ウィスパリング同時通訳研究会コミュのRessurecting the Mammoth - Ben Lamm & lEriona Hysolli - GLEX Summit 2022

Richard: (00:03)
The vast mammoth step of the Pleistocene Era. Wooly mammoths now long extinct once roamed these northern landscapes in large herds, playing a critical role in the stability of their ecosystem. In the last half century, however, these permafrost regions have begun to thaw at an alarming rate due to climate change and the loss of this keystone species. Over the last decade, humanity has made significant advances in understanding DNA and the field of genetics. Breakthrough genetic engineering technologies like CRISPR and others have made it possible to read, edit, and even write genomes.
(00:46)
Combining these modern genetic engineering technologies with ancient mammoth DNA recovered from frozen specimens allows for the de-extinction of the wooly mammoth. Reintroducing the wooly mammoths to their former homes in the Arctic regions will help to bring balance back to the habitat and slow or even reverse the damage that climate change has done to our planet. Colossal. Restoring the past for a better future.
(01:14)
Now I would like to introduce to the stage two of the principles involved in this amazing technology of de-extinction. First is Ben Lamm. He’s the CEO and founder of Colossal. He’s a fellow entrepreneur from Texas that I’ve known for many years and has had great successes. As well as Eriona Hysolli, who’s head of the biological sciences at Colossal, and is really doing probably the heavy lifting in bringing back extinct species. I’m going to let them speak at the podium here for 15, 20 minutes. Then we’re actually going to sit down, have a little conversation, and you will get a chance to ask some questions too, if you would like. Think about your questions as they do their initial presentation. Thank you.

Ben Lamm: (01:56)
Thank you so much, Richard. I’m Ben. This is Eriona. I think Ken couldn’t have done a better job telling you about how everything’s going to die and extinction, and then we’re going to tell you that we think we can go the other way. This journey started actually about 10,000 years ago. I started working on it about four years ago. Eriona started working on it, what, seven years ago with George. It’s been a whole like cast of characters that have really been involved in this event.
(02:31)
One is, obviously, the incredible Russian scientist, Sergei Nikita Zimov, from Ben Mezerek who’s been like chronicling the whole thing, to George Church, to Ryan Veeland and Stewart Brand from Revive and Restore. There’s just been an incredible movement around about what’s possible using genetic rescue in de-extinction.
(02:54)
I mentioned George, and I think Richard definitely mentioned George briefly earlier, but George, if you don’t know him, he’s the father of synthetic biology, the lead geneticist at Harvard University. He’s the one that really took the opportunity to bring all these people together and really start the movement of bringing back the wooly mammoth for the purposes of Arctic re-wilding.

Richard: (03:17)
If I could throw in a comment here, Ben, as we discussed, I just find it interesting to note that my wife Latisha, we happen to be investors in SpaceX. My wife was with Elon Musk about 10 years ago, 7, 8, 10 years ago, and said, “Hey, Elon, we’re big fans of you, who is the one person on earth that we should talk to other than you about the future, who’s going to really change the world coming, going forward?” And he mentioned one name and that one name was George Church. We also had gone out about the same time to go visit George Church. And obviously, we were very excited when these guys got together and started Colossal.

Ben Lamm: (03:53)
Yeah. And George is amazing. If you don’t know George, he’s not only a genius, he’s also super interesting, funny, and kind of weird. He’s awesome. He’s just great. The momentum really started in 2013, when this group of incredible folks came together and launched the first TedX de-extinction event. In that event, they had speakers from a wide variety of species talking about the thylacine, the passenger pigeon, the dodo, and obviously, George talked about the mammoth. But what was really clear about leaving the presentation from George was that every single person left and thought, “Wow, we actually have the technologies to do this. We have a purpose to do it for arctic re-wilding, and it really just needed focus and funding.” And that really created an opportunity from filmmakers and others to start pouring resource dollars into the research and helping them go on their first adventure back to the Arctic, to Russia.

Eriona: (04:54)
This is essentially my journey to de-extinction. I was finalizing my program in grad school, and I was looking at various postdoc opportunities for me when I was reading about George Church and his efforts for de-extinction and how to do that through synthetic biology. I was mesmerized. And mammoth changed my life afterwards. I got a chance to travel with him in 2018 to Siberia. We traveled across 14 time zones, 4,800 miles, and it was incredible. It was an incredible journey. We were there with a film crew. We were there with Stewart Brand, who’s a writer, a conservationist, former editor of Whole Earth Catalog and founder of Long Now Foundation. And he’s an incredible figure. The documentary was called, We Are As Gods, which we are not, but we are learning from the best, I guess. We got a chance to meet the Zimovs. Serge and Nikita Zimov who ran the places and park around Chersky. It was an incredible journey. There have been instrumental advocates of returning to biodiversity on a mammoth step ecosystem. It was an incredible journey for me as well. You can see here, George. George really reveled into the discovery of the past. Essentially, our work has benefited a lot from the work of Yakutian scientists and mammoth task hunters who found some of the best specimen out there. And here is shown, we took a lot of boat rides, a lot of trips around places and park. We went into these ice caves that locals used to store fish, but also for measurements. Scientists use for measurements for permafrost changes. We learned a lot and I think this particular journey drew the attention of a lot of media. But more importantly for us, we were actually able to sample some of their best specimen, which is shown in the next picture as well.
(06:55)
This is me in a cold room and George took a picture of me next to the skull of wooly mammoth. The specimen were very, very well preserved. We were able to sample them and the flesh was quite juicy actually, but in this case, there was actual fur in the room. You can see the scale here. I think I cannot compete I guess there. This was an incredible journey, incredible experience for me.
(07:17)
As I mentioned, it drew a lot of media attention and we were also subject of a documentary on 60 Minutes, which is what essentially drew the attention of Ben, and it started the whole Colossal’s extinction journey to actual de-extinction actualization.

Ben Lamm: (07:35)
Yeah. And I think Kent talked a little bit about the fate or the luck that humanity has with the asteroid impacts, but this was definitely fate. I had been talking to George for, I guess, two or three months at the time. I’d been in the lab a few times. I literally got back and I was running a different company at the time. I was like, “Can I go raise money for elephant conservation and de-extinction?” And in that process, I got home was starting to talk to my wife and then I got a random call. And it’s like, I think the guy that you just met with is on 60 Minutes talking about mammoths. And so I turned on the TV and sure enough, and this happened literally the day I got home and so it was definitely a cosmic fate that I guess forced it. And that next morning, I texted George and said, “I’m in. Let’s go figure out how we bring back a mammoth.”

Eriona: (08:27)
So how do we get from extracted DNA to an actual living mammoth? And I think I have to say, it’s no easy task. It’s no walk in places and park, by no means. But we start with just a lot of specimen. And that includes living elephants as well as woolly mammoths. And we have, on the wooly mammoth specimen alone, over 50. And we continue to sequence elephant specimen that we receive from our partners and collaborators. So we create this whole genome profiles of the specimen we have. We analyze them computationally. We tabulate all these results, especially focusing on the ones that are fixed. That means these DNA changes are different and that’s what makes woolly mammoths different from their closest living relatives, which are the elephants. And then we try to narrow down to a list that actually correlates with some of the phenotypes that give us the clear code adaptation traits, such as shaggy hair, dome shaped cranium, the curved tusks, cold temperature resistant and fat deposits.
(09:31)
And what you do is you actually use cutting edge DNA editing technologies that we license. And we work in collaboration with Church Lab at Harvard. And we introduced these components into the cells. We screen cells. We use next generation sequencing technologies in order to actually make sure that their edits are correct. And then we get to the testing stage, where we validate that these edits are associated with phenotypes through various functional assays. And then once we actually have validation at the cellular and animal model level, then once we have those validation of the traits, we will move on to nuclear transfer, embryo generation, implantation into a healthy surrogate and the gestation. And of course, the early steps would be to use healthy surrogates. But what Colossal wants to do is move away from using endangered species completely for their conservation. And for that, which we’ll be talking a little bit about later, we’ll be using in vitro gametogenesis and [inaudible 00:10:32] technologies.

Ben Lamm: (10:34)
And you’ve probably all heard the phrase, it takes a village to raise a child. It takes a lot more than a village. It takes a worldwide effort to build a mammoth. And we’re very, very grateful for our collaborators across the world. We’ve got incredible bioethicists, conservationists, leading scientists in various fields. We have Richard. And so we’re very, very grateful for it. And in the last, last two days, there’s been several of you that I think may also join our scientific advisory board. So we’re very grateful for you guys. And if there’s anyone that after this presentation wants to talk about collaborating, it’s really, really important.
(11:10)
And just a key point on that, that I wanted to point out is we have over 54 mammoth genomes in our possession. We think we have the largest set of sequence genomes in the world for mammoths. And that’s come largely from some of our excavations as well as our partner collaborations. But we were planning to go back to the [inaudible 00:11:30] this summer, and given the conflict that’s happening right now in Ukraine and Russia, that’s impossible. And so it’s really the partners that have helped step in and help solve that. And so when I gave some of this data to Richard, Richard said, “Why don’t you come to Alaska with us?”

Richard: (11:44)
Yeah. And in fact, for those of who have been following the club calendar, we’re going to hold our next board meeting in September up in Alaska. And so they’ve already actually been in touch with the folks that run a site up there called the Boneyard and the research up there that are pulling out woolly mammoths in Alaska and our thinking of rewilding. In fact, discussions have gone not only from an extraction standpoint, but all the way up to how can we help reintroduce the woolly mammoth back into the wild. So the club and its members are really already stepping in, in a big way.

Ben Lamm: (12:17)
We just couldn’t be anywhere without our partner, so we are just super grateful. And then also, our incredible team. So in our eight months since launch, we’ve actually stood up three labs, we’ve hired 70 people. And we’re hiring more across everything from embryology and cloning all the way through sequencing and computational biology and then actually editing itself. And so we’re very, very grateful to hire this incredible diverse team from across the world. And Eriona’s going to talk a little bit about some of the major, there’s a lot to cover in the science, we don’t have forever, but Eriona’s going to cover some of the major things we’re working on, on her team.

Eriona: (12:54)
Yes. Let’s get a little bit deeper into the actual workflows that we use at Colossal. We start, of course, with the help from great partners and collaborators who share with us these very, very precious specimens from various elephants throughout zoos. And so we have a combination, of course, of male and female elephants, and of course, African and Asian elephants. Those are the closest living, especially Asian elephants, are closest living relative to the woolly mammoth. But we are also interested in conservation. And so we would like to actually collect specimen and sequence the other all existing elephants. And in fact, just from the previous slide, we are collaborating with a vertebra genome project in order to sequence, make telomere to telomere high quality reference genomes for all existing elephant species, African, Asian, Bornean and forest elephants. And so we collect tissues, we derive these cell lines, and then those are our input for our workflows, which they’ll be edited, they’ll be screened, they’ll be sequenced, and then there will be [inaudible 00:14:00]. So this is an iterative cycle that we use in order to implement all the edit that we want.
(14:06)
We also run kind of a mini frozen zoo at Colossal, where we collect these specimen, both for our de-extinction efforts and for conservation. So we start with tissues and we generate thriving, growing elephant cells that will be used for sequencing. As I mentioned, our reference genome work with the VGP, but as well as our editing work.
(14:28)
This is an overview of the workflow of the editings. We use gene editing technologies, of course not only CRISPR based, but mostly CRISPR based and editing based. And we start with cells. We deliver the CRISPR or gene editing component. We screen the cells. We use next generation sequencing technologies after these cells have been enriched. That increases the efficiency of the editing and making sure that there is an actual correct edit versus screening for cells that have also off target effects. So we would like to eliminate those from the population of desired targets. And then we use computational tools in order to analyze and screen the best cells we can get with all the edits that we desire.

Ben Lamm: (15:12)
And one of the big things that we’re focusing on, because a lot of the team is also some AI folks and some great engineers, is then how can we operationalize and systemize the process for de-extinction and how can that also apply to human healthcare? So a lot of the great findings that we’re getting out of this, we’re now looking to apply to human healthcare, which we think is really fascinating.

Eriona: (15:31)
Because we have such a wealth of genomic data, genomic sequencing data, we are not finished with just that initial list of genes that we correlate with cold adaptation traits. We have a whole proprietary discovery process where we actually look at other genes and other gene pathways that are responsible for these cold adaptation traits. And so we go through the cycle of analysis, looking at the genomes computational analysis, looking at the correlation with the potential traits, and for this particular discovery-
(16:03)
With potential traits. And for this particular discovery process, we really are thankful for our computation, our bioinformatics team, because they do an incredible job, not only analyzing but also potentially building all the tools that are needed to actually expedite and make this process more efficient.

Ben Lamm: (16:18)I guess, you want to talk about that iPSC work?

Eriona: (16:19)
Yeah. And I mentioned a little bit about our cell work and I briefly alluded to our in-vitro gametogenesis and ex-utero development. But to develop those kind of functional assays with these powerful cells that are called pluripotent stem cells, you need to actually derive the pluripotent stem cells, not just go and harvest them from the animal. And here some of you at least might have heard of an induced pluripotent stem cells, which are very, very similar to embryonic stem cells. In fact, I think they evolutionized the field of stem cell biology, but they’ve been somewhat finicky and tricky to derive elephants iPSC cells. And we have what we call partially programmed because we’re actually still characterizing the cells, African elephant but no one has ever derived Asian elephant iPSC cells. So, we’re very excited to show some promising images of Asian elephant iPSC cells that will actually be crucial to our work for in vitro gametogenesis and functional assays. So very, very excited about this image. We’re still characterizing and sequencing, but hopefully that work will be completed in the next few months.

Ben Lamm: (17:34)
This is the first time, as Arianna mentioned, that we’ve ever shown it outside the lab. It is my favorite slide in the deck just because the ramification’s not just for the Mammoth Project are pretty impactful, but also how it can help for conservation. We’re pretty excited.
(17:46)
So a little bit about why should we do this? Like how does this help, not just bring back the mammoth but it sounds cool and interesting, but why should we do this? How does this help elephants and how does this help the broader kind of ecosystem? And so we’re really kind of focused on three big areas as it relates to elephant conservation. One is attacking different issues that elephants are currently facing. One being disease states. Two is Arctic re-wilding. And then three is then building advanced gestational technologies, which we have the science to do we just haven’t had enough focus in funding and engineering support to make some of these breakthroughs that could be revolutionary for species preservation.
(18:25)
One of those is EEHV I didn’t know this until I started working with George a few years ago on this project. But EEHV is a herpes virus that kills about 25% of all Asian elephants, which are endangered, at the time of weening when they’re moving off their mother’s milk. And it’s something that is curable, we can create treatments. We are currently in the process of synthesizing the virus in our lab. We’re currently doing work at Harvard. We’re currently funding some incredible work with Dr. Paul Ling at the Baylor College of Medicine around this. And we believe in the next two to three years that we’ll either have a cure or we’ll have major therapeutics that could save elephants. And when an elephant gets, EEHV officially in captivity, they typically die within 24 hours. And so it’s a terrible deliberating disease. It’s also affecting both Asian elephants and African elephants in captivity.
(19:17)
In addition to that, Arctic re-wilding is a second major tenet of what our long term goals with project are.