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.
Two-and-a-half year-old Huckleberry, a blue merle Australian shepherd, pulls hard at her leash; her yelps can be heard by skiers and boarders high above on the chairlift that carries them over the ski patrol hut to the top of the mountain. Huckleberry is an avalanche rescue dog — or avy dog, for short. She lives and works with her owner and handler, a ski patroller at Breckenridge Ski Resort in Colorado. As she watches the trainer play a game of hide-and-seek with six-month-old Lume, a golden retriever and avy dog-in-training, Huckleberry continues to strain on her leash; she loves the game. Hide-and-seek is one of the key training methods for teaching avy dogs the rescue skills they need to find someone caught in an avalanche — skier, snowmobiler, hiker, climber.
Lume’s owner waves a T-shirt in front of the puppy. While another patroller holds him back, Lume’s owner runs away and hides. About a minute later — after a lot of barking — Lume is released and commanded to “search.” He springs free, running around the hut to find his owner who reacts with a great amount of excitement and fanfare. Lume’s scent training will continue for the rest of the ski season (Breckenridge plans operating through May or as long as weather permits) and through the off-season. “We make this game progressively harder by not allowing the dog watch the victim run away,” explains Dave Leffler, Breckenridge's ski patroller and head of the avy dog program, who has owned, trained and raised many of them. Eventually, the trainers “dig an open hole in the snow to duck out of sight and gradually turn the hole into a cave where the dog has to dig to get the victim,” explains Leffler.
By the time he is three, Lume, like Huckleberry, will be a fully trained avy pup and will join seven other avy dogs on Breckenridge ski patrol team. Some of the team members, both human and canine, are also certified to work with Colorado Rapid Avalanche Deployment, a coordinated response team that works with the Summit County Sheriff’s office for avalanche emergencies outside of the ski slopes’ boundaries.
There have been 19 avalanche deaths in the U.S. this season, according to avalanche.org, which tracks slides; eight in Colorado. During the entirety of last season there were 17. Avalanche season runs from November through June, but avalanches can occur year-round.
High tech and high stakes
Complementing avy dogs’ ability to smell people buried in a slide, avalanche detection, rescue and recovery is becoming increasingly high tech. There are transceivers, signal locators, ground scanners and drones, which are considered “games changers” by many in avalanche rescue and recovery
For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
A drone can provide thermal imaging of objects caught in a slide; what looks like a rock from far away might be a human with a heat signature. Transceivers, also known as beacons, send a signal from an avalanche victim to a companion. Signal locators, like RECCO reflectors which are often sewn directly into gear, can echo back a radar signal sent by a detector; most ski resorts have RECCO detector units.
Research suggests that Ground Penetrating Radar (GPR), an electromagnetic tool used by geophysicists to pull images from inside the ground, could be used to locate an avalanche victim. A new study from the Department of Energy’s Sandia National Laboratories suggests that a computer program developed to pinpoint the source of a chemical or biological terrorist attack could also be used to find someone submerged in an avalanche. The search algorithm allows for small robots (described as cockroach-sized) to “swarm” a search area. Researchers say that this distributed optimization algorithm can help find avalanche victims four times faster than current search mechanisms. For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
An avy dog in training is picking up scent
Sarah McLear
While rescue gear has been evolving, predicting when a slab will fall remains an emerging science — kind of where weather forecasting science was in the 1980s. Avalanche forecasting still relies on documenting avalanches by going out and looking,” says Ethan Greene, director of the Colorado Avalanche Information Center (CAIC). “So if there's a big snowstorm, and as you might remember, most avalanches happened during snowstorms, we could have 10,000 avalanches that release and we document 50,” says Greene. “Avalanche forecasting is essentially pattern recognition,” he adds--and understanding the layering structure of snow.
However, determining where the hazards lie can be tricky. While a dense layer of snow over a softer, weaker layer may be a recipe for an avalanche, there’s so much variability in snowpack that no one formula can predict the trigger. Further, observing and measuring snow at a single point may not be representative of all nearby slopes. Finally, there’s not enough historical data to help avalanche scientists create better prediction models.
That, however, may be changing.
Last year, an international group of researchers created computer simulations of snow cover using 16 years of meteorological data to forecast avalanche hazards, publishing their research in Cold Regions Science and Technology. They believe their models, which categorize different kinds of avalanches, can support forecasting and determine whether the avalanche is natural (caused by temperature changes, wind, additional snowfall) or artificial (triggered by a human or animal).
With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides.
With data from two sites in British Columbia and one in Switzerland, researchers built computer simulations of five different avalanche types. “In terms of real time avalanche forecasting, this has potential to fill in a lot of data gaps, where we don't have field observations of what the snow looks like,” says Simon Horton, a postdoctoral fellow with the Simon Fraser University Centre for Natural Hazards Research and a forecaster with Avalanche Canada, who participated in the study. While complex models that simulate snowpack layers have been around for a few decades, they weren’t easy to apply until recently. “It's been difficult to find out how to apply that to actual decision-making and improving safety,” says Horton. If you can derive avalanche problem types from simulated snowpack properties, he says, you’ll learn “a lot about how you want to manage that risk.”
The five categories include “new snow,” which is unstable and slides down the slope, “wet snow,” when rain or heat makes it liquidly, as well as “wind-drifted snow,” “persistent weak layers” and “old snow.” “That's when there's some type of deeply buried weak layer in the snow that releases without any real change in the weather,” Horton explains. “These ones tend to cause the most accidents.” One step by a person on that structurally weak layer of snow will cause a slide. Horton is hopeful that computer simulations of avalanche types can be used by scientists in different snow climates to help predict hazard levels.
Greene is doubtful. “If you have six slopes that are lined up next to each other, and you're going to try to predict which one avalanches and the exact dimensions and what time, that's going to be really hard to do. And I think it's going to be a long time before we're able to do that,” says Greene.
What both researchers do agree on, though, is that what avalanche prediction really needs is better imagery through satellite detection. “Just being able to count the number of avalanches that are out there will have a huge impact on what we do,” Greene says. “[Satellites] will change what we do, dramatically.” In a 2022 paper, scientists at the University of Aberdeen in England used satellites to study two deadly Himalayan avalanches. The imaging helped them determine that sediment from a 2016 ice avalanche plus subsequent snow avalanches contributed to the 2021 avalanche that caused a flash flood, killing over 200 people. The researchers say that understanding the avalanches characteristics through satellite imagery can inform them how one such event increases the magnitude of another in the same area.
Avy dogs trainers hide in dug-out holes in the snow, teaching the dogs to find buried victims
Sarah McLear
Lifesaving combo: human tech and Mother Nature’s gear
Even as avalanche forecasting evolves, dogs with their built-in rescue mechanisms will remain invaluable. With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides. (Humans in comparison, have a meager 12 million.) A new study published in the Journal of Neuroscience revealed that in dogs smell and vision are connected in the brain, which has not been found in other animals. “They can detect the smell of their owner's fingerprints on a glass slide six weeks after they touched it,” says Nicholas Dodman, professor emeritus at Cummings School of Veterinary Medicine at Tufts University. “And they can track from a boat where a box filled with meat was buried in the water, 100 feet below,” says Dodman, who is also co-founder and president of the Center for Canine Behavior Studies.
Another recent study from Queens College in Belfast, United Kingdom, further confirms that dogs can smell when humans are stressed. They can also detect the smell of a person’s breath and the smell of the skin cells of a deceased person.
The emerging avalanche-predicting human-made tech and the incredible nature-made tech of dogs’ olfactory talents is the lifesaving “equipment” that Leffler believes in. Even when human-made technology develops further, it will be most efficient when used together with the millions of dogs’ smell receptors, Leffler believes. “It is a combination of technology and the avalanche dog that will always be effective in finding an avalanche victim.”
Living with someone changes your microbiome, new research shows
Some roommate frustration can be expected, whether it’s a sink piled high with crusty dishes or crumbs where a clean tabletop should be. Now, research suggests a less familiar issue: person-to-person transmission of shared bacterial strains in our gut and oral microbiomes. For the first time, the lab of Nicola Segata, a professor of genetics and computational biology at the University of Trento, located in Italy, has shown that bacteria of the microbiome are transmitted between many individuals, not just infants and their mothers, in ways that can’t be explained by their shared diet or geography.
It’s a finding with wide-ranging implications, yet frustratingly few predictable outcomes. Our microbiomes are an ever-growing and changing collection of helpful and harmful bacteria that we begin to accumulate the moment we’re born, but experts are still struggling to unravel why and how bacteria from one person’s gut or mouth become established in another person’s microbiome, as opposed to simply passing through.
“If we are looking at the overall species composition of the microbiome, then there is an effect of age of course, and many other factors,” Segata says. “But if we are looking at where our strains are coming from, 99 percent of them are only present in other people’s guts. They need to come from other guts.”
If we could better understand this process, we might be able to control and use it; perhaps hospital patients could avoid infections from other patients when their microbiome is depleted by antibiotics and their immune system is weakened, for example. But scientists are just beginning to link human microbiomes with various ailments. Growing evidence shows that our microbiomes steer our long-term health, impacting conditions like obesity, irritable bowel syndrome, type 2 diabetes, and cancer.
Previous work from Segata’s lab and others illuminated the ways bacteria are passed from mothers to infants during the first few months of life during vaginal birth, breastfeeding and other close contact. And scientists have long known that people in close proximity tend to share bacteria. But the factors related to that overlap, such as genetics and diet, were unclear, especially outside the mother-baby dyad.
“If we look at strain sharing between a mother and an infant at five years of age, for example, we cannot really tell which was due to transmission at birth and which is due to continued transmission because of contact,” Segata says. Experts hypothesized that they could be caused by bacterial similarities in the environment itself, genetics, or bacteria from shared foods that colonized the guts of people in close contact.
Strain sharing was highest in mother-child pairs, with 96 percent of them sharing strains, and only slightly lower in members of shared households, at 95 percent.
In Italy, researchers led by Mireia Valles-Colomer, including Segata, hoped to unravel this mystery. They compared data from 9,715 stool and saliva samples in 31 genomic datasets with existing metadata. Scientists zoomed in on variations in each bacterial strain down to the individual level. They examined not only mother-child pairs, but people living in the same household, adult twins, and people living in the same village in a level of detail that wasn’t possible before, due to its high cost and difficulties in retrieving data about interactions between individuals, Segata explained.
“This paper is, with high granularity, quantifying the percent sharing that you expect between different types of social interactions, controlling for things like genetics and diet,” Gibbons says. Strain sharing was highest in mother-child pairs, with 96 percent of them sharing strains, and only slightly lower in members of shared households, at 95 percent. And at least half of the mother-infant pairs shared 30 percent of their strains; the median was 12 percent among people in shared households. Yet, there was no sharing among eight percent of adult twins who lived separately, and 16 percent of people within villages who resided in different households. The results were published in Nature.
It’s not a regional phenomenon. Although the types of bacterial strains varied depending on whether people lived in western and eastern nations — datasets were drawn from 20 countries on five continents — the patterns of sharing were much the same. To establish these links, scientists focused on individual variations in shared bacterial strains, differences that create unique bacterial “fingerprints” in each person, while controlling for variables like diet, demonstrating that the bacteria had been transmitted between people and were not the result of environmental similarities.
The impact of this bacterial sharing isn’t clear, but shouldn’t be viewed with trepidation, according to Sean Gibbons, a microbiome scientist at the nonprofit Institute for Systems Biology.
“The vast majority of these bugs are actually either benign or beneficial to our health, and the fact that we're swapping and sharing them and that we can take someone else's strain and supplement or better diversify our own little garden is not necessarily a bad thing,” he says.
"There are hundreds of billions of dollars of investment capital moving into these microbiome therapeutic companies; bugs as drugs, so to speak,” says Sean Gibbons, a microbiome scientist at the Institute for Systems Biology.
Everyday habits like exercising and eating vegetables promote a healthy, balanced gut microbiome, which is linked to better metabolic and immune function, and fewer illnesses. While many people’s microbiomes contain bacteria like C. diff or E. coli, these bacteria don’t cause diseases in most cases because they’re present in low levels. But a microbiome that’s been wiped out by, say, antibiotics, may no longer keep these bacteria in check, allowing them to proliferate and make us sick.
“A big challenge in the microbiome field is being able to rationally predict whether, if you're exposed to a particular bug, it will stick in the context of your specific microbiome,” Gibbons says.
Gibbons predicts that explorations of microbe-based therapeutics will be “exploding” in the coming decades. “There are hundreds of billions of dollars of investment capital moving into these microbiome therapeutic companies; bugs as drugs, so to speak,” he says. Rather than taking a mass-marketed probiotic, a precise understanding of an individual’s microbiome could help target the introduction of just the right bacteria at just the right time to prevent or treat a particular illness.
Because the current study did not differentiate between different types of contact or relationships among household members sharing bacterial strains or determine the direction of transmission, Segata says his current project is examining children in daycare settings and tracking their microbiomes over time to understand the role genetics and everyday interactions play in the level of transmission that occurs.
This relatively newfound ability to trace bacterial variants to minute levels has unlocked the chance for scientists to untangle when and how bacteria leap from one microbiome to another. As researchers come to better understand the factors that permit a strain to establish itself within a microbiome, they could uncover new strategies to control these microbes, harnessing the makeup of each microbiome to help people to resist life-altering medical conditions.