Carmela Sidrauski wasn’t looking for a wonder drug. Testing thousands of molecules during high-speed automated experiments in the lab of Peter Walter at the University of California, San Francisco, she plucked one of the compounds out of the reject column and moved it into the group that warranted further study. Something about its potency intrigued her.
That was in 2010; today the list of potential therapeutic applications for that molecule sounds almost too good to be true. Since Sidrauski’s decision to look closer, the molecule has restored memory formation in mice months after traumatic brain injuries and shown potential in treating neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease (also known as amyotrophic lateral sclerosis, or ALS). Oh, yeah—it also seems to reduce age-related cognitive decline and has imbued healthy animals—mice, at least—with almost photographic memory.
Sidrauski believes the reason the molecule can do so much is that it plays an essential role in how the brain handles stress from physical injuries or neurological diseases. Under siege from such problems, the brain, in essence, shuts down cognitive functions like memory formation to protect itself. The new molecule reverses that. “We didn’t set out to find this—we just kind of bumped into it,” Sidrauski says. “But having a new way to modulate a pathway that could be central to a lot of different pathological states is very exciting.”
Will it work to reverse cognitive decline in people? We still don’t know. So far most of the work has been done in mice or human cells in a petri dish. But we will soon know more: in 2015 the molecule was licensed by Calico Labs, the Silicon Valley biotech established by the founders of Google to find drugs based on the biology of aging. It hired Sidrauski as a principal investigator to help transform her molecule into a treatment for a wide array of disorders, including ALS and Parkinson’s disease, as well as the damage from traumatic brain injury. In February, Calico announced that human safety trials had begun on the first drug candidate for neurodegenerative diseases it had developed based on the molecule, and that a study in ALS patients was slated to begin later this year. Other possible drugs for Parkinson’s disease and traumatic brain injury are likely to follow.
Such drugs might still be a long shot (most candidates in early clinical trials fail), but early successes, coupled with research done by Walter and others around the globe in recent years, have added weight to an electrifying hypothesis: that crippling cognitive problems seen in victims of traumatic brain injuries, people with Alzheimer’s, and even those born with the genetic problems implicated in Down syndrome are not caused directly by the diseases or genes or trauma but by the way cells respond to the resulting stress.
In mice, Sidrauski and Walter have shown that the molecule, which they now call ISRIB, works by hacking a master pathway in neurons that regulates the pace at which cells are able to synthesize new proteins, a process essential to memory formation and learning. When cells are exposed to stress, Walter and others have shown, it can shut down protein synthesis altogether. Sidrauski’s molecule seems to have a beautifully simple mechanism of action, turning it right back on.
If it works in people, the implications for therapeutics could be immense and sweeping; the cognitive problems resulting from a wide variety of conditions could be reversed by simply tweaking the cellular response. But that comes with a danger: manipulating such a fundamental process also raises the risk of inadvertent and damaging changes.
“We need to understand if there are side effects,” says Arun Asok, a neuroscientist at the University of Wisconsin and an expert on memory, who has not been involved in the research. “But people are in need of drugs like this. This could help a huge number of people suffering from conditions where there aren’t many solutions right now.”
Shutting down the brain
From the earliest days of neuroscience, investigators have suggested that our memories—those unique constellations of sensory experience and thoughts that we summon up when we recollect an event—are somehow encoded in the many connections between neurons that constitute the human brain.
We now know that protein synthesis likely plays a key role in this process: proteins, which make up those connections between neurons, are the raw materials needed to etch an experience into the brain. In fact, research done in the 1960s showed that when scientists chemically blocked protein synthesis, new memories were unable to form.
In the 1980s and 1990s, Walter demonstrated that when too many unfolded or misfolded proteins—which are characteristic of neurodegenerative diseases—were detected inside a cell, it triggered the equivalent of an emergency shutoff switch that halted all protein construction until the problem was solved. The action, which Walter dubbed the “unfolded protein response,” was akin to a blaring red alert at a busy worksite, stopping work; cellular repair crews would then converge on the site, attempt to fix the problem, and if all else failed, eventually order the cell to commit suicide.
Misfolded proteins, other researchers discovered soon after, were just one of many problems that could cause the cells of the body to temporarily shut down protein production. Starvation, viral infections, physical force that damaged the cellular architecture, the oxidative stress common in aging cells, and many other stressors could also trip cellular circuit breakers that would stop the protein assembly line. In fact, researchers now know that almost any metabolic disruption can halt production and potentially trigger cell death. Eventually others gave a name to a broader pathway that overlapped with Walter’s unfolded protein response. They called it the integrated stress response (ISR).
It didn’t take a big leap of imagination to wonder what role the response might play in brain diseases that affected memory. Could the misfolded proteins and oxidative stress that accumulate with aging explain age-related cognitive decline? Might the stress response explain why physical damage caused by traumatic brain injuries often proved so devastating?
The molecule that Sidrauski found back in 2010 is providing a critical clue, and possibly a way to manipulate the responses.
A few years before she discovered the miracle molecule, Sidrauski had thought her scientific career might be over.
The daughter of two Argentinian scholars who met while pursuing graduate degrees at MIT, Sidrauski had initially been drawn to science by a personal tragedy. Her father, Miguel, an economist, was a world-renowned expert on hyperinflation, and after completing his PhD he had earned a faculty slot in the MIT economics department. At 29, however, when Sidrauski was just two months old, her father died suddenly of testicular cancer.
Twenty-four years later, in 1992, Sidrauski returned to MIT as a graduate student in the lab of Tyler Jacks, a leading cancer researcher. Then cancer struck again; her mother was diagnosed and died soon after. Sidrauski’s job talking and thinking about oncology became too painful. So in 1994, she transferred to UCSF and joined Walter’s lab to focus on more basic questions of cell biology. She earned a PhD in 1999, started a postdoc, and coauthored a number of papers on the unfolded protein response.
In 2000, however, Sidrauski decided to step away from academia to care for her two young children. And by the time she was finally ready to return, in 2008, she discovered she’d been out of the workforce too long to get the kinds of research grants that would allow her to pick up where she left off. Around that time, in 2009, she was horrified to discover that Walter had been diagnosed with neck cancer and was in the midst of aggressive treatment.
Without the help of her old mentor, Sidrauski found it hard to get a job. She was still searching when Walter, by this time recovered, enlisted her help on a project. He wanted to find molecules that he could use in lab experiments to turn the unfolded protein response on and off, in the hopes that better understanding of the basic mechanism would one day lead to new drugs.
To find such molecules, Sidrauski genetically engineered mammalian cells to emit light any time protein production was shut down. An automated robotic assembly line exposed the cells to more than 100,000 different molecules, one at a time; also added to the cells was a brew of chemicals toxic enough to trigger a stress response and stop protein synthesis. Those cells that failed to light up pointed to promising new molecules.
One day when Sidrauski was scrutinizing a pile of cards with the readings for rejected molecules printed on them, something caught her eye. One molecule seemed to be far more powerful than the rest. It had landed in the reject pile because a second set of tests had suggested it was too insoluble to be a potential drug.
“This is not the point to stop,” she thought. “It’s very potent.” It was too good not to try.
Following her gut, Sidrauski ordered samples in large quantities and began conducting tests on its properties. The rejected compound wasn’t just extremely effective at preventing activation of the stress response; further experiments showed it could restore protein synthesis after a stressor. What was more, it seemed to work when the cell shut down after any stressor. She had stumbled, it seemed, onto a possible drug candidate capable of modulating the master switch.
Then came more good luck.
In 2007, a postdoc at McGill University named Mauro Costa-Mattioli had also conducted research on the ISR. To do so, he gave mice a drug that activated the response. These mice, he demonstrated, were incapable of learning or forming new memories. When he then deleted a key gene needed to turn on the ISR, he discovered that something even more remarkable happened: the animals demonstrated the equivalent of photographic memories.
Costa-Mattioli had since moved on to the Baylor College of Medicine, where he had set up his own lab to test the ISR pathway further. But Nahum Sonenberg, who ran the McGill lab and is an old friend of Walter, was still working on the problem. Did Walter want someone in Sonenberg’s lab to test this new molecule out on his mice and see what happened?
It seemed like a long shot. But when Sonenberg’s team injected Sidrauski’s molecule into the stomachs of the drug-impaired mice, they formed new memories—and remarkably, the drug seemed to erase any evidence of the impairment.
“It crossed the blood-brain barrier, which usually doesn’t happen—and amazingly, it was not toxic,” Walter recalls. “And this was probably the biggest surprise.”
There was something else that was remarkable too. When they injected the molecule into the stomachs of normal mice, the rodents were able to remember the location of a platform in an underwater maze and find it three times faster than mice that had received sham injections. Sidrauski’s molecule appeared to be a cognitive enhancer as well as a treatment.
When the scientists announced the results in 2013, the news caused a sensation, and it also captured the attention of Silicon Valley. In 2015, Calico announced it had licensed the technology, and the company hired Sidrauski to help find possible drugs based on ISRIB.
It was a “very easy decision” to leave academia, she recalls. The startup offered her the opportunity to optimize the drug-like properties of compounds based on the molecule. It was the chance to turn her discovery into a safe and effective treatment.
In 2017, Walter and Costa-Mattioli teamed up with Susanna Rosi at UCSF, an expert on traumatic brain injuries. Caused by everything from car accidents to sports to simple falls, these injuries are shockingly common and often lead to lasting damage. Some 1.5 million Americans suffer from such brain injuries every year.
Impaired spatial memory is one common effect, making it difficult to navigate through the world and complete routine everyday tasks. Another effect is degradation of “working memory,” which is critical for reasoning and decision-making.
In Rosi’s experience, animals with such brain damage generally never learn well again, but the molecule did the impossible—it restored their ability to learn how to, among other things, navigate an underwater maze as well as normal mice. Researchers in the field of traumatic brain injury had long believed that therapeutic interventions needed to be administered soon after the injury to have any chance of being effective. Amazingly, the drug worked more than a month after an injury, and the effects seemed to persist indefinitely.
Noting that symptoms in patients with brain injuries share many similarities to the cognitive decline associated with aging, the team next decided to test whether the compound could reverse the symptoms of aging itself. There was reason to believe it might work: as we grow older, damaged cells begin to accumulate, leading to a slow buildup of inflammation that the team suspected might be sufficient to trigger cellular circuit breakers and slow protein production.
The team tested the recall abilities of different populations of mice in the watery maze, this time segregating them by age. Elderly mice given small daily doses of ISRIB during a three-day training process were able to accomplish the task far faster than geriatric peers that did not take the medication. Some were even able to match the performance of young mice.
Within a day of receiving a single dose, the mice had none of the common signatures of neuronal aging normally seen in the hippocampus, which plays a key role in learning and memory. Electrical activity in the brain became more robust and responsive to stimulation; the ability to form new connections between cells increased to levels normally seen only in younger mice. The changes were long-lasting, persisting when researchers tested the mice three weeks later.
In other studies, the drug also showed promise in reducing age-related cognitive decline.
“We can make old brains young,” Costa-Mattioli says. “We can rejuvenate the brain. We can take an adult brain and make it adolescent in terms of the response to stimuli. This is a universal way to enhance memory in pathology, Alzheimer’s, traumatic brain injury, Down syndrome, but also normal memory in different animals and species.”
There’s still a long way to go before drugs based on ISRIB are used to treat humans for neurodegenerative disease, and it will be even longer before any potential cognitive enhancer is possible.
Though no side effects have yet been found in mice, testing in humans will need to be extensive to see how the compound affects other molecular processes in the cell, says the University of Wisconsin’s Asok: “How is it affecting the structure of neurons themselves over time? Is it causing a long-lasting change in the ability to form memories?”
Even if there are no side effects, longtime memory researchers are cautious about trying to use drugs to enhance cognition in healthy people.
In the 1970s, 1980s, and 1990s, a long list of pharmaceutical candidates aimed at improving memory in normal people failed in human trials, says James McGaugh, a neurobiologist at the University of California, Irvine. Virtually all of them were successful in lab animals. In people, almost all caused severe side effects or failed to work as hoped.
There’s a difference, says McGaugh, between developing a drug that might help people with memory problems and creating one that will generally improve memory in healthy people. The latter, he suggests, is unlikely to happen—or at least there’s no evidence in the history of drug research that it will.
“I’m not convinced that you’re going to supercharge the system generally and make learning go better,” McGaugh says. “As a matter of fact, let me take it a little bit further. If it’s a normal condition, you can make things worse. You could start firing all kinds of stuff that doesn’t need to be fired.”
As human testing begins on potential drugs based on the molecule that Sidrauski discovered more than a decade ago, we could begin to get answers about its potential to treat some of our most devastating neurodegenerative diseases. Whatever the outcome of those tests, this research is a remarkable scientific story of good luck and the whims of fate.
Had Walter not offered Sidrauski a new position, had she not chosen to look more closely at a rejected molecule, and had her mentor not called his friend at McGill, the discovery would never have been made.
Now running her own lab at Calico, Sidrauski has a memento—a gift from the art studio of her mentor Walter, who’s an amateur sculptor. Forged out of metal, the glimmering toaster-size piece is a representation of the magic molecule ISRIB. Walter presented it to Sidrauski shortly before she left to join Calico.
“It’s beautiful,” she says. “It’s got all the atoms—all the atoms and hydrogens. It’s very pretty.”
Adam Piore is a freelance journalist based in New York. He is the author of The Body Builders: Inside the Science of the Engineered Human, about how bioengineering is changing modern medicine.
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