’s been great.
Lisa: Thanks for listening to this episode of Pandemic Perspectives. We’ll be bringing you more interviews from all sides of this crisis so stay tuned and watch your feeds. As always, you can find all of our episodes plus transcripts and show notes at distillations.org.
And you can find tons of educational resources on our website at sciencehistory.org/learn.
The Science History Institute remains committed to revealing the role of science in our world. Please support our efforts at sciencehistory.org/givenow.
For Distillations, I am Lisa Berry Drago.