I recently had a chance to sit down for a really fun conversation with my friend Dr. Chris Mason. Chris is a professor at Weill Cornell Medicine, and he works on a battery of cool stuff, among them the NASA Twin Study – comparing genomic changes in the human body as a result of space travel – and METASub – analyzing the metagenomics of subways and urban biomes. Chris has a new book out titled The Next 500 Years: Engineering Life to Reach New Worlds. We’ll talk about how he envisions humanity preparing to move beyond our home on earth in the next few centuries, and how that relates to precision medicine over the next few years.

Chris, thanks much for being here. Can you give us a quick overview of the book for people who might not be familiar with your work?

My pleasure, thanks so much for having me, it’s great to be here. The book is really a treatise of hope and a series of dreams for humanity. It’s that big, I really hope that we can understand biology well enough that we can keep people safe for long-duration space flight and potentially engineer life — add things back in that have gone missing, do things that we do for immuno-therapies and have a better monitoring and treatment of cells that go awry. And we’ll need all these tools, I think, to be on Mars and go to other solar systems.

It’s 500-pages, there’s a lot in there, but basically it is a rich detailed look at what would happen if we looked at what we’ve learned from other NASA missions and what we’re learning with astronauts right now about engineering microbes, engineering human cells — really a look at the latest tools and technologies in genomics that enable an extraordinary application of medicine today but also what will likely come in the near future.

And at the end I say it’s actually our duty to use these tools not only to better understand life, but also to protect life. That we are the only ones with awareness of life’s fragility and extinction, so it’s actually why I propose actual duty for our species for the long term.

Tell us a little bit more about what you think is going to be the role of these tools in helping us make that trip across the universe, or at least across our galaxy.

Yeah, I stop in the galaxy. There’s a really a cool map in there of where all the known exoplanets that are close enough to earth that we could at least get there and survive, or at least arrive and someday survive there. It’s called the earth similarity index. It’s extraordinary, if you jump back 25 years ago, we had one genome that had been sequenced, we had no human genome, we had no exoplanets discovered, maybe one with little evidence.

But now we have thousands of genomes, hundreds of thousands and millions of genes identified, the genetic catalogue of evolution’s toolkit. And we also have thousands and thousands of exoplanets, we have places we can actually go to and potentially survive. I think the tools of sequencing, genome synthesis, the ability to do genetic engineering will enable this extraordinary new future that will help us survive on other planets, but that is already happening here. You can think of engineering T-cells, CAR-T therapies, we’ve basically tweaked the genome of a cell to be therapeutic.

That’s one of the big points I make in the point, a lot of these ideas seem like science-fiction, like engineering or tweaking life to survive on another planet. But we are already modifying and tweaking life here therapeutically because we want to avoid dying of cancer. Everything in the book is based on things we know today; I require not a single technological leap from something that doesn’t exist already. I think it’s really exciting, the tools that help us eke past disease are the ones that are going to help us survive even when the environment gets harsher.

It’s interesting, I think there are a number of examples of NASA-developed technologies that have a positive impact on society. Is there something you can foresee that would be the case as we take this trip to one of these planets, something we would have to develop for that trip that would have a role in today’s healthcare?

I think a lot of them will be tools, some of them are simple tools that we already developed. One of the missions I talk about involves sequencing in space, doing rapid diagnostics with a MINion sequencer. You can do sequencing anywhere and this is something that has been established for 7 or 8 years even before we started doing it on this space station. Some of them are tools that build out a molecular characterization of anything, whether it’s a weird growth on your skin or something in your mouth or something on the space station. So that we’ve shown, we know that’s possible.

But I think looking forward the tools — things like Velcro that NASA has all over the space station, we all use Velcro every day; a lot of lasers and electronics that work in very small environments with limited power, things that have helped our cellphones get better. I think looking forward one of the really interesting things is things that are in our genome that maybe we could reactivate. For example, being to make your own vitamin C. If you don’t get enough vitamin C, you’ll get scurvy. But a lot of other mammals have the ability to make their own vitamin C, and we used to do it. If we look back in primate lineages, there are other lineages that still do, it just got lost. Multiple times it’s been lost in lineages, for example bats no longer make vitamin C because they get enough of it from their diet, it’s the same thing that happened with us. There’s a lack of selective pressures, so you don’t need it in your genome, but the gene is still there, it’s like a pseudogene.

In one of the sections of the book I talk about reactivating that gene. We have to get 9 of our essential amino acids from our diet, otherwise we’ll die. I think it’s kind of unfair, these pathways to generate all 20 amino acids that exist in nature. Why don’t we actually put them in human cells? Engineering the genome to make that possible might be a bit of a tall order, at least in the next few decades, but at least understanding those pathways and integrating them into yeast, for example, for production might not only help people in faraway missions but also everything from bread to beer to everything else we make with yeast here on earth, and therapeutics as well.

Do you envision that, in some way, the fact that we have this mRNA vaccine that came online might be a path through which people could start to edit their genetic information, but just in a way that is more transitory?

I think it will start there first. A lot of the discussion is about genome engineering, but also included in that is also cellular engineering, which includes the genome, the epigenome where you can turn genes on and off. The technologies for that are only a few years old, but they’re extraordinary because you can turn on the genes for, say, radiation response only when you know there is a high radiation event. Or maybe you have enough food for a while so it might be more energy efficient to just eat your food; but if you really do run into a harsh situation, only then do you activate some of these other pathways.

I think viewing the genome and the epigenome as these two distinct canvases on which you can paint your function is really enabling a different view of how you can survive better, avoid disease, treat disease, and of course if you’re going to a different planet how you might hopefully be able to survive there. mRNA vaccines are one example where we will essentially just synthesize the proteins that we want the body to make so that our immune system can recognize those epitopes and make it easy. There’s already  discussion of a multi-valent vaccine for Moderna and Pfizer, probably coming out in a few months, maybe every year. It’s this brave new world of “let’s synthesize what we need, train our immune cells for what we need them to do, and eventually we can train other cells to do what we want them to do.”

Can you tell us a little bit about, what are some of the most interesting facts that you found out while you were doing research for the book? Anything that jumps to mind?

There’s a really strong thread of optimism. A lot of the papers that I’ve read over the years, I know that the technologies enabled extraordinary leaps in precision medicine for treating cancers, leaps in engineering cells. I was really excited to read some of the ways you could modify the rods and cones in the eyes and maybe even enable night vision. What used to be kind of science-fiction, there’s already proof of principle papers that have been published that I got to do a deep dive on. Lessons from tardigrades, or elephants that have extra copies of p53, the lessons of evolution are written in the DNA of all the species on earth and we’re just now starting to discover all these genetic lessons that are in their DNA. That was the fun part.

The saddest part of writing the book was in the last chapter where I describe what’s going to happen in the next 5 billion years and then afterward. That was actually the hardest chapter to write because I’m a humanist and I’m really excited and hopeful for humanity. It’s a deep dive on everything about how the planet will likely end, and in my head I had always had it as a kid that we have 5 billion years before the earth is engulfed by the sun. We’ve got lots of time, 5 billion years, that’s a long time! But then when I finished doing the research and updating some of the cosmology, it’s actually about 1 billion years before the sun’s luminescence starts boiling the oceans. So even if we’ve achieved perfect world peace and we have amazing technologies and medicine, if we’re still here, that’s the end date. We probably won’t survive much past that, maybe underground, maybe.

I’d always thought humanity could live at least 5 billion years, but it quickly because one-fifth of that. It’s like thinking that your child might live to be 100 but then finding out one day that it’s only going to be 20. I had this sense of sadness, and my wife was asking me in the kitchen, “why are you so sad?” And I was like, “I just thought we had more time.” She said, “yeah but it’s still a billion years.” No, it’s a lot less time! So that was one thing that was disturbing in a way, but I still take great solace that we’ve got some time.

It’s funny you mention that, within a billion years? I’m guessing that even within a million years maybe we’ll be able to develop something similar to the Dyson sphere. Something that we put around the sun to harvest the energy. There must be a way that by then we’ll find a way to sort that out, I’d think.

I’m hopeful. It’s so much time, and we’ve done so much just in the last few hundred years, let alone thousand. I am very hopeful in that regard, and I’m also hoping it will also be coincident with technological change, and social and economic adjustments as well. I describe a lot in the book this idea that you need technology put in the context of the social impact. If you alleviate your suffering, does it increase the burden on someone else? What’s the broader impact, what’s the cost? How do we have equitable distribution of resources and treatments whenever possible? We want to make sure that anything we do is in the context of its broader impact rather than just for one person and one family.

It sounds like 500 years could be accelerated. I know it’s a question Peter Thiel asks in interviews, “What is your 10-year plan, and what would it take to do it in 6 months?” What would it take for us to implement this plan in 50 years, is it possible, is it funding, is it anything else?

That’s a great question, actually. Yeah, my 500-year plan is really predicated on the fact that we’ll continue about as we have, although what we have been doing has been at a super exponential pace for most of science. But even with that pace, some things are hard or are politically fraught or underfunded. If you accelerate the funding and development on a lot of the ideas in the book, I think it could be done in 50 to 100 years.

The best example is, look at what happened with COVID. When almost the entire world’s scientific community is focused on one problem, we rapidly learn fundamental facets of the disease, we learn about the sequence of the virus, we develop vaccines; really only 14 months ago did we know this virus existed, and we already have a widely deployed vaccine where some countries are almost completely vaccinated. It’s extraordinary, and that’s because everyone was focused on one thing.

If we did that, if we just focus on one thing as a global scientific community, one per year, that would probably solve the majority the big problems in 20 years. Or at least we’d make big progress, I’m sure.

It was my impression, I’d say, as I was reading the book that some of these aspects are actually going to get there earlier.

I hope so. In the beginning I talk about, when I wrote the first bullet point: 500-year plan in 10 phases, and I wrote these bullet points. It was like many things started, there was a bar napkin and some beer and I was just writing some things down. And I proposed that genome editing would require a lot more technological work, but that was in 2010 when CRISPR was just beginning. There were a lot of preliminary papers on it, but I couldn’t have foreseen then how easy it would be to be doing variations of CRISPR at scale, as well as epigenetic modifications, so there I have been pleasantly surprised at how easy and fast that genome editing has come of age. I’m hoping I’ll be proven wrong on all of it in terms of the timeline.

The comment you made about COVID reminded me of something. I believe that Moderna and BioNTech never had a copy of the virus on their site, they just bioinformatically received the information and were able to develop the vaccine. That makes me think similarly wouldn’t it be easier to just beam the information to make a human as opposed to beaming the human? Wouldn’t that be the easier way to exit the galaxy?

It would, I call it point-to-point biology, or interplanetary directed evolution. For example, say we see microbes or humans that have adapted on Mars, and it looks like they’ve evolved over several hundred years to be very distinct and we’ve sequenced them and understand genetically why that is. But we’re research limited on Mars, so we send the data back to Earth then synthesize the creature or microbe or and then do further studies on Earth where you a lot more resources and ability to understand it. Then you have basically a point-to-point virtual cycle of transmitting the data of the genetic adaptions and the genetic substrates and then doing further testing on both planets. You’d continue to learn about how life is evolving in these very different environments, and then put that to good use because you might find new antibiotics, new peptides, entirely new structures that let you survive on Mars better, maybe it’ll help us avoid cancer on earth.

As evidenced by CRISPR, which was basically found by mining sequence data originally, if you start to look around at what life has done to solve problems, there’s this entire wide panoply of really amazing tools right under our fingertips. I think we’ll see more of that even if it’s on other planets. A lot of it will be, probably.

The three of here, we’re very interested in the future and in technology. But there’s plenty of people in the world who don’t have that natural inclination, but regardless would still benefit from technology byproducts that come out of these types of endeavors. So how do you make the case to somebody who just doesn’t have the natural inclination toward preservation of the human species that there’s going to be good things that come about in all kinds of facets?

It’s a great question, some people say why bother? Some people say, “humans are not that great, we cause all this pollution, there’s infighting, there’s murder, there’s crime; what’s so great about humans?” To that I say, there’s a very easy answer: to our knowledge, humans are the only species that have the capacity to understand extinction, and that alone is enough for preservation. Because only that kind of species can serve as the guardians to protect other species, to preserve life as we know it. We are IT.

So even with all our faults included, there’s still a really amazing benefit that we are, to our knowledge, the only species in the universe that can do this. You think about ecosystems how normally works: there’s producers, consumers, and decomposers. You remember that picture from your elementary school? There’s the sun and there’s snails and plants and decomposers; it’s just three kinds of species. And we always thought we’re just one kind of consumer, that’s what humans are.

But what I argue in the book — and strenuously and feverishly believe — is that we are a very unique a fourth kind of species that is distinct from everything else, because we are aware of the frailty of life, the extinction possibility. And we’re the only ones that can prevent. Of course, we can cause it too, we can totally screw it up. But we’re the only ones that can do either. Well other invasive species could I guess, but the only ones that can consciously cause the extinction, and certainly the only ones that can consciously prevent extinction. And actually, eventually, if you get enough synthesis, you could create new life.

The creative aspect is something that’s unique to us, so even if you don’t like anything about humans, just that we have the capacity and ability to preserve life is unique in the entire universe. And everyone has the ability to at least think about it and to plan ahead. I think it’s worth preserving.

Let’s talk about spatial omics a bit. You’ve talked about extra high spatial resolution, to what extent do you think it’s important to go sub-cellular? The cell is the unit of life, right, so what do you need to go sub-cellular on in terms of resolution?

It’s a great question of more resolution, higher throughput, more data. Everyone always presumes more is better. And in this case, we’re finally reaching below the fundamental unit of life the cell, but we don’t know what we’re going to find yet.

I would put it akin to taking telescopes and saying, well we’re going to find more stars and more planets, but will it matter? We’re just going to find more of them. And to some degree that’s true, we have found a lot more of them, but as I describe in the book, we now have habitable exoplanets. We didn’t just find planets, we found ones we could survive on.

The same thing is going to be true for high resolution spatial. You’re going to get sub-cellular resolution of the endoplasmic reticulum, see what the Golgi’s doing, where are the mitochondria moving, or when they’re damaged what are they doing? We’ll have these weird measures, and we don’t know – the majority of them will be like the planets we found far away with a better telescope, most of them will be just, oh we found other planets.

But I’m sure we’ll find new signatures or new indicators of disease or stress or progression or resistance to different treatments that we just couldn’t see because we didn’t mechanistically what was driving them before. Most of it won’t be. Most of it will be prettier, higher resolution pictures of what’s in the cells. But I think like most things, technology gives you a lens to peer into biology, and every single time we’ve done that technologically we’ve found new fundamental biology, which usually then translates to better understanding of disease and better therapies.

How do you think that pure single-cell technologies like Chromium are going to interplay with these spatial -omics? Are they going to play hand-in-hand? Or do you think they’re going to be competing with each other?

I think the right now the spatial technologies are still laborious and slow, relative to running 8 or 16 single-cell experiments at a time, getting a million cells back and having extreme high-resolution data. I think there’s still going to be a good long road where single-cell is going to become the default for basic functional genomics. But once the platforms get faster and the data and analytics improve and get more integrated, I think eventually most of it will switch to spatial. Not all of it, because at some level tissues can be degraded, or you might not have enough.

It’s also still much more expensive, and both platforms and tools are expensive, but they give you amazing data so people are willing to pay it. But I think single-cell’s coming down in price, at least per cell, but the spatial is still more expensive. The spatial technology’s not too expensive, but if you want to have 40 or 80 or 150 antibodies you’re profiling at the same time, then the antibodies become more expensive. I think there’s strange cost structures that have not yet been resolved yet that’ll eventually come down. If I had to place my bet long-term, I’d put it on spatial once it gets higher throughput and cheaper. There’ll still always be single-cell, and I think it’ll eventually become a minority, but not soon.

Which technology are you most excited to use in your lab? There’s the GeoMx from NanoString, the 10X Vizgen, at some point it seemed like there were new companies coming out every other week. I know you want everyone to win, but is there one in particular that you’re excited to bring into your lab or have been using and really happy with?

Yes, and knowing that I am fully conflicted with just about every company on the market, take this with a grain of salt. But even just on the merits alone, I think the ReadCoor technology that was just purchased by 10X, and also the Spatial Molecular Imager from NanoString. I’m really excited about both of them because they give you this extraordinary resolution, I think we’re going to find a lot of fundamental new biology

I’m very excited, because it’s the most measures of transcripts at the highest resolution. It’s slow right now. We were just planning this mission for some future space flight, and also some COVID samples, and for both of them I was looking the SMI platform, thinking that this looks like, going forward, it’s going to be the way to get a lot of deep, rich data on these tissues. If you’re looking for the best answer for what happened to a tissue, what happened when a disease became resistant to a therapy, what happened to cells when they got into space? I want to have the highest resolution, so I’ve been looking a bit at the SMI. I’ve seen it a lot, I know a lot of the NanoString people, I’ve been hearing a lot about it. It’s what’s in my ear, especially these days.

I know the two of us have talked about us in the past, what are some of the results you’ve gotten out of this platform that you could not have gotten any other way? What is that technology really enabling that you couldn’t do using IHC, FISH, or single-cell?

We just had a preprint on this, this has been from some COVID autopsy work we’ve done. We were using the Fluidigm Hyperion system, as well as the NanoString GeoMx. In both these platforms, what I like is not that we can see things that go up and down for genes or proteins, you can do that any way. You can grind up the cells, you do it with single-cell, you can do it with IHC.

But what we started to see was exquisite cell deconvolution: what cells are where in a tissue, and what are they next to. You could do a little bit of that with IHC, but then we have not just 2 or 3 markers but thousands of markers. We knew very specific cell subtypes and what neighborhoods they were in inside of a tissue. We could see in COVID patients, for example, a deconstruction of cells that are normally together, where natural killer cells and B-cells suddenly being near each other where they weren’t before. Or we see neutrophils suddenly engaging in invading into a space where they didn’t normally within the lung.

Some of that you can see, not just are there differences, but exactly which cell type, which sort of normal cell architecture and tissue architecture has been changed. You can kind of see with IHC, you can see, “there’s some differences here, more of here, less of it there.” You might know a few cell types, but you don’t know simultaneously dozens and dozens of cell types and where they’ve all gone within the same tissue.

We can see tissue destruction in situ, which you just couldn’t do before in the actual stage of where the disruption is occurring. There’s been some spatial papers that’ve shown that organizational structure of tissues and how cells are arranged may have some prognostic value, which is most of what IHC does. It’s just the beginning, but I think we’ll see more of that.

That has to be the answer, it can’t be “we saw things be higher or lower for genes or proteins.” If you want that, just do RNA-seq or something much cheaper and simpler. It has to be a question of the organization of the tissue, the structure, the cell subtype, and what it was doing with another cell.

In terms of clinical application, do you think it’s going to be oncology where it can have the most immediate impact, the spatial omics platform looking at the tumor microenvironment? Because in the case of COVID it’s probably not really practical.

Yeah, COVID will mostly go away. I think you’re right, like with a lot of technologies it’ll really be deployed to oncology first. That’ll be the first spot because there you can complement existing assays, you could potentially replace some of them, oncology is a huge market.

But also, infectious disease might be a place where we start to see it pick up because you can make probes for anything you want, any protein or any gene in any organism. I think eventually we’ll start to see it be used there, too.

This has been fun, thank you very much. Can you give us the name of the book one more time and where people can find it?

Pleasure to be here, it’s The Next 500 Years: Engineering Life to Reach New Worlds, and you can find it on Amazon or Barnes & Noble or anywhere books are sold.

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