Are rats with human brain cells still just rats?

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This week I wrote about a fascinating experiment that involved implanting human brain cells into rats’ brains. The brain cells from both species were able to form connections and work together. The human cells became part of the rats’ brains.

The idea is to get a better sense of what happens in the brains of living people—something that is notoriously difficult to do. For the last decade or so, scientists have been studying lab-grown clumps of brain cells called organoids. The new study shows that these organoids start to look much more like functional human brain cells when they are implanted into the brain of a baby rat.

A few months after they’d been implanted, the human cells made up around a sixth of the rats’ brains and appeared to have a role in controlling the animals’ behavior. Which invites the question: Are these animals still 100% rat?

It’s a tricky one. The scientists behind the work argue that there’s nothing really human about these rats. Throughout the study, the team examined the rats to see if those with human cells were any smarter, or experienced more suffering, than rats that didn’t receive organoid transplants. They found no sign of human traits or behaviors.

But the whole point of implanting human cells is to get some insight into what happens in the human brain. So there’s a trade-off here. Essentially, the animals need to represent what happens in humans without becoming too human themselves. And if the rats don’t show any human behaviors, can they really tell us that much about human disease?

“The question is: What percentage of animal cells would be needed in the brain to reduce animal behavior and see a different type of behavior?” asks Jeantine Lunshof, a philosopher and ethicist at the Wyss Institute for Biologically Inspired Engineering at Harvard University.

This raises another question. What would it take for us to accept that an animal is no longer a typical member of its own species? Many of the discussions on this topic focus on moral status. Most people would agree that humans have a greater moral status than other animals—and that it is not acceptable to treat people the same way we treat animals, whether for research or in other contexts.

It can be difficult to pinpoint exactly what it is about us that makes us special, but the consensus is that it has something to do with our brains, which are larger and more complex than those of other animals. It is our brains that allow us to think, feel, dream, rationalize, form social bonds, plan our futures, and, more generally, experience consciousness and self-awareness. Could rodents with human brain cells have these same experiences?

It’s an important question for bioethicists like Julian Koplin at Monash University in Victoria, Australia. “If we’re talking about humanizing the brains of non-human animals … by introducing human brain organoids and allowing them to integrate into the animal brain,” he says, “I think we do need to start thinking about whether this could have any follow-on effect for the moral status of the research animal.”

In the current study, the answer appears to be no. But that doesn’t mean we won’t see “humanized” or “enhanced” rats in future, according to Koplin and other bioethicists who specialize in this field.

We need to tread carefully.

In this study, scientists put human brain organoids into a region of the rats’ brains that helps them sense their environment. But there’s no reason they couldn’t put the same organoids into regions that play a role in cognition or consciousness—which might make cognitive enhancement more likely.

Then there’s the question of how much of the rat’s brain is made up of human cells. Transplanting bigger organoids might mean that the rat is technically “more human” at the cellular level—but that’s not what’s important. What matters is how, if at all, its mental state changes.

The mental changes aren’t just about how “human” the rats’ mental states become, either. “You might have an animal that thinks in a very different way to we do, but is acutely susceptible to suffering, or is really intelligent in ways that are not familiar to us as humans,” says Koplin.

So far, we’ve focused on rats. But what would happen if the organoids were put into baby monkeys instead? Non-human primates have brains that look and work much more like ours, so they’d be better models for studying human disease. But “it does raise the possibility that you will create a humanized primate,” says Julian Savulescu, a bioethicist at the National University of Singapore.

Savulescu is also concerned about cloning. The cells that make up organoids contain a person’s DNA. What would happen if a large chunk of a monkey’s brain were made up of cells with an individual’s genetic code?

“If you were to introduce an advanced organoid into a developing primate, you may well essentially create a clone of an existing person,” he says. “Not only would it be humanized—it would be a clone of somebody that’s already in existence.” This would be the very bottom of an ethical slippery slope, says Savulescu.

There are a lot of questions here, and few definitive answers. No one really knows how to measure moral status, or the point at which animals with human cells become special—or even some kind of new animal.

But it provides plenty of food for thought. To read more, check out these articles from Tech Review’s archive:
 
In this piece from 2016, Antonio Regalado describes researchers’ attempts to grow human organs in pigs and sheep. The aim here is to create new organs for people who need transplants.

A Spanish stem-cell biologist told a reporter that the pope had given his blessing to this kind of research. But the Vatican later disputed the claim and called it “absolutely unfounded.”

A few years later, that same biologist went on to create embryos that are part human and part monkey, as reported by El País. Antonio explained why the research was so controversial.

In this recent piece, Hannah Thomasy explores eight technologies that are helping us understand the mysteries of the human brain and how we form memories.

And you can read more about how our brains make our minds in this piece from Lisa Feldman Barrett, which was featured in last year’s Mind issue.

From around the web

Could an algorithm help people who choose to end their own lives? The founder of this nonprofit thinks so. (MIT Technology Review)

Monkeypox cases have been declining for a couple of months now. But there are several ways things could play out from here. (Nature)

Covid boosters have been approved for children as young as five in the US. (Reuters)

Long covid is an enduring problem. Almost half of those who get sick with covid still haven’t fully recovered months later. (New York Times)

Watch this game of Pong. And then realize that it is being played by brain cells in a dish. (Neuron)

Why the sci-fi dream of cryonics never died

When Aaron Drake flew from Arizona to the Yinfeng Biological Group in China’s eastern Jinan province in 2016, he was whisked into a state-of-the-art biotech hub. More than 1,000 staffers—including an army of PhDs and MDs—were working on things like studies of the stem cells in umbilical cord blood. The center specialized in research on human cells, from gene testing to tailored cancer treatments. 

But it also had other plans: cylindrical stainless-steel tanks would eventually contain corpses suspended in liquid nitrogen. The tanks weren’t installed yet, but Yinfeng hoped Drake would help with that while it invested some $7 million to get the new project off the ground. As its high-profile new hire, he was there to guide China’s first forays into cryonics, or freezing corpses for reanimation.

The environment was something of a shift for Drake, who had spent the previous seven years as the medical response director of the Alcor Life Extension Foundation. Though it was the longtime leader in cryonics, Alcor was still a small nonprofit. It had been freezing the bodies and brains of its members, with the idea of one day bringing them back to life, since 1976. 

The foundation, and cryonics in general, had long survived outside of mainstream acceptance. Typically shunned by the scientific community, cryonics is best known for its appearance in sci-fi films like 2001: A Space Odyssey. But its adherents have held on to a dream that at some point in the future, advances in medicine will allow for resuscitation and additional years on Earth. Over decades, small, tantalizing developments in related technology, as well as high-­profile frozen test subjects like Ted Williams, have kept the hope alive. Today, nearly 200 dead patients are frozen in Alcor’s cryogenic chambers at temperatures of −196 °C, including a handful of celebrities, who have paid tens of thousands of dollars for the goal of “possible revival” and ultimately “reintegration into society.”

But it’s the recent involvement of Yinfeng that signals something of a new era for cryonics. With impressive financial resources, government support, and scientific staff, it’s one of a handful of new labs focused on expanding the consumer appeal of cryonics and trying anew to bring credibility to the long-disputed theory of human reanimation. Just a year after Drake came on board as research director of the Shandong Yinfeng Life Science Research Institute, the subsidiary of the Yinfeng Biological Group overseeing the cryonics program, the institute performed its first cryopreservation. Its storage vats now hold about a dozen clients who are paying upwards of $200,000 to preserve the whole body. 

Still, the field remains rooted in faith rather than any real evidence that it works. “It’s a hopeless aspiration that reveals an appalling ignorance of biology,” says Clive Coen, a neuroscientist and professor at King’s College London.

Even if one day you could perfectly thaw a frozen human body, you would still just have a warm dead body on your hands.

The cryonics process typically goes something like this: Upon a person’s death, a response team begins the process of cooling the corpse to a low temperature and performs cardiopulmonary support to sustain blood flow to the brain and organs. Then the body is moved to a cryonics facility, where an organ preservation solution is pumped through the veins before the body is submerged in liquid nitrogen. This process should commence within one hour of death—the longer the wait, the greater the damage to the body’s cells. Then, once the frozen cadaver is ensconced in the cryogenic chamber, the hope of the dead begins. 

Since its beginnings in the late 1960s, the field has attracted opprobrium from the scientific community, particularly its more respectable cousin cryobiology—the study of how freezing and low temperatures affect living organisms and biological materials. The Society for Cryobiology even banned its members from involvement in cryonics in the 1980s, with a former society president lambasting the field as closer to “fraud than either faith or science.” 

In recent years, though, it has grabbed the attention of the libertarian techno-­optimist crowd, mostly tech moguls dreaming of their own immortality. And a number of new startups are expanding the playing field. Tomorrow Biostasis in Berlin became the first cryonics company in Western Europe in 2019, for example, and in early 2022, Southern Cryonics opened a facility in Australia. 

“More researchers are open to longer-­term, futuristic topics than there might have been 20 years ago or so,” says Tomorrow Biostasis founder Emil Kendziorra. 

The Society for Cryobiology has even dropped its past cryonics-related restrictions. And now its president, cryobiologist and biogerontologist Greg Fahy, is behind a company called 21st Century Medicine, which develops techniques to cryogenically preserve human organs and tissues. (Still, the society said in a statement to MIT Technology Review that cryonics “is an act of speculation or hope, not science.”)

Today, around 500 people are preserved in liquid nitrogen globally, the vast majority in the United States. Around 4,000 people are on waiting lists of cryonics facilities around the world, says Kendziorra. Alcor has around 1,500 members, and Tomorrow Biostasis already has 300 clients paying a relatively accessible monthly membership fee of €25 (with €200,000 payable at the time of death).

Despite a lack of evidence that dead people could one day be brought back to life, cryonicists perhaps unsurprisingly remain optimistic, noting that tissues like sperm, embryo, and stem cells can be successfully cryopreserved and thawed right now, and that researchers claim to have cryogenically frozen and thawed small worms and rabbit kidneys. Researchers at 21st Century Medicine, for instance, cryopreserved and thawed a rabbit brain in 2016 and a pig brain in 2018. 

But Dayong Gaom, a cryobiologist and professor at the University of Washington, points out preserving the brain’s structure does not mean preserving its functions. KCL’s Coen says it’s “disingenuous” to say these studies support the aims of cryonics and maintains that brain structures are far too complex to be adequately preserved and revived in the way cryonicists claim.  

There’s also been some progress, though, in finding a way to rewarm frozen tissues. A research group at the University of Minnesota showed that nanowarming techniques, using radio-frequency-excited nanoparticles of iron oxide, could work on larger samples of 50 millimeters. The team has now successfully thawed whole rat organs in a way that preserves cell structure and is nontoxic to cells, with a view to restoring the organ’s functions. It is now experimenting with pig organs.

Yinfeng is devoted to solving the same problem—it’s currently experimenting with cryogenic methods to preserve individual human organs and amputated extremities to boost China’s national transplant program. 

But none of these developments lead to a possible way to eventually revive a living person. Even if one day you could perfectly thaw a frozen human body, you would still just have a warm dead body on your hands. The hardest part to reverse—death itself—remains an enigma.

This is not lost on Drake. But the clients seeking cryonics services are often “either agnostic or atheist,” he says. “Instead of a faith in a supreme being, they have faith in science—that science, more specifically medical science, will eventually figure this out.”

Laurie Clarke is a technology journalist based in the UK.