Peter Walter discovered a molecule that makes mice smarter. Can it heal a human brain?

SAN FRANCISCO – ?. The mice were decidedly intelligent

Normal mice put in a water maze took more than a minute to locate the submerged platform that let them escape. But these mice – that had been injected with a curious new molecule – They found an average of just 16 seconds

.

That news surprised Peter Walter. A 61-year-old biochemist, who had spent his life, and built an excellent reputation, exposing the operation of a control mechanism in cells critical quality.

He immersed himself in the next step – try to manipulate this mechanism to heal damaged brains – when a member of his lab calls your attention to this unusual molecule. And now here he was apparently doing very intelligent mice.

The discovery caused a scientific maelstrom: A secret Silicon Valley company dedicated to the extension of human life expectancy was collected rights to the patented molecule for now, ISRIB named Walter. Laboratories are scrambling to see if it could mitigate neurodegenerative diseases like Alzheimer or Parkinson or reverse the damage caused by brain trauma. Compound word has even communities “ hackers brain ” chemical cocktails that are prepared with the hope of increasing longevity or brainpower. To the dismay of Walter, some are buying online and ISRIB ingest, long before it has been subjected to numerous tests.

Some external scientists remain skeptical. Warn that interferes with vital cellular mechanisms such as ISRIB seems to do so could lead to a number of dangerous side effects. They warn it will take years, or even decades, before it is ready for testing in humans.

But Walter is fascinated – some might say obsessed -. With the small molecule his laboratory discovered

ISRIB, he says, can only have the power to heal and rejuvenate aging or brain damage.

“It is incredibly exciting,” Walter said during an interview in an office full of cactus overlooking the University of California, campus of Mission Bay San Francisco. “What we have done to ensure that a road that is very important to open.”

Walter is not your stereotypical biochemist. A German by birth, has a constant smile and bubbly and infectious enthusiasm for his work. He calls certain cellular mechanisms “monkey”. With gray hair, twinkling blue eyes and a penchant for using red shirts, which looks a bit like Kris Kringle – but thinner, and Birkenstock. In his spare time, woodworks Walter and sculpts.

A chair in his office is permanently occupied by the pet lab :. A giant stuffed unicorn called Serendipity

This whimsy and creative spark, along with a relentless curiosity, is all part of what colleagues say is stone cold brilliance of Walter.

“If all of us were like Peter, have solved all diseases for now. And all the problems of biology,” said Nahum Sonenberg, a molecular biologist at McGill University, who has known Walter for three decades and worked with to see what effect it had ISRIB on the cognitive abilities of mice.

Peter Walter - UCSF
Elizabeth D. Herman for STAT Serendipity, a unicorn plush intended to represent the serendipity of scientific discoveries, is in Walter’s office along with a representation of the molecule he is studying.

of slobbering cows to a fundamental discovery

Walter knew I wanted to be a chemist at the age of 12. His interest was sealed by years of work in his father drogerie West Berlin, or pharmacy where medicines and household products were mixed. He made his own off the books mixing well, resulting in numerous and often explosive adventures.

Walter planned to work in Germany, but first made a short exchange program at Vanderbilt University to improve their English. His project, working on a fungus that causes drooling cows, not really inspire. But he decided to stay after experiencing how much more scientific independence offer American laboratories.

His application was rejected at first, but eventually became a doctoral student in the laboratory of biologist at Rockefeller University Dr. Günter Blobel, winner of a Nobel Prize for the discovery of how proteins work find their location correct in a cell. (Walter still sometimes shows his rejection letter as a slide during the talks.)

Walter played an important 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 cell mechanism called “the response of the unfolded protein. ” It is a critical quality control mechanism; when it goes wrong, it can lead to a number of diseases in humans, including cancer.

Work has scored Walter and co-discoverer Kazutoshi Mori of Japan, a lot of most prestigious awards of biomedicine, including Lasker . The citation for the prize Shaw $ 1 million men earned in 2014 said the discovery “one of the most fascinating stories of detectives of molecular cell biology.”

Their names surface regularly in the lists is expected to win a Nobel Prize in chemistry or medicine. But for Walter, that’s all old news.

He moved to ISRIB.

It was Walter own diagnosis of cervical cancer in 2009 that helped shape this second stage of his career. Walter does not like to discuss cancer and treatment, except to say that it was perfectly horrible. His friends say he endured the disease with characteristic optimism that has always brought to the lab table. With his keen insight into the inner workings of cells, however, Walter was exasperated by how little scientists seem really know why cancer cells grow out of control.

cancer

Walter is now in remission – and he is more determined than ever to work on tangible discoveries that can improve human health

.

“definitely influenced me,” Walter said. “The only thing to take home is that life is not infinite. If you want to do something important, you have to go ahead and do it.”

What I want to do now is to refine the cellular mechanism that helped discover in order to fix the human brain.

A curious molecule, taken from the discard pile

The unfolded protein response is critical to the functioning of our body.

Our cells are continually flowing proteins to perform all kinds of functions, from the fight against bacteria to make new memories. Proteins only function because their highly specific forms allow them to carry out their tasks. If a cell extinction of misshapen proteins starts, the unfolded protein response into action to stop the chaos by decreasing the production of new proteins and destruction of neglected.

If the proteins still appear wandering, the cell commits suicide. “If the cell can not solve the problem, the cell dies,” Walter said. “It is a decision of life or death.”

is also a matter of exquisite balance. If the answer is overactive, too many cells may die, which can lead to diseases like Alzheimer’s, Parkinson’s and diabetes. If it goes wrong in other ways, cancer cells can proliferate.

Walter is not the only one interested in handling the response to unfolded proteins to fight disease: A handful of laboratories around the world are in the hunt. The Karolinska Institute in Stockholm this month conducted a Nobel Forum on the subject, called “Unfolded Protein: from basic to the head”. Walter as he kicked out

it is a complex mechanism that involves numerous cellular response pathways. To modify it, Walter needed a molecule that could somehow jam the mechanism. So he orchestrated a projection of 100,000 mostly synthetic compounds, funded by the Howard Hughes Medical Institute, where he is also a researcher.

a trial with cells that lit up when the pathway unfolded protein response was functioning normally was established. If a molecule interfered with the track, the light went out.

Only a composite of 100,000 turned out the light, Walter said. And that one – ISRIB – was almost expelled because it was not considered sufficiently soluble to be a good candidate for a drug

.

However, the postdoc working on the project, Carmela Sidrauski, pulled him from the discard pile because it seemed effective even at very low concentrations.

“Everything is based on the fact that she was crazy enough to ignore the experts,” Walter said.

Walter is so entranced with the molecule, which even made a sculpture of her, who is in his office. Is double symmetrical, meaning it has two arms that can help keep more strongly to its binding site “It’s a beautiful little molecule,” he said. He gave the name ISRIB inhibitor integrated response to stress.

When they began working with ISRIB, scientists discovered that it was even more powerful than he had expected.

Not only altered the response of the unfolded protein, which also affected other critical chemical pathways activated when cells react to major sources of stress such as UV light, viruses and iron deficiencies. In all these situations, and also when there are too careless proteins, cells respond by disconnecting a single protein called alpha elF2.

had previously elF2 related alpha to the memory function in mice colleague Walter Sonenberg. So the two men decided to study what effect it would have on ISRIB the brains of mice.

Were these tests showed that mice injected with ISRIB were three times faster than normal in the location of a submerged platform. They were also better at remembering the signals associated with unpleasant stimuli. Apparently, Walter said that inactivation of alpha elF2 acts as a “brake” on the formation of memories. Inserting ISRIB brake blocks, so that memories can form.

“Mice learn best,” he said. “They learn significantly better.”

Jordan Tsai
Elizabeth D. Herman for STAT A doctoral student working in the living tissue culture in the laboratory of Walter.

A drug to help patients with dementia – or took the SAT?

Walter and others say ISRIB may be a type of drug-two punch, if it pans out in other studies. It could prevent the death of cells that appear to be a factor in neurodegenerative disease. And it could also help improve memory problems cause these diseases.

biotechnology companies are taking note.

Calico, a research and development secret founded by Google with the mission to prolong life, UCSF is paying an undisclosed amount of money to license the molecule.

The company hired Sidrauski, post-doctoral ISRIB first pulled from the trash heap, to lead a team in the development of therapies molecule. Sidrauski declined to comment for this article.

Walter expects the molecule may become a drug to benefit people with memory disorders such as Alzheimer’s or dementia. He realizes, as did the smart healthy mice, which could also serve as a cognitive enhancer -. Something that parents give children before the SAT, for example

That is not his ultimate goal, however: “We are not here to give the Tiger moms,” he said

.

He was surprised to see that there are Internet chat people buy ISRIB and administering it themselves. While jokes about “Breaking Bad” be a good career choice for a chemist, Walter people strongly recommends against the use of small molecule tested on their own.

But he is excited about the multitude of ways ISRIB damaged brains could help. He is now working with Susanna Rosi, associate professor in the department of physical therapy at UCSF professor, to test the molecule of brain trauma, a devastating injury there are no pharmaceutical treatments .

“There is absolutely nothing available,” Rosi said. “There is work to do, on what to do in the emergency room, but nothing for people who suffer trauma for some time and still have cognitive deficits.”

While Walter and Rosi did not disclose details of his brain trauma studies because they are in the midst of the publication of the work, they say that the results in the injured brain healing are very promising. And working in the brains in all its complexity is exciting new intellectual territory of Walter.

“We had no idea that we would have to become neurologists,” Walter said. “I’m the new kid on the block naive, having a lot of fun.”

Like many people who work with Walter, Rosi can not seem to say enough about him and his work and surprisingly cheerful approach to life. “He’s like my 4-year-old twins,” she said, “He has this basic curiosity, intrinsic that makes it bright and unique.”

also he said Walter Rosi is always willing to share the spotlight and credit – something that is not seen in all his colleagues. Walter, who has two grown daughters, is considered a good mentor especially women. For example, Sidrauski invited back to his lab after she moved away from science altogether for eight years to raise children. That’s a rare step in a highly competitive field where job opportunities often remain restricted after absences, even short.

Peter Walter - UCSF
Elizabeth D. Herman for STAT Peter Walter walks to his lab at Genentech Hall on the campus of UCSF Mission Bay.

promise … as well as the danger?

Like many things Walter has worked on this new challenge – to adjust the response of the unfolded protein enough to create a powerful, yet safe drugs -. is not exactly going to be easy

The unfolded protein response is as essential to the basic functioning of cells that alteration can be dangerous. All changes have important effects on organs such as the liver or pancreas, which secrete large amounts of protein.

A series of earlier attempts to alter the response using genetic knockouts and other molecules was basically end the pancreas of experimental animals. In some experiments, mice lost weight suddenly and severely, which had to be euthanized.

Studies of Walter de ISRIB, and another carried out in England, have shown that it does not damage the pancreas in the short term. However, long term use of the molecule, as may be needed for chronic disease, has not yet been studied.

The response of the unfolded protein “is constantly working on their cells to eliminate misfolded proteins. This is why we must be careful,” said Jeroen Hoozemans, a researcher at the Medical Center of the VU University in Amsterdam, which She has investigated the role of the mechanism in neurodegenerative diseases in the past decade. “You can also change the normal function of the cell.”

Hoozemans, which focuses mainly on Alzheimer’s disease, is as excited as anyone about the potential of the unfolded protein response to produce new therapeutic avenues. “A new hope for drug targets is given,” he said. However, he warned that the field is so new, it is likely that it will take at least a decade before any drug could start being tested in humans.

Despite the thousands of articles that have been published in the response of the unfolded protein since its discovery, there are still many uncertainties – including which parts of it should be subject to different diseases and when therapy could be more fruitful of diseases that can be deployed in recent decades.

That challenge involve subtle careful to unlock secrets in the depths of work cells work.

Walter can not wait.

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