Dr. Peter Walter spent decades understanding the inner workings of the cell. His new goal: healing damaged brains. The mice were decidedly smart. Normal mice put inside a watery maze took more than a minute to locate the submerged platform that would let them escape. But these mice — which had been injected with a curious new molecule — found it in an average of just 16 seconds. That news startled Peter Walter. A 61-year-old biochemist, he’d spent his life, and built a sterling reputation, uncovering the workings of a critical quality control mechanism in cells. He was immersed in the next step — trying to manipulate that mechanism to heal damaged brains — when a member of his lab called his attention to this unusual molecule. And now, here it was, apparently making mice very smart. The discovery touched off a scientific whirlwind: A secretive Silicon Valley company dedicated to prolonging the human lifespan has scooped up rights to the now-patented molecule, which Walter named ISRIB. Labs are scrambling to see if it might blunt neurodegenerative diseases like Alzheimer’s or Parkinson’s, or reverse injuries from brain trauma. Word of the compound has even reached the communities of “brain hackers” who whip up chemical cocktails in the hopes of boosting longevity or brainpower. To Walter’s dismay, some are buying ISRIB online and ingesting it, long before it’s been extensively tested. Some outside scientists remain skeptical. They warn that interfering with vital cellular mechanisms, as ISRIB seems to do, could lead to a host of dangerous side effects. They caution that it will be years, or possibly decades, before it’s ready for testing in humans. But Walter is fascinated — some might say obsessed — with the tiny molecule his lab discovered. ISRIB, he believes, just may hold the power to rejuvenate and heal the aging or damaged brain. “It’s incredibly exciting,” Walter said during an interview in a cactus-filled office overlooking the the University of California, San Francisco’s Mission Bay campus. “What we’ve done for sure is opened up a pathway that’s terribly important.” Walter is not your stereotypical biochemist. A German by birth, he has a constant smile and bubbly and infectious enthusiasm for his work. He calls certain cell mechanisms “cute.” With gray hair, twinkling blue eyes, and a penchant for wearing red shirts, he looks a bit like Kris Kringle — but slimmer, and with Birkenstocks. In his free time, Walter woodworks and sculpts. One chair in his office is permanently occupied by the lab mascot: a giant stuffed unicorn named Serendipity. This whimsy and creative spark, coupled with a relentless curiosity, is all part and parcel of what colleagues say is Walter’s stone cold brilliance. “If all of us were like Peter, we would have solved all of the diseases by now. And all the problems in biology,” said Nahum Sonenberg, a molecular biologist at McGill University who has known Walter for three decades and collaborated with him to see what effect ISRIB had on the cognitive abilities of mice. Serendipity, a stuffed unicorn meant to represent the serendipity of scientific discoveries, sits in Walter’s office along with a representation of the molecule he is studying. From slobbering cows to a crucial discovery Walter knew he wanted to be a chemist by the age of 12. His interest was sealed by years of working in his father’s West Berlin drogerie, or drugstore, where medicines and household products were mixed. He did his own off-the-books mixing as well, leading to numerous and often explosive adventures. Walter planned to work in Germany, but first did a short exchange program at Vanderbilt University to improve his English. His project, working on a fungus that causes cows to slobber, didn’t really inspire. But he decided to stay after experiencing how much more scientific independence American labs offered. His application was at first rejected, but he eventually became a a PhD student in the lab of Rockefeller University biologist Dr. Günter Blobel, who won a Nobel Prize for work discovering how proteins find their correct locations in a cell. (Walter still sometimes shows his rejection letter as a slide during talks.) Walter played a major role in that discovery, then in 1983 went on to start his own lab at UCSF, where he spent decades studying yeast to unravel the workings of a cellular mechanism called “the unfolded protein response.” It’s a critical quality control mechanism; when it goes awry, it can lead to a host of diseases in humans, including cancer. The work has netted Walter and co-discoverer Kazutoshi Mori of Japan a slew of biomedicine’s most prestigious awards, including the Lasker. The citation for the $1 million Shaw prize the men won in 2014 called the discovery “one of the most fascinating detective stories of molecular cell biology.” Their names regularly surface on lists of those expected to win a Nobel Prize in chemistry or medicine. But for Walter, that’s all old news. He’s moved on to ISRIB. It was Walter’s own diagnosis of neck cancer in 2009 that helped shape this second stage of his career. Walter doesn’t like discussing the cancer and the treatment, except to say it was perfectly awful. His friends say he endured the disease with the characteristic optimism he has always brought to the lab bench. With his keen insight on the inner workings of cells, though, Walter was exasperated at how little scientists seem to really know about why cancer cells grow out of control. Walter’s cancer is now in remission — and he is more determined than ever to work on tangible discoveries that can improve human health. “It definitely influenced me,” said Walter. “The one thing it drives home is that life is not endless. If you want to do something important, you have to go ahead and do it.” What he wants to do now is tweak the cellular mechanism he helped discover in order to fix the human brain. A curious molecule, snatched from the discard pile The unfolded protein response is critical to how our bodies work. Our cells are continually streaming out proteins to carry out all manner of functions, from fighting off bacteria to making new memories. Proteins only work because their highly specific shapes allow them to carry out their tasks. If a cell starts putting out misshapen proteins, the unfolded protein response kicks in to stem the chaos by slowing production of new proteins and destroying the sloppy ones. If errant proteins keep appearing, the cell commits suicide. “If the cell cannot fix the problem, the cell is killed,” Walter said. “It’s a life and death decision.” It’s also a matter of exquisite balance. If the response is overactive, too many cells can die, possibly leading to diseases like Alzheimer’s, Parkinson’s, and diabetes. If it goes awry in other ways, cancer cells can proliferate. Sign up for our Cancer Briefing newsletter Walter is not the only one interested in manipulating the unfolded protein response to fight disease: A handful of labs around the world are in the hunt. The Karolinska Institute in Stockholm this month held a Nobel Forum on the topic, called “Unfolded Proteins: From Basic to Bedside” with Walter as the kickoff speaker. The mechanism is a complex response that involves numerous cellular pathways. To tweak it, Walter needed a molecule that could somehow gum up the mechanism. So he orchestrated a vast screening of 100,000 mostly synthetic compounds, funded by the Howard Hughes Medical Institute, where he is also an investigator. He set up a test with cells that lit up when the unfolded protein response pathway was functioning normally. If a molecule interfered with the pathway, the light went out. Only one compound of the 100,000 turned the light out, Walter said. And that one — ISRIB — was nearly thrown out because it was not considered soluble enough to be a good candidate for a drug. But the postdoc working on the project, Carmela Sidrauski, pulled it out of the discard pile because it seemed effective even at very low concentrations. “Everything relies on the fact that she was crazy enough to ignore the experts,” Walter said. Walter is so entranced with the molecule, he even made a sculpture of it, which sits in his office. It’s two-fold symmetrical, which means it has two arms that may help it hold on tighter to its binding site “It’s a beautiful little molecule,” he said. He named it ISRIB for integrated stress response inhibitor. When they started to work with ISRIB, the scientists found it was even more powerful than they’d expected. It not only altered the unfolded protein response, it also affected other crucial chemical pathways triggered when cells react to major stressors such as UV light, viruses, and iron deficiencies. In all these situations, and also when there are too many sloppy proteins, cells respond by switching off a single protein called elF2 alpha. Walter’s colleague Sonenberg had previously linked elF2 alpha to memory function in mice. So the two men decided to study what effect ISRIB would have on the brains of mice. It was these tests that showed mice injected with ISRIB were three times faster than normal ones at locating a submerged platform. They were also better at remembering cues associated with unpleasant stimuli. It appears, Walter said, that inactivating elF2 alpha acts as a “brake” on forming memories. Inserting ISRIB blocks the brake, so memories can form. “Mice learn better,” he said. “They learn significantly better.” A PhD student works in the tissue culture room in the Walter Laboratory. A drug to help dementia patients — or SAT takers? Walter and others say ISRIB may be a kind of double-whammy drug, if it pans out in further studies. It might prevent the cell deaths that seem to be a factor in neurodegenerative disease. And it might also help improve the memory problems those diseases cause. Biotech firms are taking notice. Calico, a secretive research and development company founded by Google with a mission to extend life, is paying UCSF an undisclosed amount of money to license the molecule. The company hired Sidrauski, the postdoc who first pulled ISRIB out of the trash pile, to lead a team in developing therapies from the molecule. Sidrauski declined to comment for this article. Walter is hoping the molecule may turn into a drug to benefit those with memory disorders, such as Alzheimer’s or dementia. He realizes, since it made healthy mice smarter, that it also could potentially serve as a cognitive enhancer — something parents give children before SAT tests, for example. That’s not his end goal, though: “We’re not here to give it to the Tiger Moms,” he said. He was surprised to see that there is already chatter on the Internet from people buying ISRIB and administering it to themselves. While he jokes about “Breaking Bad” being a good career choice for a chemist, Walter strongly advises people against using the little-tested molecule on their own. But he is excited about the myriad ways ISRIB might help damaged brains. He’s now working with Susanna Rosi, an associate professor in the department of physical therapy at UCSF, to test the molecule on brain trauma, a devastating injury with no pharmaceutical treatments. “There is absolutely nothing available,” Rosi said. “There’s a of work going on, on what to do in the emergency room, but nothing for people who suffered trauma some time ago and still have cognitive deficits.” While Walter and Rosi would not divulge details of their brain trauma studies because they are in the midst of publishing the work, they say the results on healing injured brains are extremely promising. And working on brains in all their complexity is exciting new intellectual territory for Walter. “We had no clue we would have to become neuroscientists,” said Walter. “I’m the naive new kid on the block, having a great deal of fun.” Like many who work with Walter, Rosi can’t seem to say enough good things about him and his surprisingly joyous approach to work and life. “He’s like my 4-year-old twins,” she said, “He has this basic, intrinsic curiosity that makes him brilliant and unique.” Rosi also said Walter is always willing to share the spotlight and credit — something she doesn’t see in all her colleagues. Walter, who has two grown daughters, is considered an especially good mentor to women. For example, he invited Sidrauski back to his lab after she stepped away from science completely for eight years to raise children. That’s a rare step in a highly competitive field where job possibilities are often curtailed after even short absences. Peter Walter walks toward his lab in Genentech Hall in the UCSF Mission Bay campus. Promise … as well as peril? Like many things Walter has worked on, this new challenge — tweaking the unfolded protein response enough to create a potent, yet safe, drug — is not exactly going to be easy. The unfolded protein response is so central to the basic functioning of cells that altering it can be dangerous. Any changes have major effects on organs, like the liver or pancreas, that secrete large numbers of proteins. A number of early attempts to alter the response using genetic knockouts and other molecules turned out to basically wipe out the pancreas of experimental animals. In some experiments, mice lost weight so suddenly and severely, they had to be euthanized. Walter’s studies of ISRIB, and one other conducted in England, have shown that it does not damage the pancreas in the short term. But long-term use of the molecule, as might be needed for chronic disease, has yet to be studied. The unfolded protein response “is constantly working in your cells to remove misfolded proteins. That’s why we should be careful,” said Jeroen Hoozemans, a researcher at VU University Medical Center in Amsterdam, who has studied the mechanism’s role in neurodegenerative diseases for the past decade. “You can also change the normal function of the cell.” Hoozemans, who focuses largely on Alzheimer’s disease, is as excited as anyone about the potential of unfolded protein response to yield new therapeutic pathways. “It gives new hope for drug targets,” he said. But he cautioned that the field is so new, it’ll likely take at least a decade before any such drug could even begin to be tested in humans. Despite the thousands of papers that have been published on the unfolded protein response since its discovery, many uncertainties remain — including what parts of it should be targeted for different diseases and when therapy might be most fruitful in diseases that can unfold over decades. That challenge will involve subtle, careful work to unlock secrets within the deepest working of cells. Walter can’t wait. Source
