with segments:   &  and host ... 
                                                                                       Dr. Moira Gunn

2020 Tech Nation / BioTech Nation Interview

      -- Jacob Glanville

        Co-Founder, CEO & President, Distributed Bio


        Tech Nation/BioTech Nation Jake Glanville - Distributed Bio + Moira Gunn - 2020


Interviewer: Moira Gunn, Host, Tech Nation

Guest: Jacob Glanville, Co-Founder, CEO and President, Distributed Bio

Source: 2020 interview with Jacob Glanville recorded in San Francisco, CA, USA

Audio Length: 49:07

Recording Date: March 18, 2020

Air Date: March 24, 2020, Tech Nation/BioTech Nation, Release

Transcript Release Date: March 31, 2020

Tech Nation Media retains full rights regarding this transcript and the audio it reflects, which aired over NPR Now and other broadcast and Internet venues. Attribution should be given as “Tech Nation interview with Jacob Glanville by Moira Gunn, March, 2020”. Quoting, e-publishing, and/or re-airing on any medium beyond “fair use” requires the express written permission of Tech Nation Media. Contact technationmedia@gmail.com.

Transcript edited for written publication.

GUNN: From San Francisco, I'm Moira Gunn, and this is Tech Nation. Today on Tech Nation, the efforts of one team to target antibodies against the coronavirus which becomes COVID-19. This is not a vaccine, which your body has to take in so that your immune system can create antibodies. Rather, they are attempting to directly engineer antibodies which make you immune. But wait, there's more. Their target on the coronavirus is that small part of the virus which does not generally mutate as it replicates, and so the therapeutic effect may circumvent, chasing the mutations of the virus over time. To fully understand this interview, you need only remember one term: antibodies. You already know what they are. Your body creates them naturally to keep you healthy. And for what your body does not create naturally, we humans have created vaccines. When you were a child, you likely received the polio vaccine. What you likely do not recall is that it took 7- 21 days to take effect, where “taking effect" means that your immune system started producing antibodies to protect you.

The difference in this team's approach is that they're working to engineer the antibodies directly with the idea that, after administering the therapeutic they are working on now, it will result in an immediate resistance to the coronavirus which causes COVID-19. And why? Because you would have the antibodies to fight it.

One further note in terms of language used, in addition to hearing the term “antibody,” you will also hear the terms “monoclonal antibodies” or “monoclonals.” When you do, simply think “engineered.” It's an “engineered antibody.” “Monoclonal antibodies” are the type of engineered antibodies this team is working to build. My guest today is Gates Foundation award-winner, Jacob Glanville, the Co-Founder, CEO & President of Distributed Bio. He joins me to talk about their work engineering antibodies, as well as creating a universal flu vaccine. Remember, the flu is caused by a virus. Could any of this work be used to fight the coronavirus, and specifically, the virus that causes COVID-19? You may already know our guest today from the recent Netflix documentary, “Pandemic.” You can't miss their research involving pigs in a remote area of Guatemala. Today, Dr Glanville will update us on what they're doing in this time of crisis.

And now, Jake Glanville.

GUNN: Welcome back to Tech Nation, Jake.

GLANVILLE: Thank you very much for having me on.

GUNN: When last we left you, you had corralled your mother and father, who own a hotel and restaurant on a remote lake in Guatemala, into letting you set up a research lab with pigs, so you could test your methodology for a universal flu vaccine. Yes, you heard that right, listeners. That whole story. So give us the backstory. What were you doing from a scientific research perspective? Why Guatemala? And how much does a research pig cost in Guatemala compared with the United States?

GLANVILLE: Sure. So back in 2012, right when I founded my new company, Distributed Bio, I'd come up with an idea for how we could make a vaccine teach the immune system to recognize conserved parts of viruses that don't change from year to year. That was exciting, if it worked, because that could form the basis of a universal vaccine for influenza, and it could also serve as the basis for vaccines that could work against HIV and other rapidly mutating viruses.

GUNN: Now let me just stop you right there. People say, well, what do you mean, “There's a part that might not mutate?” I always think about when parents get together, and they have a child, a certain portion of that DNA, a small portion, is the mitochondrial DNA. You get it from your mother, you don't get it from anybody else. It's not mixed. We can track who is the mother right down – it takes more complications to figure out who’s the dad -  but for mom, if you have that mitochondria, you actually got it from your mother unchanged. Is it similar to that type of thing?

GLANVILLE: Yes, in some respects, it's similar. So for a while, people thought that the flu mutated so rapidly that we'd never be able to make a permanent vaccine, that every time you make a vaccine, it might work for a year or two, but then the virus would change, and we'd have to create a new vaccine, because the old vaccine had become obsolete. Then, around 2000, there were these really exciting sets of studies that came out, that showed that some lucky people had managed to make antibodies that recognize little parts of the surface coat protein on the outside of the influenza virus that couldn't change, that if the virus tried to mutate those sites, the virus would no longer be infectious. And so those lucky people had what are called “broadly neutralizing antibodies” that can protect them against a whole bunch of different strains of influenza. And so as soon as the research community saw that, then instead of tearing our hair in despair that we would ever make a permanent solution, it actually caused us to ask a very different question, which was, why aren't we all protected?

If there's a spot on the surface of the protein of the virus that doesn't change, why aren't all of our immune systems responding to that? Why are they getting distracted by the parts that do change easily? And that gave rise to a feverish amount of research into trying to create a universal vaccine, or a broad-spectrum vaccine, that would focus the immune response on the parts of the virus that don't change. We now know why those parts don't change. The outside proteins on the virus of influenza, they have a protein called hemagglutinin, and it acts like a little three-way grappling hook that helps it to grab onto the cells in your body, and then inject the genetic information from the virus to infect you. And the parts that are not able to change are sort of stuck because they're almost like the springs of the grappling hook. And so if you mutate those to avoid the immune system, then the grappling hook doesn't work anymore.

GUNN: Hahaha, virus!

GLANVILLE: Exactly. So if you can focus on those sites, they're like the Achilles heel of the virus. You can protect yourself, and so that's the history of the work.

The challenge was that no one managed to come up with a way to force the immune system to focus on those parts. It just kept really enjoying going after the wrong parts of the virus, and that was a frustrating mystery of, “why do we miss?” and that was also the insight that I had. I was riding home on a motorcycle one night and I was thinking about populations that were related proteins, and it occurred to me that rather than trying to engineer the protein to sort of force it into a shape that would be really tasty to the immune system to focus on the right parts, why not just realize that every protein is imperfect, and you're never going to solve trying to engineer a single protein.

Instead of doing that, what Centivax - our technology - does, is instead we take 30 different versions of influenza from across the last hundred years - the last century. Then we mix them - just that grappling hook, the hemagglutinin - and we administer them all at once to a pig, or a person. So that each component is it really at a very low, low dose, so that the immune system basically can't focus on the parts of the grappling hook that are at too low of a dose for an individual strain. But the shared parts, the spring-loaded part of the grappling hook – because it's in all 30 different versions and hasn't changed – you've basically given a 30-fold higher dose with the parts that haven't changed. And the immune system focuses on the parts that haven't changed.

GUNN: So you’re not worrying about the strain. You’re saying, what's the deal on each one of the grappling hooks for all of these various flus? And does that include the famous 1918 Spanish influenza?

GLANVILLE: It does indeed. And it goes all the way back to 1918, and all the way up to the present. And so we went, and my project lead, Sarah Ives, worked with me, and she ran the laboratories down in Guatemala. And then we have laboratories up in the States, and we proved that when you take that mixture, and you inject it into a pig, the parts that change from year to year are sort of diluted out. And so the immune system just focuses on the parts that haven't changed over a century. And if you can make a bunch of antibodies that recognize the parts of flu that's never managed to mutate over a century, you can be pretty sure that they're going to be protected over the next 20, 30 years. And indeed, we saw that with those pigs, which really takes me to the story of “why Guatemala, and why pigs.”

GUNN: Which should strike fear into the heart of any parent. You never know when you're going to get a phone call …

GLANVILLE: Yes, so I had this idea, and it's called “conservation reward coupling”. That was the way of getting the immune system to focus on the conserved sites of these mutating viruses. But the problem was in vaccine science, there’s really not much you can do in a test tube there. Basically to prove your idea, you have to go in and show that it works in an animal. And that's because the immune system is so complicated, and it's got so many moving parts. It's really hard to mimic one little piece of that in a test tube. So you have to go in to prove it works in an animal, or you don't have much. And the problem with animal research is that it's very expensive. And I was going to either need to find ways to get grants, or I was going to try to find ways to get venture capital, which is the traditional way you'd approach this.

But I was sort of a no-name at the time, and the vaccines were really hot at the time. So the venture capitalists I talked to were like, “Well, why don't you work on cancer? That's a more profitable way for us to invest”, which I understand. Their job is to give their money to someone who can give them the best returns right away. Grants were going to take a long time. So I basically had Distributed Bio. We were making money. We were a profitable company by being basically “hackers for hire”, where people could come to us, and we could engineer antibodies for them as drugs. And we were very good at this, and the profits of that allowed us to build out laboratories in the United States.

At a certain point, I realized I need to test this in an animal model. I called a friend of mine who is a veterinarian, and I said, “What's the biggest market for an animal vaccine where the virus mutates, so you have to change it?” And he's like, “Well, it's definitely pigs and flu. That's a $175 million per year market. That's the one you should work on.” Which was great. Because my goal is that I wanted to go prove this in an animal that actually gets the disease, to make sure that we're not testing on a system that is sort of irrelevant to humans. And I want it to be the same viruses. There are some versions that are a little bit more popular in pigs and more popular in humans.

But pigs are also kind of a special species, because they can get infected with viruses that come from birds, much easier than we can, and that's pretty scary, because if you get a pig that's infected with the swine flu, or a human flu, and also with a bird flu, the pieces of the virus will shuffle up, and they'll create a new recombinant version of a flu. And that's where pandemics come from.

We've had five pandemics in the last century, and all of them looked like they'd gone through shuffling in pigs. So making a good vaccine for pigs … first off, it's smart business, because you can get a vaccine and start making money. [You can get] access to that $175 million a year. You can do that in three years, whereas going to produce a vaccine for humans is going to take more like seven. And there are good reasons for that. We want to be really sure that new medicines we introduce to humans are safe, and do no harm, and help people. That process is just faster with veterinary work.

And then the other benefit is that if you can make a universal (flu) vaccine for pigs, then suddenly you've gotten rid of this zoonotic infection network, which is to say that if the pigs are no longer vulnerable to infection by avian flus, and by pig flus, and by human flus, then suddenly you've created a barrier of insulation between the human populations, and those really dangerous bird flus we want to avoid. It occurred to me that I wanted to work on pigs, but that also made it almost depressingly far away to solve, because pigs are much more expensive than mice, which are already quite expensive.

And that's when my kind of weird history of my life kind of all came into focus, and I realized that I had this unique opportunity. I had grown up in Guatemala, on Lake Atitlan. My parents are innkeepers, we have a little bed and breakfast on the Lake there, and I went to school there until my last year of high school. I retained relationships with the professors at the University of San Carlos, and so right when I realized that pigs could be a good animal model, I also realized that back in Guatemala we have a thriving industrial production of pork. And so I called the professors down there in Guatemala. I called a couple of these professional groups. It's called Genetiporc. It's the brand of pigs that are produced for like Costco, and so forth.

And then I also called my father, and basically I was just like, “How much does it cost to get a pig in Guatemala?” And that number is about $50.

GUNN: So how much does (it cost in) San Francisco?

GLANVILLE: To run animal studies in the United States in a facility, you'd go through a contract research group, and you could be spending hundreds of thousands of dollars, which we currently are - using the Gates foundation money at the Pirbright Institute - which is good. I'm glad we're doing that.

GUNN: But you don't start out there.

GLANVILLE: You don't start out there. I didn't have that kind of money to start with, and I never would have gotten there had I waited for that process. I think it's called the “Silicon Valley of Death,” and it's this distance of things that are too new and too different – they aren't going to get money. They wait until somebody else supports them and de-risks them. But that means that really new ideas aren't going to get funding right away. So going to Guatemala was my way of testing a really new idea and also iterating, because good engineering requires iteration. Like for the manned moon missions. If we had tried to do it all in one shot, we would have failed. And instead, what NASA did, and what Russia was doing at the same time, was first you'd build the booster rockets and test them out, and then you try to get up into orbit. Then you try to go to the moon and come back. Then you try to go and eventually land. And it's that rapid iteration that's required across science, and that's what Guatemala enabled me to do. So we were able to build an animal facility on Lake Atitlan. We had a local veterinarian named Karina Reyna.

We had partnerships with the University of San Carlos, and then Sarah Ives was leading the group that was managing the immunization schedules and the drawing of blood. We had a small laboratory down there to process the blood products to extract RNA, and to extract serum and plasma, and then that would all be shipped back to the United States, where in our much nicer facilities up here, we could run tests to see: Did those antibodies neutralize the different influenza strain viruses? And so that was our setup and we were able to run a pilot study, and then four other studies, in four years.

GUNN: And you don't even have to imagine this. You can see it all on “Pandemic”, the Netflix documentary, which we'll get to, and we'll get to Sarah, and to all of that effort, and so you were down there. And what's the idea? You inject a number of pigs, you'd have some control with no injections, and then you give them the virus?

GLANVILLE: We never were able to give them the virus in Guatemala. That's called a “live challenge” and that's what the Gates foundation is now supporting. In the first study we just wanted to know: Is this principle correct? Can we give an extremely dilute amount of 30 different virus coat proteins, and then see that the immune systems respond to only the shared sites? So what we did is – I think there were 35 piglets in that study, they start off as little lecheros, which means little milkmen – about 21 days. They get big over the course of these studies. So they're 300 pound animals by the time the study is complete, but we had seven pigs to receive no vaccine. They have something called “vehicle control” which just basically means it's like salt water and the adjuvant.

We had seven pigs to receive the normal bivalent. And for these studies we would pretend it was 2007, so they got the 2007 shot, and we pretended we had no knowledge of anything after 2007. Then what we could do is we could check their blood against future viruses to see whether this vaccine can protect against the future. We chose 2007 because in 2009 there was the pandemic outbreak of swine flu. So that was a way to be like, “Can our vaccine protect against a pandemic?”

Then we had three different groups of our pigs, seven pigs in each group, and each group had a different dose because we had these 30 different components, and what is the number of components? And what's the optimal dose to get the biggest feedback?

We did some other studies on other pigs where we were diluting down the dose of individual components, and we'd basically doing some testing to go: What's the right amount where the individual strains are below the threshold of enough medicine to matter? Whereas the shared sites are well above that threshold. So that was the initial experiment. We’d go down there, and we’d check their little ear tags, check the little ID on each of the vaccine syringes, give them their shots. Seven days later, and then 28 days later, after each boost, we take some blood. And process that in the laboratory, and then send all that back up to our labs in the States. And then up in the States, Sarah first would check: Do the antibodies bind? And she checked against a panel of like 45 different hemagglutinins from 1918 all the way up to 2015 at the time.

GUNN: And why is that important?

GLANVILLE: So the first check is basically: if the vaccine works, then the pig's blood will start flooding with a series of antibodies that go bind to and recognize the hemagglutinin. That's basically how the HIV rapid tests work. And when people check your blood to see if you have reactivity to chickenpox, and so forth. And so we were doing that test first, and that was remarkably successful. That was our first time that we knew that the seven months of us building up this facility… and I should mention also that my brother, Keith Glanville, is a construction worker. And so he became the foreman of building up the animal facility down there. So really everything came into focus - like my life in Guatemala, and my father with his property, and my brother who's a construction worker, meeting Sarah Ives from USF, my team members here in the States, and my partners Karina Reyna and Erwin Calgua, the professor from University of San Carlos. We were able to come together to test this thing. And yes, we saw that we were getting this super broad reactivity. So the pigs who received our Centivax vaccine were responding to a century of influenzas. And that was super exciting for us.

But just binding isn't enough. The problem that other universal vaccine companies or groups had run into was that sometimes they get binding, but they wouldn't get enough binding to neutralize. And so antibodies would kind of stick onto the different viruses, but they were kind of wimpy, so they’d fall off. And that's not good enough to protect you - sometimes that can actually make things worse. For our next question, we needed to know: Did our shot actually neutralize? And so the way you do that was that Sarah Ives would go in chicken eggs - we got approval from the US government to go get 15 different strains of influenza, and then working in a very careful biosafety facility, she would inject those influenza viruses into chicken eggs - they’re specially cultured, and you grow up a whole bunch of virus and you extract that liquid. It's pretty cool, and gross, and scary. I would say I've never had so much respect for a biohazard bag until after she's been working on that all day and she's got like, I don’t know, 12 kilos of chicken refuse. So the leftover egg that doesn't go into the vials is just hanging there and if you leaned your head in and took a whiff, you’d just get like 15 viruses at once. But she didn't, she's very precise.

So you get all those viruses, and that let her do this amazing experiment where you take the blood from the pigs, we send that back to the States, and then she would mix the serum from the pig - that's the clear part of the blood - with the virus, from each one of those 15 viruses and then a cell type that the viruses would normally infect and so if the vaccine didn't work, then you'd mix the serum, and it didn't matter. The virus would happily go in and infect the cells. Whereas if the vaccine worked, then the serum would go in, and the serum would be full of antibodies, just chock full of antibodies that would go block up the virus and the virus would be neutralized.

That result was what really got us excited, because we were the first technology, to our knowledge, which was able to achieve broad future neutralization of pandemic strain. Our pigs were basically iron clad, protected against getting infected with influenza at that point. That's really the data that got us in front of the U S military, and it got us in front of the Gates foundation.

Suddenly a project that started as an idea on a motorcycle and developed in the jungles of Guatemala was suddenly being presented to Bill Gates and his deliberative body, and ultimately won us a Gates Foundation grant, the “End the Pandemic Threat” Grand Challenge Award, which is now supporting our research at the Pirbright Institute on pigs and ferrets, which will prepare us to go to the veterinary market with pigs. But with the ferrets, we're getting ready to do human trials.

GUNN: We have this working in the flu, and now suddenly we have this new coronavirus. Is there any reason to think it might not work?

GLANVILLE: Our flu vaccines won't work on the coronavirus, but our broad-spectrum technology could. We are looking at the novel coronavirus outbreak, which started blowing up right around the time that the Netflix documentary series that tracked our influenza program came out, in January. We looked at this, and the novel coronavirus has some unique properties to it that make us decide that, rather than a vaccine at this point, we are focusing on a monoclonal antibody - a single antibody rather than a vaccine that makes you make your own antibodies. Here's why.

Right now, the coronavirus is at this point a pandemic, as declared by the World Health Organization (WHO). It's a national emergency. It's all over the world, and it's growing, and you're starting to experience - pretty much anywhere you live - pretty severe social distancing policies, which seems scary, but the truth is, you're much safer now than you were five days ago.

The problem is that this virus is a much more deadly than flu, and it's much more infectious, so even with all these pretty severe social distancing policies and quarantine campaigns and basically a reduction of global travel, and even within cities, and across to your friends, that's not going to be enough to stop this virus.

The current projections are that we are buying ourselves very valuable time by slowing the growth, but eventually this will keep growing and infect more and more people. Furthermore, it appears that some people that have already gotten the virus may either be getting it again, or it maybe they never cleared it.

There's a long-term concern that we really do need a permanent medicine to solve this problem, and people are working on this a couple of ways. There are some old existing antivirals or an anti-malarial, some existing drugs that are being repurposed. There's some evidence that Chloroquine, an off-patent drug that's been around for 70 years, could be effective. The Chinese and the South Koreans are using it. Remdesivir from Gilead and then Kaletra from AbbVie are all medicines that are being evaluated.

And that's the best. If you can take an existing medicine and find that it actually works here, then then you can start administering that immediately. But as a backup position, because those may not be effective, people are developing vaccines, and they're also developing monoclonal antibodies. The vaccine programs are exciting. They're moving quickly into testing, which is the good news. And there are groups like Moderna, the NIH, Israel and the Chinese – (they) are all developing various vaccine solutions. The bad news is that vaccines take a really long time to prove that they work. Because the vaccine, you're giving pieces of the virus to someone and you're waiting for their immune system to give rise to protection. Just like I had to do with my pigs. And that often can take six weeks or more and you have to give a couple of booster shots.

So that's too long. If you have someone who's already sick, you can't give them a vaccine to protect them because six weeks later, by the time the vaccine would actually be any help, the person's either recovered or dead. You have to give them to healthy people. And that also makes it harder and slower to run a study - human phase trials - to understand whether the medicine's effective because instead of giving it to patients and getting your answer within 10 days, whether your drug worked, you have to give it to many, many, many healthy people and then monitor them for many, many months to see if there's a difference statistically in the number of people who got infected of the people who received your vaccine or not. And for those reasons, we're looking at about 18 months before the vaccine’s being developed. Now it would be available for coronavirus.

That's still helpful because at this point, we are thinking that this thing could become seasonal, that it will circulate, and it will mutate enough as it goes. That we're going to have to deal with this, not just as one outbreak, but as a permanent thing. Like the influenza except much more deadly and much more infectious. But 18 months is a long time away, and we want something faster. For our purposes at Distributed Bio, what we chose to do is instead to engineer a monoclonal antibody.

GUNN: Which you do all the time!

GLANVILLE: Yes. So that's actually how we make our money. We work with over 50 pharmaceutical companies that come to us to help engineer, bio-engineer antibodies to act as drugs. We're industrial-scale good at this, and we use these new technologies, these computational immuno-engineering technologies, that we're uniquely good at to go after some of the hardest targets, things like GPCRs and ion channels and antivirals.

And we're actually specialists at going after tough antivirals. We worked with Peter Kim at Stanford to make broadly neutralizing antibodies against HIV, and we were able to do that in under four weeks. So that work proved that our platform could work on these really hard targets and these hard epitopes. And it got the attention of the military, which will come up in a second. We looked at this problem and I was like, what we should do? We should go create an antibody. And the reason an antibody is attractive is that unlike a vaccine where you have to give it to someone for six weeks for them to make their own antibodies. An antibody you can get, you can skip the middleman, and just give it to someone. And within 20 minutes of injecting it into them, their body is now filled with that antibody, and it's going to provide them protection.

And what it does is, it goes and binds all over the virus and blocks it from infecting you. So that's a very valuable thing to have. The other advantage of it is that vaccines are reliant on the immune system of the person you're injecting it into, which means they don't work very well on old people or people who are immunosuppressed. And unfortunately, COVID-19 is particularly dangerous to those groups of people. A vaccine is actually going to be least useful in the area where it is needed most. An antibody in contrast, you're not reliant on the person's immune system. You're kind of skipping that process, short-circuiting it. And so you can give that to people in the hospital, or you can give it to the elderly, and it'll provide about eight weeks of protection, like one shot or one infusion. And that means you could also give it to hospital workers to basically immunize them for eight weeks against getting it.

GUNN: Immediately?  

GLANVILLE: Yes. And so our feeling was that it was the better solution. And our way of saving a bunch of time is that instead of starting from scratch, we use this trick where we went back almost 20 years to the SARS epidemic, and we found a set of five antibodies that were very well studied to be able to neutralize SARS. People spent about two years researching these things after the SARS outbreak. If SARS ever came back, any one of those antibodies would have been a great drug against SARS. But the problem is, we're not dealing with SARS anymore. We're dealing with its ugly cousin, the COVID-19 agent, SARS-CoV-2. They're actually pretty related genetically, if you look them up. The part we're focusing on is about three out of four residues. The amino acids haven't changed, and one out of four has. So about 25% change.

GUNN: And let me just say, when you hear SARS, you're talking about SARS-CoV-1. And when you hear COVID-19, that's actually the disease for SARS-CoV-2.

GLANVILLE: That's right.

GUNN: We’ve got some nomenclature challenges here. It can be very confusing, but you're concentrating on SARS-CoV-2, but you get clues from SARS-CoV-1?

GLANVILLE: That's right. That's absolutely right. So yes, we can think about the relationship is like HIV versus AIDS. HIV is the virus that causes AIDS, the disease. And so here, SARS-CoV-2 is the virus that causes COVID-19, the disease. My laboratory gets tired of saying that whole thing. We just call it CoV-2 (“C-O-VEE-TWO”). That's our shorthand. And so SARS – the original SARS, from 2002 – that is a cousin of CoV-2, the agent that causes COVID-19.

What we did is we went back to those five antibodies, and we're using a way to tweak them – a bioengineering technology that we've developed in our laboratory -- to create billions of versions of each of those antibodies. They're all pretty similar, but they're sort of evolved a bit. And what we do is we take that huge population of billions of versions of those antibodies from 2002 and somewhere - if you make a billion versions of something, that are all a little different from each other - somewhere in there you've found one that's adapted to recognize the COVID-19 causing agent, and that has proven to be successful. So we've been applying that technology.

We're partnering with DARPA (Defense Advanced Research Projects Agency) and USAMRIID (U.S. Army Medical Research Institute of Infectious Diseases), which are two arms of the US military that help us bring medicines really quickly. Our expected delivery date was going to be just a couple of weeks from now, April 6th to April 13th, and we were chugging along, and then suddenly a couple of days ago we got this horrifying announcement, which I'm glad that on an abstract level, I'm glad they did it. They told everyone to go shelter-in-place, which basically means go home. All businesses that are nonessential are frozen in time, and everyone should go hide with their families and basically quarantine in their homes until April 7th. But that would obviously be catastrophic for this project.

So we called everyone we could, and we basically asked for special permissions just to say, “Hey, look, I know we're sending everybody home for all the contract research, and you know that all our pharmaceutical companies will wait, but we were working on COVID-19. We're trying to create a cure. Please don't pause that program. Then this means that we won't be able to continue that.” And we got this thing called an exception 10b, which allows us to continue work on that specific project.

But of course, there are personal considerations here. So what I did to my team is I told them all that this is entirely voluntary at this point. You can go home and be with your families, and you should have that discussion tonight with them, and decide if you want to come back. If you choose that it's better to stay home, tell me privately, and I'll keep that anonymous, and we'll just say to the group as a whole, we don't have enough people to carry this forward, the decision was to stay, so that there's no personal pressure. And if you want to come back, we'll create small groups that'll work in the laboratory. I'm like, no more than five at a time, so that we can continue coordinating our drug to be able to move forward towards a cure.

And it was incredibly humbling, how many of my people stepped up, and said, “No. This is something we believe in.” And paradoxically, we're actually going ahead of schedule now, because our entire company is essentially entirely focused on this project. I had just come from the laboratory here to meet with you and talk with you, and I'm heading back to the laboratory afterwards. We are on schedule, so we are aiming to have our final one or more of those optimized molecules, and we're engineering them to be super high affinity, to basically bind super well to the virus, to be super thermostable, so that you can concentrate these and deliver them as a subcutaneous little shot rather than an IV bag, and it's just more practical to give to lots more people, if you can do that.

And that material is going to be ready on the week of the sixth or the week of the 13th, depending on some tests we're going to run. And what's going to happen is some of that material goes straight to USAMRIID, which is that arm in the military, and they've agreed to take our antibodies, and they're going to test them to see how effectively they neutralize these viruses. So they're going to look at CoV-2, but they're also going to check our antibodies back to the original SARS, because we think our antibodies will actually be a good drug for both.

We will also work with Charles River Laboratories. They're a 16,000-person company that specializes in safety profiling of medicines. And so they've volunteered to help us take our antibodies, and they're going to test them in rats and potentially primates to basically make sure that these are really safe molecules.

And both of those pieces of information let us just barrel forward into early summer where we're going to start running phase trials. This is also an area of acceleration, so we are literally putting our thinking hats on and hacking every part of the discovery process of making drugs to be able to deliver a medicine as quickly as possible. This stuff does take time. You can't do it in no time, but there's ways we can be smart to take less time because this is a global crisis. Normally there's a process called GMP, which is a manufacturing process that once you've proven your drug, and you need to spend some time doing that - and that can take 18 months when you're on your normal (schedule). You know, ho hum, come into work and have some coffee, leave at five, kind of process, which we're not in right now.

GUNN: No. Coffee, coffee, coffee, all the time!

GLANVILLE:  Because we have directives at every level. We have interest by the military, we have the president talking about running to cut red tape. And we have partners. So we have a company called SwiftScale Biologics, and there's some other options for these, like rapid methods for making the medicine really quickly. We think that process can be cut down to a couple months, potentially even less. Then once you have the material that's produced - GMP is just a manufacturing stamp of approval saying this stuff's good enough, that it's safe to test in humans. So then you actually need to put it into some people.

And normally for drug discovery, there's these three phases. There are human trials, Phase One, Phase Two, Phase Three. In Phase One you're giving it to not that many people, like 20 healthy people, just to make sure your drug doesn't cause harm. It doesn't make healthy people sick. And then after that you do a bunch of paperwork, and you go into a bigger study Phase Two, which is where you put it into like 200 or 600 people to see “is your drug effective, is it efficacious?” And then if that looks good, then you go into a huge Phase Three study that involves 8,000 people. And that's really making sure that you get a much better handle on how safe this thing is. And are there any weird tales, rare but problematic side effects. And then if that looks good, then you approve it.

So for here, for this process, we definitely don't want to do that whole thing, because that thing could take years, and we don't have time for that. So instead what we're doing is after the rapid GMP, we're going into something called a Phase One/Two. So this is an approach borrowed from the oncology communities where people do cancer drugs where they convinced the FDA: “Instead of us like putting into 20 people that are healthy, why don't you just let us spend the money, and we'll put it into 200 people that have cancer right now? They're willing to try the medicine early. We will learn right away, “is it safe?” And we'll also gain some statistical advice on whether it is efficacious right away, and that's good.” That could save you half a year right there. And so that is routinely accepted in cancer patient research because the risk of not having a medicine causes a shift in the calculation of risk for people. And then also when you do those phase ones, they still do a rolling enrollment thing where on the first day, six people get it after the second day, like 36 people get it. So if you have a major problem with your drug, you're going to find out that first day and you're not going to give it to 600 people before you'd pull the plug. The advantage of that, which is what we're going to do, is that we’re going to give it to patients, and we’ll know within 5-10 days whether the drug worked or not.

It happens in the summer and that whole study, even with enrollment, is going to take less than a month, and that basically tells you “how effective is this at neutralizing the virus?” and therefore saving the lives of patients who are sick, and you can go into hospitals - there's a huge number of people, and there's no effective medicine, so people are going to sign up, and antibodies are super safe. Your body makes antibodies all the time, and the antibodies we're making are fully human, so the safety profiles are super good. We'll have that data from Charles River Laboratories, we'll have the neutralizing data from the military, so we're going in there well-armed.

GUNN: And if you have antibodies against something you don't have

GLANVILLE: They just float right in and help you out. Yes, that's right.

GUNN: We're ready if something happens.

GLANVILLE: That's exactly it. Yes. So then, this is where you get that, and now at that point you have efficacy. And really, we have money here to mobilize to support this, so we would give this, like our Phase One/Two, we'd have like 600 plus people. On that, looking good, you could move into Phase Two/Three, which you would do. But at that point, really the reason for doing a Phase Two and a Phase Three trial is to set yourself up to be able to make a lot of money eventually when your medicines get released. But because this is an emergency, as long as the data looked good and the drug worked in that Phase One/Two, once you get into the Phase Three, you can either add a huge protocol, so instead of having like 600 people, you could have say, 600,000 people in that protocol. Or you could start releasing your drug for something called “compassionate use,” which was used in the Ebola outbreaks. And that says that: “Look, we know this drug works. Let's just start building vats of it. Let's work with SwiftScale Biologics or other companies to build up hundreds of thousands of doses and start distributing them to everyone who needs them.”

And so given those sets of steps, assuming things work - this is science, so things could fail - our timelines are such that that Phase One happens during the summer, and that means we could release it out for mass usage by September. That assumes not just technologically things run smooth, but that also assumes that like the red tape gets processed. We have the partnerships with the United States government and the military to help us do this. They're really good, and we want their support, but we want to use our biotech leanness in order to hack our way through that red tape very efficiently. And the thing that will help us here, is that the whole world realizes that we have no medicine for this and we need one as quickly as possible, and that's what we are working to accomplish.

GUNN: I'm going to steal something from the Bill and Melinda Gates Foundation and Page Family Universal Influenza Vaccine Development Grand Challenge. And you were one of the awardees here. One of the requirements is, “Present concepts and strategies that are off the beaten track, significantly radical in conception, and daring in premise.” What [are we] talking about here? How “off the beaten track” is this, Jake?

GLANVILLE: The idea of making monoclonals against the virus, that's not off the beaten track - the biotechnology community all saw this. And I'll be blunt. I think the best solution is that we get lucky and like Chloroquine or Remdesivir.

GUNN: Something established, we’ve been taking, it’s approved, distribution is out there, that’d be great.

GLANVILLE: That'd be the best, because we'd have that ready in April. My guess is that they're going to show some data that show they work okay. And Remdesivir didn't work in Ebola very well, so we can be hopeful, but it may not work that well here either. We think Chloroquine probably is efficacious. It's being used by the Chinese and the South Koreans a lot, but they're also throwing all the spaghetti against the wall to see what sticks with these patients.

We'll see. That would be our best bet. Vaccines are great, but they're too far away. It's 18 months, it's too far away to help our current outbreak. We need something now. Antibodies are definitely, in my mind, the best way to go, because they're just a superfast way to make a very effective medicine. It's why our bodies choose this. It's why all vertebrates have chosen antibodies as their drug of choice to defend themselves. In that sense, there are multiple good companies working on antibodies.

The thing that we are doing that is “off the beaten path” is that we didn't start from scratch. Most of these groups are starting from scratch to try engineering antibodies and characterizing them, where we were able to skip two years of research by going back to those old anti-SARS antibodies from 2002, and then just manipulating them a bit to engineer them and repurpose them.

The advantage of that was made possible by a technology that I invented in my laboratory called Tumbler, which is a computational immuno-engineering technology. It lets me create billions of versions of near-native forms of an antibody very, very quickly. And then I’ll be able to use robotics, automation, and some methods in my laboratory to search through all of those really quickly to find the best mutant that does the best work. So that process is pretty unique. There are other types of ways to engineer an antibody, but they probably wouldn't have nearly worked as well because the Tumbler technology basically lets you explore the entire complicated surface of an antibody all at once, whereas most of the other engineering methods are sort of hunting and pecking on one little region at a time. And the problem is that the whole antibody was in contact with the COVID-19 receptor binding domains, this part of the virus that lets its grappling hook in and attack your cells. And that surface had changed quite a bit. So you need a way to change the antibody surface quite a bit in order to meet up and match with it.

So that was our unique advantage, our approach that let us go back to those 2002 antibodies where other companies would have thought that wouldn't have worked, because it would have been too challenging. We had this improved technology that let us do that. So we were able to basically take a shortcut through the woods and then potentially reach the finishing line faster. And the other advantage of our platform is that if you're starting with an antibody from scratch, at a certain point you're like, okay, it's good enough. Let's just go forward. But because we're making billions of versions of these antibodies, we're searching the evolutionary landscape very thoroughly, and then we can afford to be greedy.

So finding its way to cross to the new COVID-19 causing virus, that's one part of what we're doing, but because we have billions of shots on goal, we're going to do harder things than that. So we are also looking for an antibody that's very thermostable. It's super high affinity and it looks very, very human, very safe. And the effect of that is that we're not just going to have an antibody, but we're going to have a really good one. And the reason that's important to understand is that if we think back to the Ebola outbreak, there was a drug called ZMapp that had three monoclonals that was given initially to Ebola patients. And it wasn't a very good drug. The antibodies weren't very thermostable. So you had to kind of carry them on liquid. If you froze it, the antibodies would crash out and fall apart, and they wouldn't work anymore, and you had to kind of like, use lots of bags because they weren't very potent. So you'd have to basically give multiple infusions to a patient, and keep it on ice. And it was just tricky to deliver this around the world, where you don't necessarily have good cold chain, which is basically reliable refrigeration.

And so the opposite end of that extreme is if you have a very thermostable, very high affinity potent antibody, then you don't need to give people a bunch of infusions anymore. You can concentrate it enough into a syringe, you can give them one shot, and they'd be protected. And that's a much more practical medicine. And I think that's what we need, given the scale of the outbreak at this point. So the thing that's “off the beaten path” for us is that we can take old antibodies that have years of research already associated with them, and then we can apply this heavy duty engineering technology to search through billions of optimization variants to go find – it's kind of – the globally perfect antibody, the archetype, as it were, that has the best affinity, the best thermostability, the best humanness. And that becomes your drug.

GUNN: Some of you in the biotech community, or who are listening to this, say Sarah? Sarah Ives? I know Sarah Ives. Well she was a producer for us for several years on BioTech Nation and of course, one of my former students. And then, of course, when you watch this great Netflix documentary, the woman who is giving the great statistics presentation, Christina Pettus, another one of my great students. And you turn around to the couch there? David, the whole crowd. These were all my students. You love my students. Thank you so much, Jake.

GLANVILLE: I should be thanking you. I think the relationship with the University of San Francisco was part of what enabled my company to become successful. They have this remarkable master's program in biotechnology, the PSM. And I've been fortunate enough to have maybe 40 or 50 interns from that program, of which I've hired 10. And then we were able to work with people who already had an undergraduate degree, maybe had an existing career, came back, and as they were doing a master's program, they could work during the day. And so first off, I got to meet a large number of super motivated people. And then you find the right ones who are just outstanding, like Sarah Ives, Christina Pettus, and so forth, that you know that they work great with other team members. They picked up all your protocols. And so by the time they're getting ready to graduate, because they're interning with you while they're doing the (masters) program, they are already like part of your team and really essential to operations. And I think that was, we wouldn't be here where we are now, where I was able to grow a successful company without venture capital, without the relationship with the USF program and without specific remarkable stars that I was fortunate enough to meet through that program.

GUNN: And if you've ever met one of the BioTech Nation or Tech Nation producers in this area, they're all from that program. They do all kinds of things – teamwork, they know the science, they know the business, they know “how do you get in there and work?” And so it's a very refreshing crowd. It seems to attract those kinds of people. And I think what's also important is in these times now where we're all hunkering down, sheltering in place. It's like you can't come to the university. What are we going to do? So we're strategizing now. So you can start that program just with bio-entrepreneurship. You could do that online. You could wait for the science a bit until we can get you back in the lab, but we got some other ways to strategize that. So this is really causing us to rethink how we deliver this kind of education so people can go out right away and contribute to this great body of science.

GUNN: This also must be causing you to rethink some science along the way. Not just what you're doing here, but you must be learning new things to inform your science.

GLANVILLE: Yes. I mean from the business perspective and the science perspective. From the business perspective, I think everyone's focusing on the negatives, from having to go engage this social aversion, the social distancing policies. But I think as you were just describing with the USF program, I think Americans are innovative, people are innovative. They're going to come up with various ways to keep their businesses going and take advantage of various networking, social networking, face to face time, Internet enabling technologies, to let them ensure that the show goes on in the face of the pandemic.

From an engineering perspective, it has been almost an interesting and exciting opportunity for my entire company to focus on one project and coordinate together, because it's given rise to a whole bunch of conversations where we're evaluating all of our processes, and we're pretty proud of our processes. We work on a lot of projects with a lot of companies, but this has given us a chance to just take on laser focus. And because we're deliberately only having like five people in the lab at a time, and we take shifts to avoid having too many people present, then that gives everyone else - they're reviewing data, they're having analysis, they're looking over SLPs and protocols and they're asking: Every way we've done it until now, especially because this project is – we're just pouring rocket fuel on it – to figure out how quickly we can get it done, which means we're having all these awesome conversations and kind of getting a side of me like, well, what if we did this way instead of like the panning protocol? For instance, it used to take two weeks, and now we've got it down to four days because of this project.

And so I think that's the kind of thing that we're learning here is really taking all of our expertise, giving everyone permission and breathing room to focus on a problem together and problem-solve. And I think what we're going to emerge from this, not just with a medicine for COVID-19, but also with kind of a forced think-tank on how to optimize all of our engineering technologies.

GUNN: Well, Jake, you're always welcome on Tech Nation and BioTech Nation. You just come back, and see us anytime.

GLANVILLE: Thank you again for having me on.

GUNN: My guest today is Jacob Glanville, Co-Founder, CEO and President of Distributed Bio. You'll see Jake and his team on the Netflix documentary “Pandemic: How To Prevent an Outbreak”. It's available on Netflix.

GUNN: For Tech Nation, and this special edition of BioTech Nation, I'm Moira Gunn.

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