Make People Better twitter spaces

2023-03-13

https://twitter.com/kanzure/status/1635374555291324416

episode 1: https://diyhpl.us/wiki/transcripts/makepeoplebetter/episode-001/

spaces: https://twitter.com/kanzure/status/1635359570657943552

Samira: Hi everyone, welcome in. I hope you can hear us. We are having some technical issues. We're waiting for Antonio and Cody to be able to become speakers. We're working on it now.

BB: Gotta get the twitter app.

Cody: Are we ready to start? Is Antonio on board?

Samira: Antonio says he doesn't have the twitter app.

Cody: Maybe what we should do is get started and we will ask Antonio to kindly install the app on his phone. Once he is up and running he can join the conversation at that point.

Samira: Could you install the twitter app on your phone to be able to speak? That would be great.

Cody: I just texted him. I will just lead us at the beginning. First off, thank you everyone for joining. I am sorry for the technical difficulties but obviously we're new to twitter spaces. Hopefully this will go smoother in the future. Thank you for bearing with us.

Cody: We're excited to get everyone else's comments and thoughts as part of this discussion. It's really the reason Samira and I set out to make the film many years ago and why we were doing the podcast. I think this is going to be an exciting group. This podcast and discussion is brought to you by the Random Good Foundation who are awesome partners. My name is Cody Sheehy and I'm the director of the Make People Better documentary and writer and editor of the podcast. Samira is a genetic engineer, medical doctor, science communicator, and an associate professor at Pittsburgh and the founder of GenXGen. Antonio will join us later. He is senior editor at MIT Technology Review and he is the one who originally broke the CRISPR baby story back in 2018 and also a principal subject in the film.

Cody: In episode 1, just a quick recap, this- hopefully you had a chance to listen to it. We sat down with Ben Hurlbut from Arizona State University and also Jiankui He who we will refer to as JK. He is a scientist who secretly created the first designer babies Lulu and Nana and then there was a controversy and he spent 3 years in jail. We asked him some tough questions about why he did what he did and we looked into what happened to the US scientists that supported him and what the status of Lulu and Nana might be now and what JK is up to right now- turns out muscular dystrophy and somatic editing. We hope to focus on germline editing which is related to medical advances and editing of adults. With that, that's our recap.

BB: I thought he was working on DNA synthesis? He posted on Chinese twitter about hiring some bioinformatics people for enzymatic DNA synthesis. I also saw his posts about DMD though.

Cody: He told us he is working on a company to do muscular dystrophy. I wouldn't be surprised if he is doing more than one thing. I don't know what the funding status is on anything that is up to. Maybe you can explain on what that might mean for some of the more laypeople like myself.

Samira: As you know, JK came from the field of gene editing from the field of DNA synthesis. His training was mostly as a PhD and a postdoc was in that space. When we talked to him after getting out of prison, his ambition was to push forward the concept or the work of gene editing for adults or people who are already born with muscular dystrophy. His whole point is that he wants to setup a non-profit and he wants to make gene therapy more affordable and less expensive. It's a noble ideal and goal to me. From outside, when you listen to that. But there's questions baout how he can achieve that and what hurdles he will have to overcome and how genuine is that goal? I know he also mentioned that there are ways to use Chinese infrastructure to scale up gene therapies to make them more cheaper and more accessible. He didn't elaborate how he wants to do that. I think he has some ideas. We don't know much. I think Antonio is now and he can speak. Can you hear us?

Samira: Antonio, can you speak now?

Antonio: Yeah, maybe. I broke all my rules by installing twitter on my phone which I never do and gave my phone the ability to listen to me which I also don't have on. That took a little while.

Samira: Thank you for breaking the rules.

Cody: Welcome to the discussion. One thread that we might jump to is that I know you just got back from the human genome editing summit. Maybe you attended virtually? Either way, what do you think the highlights were of that? Anything that relates to the JK story or anything else?

Antonio: I didn't go to London. One of my colleagues here Jessica was there from the Review. But we can talk about the statements. Each of these summits ends with a statement. Interestingly the one from this summit that just happened was more restrictive and more negative towards germline genetic engineering than the previous statement than 2018... In the 2018 one, I'm looking at the statement that is on the website of the national academy of sciences. Actually the first thing is that it says is a proposed translational pathway. That is the very first piece of information in their statement about germline editing. That is essentially the proposal that researchers, scientists, doctors should figure out how to apply this technology to embryos and to people being born. That's what they emphasized. Such a pathway is going to require established standards and preclinical assessment of competency for practicioners of clinical trials, professional behavior standards, etc. That one ended with a proposal kind of to move forward and to figure out what that path would be. That is not the case for the 2023 summit statement, 5 years later. They instead say that they don't have a pathway here- they just say that heritable germline editing remains unacceptable at this time and there needs to be governance and ethics none of which exists and necessary safety and efficacy standards. It's a hard no which is an interesting update from 2018. There is one little asterisk that I thought was interesting. They then have a section about somatic genome editing which is of course editing or CRISPR in adults but there's a footnote and in the footnote it says they have now shifted editing of embryos, sperm and egg so long as they remain in the lab. It's now in the category of somatic. That's acceptable, that could move forward. That's interesting. Why would you work on that stuff unless you were practicing for eventual clinical use of germline editing?

Samira: I also found the emphasis on equitable access. That there are things we should do now to make sure this is accessible to every corner of the world which is very good. I admire that. The only thing is that I am yet looking forward to seeing real action taken to make this happen. The way that the whole practice is setup right now doesn't support such a statement.

Antonio: Right. There's something like 50 clinical trials going on in adults with CRISPR. I think that's what the "equitable" discussion is getting at. They referencing treatments to adults when they say equitable. Gene editing delivered as a gene therapy. It happens through kind of good luck or good biological luck that sickle cell is the first disease where we are likely to have an approved CRISPR drug. There's a big clinical trial by Vertex where they have treated 75 people with sickle cell and beta-thal which is a related disease. You can use CRISPR in its most basic implementation which is to just smash a gene and that unlocks another copy of hemoglobin called fetal hemoglobin which is the missing gene you need to address sickle cell. Sickle cell is amenable to CRISPR 1.0, it's the most common rare disease I think, quite a few people have it, but it's more prevalent in the tropics. In places that are not wealthy. So actually the Vertex treatment they told me clearly requires a bone marrow transplant where you need to get the cells out, CRISPR them, and put them back in. It won't be accessible in poor countries that don't have the infrastructure to do bone marrow transplants. This equitable access discussion is I don't know which drug they are talking about.

Samira: Bryan and I had some discussion through twitter a while back-- this is all the conversation about who gets access to these technologies. If you look at the patterns of CRISPR for human application which is owned by Broad Institute and Editas, which really creates an exclusive market for development. I don't see any willingness or any action taken by these big giant gene editing companies to do anything about decreasing the cost. They play into the common narrative of how to innovate and put a product out there. It's crazy expensive. It's $2-3m price tag. How can people afford that? It's good to say that we need to do something about that. It's not enough to say that. It's not just about checking a box. We need to do something about that.

BB: There's not enough people with rare diseases to support cheap gene therapies. Clinical trials cost a lot of money, and pharmaceutical companies justify high prices by pointing to all the loser drugs that don't make it. You won't get enough scale by only focusing on diseases to get really cheap pricing. It's going to be expensive if you limit yourselves to disease.

Antonio: New technology could lower the cost. Why is the cost high? That's what Bryan is asking. Vertex has said well this treatment is really only suitable for severe cases of sickle cell disease. If you have a mild case, you aren't going to do a self-to-self bone marrow transplant. Or they don't think. If there's 32,000 people in the US and Europe which is the only countries they are targeting right now or North America and Europe. That's the market. 32,000. Drug companies want products that move the bottom line. They need billions of dollars per year. That's why the price tag is in the millions. It's made reference in the summit statement from the organizers that there might be future technologies that could make it much cheaper. Whta if you can deliver the CRISPR in vivo while the cells are still in your body? That would be a big advance and make it quite a bit cheaper.

Samira: It still requires fundamental changes on how these therapies are developed as long as any new company that starts in this space needs to go back to Editas to request the license for that and has to pay hefty royalties to the major license holders. These will add up to the prices to these treatments. The question is that, you know, when we are dealing with-- should these be profitable businesses? or should it be non-profit?

BB: There's no core reason it has to be expensive. Let's get back to germline. Profitable companies can drive the cost down to zero. There's no reason why not.

Antonio: I assembled a list of the different genetic or eugenic proposals that scientists have made over time for sickle cell disease. We will find out here that the treatment of adults is by far the most expensive. Linus Pauling infamously suggested that people got a tattoo if they were a carrier so that people could avoid getting married or reproducing with the gene. Preimplantation genetic diagnosis can also help here with making sure you don't have an embryo-- it's IVF + a test, so maybe $30,000. All those options are really cheap compared to a $3m CRISPR adult gene therapy. Also cheap and also relatively cheap would be editing the embryo to remove or fix the sickle gene. I don't know if JK ever ballparked what it cost him. I don't know if he did it in a bargain basement kind of way, but the introduction of these molecules of these reagents into the embryo is in of itself not an expensive thing to do.

Cody: What is your reaction to JK's reappearance into the public?

BB: He started deleting tweets. They were perfectly okay tweets. There was one tweet he did about the Lulu and Nana Foundation and just recently receiving its first donation for $5,000 which is surprising in two ways. One, given the level of uproar and reaction that the whole world had, how is it that only now there are any donations? Two, it is surprising that this is the amount. $5,000 is basically nothing in the grand scheme of the future of humanity if you want to talk in broad strokes. You would think that there would be more donations if people were actually concerned. I think it's unfortunate that modern academia is incompatible with having these kinds of discussions in private much less in public. There needs to be a way for this sort of discussion to happen. The kneejerk reaction is really unhelpful and in fact even attacks its own motive ((having further discussions, which I argue shouldn't continue endlessly anyway)).

Samira: It's important to have discussion with opposing viewpoints.

Cody: His reputation has suffered and I wonder if that was part of the problem with the foundation.

BB: I don't even know the story behind it. Where is it registered? Who operates it? I don't know. Is it operated by someone else?

Antonio: JK's reapparance on the scene from about a year ago has been interesting. I want him to tell the full story of what happened with the Lulu and Nana and the third baby. What actually happened? Can he tell his story? It has been a disappointment for people that he has not been willing to tell that story. Maybe he can't tell that story. People give him the podium at different events. People try to give him the podium hoping to get some kind of insight but he only wants to talk about his current projects. This is a conflict in his current communications. ... children with muscular dystrophy or young people with dystrophy with gene therapy, I was pretty surprised that out of all the things he could do he would again propose to do it on young people. That is, I don't think he is going to find a great deal of support for that because of his history with the CRISPR babies. It was surprising that he didn't- from being in prison and detention for 3 years that he would again position himself to be in a sensitive area of biomedical research.

BB: Maybe he believes this is ethical work and important.

Antonio: He may believe that. When you do these kinds of experiments, there are lives on the line. There was a one-off CRISPR gene therapy for muscular dystrophy that was provided to a patient by a foundation started by his brother and that patient died. It's just a reminder of what the stakes are. That there is risk. I don't know that JK has demonstrated that he is the person to weigh those risks. He could be ethical but there's another area where we can judge him which is in his risk tolerance you might say.

Cody: In terms of when we interviewed him for episode 1 for the podcast, there were strict guidelines around what we could talk about and what we couldn't. We didn't know if he was in control of that- was this something he was deciding and hoping that this was for public rleations going forward and not a good idea to talk about the past baby experiments? Or was it from the government? It wasn't clear. In personal conversations with him leading up to the interview, he discussed some things but in general my takeaway is that people give him an opportunity to take the microphone and we don't get that satisfying insight that we're searching for. After many years of doing this with the documentary and the podcast now interacting with JK I almost think it's not possible. I don't know if he is a reflective person. He might not have these answers for us. Bryan, I absolutely believe that JK believes it was ethical and he was told it would be ethical and controversy and that time would eventually put the ethics on his side. There's some kind of long game in not admitting any guilt and not admitting that you did anything wrong and continuing to do what he wants to do which is this kind of work. Maybe in the long term he believes that he will be vindicated. That's one thing to consider.

Samira: For someone taking on an important job, they need to be more open and build that trust. People have given him an opportunity to discuss more about his real -- being closed off doesn't really help him.

BB: He owes the world absolutely nothing. He doesn't owe any answers or reflections or deep thoughts. The way that the scientists and academia treated him was absolutely horrible . There were calls for this man to receive the death penalty. That's completely over the top and ridiculous. Academia is not setup to discuss these things and it doesn't have room for these kinds of alternative views. Maybe fix that problem first if you expect him to take the podium or the microphone and say something eloquent and profound.

Samira: But when you talk about everyone's potential future, there is more responsibility here. I agree that the academic circle needs a lot of changes and it's not at all supportive of these types of reflections. As an individual, there is more like okay I'm doing this and I'm starting to appear more responsible. That's my thought.

Cody: The implications to opening the door to future enhancement of babies and that kind of thing is something that should be discussed by the entire public and he was willing to move the ball forward before doing it.

BB: What are your thoughts about IVF escape velocity? Why did we achieve IVF escape velocity?

Antonio: I hear the history of IVF cited. It's in their film. There's the first IVF baby right. The way it's presented was it was done in secrecy as well and then presented to the world as a done deed. For a long time I don't think-- IVF was difficult. Producing that first IVF baby there were dozens of attempts. What I can say is that with germline editing, when it comes to the reasoning or the justification that the scientists might apply they often invoke fertility or the ability to have a child. The reasons to do germline editing in an embryo to change the genes for an embryo are really not that many for treating diseases. There's other ways to deal with it, often with polygenic screening or scoring. If you want the child to not have a gene, it's a game of numbers at the IVF clinic. So the justification for embryo editing really is this ability to have a child. That's the way it has been presented by sort of the only US group that is actively working on editing embryos for research which is in Oregon. It's Shoecraft and ... first name I don't remember, Dr. Amada... positioning it as a fertility technology in which case nobody can object to it.

Cody: Bryan, what are your thoughts on enhancement in general? Are you more transhumanist?

BB: I am in favor of enhancements. In fact, I think there's enough work on diseases. There's enough people focused on diseases. I'm fairly confident that we have enough eyeballs and enough people working on curing diseases so I'm not so worried about that. Therefore I am not so interested in disease. I think that enhancements on the other hand are not pursued at all by comparison and there's a lot of low hanging fruit there.

Cody: What's your favorite?

BB: I have a few favorites. It's not up to me to decide what parents choose. I do have a few personal favorites though especially around intelligence and memory. It's on our wiki (ref).

Samira: What about this technology driving inequality? We have so many problems, wouldn't this make it worse?

BB: I don't think inequality is a problem that genetic engineering is responsible for. I want this stuff to be super cheap, remember?

Antonio: Bryan mentioned the list on George Church's website where if you knockout these genes then you get basically a superpower, for example stronger bones. People without CCR5 don't get HIV. ... this was discovered because of a Berlin patient who got cancer, got a bone marrow transplant, and got bone marrow from someone who didn't have CCR5. George's list is part of what inspird JK, clearly, these sort of enhancement tricks. This was told in JK's movie and podcast. We recently at the Review wrote a story about a company which is using a CRISPR therapy on adults to knock out another gene in their livers called PKCS9 involved in cholesterol metabolism. If you have this, then you have bad LDL levels. Although they are starting this trial in people with super high cholesterol like incredibly high their blood is like butter hypercholesteralemia. They do see though that in the future maybe everyone in their 20s get this treatment. In the view of heart doctors, it's really good to have low cholesterol throughout your whole life because it's sort of a toxin.... It's kind of an enhancement. He was one of the harshest critiques of JK. He's dead-set against editing an embryo but he might treat a 20 year old with CRISPR to knock out their PKCS9 gene in their liver which is the site of cholesterol metabolism.

Samira: I want to invite the listeners to speak.

Cody: Why do you think that the officials in China or whoever was responsible for .. and they were censoring JK's story across China. It was censored, not known and not talked about. Why did they allow or encourage the story to get out in the West and not within their own borders once the controversy happened?

Antonio: I don't know the answer to that question. I think it's answered partly in episode 1 of your podcast when Hurlbut the ethicist who spoke with JK during his detention or during his house arrest rather... he... asked JK.. was he allowed to.. They very clearly have the wanton attempt to build a counter-narrative which is the JK didn't really do anything wrong. He was thrown to the wolves in the West by western scientists. This is something that Western scientists do to .. and let him get published so that they can move the project forward.. in fact.. surely.. after the episode in 2018, I ewnt down to ---

BB: Could you please point your phone towards Elon's satellite in the sky? You're breaking up.

Antonio: There was a narrative that was building up that this was about ethics washing where China would be blamed for doing something that the West wanted to do and will do anyway. I went to Hopkins and met an important Chinese-American researcher there that has recently gone back to China to do research... I saw an editorial in Nature magazine on the subject of ethics washing on his table when I visited him. It was an interesting way to start the conversation. If you want to have that other narrative pushed or constructed to deflect blame off of China then you need to have JK speak and speak with Hurlbut who is an influential sociologist of science and is the one more than anyone who has said JK was not a rogue actor and he was actually doing what Western scientist had put him up to. I don't know if Ben got used by JK in this regard but certainly Ben for his own reasons was interested in that narrative. Long story short, I think they let him talk to Ben to construct a counter-narrative about this event.

Cody: It makes total sense. My next question is that in that time in 2018, China was really pushing the boundaries and it seemed like someone if there was going to be a baby created it would be in China because that was where activities were happening. What is the situation today? Is it still a place where boundaries are being pushed? I know germline editing is illegal there but there's special regulatory zones in China where you can do things that are illegal. Where are boundaries being pushed the most?

Antonio: I don't know. After this event, a lot of my sources some of them were good sources in China kind of dried up. Their interest in speaking to a US journalist and maybe in particular to me definitely went down. They are not interested in having those conversations. COVID happened next and the whole lab leak controversy layered into the cake there. There's a lot of reasons that Chinese scientists are not engaging with Western journalists much possibly even it extends to Western scientists certainly it does in the case of COVID and the origins of COVID. ... There was other work around cloning, embryonic stem cells, all these technologies relevant to germline genetic engineering and I haven't heard as much- maybe they shelved it or they communicate it in a different way or not communicating as much. Sometimes you do see a publication in Cell often is the venue where they will be doing really advanced stuff with embryonic stem cells and embryos and genetic engineering but of course we're talking about animals, like mice or monkeys.

Cody: We're at 1h for this discussion. Before we end or approach the end, I wanted to see if anyone had any particular questions for Antonio or for Samira or I or any thoughts that they would like to add at this point. We did hear some interesting things on social media. I love all those comments. We will do one of these every week, every time an episode drops we will have a discussion. We really hope everyone will join us for those. Antonio do you have any closing thoughts or ideas that you want ot leave this discussion with?