Geoff

Dr. Josiah Zayner, welcome back on the program. It's always fun to chat.

Josiah Z.

Yeah man. I love being here. You guys are great.

Geoff

Topic of the moment, human CRISPR babies.

Josiah Z.

Yeah, right?

Geoff

Let's unpack that.

Josiah Z.

All right, here's what happened. It was actually pretty crazy because apparently the Associated Press, AP, has been sitting on this story for a few months. Last Sunday, not yesterday but a week ago, Antonio Regalado from the MIT Tech, broke the story. I don't how, how exactly he found out. He found out and he broke the story on MIT Tech. Sunday night, Monday, Tuesday, Wednesday, Twitter just blew up. It hasn't reached public consciousness yet. It hasn't hit the zeitgeist, right. We haven't had Trump comment on it or anybody like that.

Geoff

I would say in terms of science news, it's probably the biggest science news at least of this year.

Josiah Z.

Probably of next year also.

Geoff

But is it breaking the Trump stratosphere of PR? Not quite yet, I agree.

Josiah Z.

Which is really interesting. That's super interesting. We could talk about that in a bit because it's one of the most monumental things to me that's happened to humanity.

Geoff

Absolutely. If you look at historical context, this is the first time that we've genetically engineered ...

Josiah Z.

... a human being, and it was born.

Geoff

... a human being.

Josiah Z.

Yeah, it's crazy. It happened and everything just exploded. It's interesting because if you look at all the scientists, all the academic scientists, all the PhDs, almost 100% ... There's a few here and there but almost 100% of them are against genetically modifying embryos and allowing them to turn into humans. Almost 100%, which is crazy.

Geoff

Let's talk about the ethical and moral questions. I want to just zoom back.

Josiah Z.

Wait, hold on. Let me finish, one second. You can go on Twitter and you look at all the comments from just non scientists, non PhDs. It's weird because there's a large percentage of them that are pro. There's even been studies that have come out in the past year that have shown that only 11% of people are against. You are talking across the globe, 11% of people are against using human genetic engineering in case of disease. Only 11% are against, and the academics who were for it before this happened all of a sudden are against it now.

Geoff

I think there's an interesting social phenomenon there in terms of how to have the higher moral ground or don't be criticized or castigated academically. I think some interesting-

Josiah Z.

I think there is a lot of that.

Geoff

... social political phenomenon that might be reflected in the larger political landscape where it's very easy to be polarized and easily shunned these day.

Josiah Z.

Well, you have to ask yourself, how do academics store value? As business owners you and I we store value through revenue of our company, through our salaries and all of these things. But academics don't have those things, right? Their salary doesn't really grow.

Geoff

It's reputation.

Josiah Z.

In the whole outside world they don't really have anything to offer besides the fact that they're PhD, besides the fact that they are smart and no better than everybody else. Knowing better is their thing. Like you said that's the position they seem to take is I know best. It's interesting because a lot of people on Twitter I've seen say that. They're like, well I have a PhD and I'm an expert. I'm like, "Hey, look, everybody can read the same scientific papers you can." Just because somebody doesn't have a PhD doesn't mean you know more than them or are smarter.

Geoff

That's an interesting point. It's like, do you have a PhD in ethics and human value and human morals. It's like their PhD is in some fine space and biochemistry or human physiology but this almost a philosophical moral question, or political question more than a science question.

Josiah Z.

Maybe even, but I don't know. To me ethics, as much as we try to tell them. Of course I don't want to kill people for no reason or something like that. Even though somebody's going to say I said that. To me ethics and morals are just some made up thing that we use to control people.

Geoff

Yeah. Let's talk about that. For folks who haven't followed the story let's just set the landscape, the framework-

Josiah Z.

Yeah. That's a good point.

Geoff

Dr. He Jiankui, Chinese scientist, made some CRISPR babies.

Josiah Z.

Yes.

Geoff

Can we lay out the facts and the timeline.

Josiah Z.

What he did is, Dr. Jiankui, he did his PHD at Rice University. Then did a post doc at Stanford. After that he went back to China and started working at a university in Shenzhen and they gave him some money to start working on these things. He started doing experiments on embryos. On rat or mice and then on monkey embryos using gene editing to see if he could remove diseases and doing all this stuff in embryos and grow them then into adults and if it affected anything or if there were negative consequences. He saw very promising results across the board.

Geoff

Was he known to be a leader in the space or was he-

Josiah Z.

No. Not at all.

Geoff

He was just some minor researcher out of China.

Josiah Z.

Well, for the past at least two years we've had the capabilities to use gene editing, CRISPR gene editing in embryos. We had the capabilities to gene edit embryos for much, much, much longer. But to use CRISPR gene editing, at least the past two years we've had the capabilities. That's when the papers were published. There's been some papers published from China and other places. Nobody was really doing anything with it. There's a rule in science. You can't let an embryo live past 14 days. It's pretty arbitrary I think. I don't know exactly why it's 14 days, but that's the rule. Once the embryo hits 14 days you have to destroy it and dispose of it.

Geoff

Some prestigious committee of top researchers decided this is the ethical balance. We're going to kill all embryos at 14 days.

Josiah Z.

This is where it gets weird because all these same people generally are on the pro choice side of the abortion debate.

Geoff

Fair enough because they are probably left leaning in terms of politics. I agree.

Josiah Z.

Yeah. And so, when the embryo is 14 days it's a human but when the embryo is, I don't know ...

Geoff

Six to three months. Six months.

Josiah Z.

It's not human? I think that's weird. One of those ethical weird cross overs where you're like, "Wait."

Geoff

You can't have both. You've got to have one or the other.

Josiah Z.

Anyway this guy was just like, "Why isn't anybody doing this?" Kind of similar to when I injected myself with CRISPR but this is on another level. He was just like, "Fuck it, I'm going to try to make this baby."

Geoff

That's actually a good comparison just to help elucidate for the folks listening. When you injected yourself with CRISPR you have your fully formed natural DNA and you just tried to manipulate a small section of your genome. This is muscle growth gene in your arm. Ostensibly there you would have a little bit of editing in that small spot. For this experiment this is full embryo. You're changing the DNA at birth.

Josiah Z.

He decided to do this. He chose this gene, CCR5, which there's naturally occurring mutations in the CCR5 gene. Basically it's a receptor on your cells that HIV uses to enter your cells and replicate. If it's mutated, sometimes HIV can't get in. We've found that mutations to the CCR5 gene prevents HIV infection. It basically makes you immune to HIV. It's naturally occurring in primarily European populations. It's super well studied. They've done it in embryos before, or maybe it was hematopoietic stem cells or stem cells and stuff like that. They've well studied the CCR5 gene. I'm pretty sure that's the reason he chose it. It was the lowest hanging fruit. We already knew how to use CRISPR to target it. We already knew what was the best ways to target it with CRISPR and all this stuff, super well studied.

Josiah Z.

He went to HIV support groups and recruited some parents to participate. Where the father had HIV and the mother didn't and set about engineering these embryos to have mutation in the CCR5 gene so that the children would be immune. Technically it can be passed on to future generations, but because you need two copies of it, it won't 100% be passed on and it's unlikely for it to invade any population or anything like that because you need multiple.

Geoff

It's a fairly rare genotype.

Josiah Z.

Yeah. He did a ton of analysis and experiments to confirm how it worked and what happened. It was super rigorous. He said he paid for it all himself which I'm skeptical of.

Geoff

Because this is expensive stuff. Given your experience here, how much do you think this would have cost?

Josiah Z.

Oh gee, it depends on a lot, but we're talking what happened. He had multiple couples. They had to harvest the eggs. Then they had to take the eggs, do DNA sequencing, genome sequencing, on all of them. Then what they had to do is genetic engineering experiments on them. Sequence the embryos after they do the genetic engineering.

Geoff

You put CRISPR on it to see if it actually holds and manipulates.

Josiah Z.

It's really cool what you can do nowadays. What they learned is when you have an embryo and you try to genetically modify it, you let it grow a little bit bigger until it has, lets say, 16 cells. Then you can take off two cells using a micro pipette and you could sequence those cells to see how the gene editing effected the embryo. It doesn't hurt the embryo at all. Not even a little.

Geoff

You take off one sixteenth of the bio matter?

Josiah Z.

No, because those cells eventually expand and grow. Those are basically stem cells. They haven't really been defined yet so it doesn't matter too much. But yeah. He was able to do that, sequence them. To me it was a really great rigorous experiment and nobody doubts the science. The science he did is pretty straight up legit. I don't know if he self funded it.

Geoff

He's not a hoax, not a fraud.

Josiah Z.

As far as we know. Wow, I am so impressed. If it was me I don't know if I would have presented the data. What happens a lot with scientists ... You know when you've done research with the ketones and stuff like that. Scientists they don't want to see and what the truth is. What they just want is an avenue to criticize each other. That's basically all data is, an avenue for scientists to criticize you. It's funny, but he did it and it was so rigorous nobody criticized the science at all. That's impressive in and of itself. If he did all this stuff with himself and a couple other people, wow, I am impressed. That's what he claims. If so it's the ultimate bio hack.

Geoff

He's super scrappy with efficiency in terms of capital. It sounds like he didn't have crazy amounts of funding, didn't have crazy amounts of government ... It sounds like the government has backed away. The university has backed away in terms of the support and all of that.

Josiah Z.

I think that's kind of show though.

Geoff

You think it's show?

Josiah Z.

Totally.

Geoff

It sounds like from your perspective this is a serious rigorous effort that required a lot of time, money, and diligence and not some back room operation.

Josiah Z.

No, no. They worked with legit medical researchers. Apparently they just mislead them what actually was going on. They told them that they were just trying a new sequencing technology out on the embryos before they implanted them or something.

Geoff

I think if you just gather all the critiques, it seems like the biggest concerns I've read is that, one, the ethical forms were a little bit misleading. The couples, the patients, didn't exactly know that they're going to get their babies genetically engineered. That seemed to be one thrust of attack. Two is that, again, from the ethical or longitudinal critique, this has never been done before. Are these babies going to be harmed in the long term. You've just manipulated their genes in a novel way.

Geoff

I guess third is that ... a critique is that this is more of an engineering project than an actual medical use case in the sense that CCR5 HIV prevention, some scientists are saying that that's kind of like a hand wave excuse to do the experiment. It's really more of an engineering challenge. The medical use case is a little bit of an excuse to do this experiment. I guess the last point was that there's some nit picking around the deletion and the addition of the exact CRISPR site. Where one of the twins ...

Josiah Z.

I looked into that. Yeah, yeah, no.

Geoff

One of the twins is heterozygous, so it wasn't a full deletion, a full manipulation of the CCR5 gene. The other one had four deletions, one addition. There was some concerns around exactly what they did on the exact allele.

Josiah Z.

The ethics stuff kind of blows my mind because if somebody asked you like, "We can make your child HIV resistant and I'll do it for $5000 or $10,000. Or if you can't afford that lets just say $500 or something." How many people would turn that down?

Geoff

I guess it's what are the side effects and risks. It sounds like they told them that this was somewhat risky.

Josiah Z.

Here's the crazy thing. Right now when you have a child what they do is they draw blood from the mother. They collect fetal cells. They do a couple experiments. Normally they look for just chromosomal abnormalities. Those are the major things, but you can pay extra and they'll look for 30 or 40 different genetic diseases. What these people did is they did whole genome sequencing on these embryos. Seriously. The embryos have the cleanest bill of health of any embryo that's basically been born, number one.

Geoff

This is state of the art. This is beyond standard care.

Josiah Z.

Which is crazy because normally there's a lot of things that can happen that you can't ... that aren't detected by normal things. Stuff like cystic fibrosis or other things like that are normally not tested for. I don't know if they are. I don't think they are. These babies are just really clean. People say you could do with pre implantation genetic diagnosis, but this is not standard in any way.

Geoff

This is research heavy stuff.

Josiah Z.

To do full genome sequence. The next thing is they did sequencing after they did the experiment. They only found one possible change that could have been made by this genetic engineering technique, CRISPR. They don't know if that's what caused it because it's wasn't at a normal off target site or anything like that. This mutation change is nowhere near any gene. No where near any non coding RNA. It's just completely in a place where it should have absolutely zero effect. Any normal scientist would conclude that if they saw it. They would say that shouldn't be any problem. When we're talking about the ethics of will this baby get hurt or have any ... we're pretty sure that there's nothing negligible that's going to happen based on bad stuff from an accident.

Josiah Z.

The next thing people argue is that, well, there's this really shitty ass paper, which is hilarious. Really shitty paper which looked at 23 people who had mutations to CCR5. 23, two who were homozygous, they had both copies were mutated so they were resistant to HIV. Was it two? No it was three. Three people, three, we're talking three here. One of them died from influenza. We're looking at does influenza cause more deaths in people with the CCR5 mutation. They did 146 people as control and they compared these two. What scientist would say that is a reasonable experiment but all scientists across the internet are touting this as be people with CCR5 ...

Geoff

Are going to be more at risk for influenza.

Josiah Z.

I'm like, "You guys ... " Scientists are terrible because they pick and choose what they want to say is true or real.

Geoff

You think that this is just noise? This one out of 13 people, or 23 people, and is dumb luck.

Josiah Z.

This was one out of three so if you look at then the heterozygous which is another 21 people, I think they saw, I forget what it was. It was slightly different than the 146 or something, but you're just like, "20 people, that's not a reasonable sample size for any sort of epidemiological study."

Geoff

Right.

Josiah Z.

It doesn't make any sense and people are citing this paper, being like, "I read this paper where influenza could ..." You're just like, "Come on." Even so you can protect these children just in case or test their T cells.

Geoff

I want to just play devil's advocate or steel man of the other side. It would be like okay, the therapeutic benefits are negligible and there's perhaps some reasonable risk of increasing exposure to influenza and some other diseases. The medical story here ...

Josiah Z.

I think West Nile is the other one. Come on. West Nile, really. Oh geeze, do people get West Nile anymore? I thought that was the scare of 2000 and then nobody got it.

Geoff

It guess it's well it's unclear if you gave them HIV resistance I guess is the con side.

Josiah Z.

It's pretty clear that one of the babies got HIV resistance and it's easy to look at. What scientists forget to ... HIV binds to this receptor at a specific place. You need specific amino acids on this receptor.

Geoff

One of the twins, they have full mutations on that CCR5.

Josiah Z.

If you look at ... The one heterozygous and the two other mutations, that binding site for HIV is completely wiped out. There's basically no chance that HIV could get into cells through that way.

Geoff

However, there are other receptors that HIV can go into but for the HIV on CCR5 you've fucked up the door, basically.

Josiah Z.

They're basically the people with natural immunity. It's a different mutation but it should do the exact same thing. There's no reason to think anything otherwise from a biochemistry point of view. The one child that had one copy that was mutated and the other one wasn't they have less chance of getting HIV and it spreading in their system but they aren't fully immune.

Josiah Z.

Apparently, he told the parents about this beforehand and they were okay with that. They wanted twins or whatever and so that's what happened. To me the experimentation on the embryo, to me it wasn't experimentation necessarily. To me experimentation is you have no idea what's going to happen. That's an experiment. An experiment is when you're like, "All right, I'm going to try this, take this drug, do this thing and see what happens." They know every single ... Normally they do 30 times coverage on a DNA sequence. They'll sequence it 30 times to make sure that they don't make any mistakes. These babies they did 100 times. More than 2X or 3X normal. They know everything in the DNA. They know everything.

Geoff

I agree with you.

Josiah Z.

They're not doing this as an experiment.

Geoff

I would say this is an engineering project. I think those techniques were known. It's never been done before. This is physically possible. This is technique wise possible but this is us actually doing the steps in a human embryo and taking it to term.

Josiah Z.

Exactly. I think that's all it is. People say he's experimenting on children. It's not experimenting on them.

Geoff

Do you buy the story that he chose CCR5 just ... do you think it was more of a ... I think we can kind of agree that this is definitely more of an engineering application and then if so it seems like there's quite a bit of, maybe scientific jealousy or ...

Josiah Z.

That's a lot. Here's the thing. When I did my experiment where I injected myself ...

Geoff

People thought you were crazy and you were horrible.

Josiah Z.

Not just that but the first thing you do is you're like, "What's the easiest target I can choose. Because I want to make sure this works." That's he chose CCR5 I think. People are like, "Oh ... "

Geoff

He chose something that's not super therapeutically relevant.

Josiah Z.

He chose it because ...

Geoff

He understood it.

Josiah Z.

He knew how it was going to work. I think a lot of that people are trying to find reasons wrong with that is because they wanted to be ... like you said they wanted to be first. They wanted it to happen for them. They wanted it to happen for America. They wanted it to happen for a lot of different things. If you look at the headline from the MIT tech it's fucking ridiculous. It says, "Chinese scientist does this." Almost in a derogatory way. If it was someone from Italy would it have said Italian scientist or somebody from the UK would it have said British scientist?

Geoff

Maybe.

Josiah Z.

I don't know. Maybe, but I don't think so. It's this weird battle.

Geoff

There's definitely some competition between the US and China.

Josiah Z.

In science to be huge though. Especially because all the embryo editing that's been going on has been in China.

Geoff

Okay.

Josiah Z.

And US scientists are almost in this, people call it the modern space race, the modern gene race against China. China already has clinical trials going with CRISPR. In the US we don't have any. No other country I think has any. China already edited human embryos with CRISPR. In the US one guy claimed he did and he was just torn to shreds. Mitalipov from up in the northwest. There's this huge battle between China and US in science right now and it's crazy.

Geoff

I think you're right. I think there's probably definitely a different level. I think there is that geopolitical context around trade war. You have one preeminent power, one rising power. I think there's been in historical record 14 out of 18 times that has happened in the past. There's a war. China's obviously developing technologies in terms of computing, AI, and genetic engineering. I think there is some concern and a fear around that. Absolutely.

Josiah Z.

Oh, yeah. I think there's a huge fear because people are afraid that they're going to be left behind. People are afraid that ... if you look at all the big fears around gene editing the big fears are always, "I'm afraid it's only going to be available to the wealthy. I'm afraid that my children are going to be left behind. I'm afraid I'm going to be left behind. I'm afraid I'm not going to be able to compete in the workforce." All this stuff. That does suck and it is sad but the thing is that instead of trying to push to ban this stuff or push it to the outskirts what we could do is work to make it accessible to everybody and then people wouldn't have these worries.

Geoff

Which is kind of your ethos and mission in terms of democratizing bio hacking or these tools, right?

Josiah Z.

Yeah, no, totally.

Geoff

I'm curious, where do you think this stands in terms of ... I think we touched upon the ethical moral question a bit but maybe this is the right time to just articulate and just explore all possible concerns here. It seems to me that ... I think I'm more along your route of thinking which is that this is going to be inevitable in the sense that someone was going to take this the first step to make this an engineering project and just do it. Do you think that that just opens the gate now where it's like, "Okay, now it's been done. We can maybe explore this more and more or do you think it's going to be the opposite effect where it's like, "Dr. He is a crazy iconoclast. He's going to be like the Galileo. We're going to put him in jail. We're going to critique him. This whole speil is going to be blocked."

Josiah Z.

I would be surprised if he gets put in jail or anything like that. He might disappear for a little while.

Geoff

Which apparently he ... I was just googling him right before we jumped on. Apparently there's rumors he's been disappeared over the weekend.

Josiah Z.

Yeah. I don't think he's literally ... I can't imagine. If it happened in the US I imagine there might be some backlash or cry but I imagine that people would find a reason to push forward with this. I think the same thing's going to happen in China. This is going be a reason to push forward with it, not hold back. Ask those questions like, "All right, where do we go from here? If we want to do this how do we do it safely and effectively? Did he actually do it safely and effectively? Is that how we're going to do it going forward?"

Geoff

Do you think the government and the university system in China who are sort of doing the lip service of criticizing it is lip service?

Josiah Z.

Yeah I think it's more global lip service. To the scientific community like, "Oh yeah, this sucks. It's terrible."

Geoff

Yeah.

Josiah Z.

You can't help but be proud. I'm proud for this person. I have no allegiance to them at all, nationalistic or university or otherwise. I can't imagine there's not other people who are proud of this person. Like, "Whoa." It's crazy and to me it's so impressive. Like you said, it's going to be done anyway. There's nothing that we can stop this stuff from happening. If you ask me, if you were to ask any scientist, when do you think embryo editing is going to happen, everybody probably would have said 10 years, maybe longer. It happened in 2018. That's just crazy.

Geoff

It wasn't a scientific question. It was just who would do it, right? Because the techniques were known. Everyone was doing it in embryo but they just killed them in 14 days.

Josiah Z.

It's like you remember the first time when you're a kid and you're going to do something wrong, like smoke weed or something. And your first friend who did it or brought the weed along and the first time you did it opened this door. Then it wasn't such a big deal after that, right?

Geoff

Sure.

Josiah Z.

Everybody was just like, "Oh, yeah, weed, whatever. I did that before. It's not that big of a deal."

Geoff

Maybe a more PC. Oh the first time I had a drink of alcohol.

Josiah Z.

Yeah, a drink of alcohol. Whatever. Everything. It's just something that happened. Even if somebody gave me the resources and was like, "Here's 50 million dollars, I want you to edit an embryo." I don't know if I would have done it.

Geoff

Because you're like, "I don't know if it's possible."

Josiah Z.

No, no, no, no. It's totally possible, just because it's scary, right.

Geoff

You opened the Pandora's box.

Josiah Z.

Yeah. I get emails from people all the time now asking me to help genetically modify them for disease. There's already clinically approved gene therapies or something to help these people and it's hard for me to even go through with. You're just like, "Why?" It's really interesting how the medial regulation has made all this stuff so sacred. It's like why won't you help somebody who's suffering? A good example is this. First gene therapy approved was called Glybera and it treats this lipoprotein lipase deficiency which is you get accumulation of fats in your blood and all this other stuff.

Geoff

Doesn't sound good.

Josiah Z.

As you can imagine it's really ... When you draw blood from these people it's white.

Geoff

It's fatty.

Josiah Z.

Anyway, they developed this gene therapy called Glybera, tested it, works, gave it to patients, it works. They were trying to charge a million dollars for it. Apparently not a lot of people could pay that. Who would have thought and they had to let their approval lapse. When you get FDA approval for these things you have to keep a certain amount of them on stock at all times in case people want them. You have to abide by all these regulations.

Geoff

It's not economically viable.

Josiah Z.

Eventually it wasn't economically viable and they let I lapse. There's a gene therapy. We know exactly how to make it. We know the exact way to give it to people. You're talking you could probably make this clinical grade for less than 10,000 dollars. Maybe less than 5,000 dollars.

Geoff

But it's not worth it for the drug companies.

Josiah Z.

To cure people of a disease. If somebody with that disease came to you right now and was like I'll give you 100,000 dollars if you do that for me, it's a moral quandary, right. You're like, I could be thrown in jail for helping cure this person of this disease. Then say something does go wrong and they get hurt or die.

Geoff

They'll sue the hell out of you too.

Josiah Z.

Maybe, maybe not. Maybe I could get them to sign a release form or whatever but let's talk about curing somebody of a disease. Curing somebody of a disease we're afraid to do. What does that say about the world? That we're afraid to cure people of diseases.

Geoff

I think that's a broader political argument around how much do you let the individual choose self responsibility and ownership of their choices. If they say, "I understand the risks, Dr. Zayner, give me this research chemical, I'll sign away all my rights. I want to take this bet." Versus, "We need to authority figures and domain experts to really make sure it's appropriate for everyone." I think that's the tension. I think specifically going back to the CRISPR babies I think the strongest ethical attack is what if you just created totally messed up children. You created sentient life going to be suffering for 10, 20, 30 a lifetime.

Josiah Z.

Totally, but we already do. That's the weird thing. When you don't make a choice it's okay but when you make a choice and something goes wrong accidentally totally not okay.

Geoff

I think it's the philosophical almost paradox. It's like the experiment where if you move the train tracks and you run over one person versus letting the train track run over five people. Does that choice of not doing anything give you freedom of responsibility? If you just end up forcing that truck to go and kill that one person you've literally murdered someone.

Josiah Z.

Maybe this is the next evolution mentally of humanity is that we realize this, right?

Geoff

Yeah.

Josiah Z.

That it's now a time to make these tough choices. We have to stop being philosophical about this stuff and stop having ethicists comment on the stuff. We have to make these choices. Look, right now millions of people are suffering and dying of these diseases, of diseases.

Geoff

HIV's a very ... A lot of people get AIDS and die.

Josiah Z.

People are like oh, well they can take drugs but there's obviously not ... There's distribution problems. There's problems with people getting the drug and paying for them in Africa and all this stuff. Imagine if they just went to Africa and were like, "Hey look, we're going to help you people out." Or, "You're going to help yourself out by learning how to do this and screening embryos and genetically modifying them and you're going to get rid of HIV." That would be crazy. But it would also ... How much suffering. There are millions ... I think it's something like ... There's ridiculous numbers like five or six percent of the population in Africa and some places it's like 30% of people who have HIV. That's an epidemic. If there's every a need for something crazy.

Geoff

It's debilitating for society. You can't function. I think it's ... I like that we're actually talking about it. I think the popular discourse is that this is horrible. Let's never do this again. I think that real question should be, "Okay, what are the risks and how do we trade these off." No one's talking about how do we do this at scale now. It is more of a prohibition conversation I think.

Josiah Z.

That's terrible. That's what I keep shouting is this stuff is going to happen. This stuff is going to happen. I know crazy bio genetic engineer, bio hacking people, who are injecting themselves with all types of crazy stuff or trying to do all types of crazy stuff with lots of different animals and all these things. There's nothing you're going to be able to do to stop it so stop having that mentality. Stop having the mentality of I'm going to ban it and I'm going to stop it because you don't know about what this guy in rural Mississippi is doing and you're never going to be able to stop him. You don't know about what this person in Dominica or Haiti is doing because they don't have an FDA so they don't even give a shit what people do. It's like we can't stop this. You can't no matter how hard you try. We need a framework to go ... something to help us go forward and people aren't thinking like that. That's the issue.

Geoff

This is a shame because America pioneered these technologies. NIH, government funding, public funding, pioneers these techniques and now we're a little bit trigger shy on applying that to actual indications or engineering actual solutions or products from these things which I think is a little bit of a shame if we're ceding that advantage to China, to other researchers, that might not have US interests in mind. I think okay, if we invented it let's double down and keep our edge there as opposed to ceding that. It's time to take advantage.

Josiah Z.

Yeah. To me, I don't give a shit about all this nationalistic stuff and advantage and disadvantage. All I think is that what's going to happen is I'm going to want to go to China and research with those people and learn stuff from them.

Geoff

Because they're worlds best now.

Josiah Z.

All these people know stuff and there's nothing wrong with that but what's eventually going to happen is you're making me leave my home. People are going to do this no matter what. You're going to force people out. To me it's like ... I'm sure people suffer discrimination in a lot worse ways but it's type of discrimination. It's just like, "Look, this is going to happen. Stop trying to ..." It's like the war on drugs, man, right? We lost the war on drugs. Drugs won. They fought hard and they beat us. Now we're giving up and we're starting to legalize stuff.

Geoff

Yeah, weeds beginning to be legal.

Josiah Z.

It's like, "Damn, that was stupid from the beginning."

Geoff

Put a lot of people in jail for ostensibly no reason.

Josiah Z.

That's crazy. Maybe the same thing will start to happen. Then it's going to be ridiculous and 20 years from now we're going to be like, "Oh shit. That was stupid. The war on genetic engineering was really terrible."

Geoff

Yeah. In terms of just framing in terms of what you think this means in terms of scientific importance or human achievement. I think to me it's pretty up there in terms of progress as a civilization. This is like the man on the moon for genetics.

Josiah Z.

It's crazier than that. Think about this. Think about this. Homo Sapiens have been the dominant human species on earth for 50,000 years or something like that. Before that there was Homo Erectus and all this other stuff, 50,000 years. And now it's going to change. We are now creating new species of humans. We already have a little bit. Now it's literal. Nobody can say that these aren't going to be new species or anything like that. Literally humanity is diverging from Homo Sapien which is just the craziest thing that you can think of. Not only that, for all of human history we've never had a choice in our genetics. No human being has had that choice.

Geoff

But you could say that I'm going to choose to mate with this certain type so I think it's kind of an animal husbandry level of selection.

Josiah Z.

I mean a literal choice. If somebody was like, "All right, do you want your baby to be immune to HIV. You could not do that.

Geoff

Green eyed, brown eyed, sure.

Josiah Z.

There was no way to do pre implantation genetic diagnosis and find one of your embryo.

Geoff

Or I'm going to find that European person and try to make a baby with them.

Josiah Z.

Still it wouldn't be if you weren't. It would only be heterozygous or something.

Geoff

True, it'll take a couple of generations. It's very, very social engineering type stuff.

Josiah Z.

Yeah, this is literally the first time where we can start to choose that stuff and it just ... To me it's the largest accomplishment humanity has ever seen because now is where the crazy stuff happens. Now humans can be engineered for different environments to do different things. You can have human beings who want to be a construction worker and they're engineered to be stronger, bigger, have more arms or something like that.

Geoff

Do you think the tech is really that prime time? I think we talked a little bit about off target affects. Do you think it's that defined?

Josiah Z.

Oh, there's definitely stuff you can do. Obviously growing more arms in a person we really know how to do yet but the experimentation hasn't been there.

Geoff

Okay.

Josiah Z.

Nobody's really that I know of, worked with monkeys and tried to get them to grow multiple limbs or anything. Stuff like that is definitely possible.

Geoff

Sure.

Josiah Z.

Whenever you look at biologics, what's possible with gene engineering, you can just look at other organisms and see what's happened with them. If you're like, "Well, that organism has multiple limbs, then it's theoretically possible to do it genetically we just have to figure out how to get it to work ...

Geoff

How to encode it.

Josiah Z.

... in humans. It's just a matter of time.

Geoff

Okay, but then I think that's one thrust. How about the off target affects? You throw CRISPR into cells and they-

Josiah Z.

No, the off target effects are something people just like to say. That it's like the boogie man. No, we understand that so well now. Not only do we understand CRISPR off target effects-

Geoff

Wasn't there a paper maybe three, six months ago talking about how the off target affects were much more likely than previously reported?

Josiah Z.

No, no, no. Let me just start from the beginning a little bit. Before CRISPR there were other gene engineering technologies. The way CRISPR and these gene engineering technologies work is they just cut DNA. They bind to a specific part DNA and they cut it and then when they cut it, stuff happens. You can insert a gene or you can just let it heal on itself and when it heals it usually has different stuff in it and you can do genetic engineering. These other generation one gene therapies, zing finger nucleases, TALENs, they cut DNA also. We've been studying off target effects on these ones for 20 years. We understand what goes into it. What the possibilities are to affect organisms and stuff like that. And they've actually just last year, late last year started doing clinical trials with these in adult humans. We know they're considered safe enough to do clinical trials in adult humans.

Josiah Z.

Now, with CRISPR, not only do we have all that previous study but they've been able to use a bunch of machine learning and a bunch of things so that we're able to design CRISPR systems that have virtually very little off target effects. Very little that can be detected.

Geoff

So, what was that paper that came out that was-

Josiah Z.

There's been multiple papers that came out after each other, and people were like, "Oh, there's a lot of off target effects or something like that but then consistently again and again it's been showing that if you choose the correct CRISPR system and do the experiments properly you don't have to worry about it.

Geoff

Got it.

Josiah Z.

Not only that, you have to understand when you do it on an embryo you get to check, right?

Geoff

Yeah.

Josiah Z.

People argue, well, you can't completely check because only having three cells, it could be like mosaicism or some cells could be edited, some cells could be not in the embryo. But, you get a pretty good look at what's going on in the gene of the embryo you edited. So you get to choose before you even implant it, you get to say, "Oh, look-

Geoff

I'm gonna check out the 16 cells and count all of them and make sure they're all properly.

Josiah Z.

Well, that one got messed up so we're not gonna use this embryo. Wow, this embryo looks perfect and beautiful-

Geoff

Let's use that one.

Josiah Z.

Let's use ... right. You can just keep editing embryos and do the same thing IVF and pre-implantation genetic diagnosis.

Geoff

Yeah.

Josiah Z.

So it's like even if there are target effects. Even if there's a problem, we understand genetics enough. We understand how to do this experiment well enough that it shouldn't be an issue.

Geoff

Sure. Got it.

Josiah Z.

It's kind of like this boogie man that people are just like off target, people are gonna get hurt. It's like yeah, if you don't screen, if you don't do it properly. If you do any ... if you do it in your backyard, sure. Any reasonable person is gonna screen and check and look and make sure they know that happens.

Geoff

Yeah interesting. What do you think we go next from here? I think there's some interesting personal drama with Dr. He and what's gonna happen with his story, but I think the consent ... I agree with you on this is that this is gonna actually unblock the Pandora's box. It's like okay, someone took the risk of being the first here. He's the Galileo, or Copernicus and now people are gonna be like, "All right. There's a path here."

Josiah Z.

Here's what I've learned my foray in science and business and everything like that and it's that when everybody else is doing one thing, do the opposite. If you wanna be groundbreaking, if you want to actually change the world or something, find something that nobody else is doing or that the mass has chosen as something that they want to be against, from some ideological reasons. Not for concrete reasons. Whenever it's ideological reasons, you're like, "Well, what happens if I did just do it?"

Geoff

Yeah.

Josiah Z.

And that's happened. And now, what do you think is gonna happen? You think people are gonna be like, "Well, we can use this for diseases but we can't use it for-

Geoff

Enhancements.

Josiah Z.

Yeah. Or do you think everybody is just gonna be like, okay, your ideological reason seems ... it's the most unreasonable ideological thing. How can you tell people that enhancements are bad? What argument do you use?

Geoff

Just on a spectrum, at a certain point if you're improving people...one is a therapeutic and one is enhancements like ...

Josiah Z.

Exactly. I get a lot of emails from people who want to increase their penis size. And it's funny but it's also like for some people that is-

Geoff

If a micropenis is actually a therapeutic problem.

Josiah Z.

Yeah. So, where do you decide where the therapeutic cut off is. Are you like, oh well if you have-

Geoff

A certain leg.

Josiah Z.

A one inch penis, or a two inch penis then it's good but if you have a two and a half inch penis, no, it's bad. No, you can't do that. And the same thing with things like height, right?

Geoff

Yeah.

Josiah Z.

When is height considered a genetic issue and when is it considered-

Geoff

An enhancement, cosmetic issue.

Josiah Z.

You can never draw these lines and those arguments, my thinking is if you can't explain it to a two year old, give them a good explanation then it's just gonna happen. Well, son we don't wanna do this because people will be taller and we can't have everybody be taller because it might make humanity all tall and-

Geoff

Not a good reason.

Josiah Z.

You can't find a good reason. And that's I think where the problem is that this stuff is just gonna explode and it's just getting faster and faster. It's a crazy thing. And it's not being done in academia. It's not being done in industry like this Doctor John [Qui 00:51:23] from China who did this experiment like people are just saying, "All right. You won't let me do it in academia, you won't let me do it in industry, I'm just gonna do it anyway." Bio hackers are just gonna keep doing it and you're gonna start to see a lot more people who are PhDs who have medical training doing this stuff.

Geoff

Do we have any guidelines? Could we think of some framework in terms of how to maybe give guidance and how to do this responsibly?

Josiah Z.

Hey, I don't-

Geoff

Or are you more of the anarchist here who's just like, hey here's technology, just do whatever we want.

Josiah Z.

I don't know. I don't know. But here's the thing-

Geoff

Like who's us to say ...

Josiah Z.

Here's the thing, it's like if you look at your product or you look at a cellphone nobody has to come along and tell you, you need to have a good product. If people buy a product and it doesn't, if you buy your new Google Pixel phone and it's broke right when you get it out of the box after a week, nobody is gonna buy a Google Pixel phone. There's no governing body, there's no FTA for cellphones-

Geoff

It's market forces. They're just the market working properly.

Josiah Z.

And it's hard to say capitalism will work for these stuff because I have no idea, but it can. We know that it can because we see in a lot of technologies how market forces drive stuff to be, happen. Cars is another example. They do have certain laws around it like Lemon laws or whatever that prevent people from getting sold cars that just break down right after they take them off. Generally, it's just the capitalistic market that drives it. I ask people, why do you drive this car? Why do you drive a Tesla? Well, because it's good quality. Good quality, right?

Geoff

Yeah. I guess, would there be some sensibility around, okay, what would be the best possible to prescreen out genetically engineered embryos, do our best effort there, but if I end up giving you a child that's defective, is a very cold way of saying it but there's some issues with the ...

Josiah Z.

People die in hospitals right now going for routine surgery and you die. You basically sign that away, right?

Geoff

Which I think ... I that it's cold but I think that's a reality.

Josiah Z.

It is.

Geoff

Is that the right model. Okay. You're signing up for this intervention. There is real risks here-

Josiah Z.

It's like anything.

Geoff

And if you die-

Josiah Z.

Maybe don't be the first person to do, maybe be like the fifth.

Geoff

If someone will want to be the first person then you should let them be the first person.

Josiah Z.

Exactly.

Geoff

Which, yeah.

Josiah Z.

It's like go do it. Sometimes we need the risk takers of the world, just go ahead with this stuff, right?

Geoff

That's why I you know Dr. He will seem like I think when history rewrites. It will just be like maybe he's the Galileo persecuted in this era but it's like someone needed to just do it.

Josiah Z.

Yeah, no totally.

Geoff

And it's like cool, he did it.

Josiah Z.

Because then he opened ... We have this cognitive block where we though that we can't do this. Not for any technical reason, just like we can't. And he removed that cognitive to where we're saying, wow, somebody had enough courage, maybe people will say it ideocy-

Geoff

Or arrogance or delusions.

Josiah Z.

... whatever. Somebody had enough of this to just go ahead and do it. That means that other people can.

Geoff

Yeah.

Josiah Z.

And that's what crazy. It's like running the first ... breaking the four minute mile. It's like, it wasn't such a monumental task because now people do it on a daily basis. But it was that cognitive block that people were just like, oh there's no way it's possible.

Geoff

Yeah. Cool. Anything else we should talk about as we wrap up here. I think it sounds like this space is gonna heat up so as new developments come on it will be great to get your thoughts and perspectives around this next time.

Josiah Z.

Oh yeah. I'd love to come back and stuff like that. It's really interesting because I see in a lot of the stuff you're doing it's this mix of it's not necessarily medicine but it's this mix you're doing clinical trials. You're trying to test out all these stuff, and you're letting capitalism drive the development of, realistically you can call it drugs, not for the FDA. It's supplements or whatever-

Geoff

Yeah, consumables. Sure.

Josiah Z.

Yeah. But really that's what's going on, right? And it's like-

Geoff

Yeah. I think we're testing a compound, a molecule and intervention and seeing how it works in proving it as medicine.

Josiah Z.

And showing the data and people can look at the data and say, "Hey, does this work for me? And did it work for other people. And that's the reason I'm gonna purchase it." And I think that it's showing that there's possibility for this market of capitalistic driven drugs in medicine.

Geoff

Yeah. Do you think that capitalism now just has a weird connotation to it. I feel it should necessarily have a negative connotation because we all ... all of us are benefiting from how capitalism has functioned the last couple 100 years to give us all the nice things that we have and what we're doing today. I think maybe that's a broader sociological, cultural question where capitalism has morphed or become this authoritarian level capitalism where you just can't get that rich anymore. I think people are back lashing against that. You think that is where some of the capital market arguments get critiqued?

Josiah Z.

So we should change the name. We should call it something else. I like when you said market driven.

Geoff

Yeah.

Josiah Z.

It's better than capitalism.

Geoff

I think when people say capitalism it's like oh...

Josiah Z.

I like that phrase. Maybe we can have market driven medicine.

Geoff

Which is basically just population driven medicine right? Just like people voting with their dollars.

Josiah Z.

Exactly. That's it. It's like people are voting for what they want, and people are like, oh people will get scammed and stuff like that. And one of the reasons that the majority of clinical trials fail is because the placebo does just as well as the actual treatment. And we're talking, has an effect. We're not talking the placebo does zero and treatment does zero. No, we're talking they both do something. Then you're talking about, well, what should be approved and what shouldn't be approved. If a placebo actually has an effect on somebody what does that say about medicine. It totally ... and we need to come to these realizations. We need to be real with ourselves and say what shall we do with medicine if placebo have an effect. Should we outlaw things that have certain labeling or things like that. You're telling me that there's nobody in the world that their cancer can be cured by grape fruit seeds. Nobody knows the answer to that. Maybe there's one person. I'm not saying eat grape fruit seeds, it's a cure for cancer.

Geoff

Can we categorically rule that out, probably not either.

Josiah Z.

Exactly.

Geoff

Fair.

Josiah Z.

And that's the interesting thing about medicine is that each person is so unique and so different. Clinical trials aren't made for human beings they're made to mass market drugs and so how do we get medicine and science to the way to where it tries to treat individuals instead it tries to treat the mass market, and maybe it's market driven is the way.

Geoff

Yeah. Our future is still being written so let's help write that and change the culture in a way that it's more positive.

Josiah Z.

Yeah. For sure.

Geoff

Cool. Thanks so much.