Peter Walter, biochemist: ‘The ISRIB molecule could become a wonder drug’

German biochemist Peter Walter and his Argentine colleague Carmela Sidrauski announced a momentous discovery just over a decade ago. They had found a molecule that was simple yet capable of tremendously enhancing the memory and learning capacity of their mice at the University of California, San Francisco. The experimental drug, called ISRIB, can be easily taken orally. The molecule has since achieved revolutionary results in animals: it has reversed age-related mental decline, restored memory loss due to head trauma, and improved memory in mice with Down syndrome.

Walter, born in Berlin 69 years ago, already made a great discovery in the 1990s. A person is made up of about 30 trillion cells. And each of them is constantly making gigantic molecules—proteins—to carry out their functions: storing memories, transporting the oxygen we breathe, killing threatening viruses. The German biochemist observed that, when a cell begins to generate malformed proteins, a mechanism is activated to slow down production and destroy the defective ones. If the nonsensical production continues, the cell commits suicide. It is a quality control system called response to misfolded proteins.

This mechanism is extremely delicate. If the response is exaggerated, the death of so many cells can lead to degenerative diseases such as Alzheimer’s and Parkinson’s. If the response results in the survival of the wrong cell, it can proliferate and cause cancer. Walter has won almost everything there is to win from this discovery. In 2014 he received the Shaw Prize, worth $1 million. In 2018, he shared the $3 million Breakthrough Prize with four other colleagues. On June 20, together with three colleagues, he collected the €400,000 of the Frontiers of Knowledge Award from the BBVA Foundation, in the northern Spanish city of Bilbao, which invited EL PAÍS to the event. And the pundits predict that he will win the Nobel Prize.

The German biochemist is one of the star signings of Altos Labs, an American company launched in 2022 with four Nobel winners on board and a huge budget of around $3 billion. The company is surrounded by secrecy. Its shadow promoter is Yuri Milner, a Russian-born Israeli physicist who became a billionaire thanks to his early involvement in Facebook and Twitter. The stated goal of Altos is to rejuvenate cells to reverse diseases and live longer, healthier lives.

The ISRIB molecule modulates the so-called integrated stress response, associated with this cell quality control mechanism. Walter, who is also a sculptor in his spare time, has made a statue with the real structure of this experimental drug. “It is made of bronze and weighs a quarter of a ton. I have it in my basement. The molecule is small and, if you are a chemist, it is pretty,” he explains. In 2015, Walter and Sidrauski licensed the ISRIB patent to Calico, a company linked to the founders of Google. The scientist answered questions from EL PAÍS in Bilbao, just hours before collecting the Frontiers of Knowledge Award.

Question. What are the potential therapeutic applications of ISRIB? You have talked about Alzheimer's, Parkinson's, amyotrophic lateral sclerosis...

Answer. We have tested it in various laboratory mouse models with neurodegeneration, cognitive defects, learning problems... And we see effects in a huge number of them. In my lab, we can basically cure head trauma in mice. After suffering brain damage, like football players, they cannot memorize anything, but ISRIB restores their memory completely. We can also take an old mouse and train it to do something, but it has a hard time learning. If you give it ISRIB, it learns like a teenager. So we can rejuvenate the learning behavior.

Q. Does it rejuvenate the brain?

A. Rejuvenates brain function, yes. What is really important is that all these diseases converge in the activation of the integrated stress response, which causes cognitive defects. We have a common node through which all pathologies pass, even if they are so different. Banging your head is not the same as aging normally, or having an extra chromosome in Down syndrome or having protein aggregates in Alzheimer’s. And yet, all these processes lead to the activation of that same mechanism. That mechanism is the bad guy. And we can act on it and achieve benefits. For now, in mice.

If you give ISRIB to an old mouse, it learns like a teenager

Q. Could we say that ISRIB is a knowledge enhancer?

A. Yes.

Q. If it worked in humans, it would be a wonder drug.

A. It could potentially become a wonder drug.

Q. Do you think it will work in humans?

A. I hope so. Mouse brains are very different from human brains, but we know that the mechanisms are the same. I think the odds are pretty high.

Q. When will we see a clinical trial to try to improve people's cognitive function?

A. A Calico trial [with 300 people] is already underway to test ISRIB as a cognitive function enhancer in patients with amyotrophic lateral sclerosis.

Q. And for Alzheimer’s?

A. I think Alzheimer’s is much more difficult, because the disease spreads out over so long. Companies have to focus on one area. Once the drug is approved for clinical use, there will be many trials for other indications, because the drug will already be known to be safe. The range of potentially treatable cognitive defects is enormous.

Q. Does ISRIB cause any relevant side effects?

A. We have never seen any.

Q. None?

A. None, it is totally benign.

P. Your mice will be happy.

A. My mice are very very happy. It’s wonderful: we have a molecule that affects reactions that occur in each of our cells and yet it is not toxic to any other function. I find it absolutely amazing.

P. There are some crazy people out there who are taking ISRIB on their own. Where do they get the molecule?

A. You can buy it on Alibaba [a Chinese e-commerce platform]. It's on the market. I totally advise against consuming it, because we still don't really know what happens. I have never taken it, although it is tempting.

I totally advise against consuming ISRIB now, because we still don't really know what happens

Q. Altos Labs was born in 2022 with an initial budget of about $3 billion, double the annual budget of the largest science organization in Spain, the CSIC. Who is behind Altos Labs? Billionaire Yuri Milner or someone else?

A. We don’t talk about the funding of the company. The idea is to bring private money into basic research. They are investors with a very long-term vision. Private investments are usually limited by the philosophy of venture capital, which wants returns in a very short time. If you want to handle a challenging problem, you need a runway that expands for years. We published the ISRIB finding in 2013 and, a decade later, it is in clinical trials. It has taken us about 15 years to reach a stage where we hope to have a new effective drug. We need those kinds of deadlines and to attract great scientists.

Q. But who had the idea of creating Altos Labs? Yuri Milner?

A. The key person who is holding it together is Rick Klausner [an American biologist who was director of the U.S. National Cancer Institute]. And there is no single source of funding, it is a combination of donors.

Q. But was the first idea Yuri Milner's?

A. I wouldn't go that far.

Q. Is Jeff Bezos [founder of Amazon and the second wealthiest person in the world] putting money into Altos Labs?

A. I don’t want to talk about money, it gets me into trouble [laughs].

Q. Altos Labs has signed on four Nobel winners and many leading scientists, but it is surrounded by secrecy. Some people believe that behind Altos Labs there are millionaires who want to be immortal.

A. It’s certainly not what I work for. Our goal is a little more attractive: we want to understand what goes wrong during aging, so we can live a longer, healthier life. We want to increase the length of life with health, free society as a whole from the burden of degenerative diseases, cancer, diabetes. Our goal is not longevity. I don’t think the planet is ready for us to live 200 years, that would cause many social and economic problems. As scientists, we can look at cells and figure out what’s going wrong, so we can fix those problems ahead of time. A good example is statins. You take them to lower your cholesterol levels and avoid a heart attack. It is a medication you take to keep your system younger and your arteries clear.

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