Resurrecting the Mammoth – Ben Lamm & lEriona Hysolli – GLEX Summit 2022 Transcript

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.

Richard: (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.

Richard: (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.

Ben Lamm: (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.

Ben Lamm: (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.

Eriona: (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.

Eriona: (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-

Ben Lamm: (08:03)
… 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.

Eriona: (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.

Ben Lamm: (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.

Eriona: (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.

Eriona: (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-

Eriona: (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.

Ben Lamm: (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.

Ben Lamm: (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.

Ben Lamm: (19:17)
In addition to that, Arctic re-wilding is a second major tenet of what our long term goals with project are.

Eriona: (19:24)
Yeah, what excites me more is actually our conservation efforts. But beyond that at the macro scale, we’ll look at what could the elephants we’re introducing re-wilding do for the environment. And we, of course, are inspired by the work that’s been done, as I mentioned before, in Pleistocene Park, this mini geoengineering project, where we try to keep the biomass that’s deposited in this permafrost, this organic biomass layer that as the permafrost thaws, going to be released in the atmosphere in the form of carbon dioxide and methane, which is a very, very powerful greenhouse gas. So, we want to keep these deposits trapped where they are supposed to be.

Eriona: (20:08)
In order to do that, the reintroduction of the megafauna, because they supported such a rich diverse ecosystem, the mammal steppe ecosystem, we believe that we’re introducing them would be able to actually combat, mammals are pretty big, so we want to get rid of the coniferous trees. As Ben likes to say, we’re not against trees-

Ben Lamm: (20:29)
We’re not against trees. We’re against small, inefficient, slow growing coniferous trees with dark bark that permeate heat in the permafrost, only.

Eriona: (20:38)
But the shrubs and the [inaudible 00:20:39] are very slow carbon and nitrogen cycling. So replacing them with a grassland ecosystem actually is more beneficial to supporting a more biodiverse life. In addition to that, the clearing of the steppe, you can actually grow more grassland during snowfall, the light and heat is reflected back. So you see like there’s a mitigation of the albedo effect. And in addition, all the animals that you’re introducing into the park trampled through the snow, the Zimovs have peer reviewed work where they show that the surface layer of earth actually is cooled by 2 to 10 degrees if there are larger animals that trample on the snow that actually make sure that the colder temperatures penetrate deeper.

Eriona: (21:22)
So all these are mitigating effects for the environment. As I said, it’s a great project in terms of when you look at the conservation efforts, but also down the line with potential the macro scale with Arctic re-wilding efforts.

Ben Lamm: (21:35)
And then the last part as it affects not just elephants, but potentially all critically endangered species is assisted reproductive technologies. Ultimately here’s a render of a artificial womb. We have a 20 person team that’s working on ex-utero development, specifically focused on marsupials and in mammoths and in elephants. But, I think from what you’ve heard a little bit of what we’re working on, if you start to look at the gametogenesis in the stem cell reprogramming, the genetic rescue technologies, the great work that the VGP and other people are doing with sequencing, you combine that with technologies like artificial wombs and whatnot, you really are starting to get not just a de-extinction toolkit, but a species preservation toolkit that can be used across a myriad of different species.

Ben Lamm: (22:17)
One like really critical fact that we learned early on is that some of the models that we’ve seen is that we’re to lose up to 50% of all biodiversity between now and 2050. I think you’ve heard that from various different folks here in their different fields. But I think that humanity does have the technology together to arm conservations with new tools to combat it. And I don’t know if many of you have seen this photo, this picture of Sudan, the last male northern white rhino that passed away a few years ago. Lucky enough for scientists and Dr. Hilda Rantan and a few others that we collaborate, actually were able to get sperm cells from a Sudan in others before they passed away. Here’s a picture of Najin and Fatu, the last two northern white rhinos that are female.

Ben Lamm: (23:04)
So without genetic rescue without some of these advanced technologies that we’re developing and that others are developing, these animals are currently functionally extinct and they will go extinct. But if we can build this de-extinction toolkit on our path to the mammoth we think that we can help certain species like the northern white rhino, grow 10 to 20 of them in the lab and then work with incredible conservation and re-wilding experts to reintroduce them ethically back into the world.

Ben Lamm: (23:32)
And then last but certainly not least, they’re not alone. It’s constantly accelerating. I think everyone’s seen what’s happened in Australia in the last few years with climate change, with the wildfires, with the pictures of koalas. Now the Australian government’s devoting tens of millions of dollars every single year to protect habitat and protect a lot of their marsupial species. And then lonesome George, the same is becoming aniconic member of the de-extinction club, where he went extinct-

Ben Lamm: (24:03)
… the de-extinction club where he went extinct in the Galapagos. And so this isn’t just mammals that are being affected. This is all species. So that’s what we’re working on. We’re really excited about being on our path to de-extinction and then on our path to species preservation.

Richard: (24:17)
All right. So first, say thank you if you would to Ben and Ariana for coming here. And I’d like to start, we’re just going to take a few minutes for questions. I know we are pushing close up here against our lunch break, but one of the things I want to start with. Something we covered at South by Southwest, I had the great pleasure to speak with these two folks just a few months ago at South by Southwest, when the company had only at that time been fewer months in existence-

Ben Lamm: (24:49)
Four months old. Yeah.

Richard: (24:50)
Four months in existence. And even at that point, you showed a slide there that was a living cell that of the 50 or 60 genes that represent the primary differences from an Asian elephant to a wooly mammoth, you already had five or so of those genes being expressed in what was an Asian elephant cell. So to me, that just shows how fast this is proceeding. So give us the big beats from here to at least an egg because we know you mentioned that it’s a two year gestation period. What are the big beats between here and an embryo?

Eriona: (25:29)
We want to get to a mammoth.

Ben Lamm: (25:31)
Yeah, the biggest beat is a mammoth, but yeah.

Eriona: (25:33)
Yeah, but I think the progress that we’re making along with our collaborators at Harvard Medical School is we really want to build on multiplex editing, push the limits on how many edits you can make per one cell at different [inaudible 00:25:47]. So the church lab has the record for a number of targets over 13,000, but that’s mostly for repetitive elements, but non-repetitive elements are still a challenge to multiplex edit, especially if you want to do multiple of those at the same time. So pushing the limits of multiplex editing, being able to differentiate into different lineages, derive these stem cells, the IPS cells that I just mentioned, so we can actually derive gamete from these animals. We don’t have to go into the actual endangered species to collect them. We can do that in vitro.

Eriona: (26:20)
And constant harvesting of eggs from healthy surrogates actually makes for fibrotic tissue of the ovaries, which induces non-reproducibility. And so being able to counter those challenges, not only for our de-extinction work, but for our conservation is crucial. But even the egg harvesting and the nuclear chancellor are going to be major milestones in the elephant research community.

Ben Lamm: (26:50)
And I think our target is 18 or 20 of the major edits this year.

Richard: (26:56)
20 edits by the end of the year. Okay. 20 of 50 to 60.

Ben Lamm: (26:59)
Yeah.

Richard: (27:00)
Yeah. And by the way, I have a couple other questions myself, but if anybody else… Back here in the back on the right. You two are side by side, so either way;

Speaker 1: (27:12)
Hi, is this working? Yeah. This is working. You guys, I see that this type of technology has so much application to preventing extinction. I guess my question is a really big one about resurrecting the mammoth. So the mammoth’s ecosystem has changed substantially over the last 10,000 years. So I guess my concern is have you done any in depth ecological modeling around what impact introducing the mammoth would have on the current ecosystem? And also given the fact that climate change is really impacting this ecosystem quickly, what impact is that going to have on the reintroduction of the mammoth?

Ben Lamm: (27:58)
It’s a great question. I mean, there’s more carbon and methane stored in the Arctic. Because unlike the tropics where there’s a constant carbon nitrogen cycle, in the permafrost, it just gets layered. Right? And so the melting of the permafrost is a pretty big issue. That’s one of the reasons why George wanted to pursue the project in the first place. And methane’s about 30 times worse in the atmosphere than carbon. And so what we know about mammoths is they actually are pretty diverse, right? And so, there was different forms. There’s the Columbian mammoths, the Arctic mammoth, Siberian mammoths, the Alaska mammoths. And they could actually traverse quite a large… We find them everywhere. They traverse quite a large range on the planet. What we are using is the Asian elephant as kind of our architecture.

Ben Lamm: (28:46)
And there’s actually zoos and whatnot in Canada that have Asian… And most people think of the Asian elephant as a tropical species, but they actually have Asian elephants outside of Toronto where they’re playing in the snow, breaking through the ice and swimming in these ice frozen lakes. And they actually love it. Right? And that’s without additional cold adaptation like hemoglobin production, the hair, the extra fat layers, the trip-B3, everything on the nerve ending. So without even all of those edits and in just kind of a baseline Asian elephant, they are pretty adaptable to that environment. We still have parts of the Arctic that get to similar temperatures. So negative 20 to negative 40 is still pretty consistent up there. And our goal is the fact that climate change is happening and that environment is changing is actually… I wouldn’t say it’s a negative.

Ben Lamm: (29:39)
It is one of the reasons why we’ve been really focused on it. And we’ve been collaborating as Ariana mentioned with Serge and Nikita Zimov that have several decades of data of showing about how permafrost [inaudible 00:29:52] using herbivores, how it actually works and how it can lower the temperature of the ground up to as far as 10 degrees, which is significantly higher than the tipping point that the world seems to be focused on, as well as some collaborators in Cambridge that are looking at just the broader Arctic Circle. And so we’re constantly looking at it and looking at the peer reviewed, published models around it.

Richard: (30:18)
And I know there’s a bunch of more questions on queue, but I’ve been asked here to go ahead and wrap up because we’re pushing into lunch. And so we’re going to take the rest of the questions out there in the next room for these folks, because we have one more thing we need to cover up here on the stage before we release. So if, again, you’ll say thanks to these folks and they’ll be ready for your questions outside in just a minute.

Eriona: (30:40)
Yeah, thank you.

Ben Lamm: (30:40)
Thank you.