Introduction:

Welcome to the Salk Institute’s Where Cures Begin podcast, where scientists talk about breakthrough discoveries with your hosts, Allie Akmal and Brittany Fair.

Brittany Fair:

I’m here today with Salk staff scientist Gerald Pao. He studies a myriad of topics, including the novel coronavirus and how to make animals transparent. Yes, you heard me right, transparent. So welcome to Where Cures Begin.

Gerald Pao:

Thank you for having me here.

Brittany Fair:

And thank you for being on the podcast today. And just to start out, are you originally from San Diego?

Gerald Pao:

No. I came to San Diego when I was 17 years old. But before that, I grew up between Spain, Germany and the East Coast, a little bit. My dad was a career diplomat and he decided to put us in a German school since I was in kindergarten. I was in the German schooling system until I finished my high school graduation. But at times I was in New York—there was a German school in New York. And then I was also in boarding school in Germany. So I’ve been around.

Brittany Fair:

Wow. And what was it like hopping in between these three different places that have three different cultures and three different languages?

Gerald Pao:

Well, I speak all four languages, so I speak Spanish, German, English, obviously, and then I speak—both of my parents are Chinese, my dad speaks Mandarin, my mom speaks Cantonese. It was okay. It was not confusing at all. People assume it’s going to be confusing, but it’s actually easy if you’re learning all these languages within your critical period.

Brittany Fair:

I see. And when did you first become interested in science?

Gerald Pao:

I became interested in science probably late in kindergarten, but definitely before first grade. Initially it was through an encyclopedia and then encyclopedia of animals and then I just ditched all the encyclopedia parts that were not science. So there was a clear interest really early on. When I was in fifth grade, I learned about DNA replication. I saw a documentary and understood how DNA replication would work. But then I went to my biology teacher who was a phage virologist. And then I asked him how gene expression in a genetic code worked. And he said, “You’ll learn it when you grow up.” That was obviously not satisfying. So I went to my dad and then he sent me [to] the center of molecular biology to do science when I was in fifth grade. Well, maybe sixth grade.

Brittany Fair:

Oh, wow. So you mean you were actually going to a university?

Gerald Pao:

Well, I was not going to class in the university, but I was in the lab in [a] university, under a postdoc from Caltech since the time I was 11 or 12 [years old].

Brittany Fair:

And what was it like to be 11 years old in a lab [full] of adults?

Gerald Pao:

Well, I felt like I was behind. So I was trying really hard to catch up. He gave me a bunch of books to read. One was biochemistry, the other one molecular biology. And then those were the main ones that I started with at that age. The professor was much more of a mentor. Actually, he’s the one responsible for me ending up at Salk. He’s the one who told me to come to UCSD because UCSD is associated with Salk and that’s where I should go.

Brittany Fair:

And why was UCSD and Salk the place you should go?

Gerald Pao:

Because at the time, as I told him, I wanted to do molecular biology. I thought Princeton was probably the best one I got in. So I even paid the dorms at Princeton. Then he told me, “What happened to your application at UCSD?” And I said, “Well, I never heard back from them.” And then [I] called the registrar. I actually was admitted, they just forgot to send me the notification. He says, “Oh, you should definitely go to UCSD” because that’s where a guy called Dan Lindsley was at UCSD and the Salk, and that’s also where Francis Crick was. So he told me to go there.

Brittany Fair:

That’s true. Nobel prize winner, Francis Crick, was here. Did you ever have a chance of meeting Francis Crick?

Gerald Pao:

Yes, but just as an undergrad that is on the other side of the conversation, but I would run into him because he had the next-door office of my boss at the time. Yes, I would see him frequently putting up posters on the floor and then making cutouts of different parts of papers and then sticking them—gluing them on to make a poster to organize his thoughts. That was interesting.

Brittany Fair:

Oh, wow. That’s really interesting. And you’ve also mentioned to me before that you had a very different type of job when you were in high school. Can you tell me about that?

Gerald Pao:

I was going to this gym and then a booker in like Madrid’s oldest modeling agency saw me there and then asked me whether I wanted to work. So initially he put me in to do stunts because I was doing gymnastics—to do stunts for commercials and then went into modeling fashion stuff. So pretty much I saved up money to go to college from modeling in high school.

Brittany Fair:

That’s incredibly impressive. Did you model for any big brands or anything our listeners may have known?

Gerald Pao:

First, being Asian, you didn’t have many opportunities back then in Europe. But there was one brand that was celebrating diversity and that was Benetton. And then I did every season of their runway for about three years.

Brittany Fair:

Oh, wow. So you were actually on the runway modeling fashion?

Gerald Pao:

Yes. That was in Madrid, Barcelona, Milan and Paris. It was some kind of thing that you could actually make substantial amount of money with, without interfering too much with high school.

Brittany Fair:

And you did decide to come to UCSD for your undergraduate degree, but it sounds like you had opportunities to come to Salk at times, is that correct?

Gerald Pao:

Yes. One of the professors at UCSD formally introduced me to Tony Hunter, actually sent me to his office to work on some signal transduction, computational stuff that I was doing back then.

Brittany Fair:

And what was your first impression of Professor Tony Hunter?

Gerald Pao:

Encyclopedic knowledge of cancer. He seemed to be the one who knew the most. Anyway, I still think that nowadays.

Brittany Fair:

Did he have a beard back then as well?

Gerald Pao:

Yes. I’ve never seen Tony without a beard.

Brittany Fair:

[laughter] Well I have to ask, was it intimidating to interact with people like Francis Crick and Tony Hunter, who are really leaders in their fields?

Gerald Pao:

Yes. It’s totally intimidating. Around [that time] there were all these cartoons, scientifically-themed jokes about oncogene, signal oncogenes and signal transduction. I remember because I was so nervous, I wanted to be there super early. I was there almost an hour early and just looking at the stuff and waiting until he came.

Brittany Fair:

Okay. And today, you’re now a staff scientist here at Salk. Can you just explain to our listeners what it means to be a staff scientist? Because people may not be familiar with that title.

Gerald Pao:

A staff scientist is basically a semi-independent position under a professor at Salk. It’s basically you’re more senior than the post-doc and you can apply for your own grants. And then basically you’re working more or less independently at that point, while receiving advice from the professor.

Brittany Fair:

So you’re a staff scientist in the lab of Tony Hunter, but you’re also pursuing numerous different independent projects. To start out, I would love to hear about your project involving squid.

Gerald Pao:

I have a friend from a climbing gym, her name is Andrea Tao. She told me about these proteins that existed in squid. And they have really high optical refractive index. So refractive index is basically the speed at which light will go through a particular material. What that does is bend light. For example, if you actually look in a swimming pool, you can see the light gets bent. For example, if somebody’s standing there and you look at them from the side, sometimes you see like these really, really short legs on somebody. It’s an optical illusion because the light gets bent. And then it makes it look like the legs are shorter. So this protein actually is super dense, it’s much more dense than glass. So this is very, very, very strange. So my idea is basically, if you can make it so that the refractive index of things is the same between two different materials, then you can make it transparent.

So what do I mean by this? So the problem that we’re dealing with is organisms, it’s a little bit similar to what you have in a cloud. In a cloud, you cannot see through it because the light scatters, although you know the cloud has made water and air, right? But the water itself is transparent and air itself is transparent. But the fact is that you actually have these tiny droplets of water and every time that the light goes through between air and water, it bends. So it actually gets bounced around many, many times through the cloud, because there are many, many droplets of water. And then you cannot see through it. You just see white because the light gets scattered. So just imagine that if you were to take the space in between the drops of water in the cloud and fill it with something that has the same density of water, just imagine it’s water for simplicity.

If you fill all the spaces between the droplets of water with water, then it would look like a giant floating swimming pool of water in the air. You could still see through it but it would be transparent. So we’re trying to do the same thing in tissue of the organisms. So the tissue is basically—you have fats that are high refractive index, similar to the level of glass, and you have the in between space of the cytoplasm extracellular space and inside a nucleus, those are pretty much filled with water. So we’re filling that space in between with those reflective proteins, diluting the reflective protein in to match the same refractive index of the fat membranes. In this way, in theory, you should be able to make things transparent.

Brittany Fair:

So you’re trying to make tissues transparent. I mean, that sounds super cool, but why would you want to do this?

Gerald Pao:

So there are techniques that use this principle to make tissue transparent, but it involves killing the organism. But if you were to see, let’s say something that I look at, for example brain activity, obviously you cannot do that with a dead mouse. So if you were to have to see other than the surface of the brain when looking for activity, then you would actually have to make it transparent somehow. So that’s sort of the major reason we wanted to look at brain activity while the mouse is living. So that is sort of the goal.

Brittany Fair:

Okay. And I have to ask because I just watched X-Men. Could this technology be applied to humans to make someone transparent?

Gerald Pao:

Right now, it’s still not efficient enough to make a human like that. But in theory, you should be able to. The fact is that you do have transparent organisms in the animal kingdom. There is a deep-sea fish, many people may have seen, that the front of the head is transparent and the eyes of the fish actually look through its own head. So these things actually do exist. So transparency is actually compatible with life. It’s just that it didn’t happen in mammals. There was no selective pressure to do this. So I think that maybe with genetic engineering and some cleverness using some things that nature evolved, we might be able to get to that point.

Brittany Fair:

That’s absolutely mind blowing, but crazy cool. And if you’re studying these squid proteins, how do you get a squid protein in the first place?

Gerald Pao:

The protein itself we actually make in the lab. But the genes that were required for this, we had to sample in the wild. We started a collaboration with the University of Tokyo and RIKEN Brain Science Institute in Tokyo, Japan. We get these squid, they’re called Bigfin reef squid, Sepioteuthis lessoniana. So when you actually start doing field work, the most critical thing is to work out your logistics. You have to find collaborators, you have to find ways to ship your samples back, and everything has to work smoothly. Especially with squid, because the squid you see in a supermarket that you buy and eat, that stuff is not in the quality that you require for cloning genes. Actually, if you don’t freeze those things immediately within five minutes, then you don’t get any RNA that you can clone.

So in order for you to get the RNA sequence, you need to actually freeze it, immediately flash-freeze. So I was going together with a fisherman and then they actually bring the squid alive. And then at the dock, basically, take the sample from the squid and then freeze it with dry ice and ethanol. When you are doing field work, you have to rely on the weather. For example, you can only sample certain times of the year. So that’s either in July or in November. Both of those seasons—especially July, it’s typhoon season. So basically you have to allot at least 14 days or so hoping that you get one day where you’re lucky, or you can get adequate samples.

Brittany Fair:

You also have some interesting studies involving essentially a fake version of the coronavirus. Obviously, we now have a vaccine, but there’s still so many things we have to learn about how the coronavirus spreads and what it sticks to, among many other things. Can you tell me about that project?

Gerald Pao:

We’re trying to make things that are mainly useful. So what do we want to do, and what can we do? One is that we found and we made viral-like pseudo type viruses and viral-like particles. So pseudo type viruses are basically viruses that are based on HIV, a lentiviral vector. The vector is a virus that has a single round infection. It cannot reproduce. It just goes into the cell. But in this case, you carry this green fluorescent protein and make the cell green, so you can actually see it. And then we coat it with the protein from the SARS-CoV-2 coronavirus. And this allows us to test the properties of the SARS-CoV-2 spike protein. And this spike protein is basically how it enters into cells. So then it’s like we can actually test which mutations are better, which mutations are worse and entering a cell.

And for example, we found that this mutation that happened late in the Chinese epidemic that made its way to Europe, spike D614G, this actually infects five to eight times better than the original coronavirus. It’s much more infectious. So pretty much everywhere where this mutant showed up, it took over. So we demonstrated in the lab that this actually has a basis, and show in the lab that the virus actually did something that actually makes it more infectious, and we showed that. So in addition to that, what we did is basically incorporated this green fluorescent protein. So now basically what you have are viral particles that are actually fluorescent, so you can actually see them. So you could actually use these and see, okay, “How do they spread in aerosol?” People assumed that every aerosol particle for example, will actually have viruses, but nobody has actually put viruses in it. “How many can you fit inside? To which surfaces does it stick to, for example.”

Brittany Fair:

Yes.

Gerald Pao:

So we can actually make this and put these viral like particles because we can visualize them. You can see, does it stick to a face mask? The face mask of this material versus the cotton one, versus the surgical one, versus the nylon one that you have, on which one does it stick? Does it go through? Does it go to the other side? You can actually measure all these kinds of things. You can actually measure whether the stuff gets stuck on the air conditioning filter. What kind of washes take the virus off? You can test all these things because you can then go and see if the virus is there by fluorescence and because it glows green. So we made these, and we’re just testing these right now.

Brittany Fair:

That sounds extremely useful. And I know a lot of people are worried now because we’re indoors and it’s winter, that circulating air, especially through air conditioning, could be spreading the coronavirus. Is that something you could possibly easily study with these fluorescent proteins?

Gerald Pao:

We can actually monitor both the droplets and the droplets that have viral particles and how much of them, how many of them and where they go.

Brittany Fair:

Okay.

Gerald Pao:

But that’s in the works.

Brittany Fair:

And you have all of these different projects going on, lots of collaborations. What is your favorite part about being a scientist?

Gerald Pao:

Well, my favorite part of being a scientist is to do things that have been underexplored. I go for the little things that are considered basically high risk, high reward, and they’re risky. They’re risky because so little is known or nothing is known, that it is very likely that whatever you guess was wrong. But if it has potential, then it’s maybe worth taking those risks.

Brittany Fair:

And just kind of a fun question here. If you were no longer a scientist, what would you do? Did you ever consider another career, a backup option?

Gerald Pao:

Nope. Yes. I’ve never considered. Yes, probably would not want to live if I was not a scientist.

Brittany Fair:

Oh, wow.

Gerald Pao:

Yes. I don’t think I have any interest in living if I was not doing science in some capacity.

Brittany Fair:

And what do you think the future holds for your field?

Gerald Pao:

So for me, personally, I don’t think I am in a particular field because for example, I just got a paper [accepted] in computer science. I do like systems neuroscience. I do theoretical neuroscience. I did molecular biology, virology, kind of material science with squid stuff and a little bit of squid biology because of necessity. But I think I’m not really tied to any particular field. But that’s the great thing about being a staff scientist, at least for me, that I’ve been able to truly develop skills to be interdisciplinary.

Brittany Fair:

That’s a really good point. So let me ask you a different question then. What do you see as the future of your work?

Gerald Pao:

So the future for my work. So we were able to do this kind of brain download finding. And this is basically where we’re able to actually take calcium imaging from brains and then convert them into a computer model that reproduces everything. In this case was a fly, that behaves like a fly and walks like a fly, based on a neural data. It’s sort of the general concept of like downloading a brain. But in reality, is not just science-fiction. So now what we’re doing is we want to make it into a new type of AI that’s based on real biology. Right now, the AI that exists is basically purely computational as sort of generally vaguely inspired in biology. But this one is basically really starting from real observations of real organisms and let it learn in the computer at the speed of computers to do new things. So we want to make a new type of AI that’s completely based on biology.

Brittany Fair:

That’s insane. So if you’re able to put the brain of a fly, essentially upload it to a computer and then have that computer start acting like a fly, is your goal to eventually do that with other animals? Could a long-term future be that humans could upload their brains to a computer?

Gerald Pao:

Yes, I think so. Actually, I think we have at least the mathematical basis to actually do that. I think we have a pretty good grip on that now. Yes, so I think that might be possible. But you might be limited to whatever you record. So for example, if you’re recording yourself walking, you can only reproduce yourself walking. Maybe a little bit more, but you might have to have recordings of you doing the variety of things that you normally do in order to be able to download yourself completely.

Brittany Fair:

Well I’m so curious to see where your work goes and it was fascinating learning about all of your different projects. So thank you so much for joining us on the podcast today. It was a pleasure speaking with you.

Gerald Pao:

Thank you for having me.

Ending:

Join us next time for more cutting-edge Salk science. At Salk, world-renowned scientists work together to explore big, bold ideas, from cancer to Alzheimer’s, aging to climate change. Where Cures Begin is a production of the Salk Institute’s Office of Communications. To learn more about the research discussed today, visit salk.edu/podcast.