To Save Lives, This Scientist Is Trying to Grow Human Organs Inside of Sheep
More than 114,000 men, women, and children are awaiting organ transplants in the United States. Each day, 22 of them die waiting. To address this shortage, researchers are working hard to grow organs on-demand, using the patient's own cells, to eliminate the need to find a perfectly matched donor.
"The next step is to transplant these cells into a larger animal that will produce an organ that is the right size for a human."
But creating full-size replacement organs in a lab is still decades away. So some scientists are experimenting with the boundaries of nature and life itself: using other mammals to grow human cells. Earlier this year, this line of investigation took a big step forward when scientists announced they had grown sheep embryos that contained human cells.
Dr. Pablo Ross, an associate professor at the University of California, Davis, along with a team of colleagues, introduced human stem cells into the sheep embryos at a very early stage of their development and found that one in every 10,000 cells in the embryo were human. It was an improvement over their prior experiment, using a pig embryo, when they found that one in every 100,000 cells in the pig were human. The resulting chimera, as the embryo is called, is only allowed to develop for 28 days. Leapsmag contributor Caren Chesler recently spoke with Ross about his research. Their interview has been edited and condensed for clarity.
Your goal is to one day grow human organs in animals, for organ transplantation. What does your research entail?
We're transplanting stem cells from a person into an animal embryo, at about day three to five of embryo development.
This concept has already been shown to work between mice and rats. You can grow a mouse pancreas inside a rat, or you can grow a rat pancreas inside a mouse.
For this approach to work for humans, the next step is to transplant these cells into a larger animal that will produce an organ that is the right size for a human. That's why we chose to start some of this preliminary work using pigs and sheep. Adult pigs and adult sheep have organs that are of similar size to an adult human. Pigs and sheep also grow really fast, so they can grow from a single cell at the time of fertilization to human adult size -- about 200 pounds -- in only nine to 10 months. That's better than the average waiting time for an organ transplant.
"You don't want the cells to confer any human characteristics in the animal....Too many cells, that may be a problem, because we do not know what that threshold is."
So how do you get the animal to grow the human organ you want?
First, we need to generate the animal without its own organ. We can generate sheep or pigs that will not grow their own pancreases. Those animals can then be used as hosts for human pancreas generation.
For the approach to work, we need the human stem cells to be able to integrate into the embryo and to contribute to its tissues. What we've been doing with pigs, and more recently, in sheep, is testing different types of stem cells, and introducing them into an early embryo between three to five days of development. We then transfer that embryo to a surrogate female and then harvest the embryos back at day 28 of development, at which point most of the organs are pre-formed.
The human cells will contribute to every organ. But in trying to do that, they will compete with the host organism. Since this is happening inside a pig embryo, which is inside a pig foster mother, the pig cells will win that competition for every organ.
Because you're not putting in enough human cells?
No, because it's a pig environment. Everything is pig. The host, basically, is in control. That's what we see when we do rat mice, or mouse rat: the host always wins the battle.
But we need human cells in the early development -- a few, but not too few -- so that when an organ needs to form, like a pancreas (which develops at around day 25), the pig cells will not respond to that, but if there are human cells in that location, [those human cells] can respond to pancreas formation.
From the work in mice and rats, we know we need some kind of global contribution across multiple tissues -- even a 1% contribution will be sufficient. But if the cells are not there, then they're not going to contribute to that organ. The way we target the specific organ is by removing the competition for that organ.
So if you want it to grow a pancreas, you use an embryo that is not going to grow a pancreas of its own. But you can't control where the other cells go. For instance, you don't want them going to the animal's brain – or its gonads –right?
You don't want the cells to confer any human characteristics in the animal. But even if cells go to the brain, it's not going to confer on the animal human characteristics. A few human cells, even if they're in the brain, won't make it a human brain. Too many cells, that may be a problem, because we do not know what that threshold is.
The objective of our research right now is to look at just 28 days of embryonic development and evaluate what's going on: Are the human cells there? How many? Do they go to the brain? If so, how many? Is this a problem, or is it not a problem? If we find that too many human cells go to the brain, that will probably mean that we wouldn't continue with this approach. At this point, we're not controlling it; we're analyzing it.
"By keeping our research in a very early stage of development, we're not creating a human or a humanoid or anything in between."
What other ethical concerns have arisen?
Conferring human properties to the organism, that is a major concern. I wouldn't like to be involved in that, and so that's what we're trying to assess. By keeping our research in a very early stage of development, we're not creating a human or a humanoid or anything in between.
What specifically sets off the ethical alarms? An animal developing human traits?
Animals developing human characteristics goes beyond what would be considered acceptable. I share that concern. But so far, what we have observed, primarily in rats and mice, is that the host animal dictates development. When you put mouse cells into a rat -- and they're so closely related, sometimes the mouse cells contribute to about 30 percent of the cells in the animal -- the outcome is still a rat. It's the size of a rat. It's the shape of the rat. It has the organ sizes of a rat. Even when the pancreas is fully made out of mouse cells, the pancreas is rat-sized because it grew inside the rat.
This happens even with an organ that is not shared, like a gallbladder, which mice have but rats do not. If you put cells from a mouse into a rat, it never grows a gallbladder. And if you put rat cells into the mouse, the rat cells can end up in the gallbladder even though those rat cells would never have made a gallbladder in a rat.
That means the cell structure is following the directions of the embryo, in terms of how they're going to form and what they're going to make. Based on those observations, if you put human cells into a sheep, we are going to get a sheep with human cells. The organs, the pancreas, in our case, will be the size and shape of the sheep pancreas, but it will be loaded with human cells identical to those of the patient that provided the cells used to generate the stem cells.
But, yeah, if by doing this, the animal acquires the functional or anatomical characteristics associated with a human, it would not be acceptable for me.
So you think these concerns are justified?
Absolutely. They need to be considered. But sometimes by raising these concerns, we prevent technologies from being developed. We need to consider the concerns, but we must evaluate them fully, to determine if they are scientifically justified. Because while we must consider the ethics of doing this, we also need to consider the ethics of not doing it. Every day, 22 people in the US die because they don't receive the organ they need to survive. This shortage is not going to be solved by donations, alone. That's clear. And when people die of old age, their organs are not good anymore.
Since organ transplantation has been so successful, the number of people needing organs has just been growing. The number of organs available has also grown but at a much slower pace. We need to find an alternative, and I think growing the organs in animals is one of those alternatives.
Right now, there's a moratorium on National Institutes of Health funding?
Yes. It's only one agency, but it happens to be the largest biomedical funding source. We have public funding for this work from the California Institute for Regenerative Medicine, and one of my colleagues has funding from the Department of Defense.
"I can say, without NIH funding, it's not going to happen here. It may happen in other places, like China."
Can we put the moratorium in context? How much research in the U.S. is funded by the NIH?
Probably more than 75 percent.
So what kind of impact would lifting that ban have on speeding up possible treatments for those who need a new organ?
Oh, I think it would have a huge impact. The moratorium not only prevents people from seeking funding to advance this area of research, it influences other sources of funding, who think, well, if the NIH isn't doing it, why are we going to do it? It hinders progress.
So with the ban, how long until we can really have organs growing in animals? I've heard five or 10 years.
With or without the ban, I don't think I can give you an accurate estimate.
What we know so far is that human cells don't contribute a lot to the animal embryo. We don't know exactly why. We have a lot of good ideas about things we can test, but we can't move forward right now because we don't have funding -- or we're moving forward but very slowly. We're really just scratching the surface in terms of developing these technologies.
We still need that one major leap in our understanding of how different species interact, and how human cells participate in the development of other species. I cannot predict when we're going to reach that point. I can say, without NIH funding, it's not going to happen here. It may happen in other places, like China, but without NIH funding, it's not going to happen in the U.S.
I think it's important to mention that this is in a very early stage of development and it should not be presented to people who need an organ as something that is possible right now. It's not fair to give false hope to people who are desperate.
So the five to 10 year figure is not realistic.
I think it will take longer than that. If we had a drug right now that we knew could stop heart attacks, it could take five to 10 years just to get it to market. With this, you're talking about a much more complex system. I would say 20 to 25 years. Maybe.
Story by Big Think
We live in strange times, when the technology we depend on the most is also that which we fear the most. We celebrate cutting-edge achievements even as we recoil in fear at how they could be used to hurt us. From genetic engineering and AI to nuclear technology and nanobots, the list of awe-inspiring, fast-developing technologies is long.
However, this fear of the machine is not as new as it may seem. Technology has a longstanding alliance with power and the state. The dark side of human history can be told as a series of wars whose victors are often those with the most advanced technology. (There are exceptions, of course.) Science, and its technological offspring, follows the money.
This fear of the machine seems to be misplaced. The machine has no intent: only its maker does. The fear of the machine is, in essence, the fear we have of each other — of what we are capable of doing to one another.
How AI changes things
Sure, you would reply, but AI changes everything. With artificial intelligence, the machine itself will develop some sort of autonomy, however ill-defined. It will have a will of its own. And this will, if it reflects anything that seems human, will not be benevolent. With AI, the claim goes, the machine will somehow know what it must do to get rid of us. It will threaten us as a species.
Well, this fear is also not new. Mary Shelley wrote Frankenstein in 1818 to warn us of what science could do if it served the wrong calling. In the case of her novel, Dr. Frankenstein’s call was to win the battle against death — to reverse the course of nature. Granted, any cure of an illness interferes with the normal workings of nature, yet we are justly proud of having developed cures for our ailments, prolonging life and increasing its quality. Science can achieve nothing more noble. What messes things up is when the pursuit of good is confused with that of power. In this distorted scale, the more powerful the better. The ultimate goal is to be as powerful as gods — masters of time, of life and death.
Should countries create a World Mind Organization that controls the technologies that develop AI?
Back to AI, there is no doubt the technology will help us tremendously. We will have better medical diagnostics, better traffic control, better bridge designs, and better pedagogical animations to teach in the classroom and virtually. But we will also have better winnings in the stock market, better war strategies, and better soldiers and remote ways of killing. This grants real power to those who control the best technologies. It increases the take of the winners of wars — those fought with weapons, and those fought with money.
A story as old as civilization
The question is how to move forward. This is where things get interesting and complicated. We hear over and over again that there is an urgent need for safeguards, for controls and legislation to deal with the AI revolution. Great. But if these machines are essentially functioning in a semi-black box of self-teaching neural nets, how exactly are we going to make safeguards that are sure to remain effective? How are we to ensure that the AI, with its unlimited ability to gather data, will not come up with new ways to bypass our safeguards, the same way that people break into safes?
The second question is that of global control. As I wrote before, overseeing new technology is complex. Should countries create a World Mind Organization that controls the technologies that develop AI? If so, how do we organize this planet-wide governing board? Who should be a part of its governing structure? What mechanisms will ensure that governments and private companies do not secretly break the rules, especially when to do so would put the most advanced weapons in the hands of the rule breakers? They will need those, after all, if other actors break the rules as well.
As before, the countries with the best scientists and engineers will have a great advantage. A new international détente will emerge in the molds of the nuclear détente of the Cold War. Again, we will fear destructive technology falling into the wrong hands. This can happen easily. AI machines will not need to be built at an industrial scale, as nuclear capabilities were, and AI-based terrorism will be a force to reckon with.
So here we are, afraid of our own technology all over again.
What is missing from this picture? It continues to illustrate the same destructive pattern of greed and power that has defined so much of our civilization. The failure it shows is moral, and only we can change it. We define civilization by the accumulation of wealth, and this worldview is killing us. The project of civilization we invented has become self-cannibalizing. As long as we do not see this, and we keep on following the same route we have trodden for the past 10,000 years, it will be very hard to legislate the technology to come and to ensure such legislation is followed. Unless, of course, AI helps us become better humans, perhaps by teaching us how stupid we have been for so long. This sounds far-fetched, given who this AI will be serving. But one can always hope.
Interview with Jamie Metzl: We need a global OS upgrade
In this Q&A, leading technology and healthcare futurist Jamie Metzl discusses a range of topics and trend lines that will unfold over the next several decades: whether a version of Moore's Law applies to genetic technologies, the ethics of genetic engineering, the dangers of gene hacking, the end of sex, and much more.
Metzl is a member of the WHO expert advisory committee on human genome editing and the bestselling author of Hacking Darwin.
The conversation was lightly edited by Leaps.org for style and length.
In Hacking Darwin, you describe how we may modify the human body with CRISPR technologies, initially to obtain unsurpassed sports performance and then to enhance other human characteristics. What would such power over human biology mean for the future of our civilization?
After nearly four billion years of evolution, our one species suddenly has the increasing ability to read, write, and hack the code of life. This will have massive implications across the board, including in human health and reproduction, plant and animal agriculture, energy and advanced materials, and data storage and computing, just to name a few. My book Hacking Darwin: Genetic Engineering and the Future of Humanity primarly explored how we are currently deploying and will increasingly use our capabilities to transform human life in novel ways. My next book, The Great Biohack: Recasting Life in an Age of Revolutionary Technology, coming out in May 2024, will examine the broader implications for all of life on Earth.
We humans will, over time, use these technologies on ourselves to solve problems and eventually to enhance our capabilities. We need to be extremely conservative, cautious, and careful in doing so, but doing so will almost certainly be part of our future as a species.
In electronics, Moore's law is an established theory that computing power doubles every 18 months. Is there any parallel to be drawn with genetic technologies?
The increase in speed and decrease in costs of genome sequencing have progressed far faster than Moore’s law. It took thirteen years and cost about a billion dollars to sequence the first human genome. Today it takes just a few hours and can cost as little as a hundred dollars to do a far better job. In 2012, Jennifer Doudna and Emmanuel Charpentier published the basic science paper outlining the CRISPR-cas9 genome editing tool that would eventually win them the Nobel prize. Only six years later, the first CRISPR babies were born in China. If it feels like technology is moving ever-faster, that’s because it is.
Let's turn to the topic of aging. Do you think that the field of genetics will advance fast enough to eventually increase maximal lifespan for a child born this year? How about for a person who is currently age 50?
The science of aging is definitely real, but that doesn’t mean we will live forever. Aging is a biological process subject to human manipulation. Decades of animal research shows that. This does not mean we will live forever, but it does me we will be able to do more to expand our healthspans, the period of our lives where we are able to live most vigorously.
The first thing we need to do is make sure everyone on earth has access to the resources necessary to live up to their potential. I live in New York City, and I can take a ten minute subway ride to a neighborhood where the average lifespan is over a decade shorter than in mine. This is true within societies and between countries as well. Secondly, we all can live more like people in the Blue Zones, parts of the world where people live longer, on average, than the rest of us. They get regular exercise, eat healthy foods, have strong social connections, etc. Finally, we will all benefit, over time, from more scientific interventions to extend our healthspan. This may include small molecule drugs like metformin, rapamycin, and NAD+ boosters, blood serum infusions, and many other things.
Science fiction has depicted a future where we will never get sick again, stay young longer or become immortal. Assuming that any of this is remotely possible, should we be afraid of such changes, even if they seem positive in some regards, because we can’t understand the full implications at this point?
Not all of these promises will be realized in full, but we will use these technologies to help us live healthier, longer lives. We will never become immortal becasue nothing lasts forever. We will always get sick, even if the balance of diseases we face shifts over time, as it has always done. It is healthy, and absolutely necessary, that we feel both hope and fear about this future. If we only feel hope, we will blind ourselves to the very real potential downsides. If we only feel fear, we will deny ourselves the very meaningful benefits these technologies have the potential to provide.
A fascinating chapter in Hacking Darwin is entitled The End of Sex. And you see that as a good thing?
We humans will always be a sexually reproducing species, it’s just that we’ll reproduce increasingly less through the physical act of sex. We’re already seeing this with IVF. As the benefits of technology assisted reproduction increase relative to reproduction through the act of sex, many people will come to see assisted reproduction as a better way to reduce risk and, over time, possibly increase benefits. We’ll still have sex for all the other wonderful reasons we have it today, just less for reproduction. There will always be a critical place in our world for Italian romantics!
What are dangers of genetic hackers, perhaps especially if everyone’s DNA is eventually transcribed for medical purposes and available on the internet and in the cloud?
The sky is really the limit for how we can use gentic technologies to do things we may want, and the sky is also the limit for potential harms. It’s quite easy to imagine scenarios in which malevolent actors create synthetic pathogens designed to wreak havoc, or where people steal and abuse other people’s genetic information. It wouldn’t even need to be malevolent actors. Even well-intentioned researchers making unintended mistakes could cause real harm, as we may have seen with COVID-19 if, as appears likely to me, the pandemic stems for a research related incident]. That’s why we need strong governance and regulatory systems to optimize benefits and minimize potential harms. I was honored to have served on the World Health Organization Expert Advisory Committee on Human Genome Editing, were we developed a proposed framework for how this might best be achieved.
You foresee the equivalent of a genetic arms race between the world's most powerful countries. In what sense are genetic technologies similar to weapons?
Genetic technologies could be used to create incredibly powerful bioweapons or to build gene drives with the potential to crash entire ecosystems. That’s why thoughtful regulation is in order. Because the benefits of mastering and deploying these technologies are so great, there’s also a real danger of a genetics arms race. This could be extremely dangerous and will need to be prevented.
In your book, you express concern that states lacking Western conceptions of human rights are especially prone to misusing the science of genetics. Does this same concern apply to private companies? How much can we trust them to control and wield these technologies?
This is a conversation about science and technology but it’s really a conversation about values. If we don’t agree on what core values should be promoted, it will be nearly impossible to agree on what actions do and do not make sense. We need norms, laws, and values frameworks that apply to everyone, including governments, corporations, researchers, healthcare providers, DiY bio hobbyists, and everyone else.
We have co-evolved with our technology for a very long time. Many of our deepest beliefs have formed in that context and will continue to do so. But as we take for ourselves the powers we have attributed to our various gods, many of these beliefs will be challenged. We can not and must not jettison our beliefs in the face of technology, and must instead make sure our most cherished values guide the application of our most powerful technologies.
A conversation on international norms is in full swing in the field of AI, prompted by the release of ChatGPT4 earlier this year. Are there ways in which it’s inefficient, shortsighted or otherwise problematic for these discussions on gene technologies, AI and other advances to be occurring in silos? In addition to more specific guidelines, is there something to be gained from developing a universal set of norms and values that applies more broadly to all innovation?
AI is yet another technology where the potential to do great good is tied to the potential to inflict signifcant harm. It makes no sense that we tend to treat each technology on its own rather than looking at the entire category of challenges. For sure, we need to very rapidly ramp up our efforts with regard to AI norm-setting, regulations, and governance at all levels. But just doing that will be kind of like generating a flu vaccine for each individual flu strain. Far better to build a universal flu vaccine addressing common elements of all flu viruses of concern.
That’s why we also need to be far more deliberate in both building a global operating systems based around the mutual responsibilities of our global interdependence and, under that umbrella, a broader system for helping us govern and regulate revolutionary technologies. Such a process might begin with a large international conference, the equivalent of Rio 1992 for climate change, but then quickly work to establish and share best practices, help build parallel institutions in all countries so people and governamts can talk with each other, and do everything possible to maximize benefits and minimize risks at all levels in an ongoing and dynamic way.
At what point might genetic enhancements lead to a reclassfication of modified humans as another species?
We’ll still all be fellow humans for a very, very long time. We already have lots of variation between us. That is the essence of biology. Will some humans, at some point in the future, leave Earth and spend generations elsewhere? I believe so. In those new environments, humans will evolve, over time, differently than those if us who remain on this planet? This may sound like science fiction, but the sci-fi future is coming at us faster than most people realize.
Is the concept of human being changing?
Yes. It always has and always will.
Another big question raised in your book: what limits should we impose on the freedom to manipulate genetics?
Different societies will come to different conclusion on this critical question. I am sympathetic to the argument that people should have lots of say over their own bodies, which why I support abortion rights even though I recognize that an abortion can be a violent procedure. But it would be insane and self-defeating to say that individuals have an unlimited right to manipulate their own or their future children’s heritable genetics. The future of human life is all of our concern and must be regulated, albeit wisely.
In some cases, such as when we have the ability to prevent a deadly genetic disroder, it might be highly ethical to manipulate other human beings. In other circumstances, the genetic engineering of humans might be highly unethical. The key point is to avoid asking this question in a binary manner. We need to weigh the costs and benefits of each type of intervention. We need societal and global infrastrucutres to do that well. We don’t yet have those but we need them badly.
Can you tell us more about your next book?
The Great Biohack: Recasting Lifee in an Age of Revolutionary Technology, will come out in May 2024. It explores what the intersecting AI, genetics, and biotechnology revolutions will mean for the future of life on earth, including our healthcare, agriculture, industry, computing, and everything else. We are at a transitional moment for life on earth, equivalent to the dawn of agriculture, electricity, and industrialization. The key differentiator between better and worse outcomes is what we do today, at this early stage of this new transformation. The book describes what’s happening, what’s at stake, and what we each and all can and, frankly, must do to build the type of future we’d like to inhabit.
You’ve been a leader of international efforts calling for a full investigation into COVID-19 origins and are the founder of the global movement OneShared.World. What problem are you trying to solve through OneShared.World?
The biggest challenge we face today is the mismatch between the nature of our biggest problems, global and common, and the absence of a sufficient framework for addressing that entire category of challenges. The totally avoidable COVID-19 pandemic is one example of the extremet costs of the status quo. OneShared.World is our effort to fight for an upgrade in our world’s global operating system, based around the mutual responsibilities of interdependence. We’ve had global OS upgrades before after the Thirty Years War and after World War II, but wouldn’t it be better to make the necessary changes now to prevent a crisis of that level stemming from a nuclear war, ecosystem collapse, or deadlier synthetic biology pandemic rather than waiting until after? Revolutionary science is a global issue that must be wisely managed at every level if it is to be wisely managed at all.
How do we ensure that revolutionary technologies benefit humanity instead of undermining it?
That is the essential question. It’s why I’ve written Hacking Darwin, am writing The Great Biohack, and doing the rest of my work. If we want scietific revolutions to help, rather than hurt, us, we must all play a role building that future. This isn’t just a conversation about science, it’s about how we can draw on our most cherished values to guide the optimal development of science and technology for the common good. That must be everyone’s business.
Portions of this interview were first published in Grassia (Italy) and Zen Portugal.
Jamie Metzl is one of the world’s leading technology and healthcare futurists and author of the bestselling book, Hacking Darwin: Genetic Engineering and the Future of Humanity, which has been translated into 15 languages. In 2019, he was appointed to the World Health Organization expert advisory committee on human genome editing. Jamie is a faculty member of Singularity University and NextMed Health, a Senior Fellow of the Atlantic Council, and Founder and Chair of the global social movement, OneShared.World.
Called “the original COVID-19 whistleblower,” his pioneering role advocating for a full investigation into the origins of the COVID-19 pandemic has been featured in 60 Minutes, the New York Times, and most major media across the globe, and he was the lead witness in the first congressional hearings on this topic. Jamie previously served in the U.S. National Security Council, State Department, and Senate Foreign Relations Committee and with the United Nations in Cambodia. Jamie appears regularly on national and international media and his syndicated columns and other writing in science, technology, and global affairs are featured in publications around the world.
Jamie sits on advisory boards for multiple biotechnology and other companies and is Special Strategist to the WisdomTree BioRevolution Exchange Traded Fund. In addition to Hacking Darwin, he is author of a history of the Cambodian genocide, the historical novel The Depths of the Sea, and the genetics sci-fi thrillers Genesis Code and Eternal Sonata. His next book, The Great Biohack: Recasting Life in an age of Revolutionary Technology, will be published by Hachette in May 2024. Jamie holds a Ph.D. from Oxford, a law degree from Harvard, and an undergraduate degree from Brown and is an avid ironman triathlete and ultramarathon runner.