Posts Tagged ‘Antonio Regalado’

by Antonio Regalado

Human intelligence is one of evolution’s most consequential inventions. It is the result of a sprint that started millions of years ago, leading to ever bigger brains and new abilities. Eventually, humans stood upright, took up the plow, and created civilization, while our primate cousins stayed in the trees.

Now scientists in southern China report that they’ve tried to narrow the evolutionary gap, creating several transgenic macaque monkeys with extra copies of a human gene suspected of playing a role in shaping human intelligence.

“This was the first attempt to understand the evolution of human cognition using a transgenic monkey model,” says Bing Su, the geneticist at the Kunming Institute of Zoology who led the effort.

According to their findings, the modified monkeys did better on a memory test involving colors and block pictures, and their brains also took longer to develop—as those of human children do. There wasn’t a difference in brain size.

The experiments, described on March 27 in a Beijing journal, National Science Review, and first reported by Chinese media, remain far from pinpointing the secrets of the human mind or leading to an uprising of brainy primates.

Instead, several Western scientists, including one who collaborated on the effort, called the experiments reckless and said they questioned the ethics of genetically modifying primates, an area where China has seized a technological edge.

“The use of transgenic monkeys to study human genes linked to brain evolution is a very risky road to take,” says James Sikela, a geneticist who carries out comparative studies among primates at the University of Colorado. He is concerned that the experiment shows disregard for the animals and will soon lead to more extreme modifications. “It is a classic slippery slope issue and one that we can expect to recur as this type of research is pursued,” he says.

Research using primates is increasingly difficult in Europe and the US, but China has rushed to apply the latest high-tech DNA tools to the animals. The country was first to create monkeys altered with the gene-editing tool CRISPR, and this January a Chinese institute announced it had produced a half-dozen clones of a monkey with a severe mental disturbance.

“It is troubling that the field is steamrolling along in this manner,” says Sikela.

Evolution story

Su, a researcher at the Kunming Institute of Zoology, specializes in searching for signs of “Darwinian selection”—that is, genes that have been spreading because they’re successful. His quest has spanned such topics as Himalayan yaks’ adaptation to high altitude and the evolution of human skin color in response to cold winters.

The biggest riddle of all, though, is intelligence. What we know is that our humanlike ancestors’ brains rapidly grew in size and power. To find the genes that caused the change, scientists have sought out differences between humans and chimpanzees, whose genes are about 98% similar to ours. The objective, says, Sikela, was to locate “the jewels of our genome”—that is, the DNA that makes us uniquely human.

For instance, one popular candidate gene called FOXP2—the “language gene” in press reports—became famous for its potential link to human speech. (A British family whose members inherited an abnormal version had trouble speaking.) Scientists from Tokyo to Berlin were soon mutating the gene in mice and listening with ultrasonic microphones to see if their squeaks changed.

Su was fascinated by a different gene, MCPH1, or microcephalin. Not only did the gene’s sequence differ between humans and apes, but babies with damage to microcephalin are born with tiny heads, providing a link to brain size. With his students, Su once used calipers and head spanners to the measure the heads of 867 Chinese men and women to see if the results could be explained by differences in the gene.

By 2010, though, Su saw a chance to carry out a potentially more definitive experiment—adding the human microcephalin gene to a monkey. China by then had begun pairing its sizeable breeding facilities for monkeys (the country exports more than 30,000 a year) with the newest genetic tools, an effort that has turned it into a mecca for foreign scientists who need monkeys to experiment on.

To create the animals, Su and collaborators at the Yunnan Key Laboratory of Primate Biomedical Research exposed monkey embryos to a virus carrying the human version of microcephalin. They generated 11 monkeys, five of which survived to take part in a battery of brain measurements. Those monkeys each have between two and nine copies of the human gene in their bodies.

Su’s monkeys raise some unusual questions about animal rights. In 2010, Sikela and three colleagues wrote a paper called “The ethics of using transgenic non-human primates to study what makes us human,” in which they concluded that human brain genes should never be added to apes, such as chimpanzees, because they are too similar to us. “You just go to the Planet of the Apes immediately in the popular imagination,” says Jacqueline Glover, a University of Colorado bioethicist who was one of the authors. “To humanize them is to cause harm. Where would they live and what would they do? Do not create a being that can’t have a meaningful life in any context.”

In an e-mail, Su says he agrees that apes are so close to humans that their brains shouldn’t be changed. But monkeys and humans last shared an ancestor 25 million years ago. To Su, that alleviates the ethical concerns. “Although their genome is close to ours, there are also tens of millions of differences,” he says. He doesn’t think the monkeys will become anything more than monkeys. “Impossible by introducing only a few human genes,” he says.

Smart monkey?

Judging by their experiments, the Chinese team did expect that their transgenic monkeys could end up with increased intelligence and brain size. That is why they put the creatures inside MRI machines to measure their white matter and gave them computerized memory tests. According to their report, the transgenic monkeys didn’t have larger brains, but they did better on a short-term memory quiz, a finding the team considers remarkable.

Several scientists think the Chinese experiment didn’t yield much new information. One of them is Martin Styner, a University of North Carolina computer scientist and specialist in MRI who is listed among the coauthors of the Chinese report. Styner says his role was limited to training Chinese students to extract brain volume data from MRI images, and that he considered removing his name from the paper, which he says was not able to find a publisher in the West.

“There are a bunch of aspects of this study that you could not do in the US,” says Styner. “It raised issues about the type of research and whether the animals were properly cared for.”

After what he’s seen, Styner says he’s not looking forward to more evolution research on transgenic monkeys. “I don’t think that is a good direction,” he says. “Now we have created this animal which is different than it is supposed to be. When we do experiments, we have to have a good understanding of what we are trying to learn, to help society, and that is not the case here.” One issue is that genetically modified monkeys are expensive to create and care for. With just five modified monkeys, it’s hard to reach firm conclusions about whether they really differ from normal monkeys in terms of brain size or memory skills. “They are trying to understand brain development. And I don’t think they are getting there,” says Styner.

In an e-mail, Su agreed that the small number of animals was a limitation. He says he has a solution, though. He is making more of the monkeys and is also testing new brain evolution genes. One that he has his eye on is SRGAP2C, a DNA variant that arose about two million years ago, just when Australopithecus was ceding the African savannah to early humans. That gene has been dubbed the “humanity switch” and the “missing genetic link” for its likely role in the emergence of human intelligence.

Su says he’s been adding it to monkeys, but that it’s too soon to say what the results are.


by Antonio Regalado

In a step that could change the definition of death, researchers have restored circulation to the brains of decapitated pigs and kept the reanimated organs alive for as long as 36 hours.

The feat offers scientists a new way to study intact brains in the lab in stunning detail. But it also inaugurates a bizarre new possibility in life extension, should human brains ever be kept on life support outside the body.

The work was described on March 28 at a meeting held at the National Institutes of Health to investigate ethical issues arising as US neuroscience centers explore the limits of brain science.

During the event, Yale University neuroscientist Nenad Sestan disclosed that a team he leads had experimented on between 100 and 200 pig brains obtained from a slaughterhouse, restoring their circulation using a system of pumps, heaters, and bags of artificial blood warmed to body temperature.

There was no evidence that the disembodied pig brains regained consciousness. However, in what Sestan termed a “mind-boggling” and “unexpected” result, billions of individual cells in the brains were found to be healthy and capable of normal activity.

Reached by telephone yesterday, Sestan declined to elaborate, saying he had submitted the results for publication in a scholarly journal and had not intended for his remarks to become public.

Since last spring, however, a widening circle of scientists and bioethicists have been buzzing about the Yale research, which involves a breakthrough in restoring micro-circulation—the flow of oxygen to small blood vessels, including those deep in the brain.

“These brains may be damaged, but if the cells are alive, it’s a living organ,” says Steve Hyman, director of psychiatric research at the Broad Institute in Cambridge, Massachusetts, who was among those briefed on the work. “It’s at the extreme of technical know-how, but not that different from preserving a kidney.”

Hyman says the similarity to techniques for preserving organs like hearts or lungs for transplant could cause some to mistakenly view the technology as a way to avoid death. “It may come to the point that instead of people saying ‘Freeze my brain,’ they say ‘Hook me up and find me a body,’” says Hyman.

Such hopes are misplaced, at least for now. Transplanting a brain into a new body “is not remotely possible,” according to Hyman.

Brain in a bucket

The Yale system, called BrainEx, involves connecting a brain to a closed loop of tubes and reservoirs that circulate a red perfusion fluid, which is able to carry oxygen to the brain stem, the cerebellar artery, and areas deep in the center of the brain.

In his presentation to the NIH officials and ethics experts, Sestan said the technique was likely to work in any species, including primates. “This is probably not unique to pigs,” he said.

The Yale researchers, who began work on the technique about four years ago and are seeking NIH funding for it, acted out of a desire to construct a comprehensive atlas of connections between human brain cells.

Some of these connections probably span large regions of the brain and would thus be traced more easily in a complete, intact organ.

Sestan acknowledged that surgeons at Yale had already asked him if the brain-preserving technology could have medical uses. Disembodied human brains, he said, could become guinea pigs for testing exotic cancer cures and speculative Alzheimer’s treatments too dangerous to try on the living.

The setup, jokingly dubbed the “brain in a bucket,” would quickly raise serious ethical and legal questions if it were tried on a human.

For instance, if a person’s brain were reanimated outside the body, would that person awake in what would amount to the ultimate sensory deprivation chamber, without ears, eyes, or a way to communicate? Would someone retain memories, an identity, or legal rights? Could researchers ethically dissect or dispose of such a brain?

Also, because federal safety regulations apply to people, not “dead” tissues, it is uncertain whether the US Food and Drug Administration would have any say over whether scientists could attempt such a reanimation procedure.

“There are going to be a lot of weird questions even if it isn’t a brain in a box,” said an advisor to the NIH who didn’t wish to speak on the record. “I think a lot of people are going to start going to slaughterhouses to get heads and figure it out.”

Sestan said he was concerned about how the technology would be received by the public and by his peers. “People are fascinated. We have to be careful how fascinated,” he said.

Comatose state

It’s well known that a comatose brain can be kept alive for at least decades. That is the case with brain-dead people whose families elect to keep them attached to ventilating machines.

Less well explored are artificial means of maintaining a brain wholly separated from its body. There have been previous attempts, including a 1993 report involving rodents, but Sestan’s team is the first to achieve it with a large mammal, without using cold temperatures, and with such promising results.

At first, the Yale group was uncertain if an “ex vivo” brain to which circulation was restored would regain consciousness. To answer that question, the scientists checked for signs of complex activity in the pig brains using a version of EEG, or electrodes placed on the brain’s surface. These can pick up electrical waves reflecting broad brain activity indicating thoughts and sensations.

Initially, Sestan said, they believed they had found such signals, generating both alarm and excitement in the lab, but they later determined that those signals were artifacts created by nearby equipment.

Sestan now says the organs produce a flat brain wave equivalent to a comatose state, although the tissue itself “looks surprisingly great” and, once it’s dissected, the cells produce normal-seeming patterns.

The lack of wider electrical activity could be irreversible if it is due to damage and cell death. The pigs’ brains were attached to the BrainEx device roughly four hours after the animals were decapitated.

However, it could also be due to chemicals the Yale team added to the blood replacement to prevent swelling, which also severely dampen the activity of neurons. “You have to understand that we have so many channel blockers in our solution,” Sestan told the NIH. “This is probably the explanation why we don’t get [any] signal.”

Sestan told the NIH it is conceivable that the brains could be kept alive indefinitely and that steps could be attempted to restore awareness. He said his team had elected not to attempt either because “this is uncharted territory.”

“That animal brain is not aware of anything, I am very confident of that,” Sestan said, although he expressed concern over how the technique might be used by others in the future. “Hypothetically, somebody takes this technology, makes it better, and restores someone’s [brain] activity. That is restoring a human being. If that person has memory, I would be freaking out completely.”

Brain experiments

Consciousness isn’t necessary for the type of experiments on brain connections that scientists hope to carry out on living ex vivo brains. “The EEG brain activity is a flat line, but a lot of other things keep on ticking,” says Anna Devor, a neuroscientist at the University of California, San Diego, who is familiar with the Yale project.

Devor thinks the ability to work on intact, living brains would be “very nice” for scientists working to build a brain atlas. “The whole question of death is a gray zone,” she says. “But we need to remember the isolated brain is not the same as other organs, and we need to treat it with the same level of respect that we give to an animal.”

Today in the journal Nature, 17 neuroscientists and bioethicists, including Sestan, published an editorial arguing that experiments on human brain tissue may require special protections and rules.

They identified three categories of “brain surrogates” that provoke new concerns. These include brain organoids (blobs of nerve tissue the size of a rice grain), human-animal chimeras (mice with human brain tissue added), and ex vivo human brain tissue (such as chunks of brain removed during surgery).

They went on to suggest a variety of ethical safety measures, such as drugging animals that possess human brain cells so they stay in a “comatose-like brain state.”

Hyman, who also signed the letter, says he did so reluctantly, because he thinks most of the scenarios are exaggerated or unlikely. It’s hardly possible a tiny brain organoid will feel or think anything, he says.

The one type of research he thinks may call for quick action to set up rules of the road is Sestan’s unpublished brain preservation technique (which the Nature editorial did not discuss). “If people want to keep human brains alive post mortem, that is a more pressing and realistic problem,” says Hyman. “Given that it is possible with a pig brain, there should be guidelines for human tissue.”

by Antonio Regalado

The startup accelerator Y Combinator is known for supporting audacious companies in its popular three-month boot camp.

There’s never been anything quite like Nectome, though.

Next week, at YC’s “demo days,” Nectome’s cofounder, Robert McIntyre, is going to describe his technology for exquisitely preserving brains in microscopic detail using a high-tech embalming process. Then the MIT graduate will make his business pitch. As it says on his website: “What if we told you we could back up your mind?”

So yeah. Nectome is a preserve-your-brain-and-upload-it company. Its chemical solution can keep a body intact for hundreds of years, maybe thousands, as a statue of frozen glass. The idea is that someday in the future scientists will scan your bricked brain and turn it into a computer simulation. That way, someone a lot like you, though not exactly you, will smell the flowers again in a data server somewhere.

This story has a grisly twist, though. For Nectome’s procedure to work, it’s essential that the brain be fresh. The company says its plan is to connect people with terminal illnesses to a heart-lung machine in order to pump its mix of scientific embalming chemicals into the big carotid arteries in their necks while they are still alive (though under general anesthesia).

The company has consulted with lawyers familiar with California’s two-year-old End of Life Option Act, which permits doctor-assisted suicide for terminal patients, and believes its service will be legal. The product is “100 percent fatal,” says McIntyre. “That is why we are uniquely situated among the Y Combinator companies.”

There’s a waiting list

Brain uploading will be familiar to readers of Ray Kurzweil’s books or other futurist literature. You may already be convinced that immortality as a computer program is definitely going to be a thing. Or you may think transhumanism, the umbrella term for such ideas, is just high-tech religion preying on people’s fear of death.

Either way, you should pay attention to Nectome. The company has won a large federal grant and is collaborating with Edward Boyden, a top neuroscientist at MIT, and its technique just claimed an $80,000 science prize for preserving a pig’s brain so well that every synapse inside it could be seen with an electron microscope.

McIntyre, a computer scientist, and his cofounder Michael McCanna have been following the tech entrepreneur’s handbook with ghoulish alacrity. “The user experience will be identical to physician-assisted suicide,” he says. “Product-market fit is people believing that it works.”

Nectome’s storage service is not yet for sale and may not be for several years. Also still lacking is evidence that memories can be found in dead tissue. But the company has found a way to test the market. Following the example of electric-vehicle maker Tesla, it is sizing up demand by inviting prospective customers to join a waiting list for a deposit of $10,000, fully refundable if you change your mind.

So far, 25 people have done so. One of them is Sam Altman, a 32-year-old investor who is one of the creators of the Y Combinator program. Altman tells MIT Technology Review he’s pretty sure minds will be digitized in his lifetime. “I assume my brain will be uploaded to the cloud,” he says.

Old idea, new approach

The brain storage business is not new. In Arizona, the Alcor Life Extension Foundation holds more than 150 bodies and heads in liquid nitrogen, including those of baseball great Ted Williams. But there’s dispute over whether such cryonic techniques damage the brain, perhaps beyond repair.

So starting several years ago, McIntyre, then working with cryobiologist Greg Fahy at a company named 21st Century Medicine, developed a different method, which combines embalming with cryonics. It proved effective at preserving an entire brain to the nanometer level, including the connectome—the web of synapses that connect neurons.

A connectome map could be the basis for re-creating a particular person’s consciousness, believes Ken Hayworth, a neuroscientist who is president of the Brain Preservation Foundation—the organization that, on March 13, recognized McIntyre and Fahy’s work with the prize for preserving the pig brain.

There’s no expectation here that the preserved tissue can be actually brought back to life, as is the hope with Alcor-style cryonics. Instead, the idea is to retrieve information that’s present in the brain’s anatomical layout and molecular details.

“If the brain is dead, it’s like your computer is off, but that doesn’t mean the information isn’t there,” says Hayworth.

A brain connectome is inconceivably complex; a single nerve can connect to 8,000 others, and the brain contains millions of cells. Today, imaging the connections in even a square millimeter of mouse brain is an overwhelming task. “But it may be possible in 100 years,” says Hayworth. “Speaking personally, if I were a facing a terminal illness I would likely choose euthanasia by [this method].”

A human brain

The Nectome team demonstrated the seriousness of its intentions starting this January, when McIntyre, McCanna, and a pathologist they’d hired spent several weeks camped out at an Airbnb in Portland, Oregon, waiting to purchase a freshly deceased body.

In February, they obtained the corpse of an elderly woman and were able to begin preserving her brain just 2.5 hours after her death. It was the first demonstration of their technique, called aldehyde-stabilized cryopreservation, on a human brain.

Fineas Lupeiu, founder of Aeternitas, a company that arranges for people to donate their bodies to science, confirmed that he provided Nectome with the body. He did not disclose the woman’s age or cause of death, or say how much he charged.

The preservation procedure, which takes about six hours, was carried out at a mortuary. “You can think of what we do as a fancy form of embalming that preserves not just the outer details but the inner details,” says McIntyre. He says the woman’s brain is “one of the best-preserved ever,” although her being dead for even a couple of hours damaged it. Her brain is not being stored indefinitely but is being sliced into paper-thin sheets and imaged with an electron microscope.

McIntyre says the undertaking was a trial run for what the company’s preservation service could look like. He says they are seeking to try it in the near future on a person planning doctor-assisted suicide because of a terminal illness.

Hayworth told me he’s quite anxious that Nectome refrain from offering its service commercially before the planned protocol is published in a medical journal. That’s so “the medical and ethics community can have a complete round of discussion.”

“If you are like me, and think that mind uploading is going to happen, it’s not that controversial,” he says. “But it could look like you are enticing someone to commit suicide to preserve their brain.” He thinks McIntyre is walking “a very fine line” by asking people to pay to join a waiting list. Indeed, he “may have already crossed it.”

Crazy or not ?

Some scientists say brain storage and reanimation is an essentially fraudulent proposition. Writing in our pages in 2015, the McGill University neuroscientist Michael Hendricks decried the “abjectly false hope” peddled by transhumanists promising resurrection in ways that technology can probably never deliver.

“Burdening future generations with our brain banks is just comically arrogant. Aren’t we leaving them with enough problems?” Hendricks told me this week after reviewing Nectome’s website. “I hope future people are appalled that in the 21st century, the richest and most comfortable people in history spent their money and resources trying to live forever on the backs of their descendants. I mean, it’s a joke, right? They are cartoon bad guys.”

Nectome has received substantial support for its technology, however. It has raised $1 million in funding so far, including the $120,000 that Y Combinator provides to all the companies it accepts. It has also won a $960,000 federal grant from the U.S. National Institute of Mental Health for “whole-brain nanoscale preservation and imaging,” the text of which foresees a “commercial opportunity in offering brain preservation” for purposes including drug research.

About a third of the grant funds are being spent in the MIT laboratory of Edward Boyden, a well-known neuroscientist. Boyden says he’s seeking to combine McIntyre’s preservation procedure with a technique MIT invented, expansion microscopy, which causes brain tissue to swell to 10 or 20 times its normal size, and which facilitates some types of measurements.

I asked Boyden what he thinks of brain preservation as a service. “I think that as long as they are up-front about what we do know and what we don’t know, the preservation of information in the brain might be a very useful thing,” he replied in an e-mail.

The unknowns, of course, are substantial. Not only does no one know what consciousness is (so it will be hard to tell if an eventual simulation has any), but it’s also unclear what brain structures and molecular details need to be retained to preserve a memory or a personality. Is it just the synapses, or is it every fleeting molecule? “Ultimately, to answer this question, data is needed,” Boyden says.

Demo day

Nectome has been honing its pitch for Y Combinator’s demo days, trying to create a sharp two-minute summary of its ideas to present to a group of elite investors. The team was leaning against showing an image of the elderly woman’s brain. Some people thought it was unpleasant. The company had also walked back its corporate slogan, changing it from “We archive your mind” to “Committed to the goal of archiving your mind,” which seemed less like an overpromise.

McIntyre sees his company in the tradition of “hard science” startups working on tough problems like quantum computing. “Those companies also can’t sell anything now, but there is a lot of interest in technologies that could be revolutionary if they are made to work,” he says. “I do think that brain preservation has amazing commercial potential.”

He also keeps in mind the dictum that entrepreneurs should develop products they want to use themselves. He sees good reasons to save a copy of himself somewhere, and copies of other people, too.

“There is a lot of philosophical debate, but to me a simulation is close enough that it’s worth something,” McIntyre told me. “And there is a much larger humanitarian aspect to the whole thing. Right now, when a generation of people die, we lose all their collective wisdom. You can transmit knowledge to the next generation, but it’s harder to transmit wisdom, which is learned. Your children have to learn from the same mistakes.”

“That was fine for a while, but we get more powerful every generation. The sheer immense potential of what we can do increases, but the wisdom does not.”