SOUTH SAN FRANCISCO — Robert McIntyre would like to get a few things straight. That "waiting list" of people plunking down $10,000 to have his company preserve their brains for future uploading? Just 30 "early supporters" of his research, he said; no one has been promised or even offered anything, certainly not silicon-based mental immortality.
The elderly woman in Portland, Ore., whose brain McIntyre obtained (via body-donation company Aeternitas Life) right after her death last year so he could practice his vitrification-cum-cryopreservation technique? Just some early research to improve brain banking, "which we feel we accomplished," he said.
Reports that his 3-year-old startup, Nectome, aims to "preserve your brain to bring you back in the future" (according to the website of its venture capital funder) or to "back up your mind," as per a now-disappeared tease on Nectome’s website? "What we’re focused on is preserving long-term memory," insists McIntyre, 30, sitting at a conference table in Nectome’s new, two-room headquarters within shouting distance of San Francisco’s airport, "not reading or decoding it. The field of memory preservation doesn’t exist. We’re trying to create it."
It has not been an easy year for McIntyre or Nectome, but they’re determined to claw their way out of scientific purgatory.
After MIT Technology Review reported in March that his technology might require death at the speed of assisted suicide, a Massachusetts Institute of Technology biologist stopped collaborating with the company, the university said it has nothing to do with Nectome, and neuroscientists offered little but scorn. Social media decided (incorrectly) "Nectome" is Latin for "I have been killed." (Necto me is Latin for "I bind myself," which probably isn’t much better. The name actually comes from "connectome," meaning the map of all the brain’s neurons, axons, dendrites, and synaptic connections; constructing that map is a holy grail of neuroscience.) Headlines painted Nectome’s intended service as "suicide, with benefits."
The ghoulish portrayals continue to haunt Nectome, which McIntyre and his former MIT roommate Michael McCanna founded in 2015. Asked about its research, MIT bioengineer Ed Boyden, Nectome’s erstwhile collaborator, replied that he "must respectfully decline." Neuroscientist Richard Brown of Dalhousie University, whose work McIntyre cites as supporting the possibility of memory preservation, was dismissive: "When you die, the brain cells die, so there is no memory after death," he said. "It is not possible to find memory in dead neurons."
The skepticism is far from universal, however.
"I think the chances that brain preservation will result in future revival are slim but not zero," says Ken Hayworth, a senior scientist at the Howard Hughes Medical Institute’s Janelia Research Campus; you just have to preserve "the pattern of synaptic connectivity and the ultrastructural features of synapses." MIT neuroscientist Alan Jasanoff agrees that "there’s a decent chance that most of what’s important [for memory] could be preserved" by a technique like McIntyre’s. He’s doubtful, however, about the deciphering part (aha, these synapses contain her memory of her Ph.D. defense!): "Just knowing what’s in the brain probably isn’t enough to extract meaning from it."
As part of its effort to gain scientific respectability, Nectome recruited University of Oxford philosopher and computational neuroscientist Anders Sandberg to assemble an ethical advisory board and identify issues raised by brain preservation, from how to ensure informed consent from future customers to what happens if a government demands access to someone’s preserved memories. Last October, McIntyre gave a talk at the MIT Museum on "Are We Our Brains?" The company — newly hired chief of staff and software engineer Jessica Radley rounds out the trio of employees — is also trying to build bridges with neuroscientists. To that end, Radley held informal "memory meet-ups" with researchers at the annual meeting of the Society for Neuroscience last November, explaining Nectome’s mission.
Nectome co-founder Robert McIntyre in the company’s South San Francisco lab, conducting research on C. elegans memory. Courtesy Nectome
And after ducking reporters for nearly a year, McIntyre is ready to try again. He spent the afternoon after his museum talk explaining to STAT his vision for memory preservation, and three months later showed off Nectome’s new lab, answered questions for hours, waxed philosophical during an evening at an intellectual-hipster bar, and let his visitor eavesdrop on his morning of Socratic dialogue with his mentee, a high school senior. Sample: "You want your epistemological framework not to break when you get to neural networks," McIntyre, whose whiskers remind one of Keanu Reeves in "John Wick" mode, told the student. Also, "it’s very, very easy to confuse your bookkeeping of reality with reality."
Nectome’s offices don’t scream "crazy science being done here." Clear plastic bins are still stacked in a corner. A blue velour couch in front of a whiteboard and video screen looks like it took a wrong turn on the way to Nob Hill. The lab is out of central casting, with high black benches, boxes of disposable plastic gloves, white lab coats on a door hook, Leica microscopes, Bunsen burners, bottles of reagents, and a sink … but no brains in sight.
McIntyre, chastened or simply more PR-savvy, emphasizes at every opportunity that all he’s aiming to do is preserve brains well enough to archive the long-term memories they contain. "I think we know enough to show that you can make a memory preservation technology," he said.
But creating a backup copy in silico — as in the British television series "Black Mirror" and countless other transhumanist fantasies — isn’t in the cards any time soon, he repeatedly insists, nor is the reanimation dangled by cryogenics companies. Although someone, someday, might figure out how to decipher memories from preserved synapses, McIntyre would settle for being neuroscience’s Sir Arthur Evans, the archaeologist who in 1900 discovered and preserved Cretan tablets written in Linear B — which scholars finally deciphered more than half a century later.
And yet … listening to McIntyre explain his dream, it’s hard to believe he’d settle for mere preservation of a brain’s long-term memories for some distant future. He peppers his conversation with references to the Library of Alexandria (burned in 48 B.C., an incalculable loss of ancient knowledge), the 2011 death of the last U.S. soldier to fight in World War I, and exasperation: "You’re going to live your whole life, and all the stuff you built up is going away?" he asked. "All your memories and all your experiences and all your wisdom, erased [by death]? That’s just a bad plan. Screw that."
The case for preservation is simple: "If you don’t preserve it, you definitely can’t do anything with it," McIntyre said, later adding, "I would be really surprised if we [the neuroscience community] couldn’t read memories in 100 years."
To realize a dream he said he has had "for as long as I can remember, like since I was 6," McIntyre has to climb two scientific Everests. He must perfect the chemistry that will lock down the proteins and other molecules forming the synapses that neuroscience considers the locus of memory. And he must show that what he’s preserved indeed encodes memories.
That’s where his roundworms come in. "I love these animals," McIntyre said about the transparent, comma-sized Caenorhabditis elegans in his lab. "They’re like little pieces of moving glass." C. elegans has long been a neuroscience favorite: Its brain has precisely 302 cells, and its connectome was mapped in 1984.
Peering through the eyepiece of a Leica S6E at a flat plate teeming with the little guys (and their lunch: clumps of E. coli), McIntyre, in disposable gloves and white lab coat over his purple dress shirt, watches the worm traffic for a few seconds and then taps the side of the plate. The animals all reverse course. He stands aside so a visitor can watch the trick. Squiggling, wiggling, tap!, reverse. Then, after they get one tap per minute for 20 minutes, followed by a one-hour break and then another "training session," the worms habituate to the tap and no longer back up. They remember that taps don’t portend danger.
McIntyre is a lonely presence in the one-room lab (Nectome plans to hire neuroscientists), but his enthusiasm fills the void. He’s delighted when the "tap-memory" demo works, like a proud papa whose little one has just belted out "Memory" for guests. He thinks tap memory in C. elegans will haul him to the top of one Everest: demonstrating that physical changes in the brain, such as an increase in the number of receptors in a synapse, are the basis of all remembrances of things past.
That’s pretty close to neuroscience dogma (it’s called the synaptic theory of memory). But McIntyre intends to nail it down in C. elegans so unambiguously that skeptics will stop dismissing the idea of preserving memories. He is therefore measuring the synaptic changes that enable worms to remember taps, as indicated by when they stop reversing course after their little world shakes. The final step: preserving the memory in a chemical fixative called glutaraldehyde.
Glutaraldehyde has been good to McIntyre. His origin story goes like this:
Growing up in Texas and Kansas, son of a physician father (emergency medicine and then psychiatry) and artist mother. Losing his grandmother when she was 72, the recordings he made of her reminiscing about traveling by covered wagon from Oklahoma to Texas and other experiences making him "realize just how much humanity is missing by not being able to preserve a living memory." Visiting a neuroscience lab, which "crushed" his dreams: Researchers seemed so far from seeing the microscopic structure of an entire brain. Starting college in 2007 at MIT. Bailing on real brains and plunging into artificial intelligence. Meeting McCanna when both were MIT sophomores, taking electrical engineering courses together and debating information theory, artificial intelligence, and neuroscience late into the night.
McCanna joined Amazon after graduation (to work on the Alexa speech-recognition system), a series of startups, and then Dropbox. McIntyre started a master’s degree in AI at MIT, but immediately decamped to his family’s Wisconsin barn (no running water, but reliable internet) to spend days and nights writing code for his AI thesis.
Halfway through his "barn year," McIntyre took a life-changing walk with his father, who asked him, what would you do with your life if you were banned from AI? I’d have to go back to neuroscience, McIntyre replied, dejected at the thought. But what if you could preserve biology? his father asked. How hard could it be? You just need biologically compatible antifreeze.
McIntyre was intrigued. They drove to a local library and devoured scientific papers on cryobiology. That field’s limited progress made McIntyre think, "Good thing I’m doing AI." But he couldn’t stop thinking about cryopreservation and one day it hit him: Sure, frozen brains have never been "reanimated," but what if all you cared about was preserving their information content? "That’s 1,000 times easier" than reversing death, McIntyre said.
Looking for anyone who might be thinking the same thing, he found the Brain Preservation Foundation. It had $100,000 from Israeli-born tech entrepreneur (Trivnet.com, Initiative Q) and world-class poker player Saar Wilf in prize money for preserving brains down to their every neuron and synapse.
"To me, it’s weird that there is not 1,000 times more funding" to encourage brain preservation research, Wilf told STAT. "There are few causes more worth supporting."
Yet only two labs were in the hunt. One, in Germany, "kept getting cracks and tears in its brains," McIntyre learned. The other was 21st Century Medicine, a Fontana, Calif., company that cryopreserves organs (not including brains) for transplant. In early 2014, "I emailed them and said, ‘I know how to win this,’" McIntyre recalled.
He was in.
McIntyre knew nothing about chemistry, tissue perfusion, electron microscopy, or, really, anything else needed to preserve brains. "I’d never quite seen brains before," he said. But during his two years as an unpaid volunteer at 21st Century, he learned on the job, working on rabbit brains left over from the company’s research on other organs.
For decades, brain banks have preserved these organs of the mind by perfusing them with chemicals called aldehydes and storing them at about 39 degrees Fahrenheit. But the brains degrade anyway, becoming like last week’s sushi. Sticking them in a deep freeze doesn’t work either. Ice forms, drying them out so badly they typically shrink to half their size and crushing their synaptic and other structural details. The best shot seemed to be to combine the two: perfuse a brain with a cryoprotective agent to prevent ice formation and then store it at temperatures as cold as Jupiter’s clouds: -220 F. That should turn the brain into a solid glass. In theory.
In practice, McIntyre recalled, for five months "I tried like 80 fixatives and nothing worked." Until he tried glutaraldehyde … and a makeshift perfusion and cryo system that would give PETA fits. His "cephalon perfusion machine" drained the blood from the rabbit’s brain and replaced it with glutaraldehyde pumped through the carotid artery. Then it slowly added ethylene glycol (antifreeze) and chemicals to, among other things, keep the brain from shrinking.
McIntyre stowed the now "vitrified" brain in a -220 F freezer. With this "aldehyde-stabilized cryopreservation," he and 21st Century’s Greg Fahy wrote in a 2015 paper, "[p]reservation was uniformly excellent. … [Axons] "were easily traceable and synapses were crisp." Their technique preserved neurons, axons, dendrites, synapses, and other fine structure so perfectly it would make scarabs frozen in amber slink away in shame.
The Brain Preservation Foundation agreed. It awarded McIntyre and Fahy its $26,735 small-mammal prize in 2016. Once he got the hang of it, McIntyre vitrified a pig brain in only one day, winning the foundation’s $80,000 large-mammal prize in 2018.
Foundation President Hayworth, of Janelia, called their brains "the first demonstration that near-perfect, long-term structural preservation of an intact mammalian brain is achievable. Every neuron and synapse looks beautifully preserved" in a way that should last centuries.
To this day, McIntyre carries in his pocket a slide containing slices of the vitrified rabbit brain.
If one sign of validation is money, Nectome got it. In 2016 it won $870,209 in research grants from the National Institutes of Health "to enable whole-brain nanoscale preservation and imaging, a vital step towards a deep understanding of the mind and of the brain’s diseases." A year ago it received seed funding (amount undisclosed) from venture capital firm Y Combinator. Nectome’s research "has the possibility to improve the human condition by preserving memories," a Y Combinator spokesperson told STAT. "There’s a future in this research and Nectome."
Brain preservation, however, isn’t memory preservation. Neither McIntyre nor anyone else has proved that what’s preserved keeps memories. Maybe that requires preserving not only the connectome but another -ome: the synaptome, meaning every feature of every synapse, such as receptors, neurons’ ion channels, and possibly even small molecules such as lipids and those regulating DNA, at least 300,000 molecules for each synapse.
That’s why McIntyre is subjecting his C. elegans to little earthquakes. His plan: tag and detect the molecules that change when the worms remember, then determine whether glutaraldehyde preserves them. "I’m not saying that if I do it in worms that’ll show everything works," he cautioned. "People don’t think this is possible. That’s why I think it’s useful to do. Does brain preservation work? Does it preserve the memories? That’s what we’re focused on."
On a night of pounding rain in San Francisco’s Fort Mason neighborhood, as he settles into an Uber, McIntyre’s chatter ranges from how rabbits’ myelin is tougher than humans’ to what happens when you scratch a DVD (that’s relevant to information theory) to whether the mind is anything beyond the physical stuff of the brain. "Qualia are the bane of my existence," he sighed. He also mentioned that he thinks he can adapt the exhaust hood in the lab to make cold-brewed coffee.
Entering the Interval at Long Now bar, McIntyre heads for its floor-to-ceiling bookcases. They contain hundreds of volumes that the Long Now Foundation (which owns Interval and is best known for the 10,000-year "Clock of the Long Now") believes might be necessary to rebuild civilization, should the need arise. ("Principia" and "The Decameron" and "Relativity: The Special and General Theory" will be needed, but also, it seems, "Ducks, Geese, and Swans of North America"). He stops at the Orrery, a prototype for the clock, points out the algorithmically controlled digital painting over the bar, and orders an espresso. "I never thought I’d find my bar," McIntyre said contentedly.
Over the next two hours, at a wooden table that fills an alcove, he hunches over his laptop. Here’s a study reporting that dogs that temporarily lose all of their blood have no (detectable) memory loss. Here’s one describing how people who fall into a frigid lake, stopping not only their breathing but also their hearts, also retain their memories. Here’s one that "zapped the hell out of people" (in electroconvulsive therapy), yet their memories, too, survived. He’s downloaded 1,561 papers supporting his conviction that long-term human memories are tough enough to withstand a little vitrification and deep freeze, that they live (and die) in synapses, and that glutaraldehyde will work.
"I’m not that good a neuroscientist, but I’m good at assimilating papers," he said as his coffee got cold. "The point is, terrible things can be done to the brain without destroying memories." Glutaraldehyde fixation, far from being "terrible," "almost certainly preserves long-term memories," he said: It "locks down" everything thought to constitute the biological basis of memories.
Seats at the bar have turned over at least twice, but McIntyre shows no signs of flagging. "Here," he said, opening a PDF. "This paper shows that glutaraldehyde preserves proteins even when you do something like what the mafia does to get rid of a body," locking in synaptic features that distinguish "virtually identical long-term memories." He scrolls along, plucking out discovery after discovery on the precise synaptic structures that encode memory and ticking them off one after another: Yup, we can preserve that. Also that. And that.
"I’ve been trying for five years to think of something [memory-related] that glutaraldehyde can’t preserve," he said, so far coming up empty. "It even glues up proteins’ phosphorylation state!"
Closing his laptop, McIntyre offers a final thought before he heads into the driving rain, sans hat or umbrella, to flag down his errant Uber. "I’m not in this to make something that almost works," he said.
He continues his pitch on the ride home. After McIntyre dashes into his apartment building, the Uber driver considers whether he would give his brain to a company that would preserve all his memories even with no promise that they could ever be read out or uploaded. "Sure, why not?" he said. "Even a small chance is better than definitely dead and gone forever, right?"