HomeScience & TechA $3bn bet on finding the fountain of youth

A $3bn bet on finding the fountain of youth

STARTUPS COME and startups go. But few startups start with $3bn in the bank. Yet that is the fortunate position in which Altos Labs finds itself. Though preparations for the launch of what must surely be a candidate for the title of “Best financed startup in history” have been rumoured for months, the firm formally announced itself, and its modus operandi, on January 19th. And, even at $3bn, its proposed product might be thought cheap at the price. For the alchemy its founders, Rick Klausner, Hans Bishop and Yuri Milner, hope one day to offer the world is an elixir of life.

Others have tried this in the past. In 2013 an outfit called Calico Life Sciences was set up under the aegis of Google (now Alphabet), with Larry Page, one of that firm’s founders, as an interested party. It has yet to generate a product. In the same year Craig Venter, who ran a private version of the human genome project, and Peter Diamandis, who started the X Prize Foundation, got together to launch Human Longevity, though they subsequently fell out. That company, too, has gone quiet. And there are a string of other hopefuls in the field, many with billionaires like Dr Milner and Mr Page lurking in the background. Indeed, there are rumours, which Altos will not confirm, that Jeff Bezos is one of its investors—for the prolongation of life is a field that seems particularly attractive to the man (and it usually is a man) who otherwise has everything.

A walk in the hills

The founders of Altos do, though, seem deadly serious about what they are up to. Looking at discoveries in biology made over the past few decades—two of these, in particular—they believe they have glimpsed the outline of an answer to the question of how to reverse the process of cellular ageing. They have also recruited a star-studded scientific cast to help them track that answer down. Illnesses potentially in their cross-hairs include cognitive disorders and neurodegeneration, diabetes and associated metabolic problems, and cancer. Dealing with these might not, in the end, greatly extend average lifespans. But it would surely increase what is known in the argot as healthspan.

The idea that became Altos was dreamed up by Dr Klausner, a former head of America’s National Cancer Institute, and Dr Milner, an entrepreneur and venture capitalist with fingers in many technological pies, in a series of covid-escaping walks in Los Altos, a hilly, well-heeled suburb on the edge of Silicon Valley. They then recruited Mr Bishop, formerly boss of GRAIL, a cancer-detection company, to be the business brains.

The two findings around which the firm is built are Yamanaka transcription factors and the integrated stress-response (ISR) pathway. Yamanaka factors, discovered in 2006 by Yamanaka Shinya of Kyoto University, are four gene-regulating proteins which serve, in essence, to return a cell to factory settings. In this case “factory settings” means a state known as pluripotency that is enjoyed by embryonic stem cells. Pluripotent cells are those that can give rise to descendants capable of differentiating into a wide variety of specialised cells.

Early experiments involving the induction of Yamanaka factors in laboratory animals often caused tumours called teratomas, in which cells turn into weird mixtures of tissues. It has subsequently been discovered, though, that a partial reset avoiding this problem is possible by turning the relevant genes on only briefly. This results in a return to youthful rude health without “unspecialising” the cells involved. Experiments on mice have shown how that can stop the progression of progeria, a mutation-induced syndrome that mimics rapid ageing, can promote the healing of injured muscles, and can protect the liver against damage by paracetamol, a widely used painkiller.

In contrast to the Yamanaka factors, which have a clear discovery date, the idea of an ISR pathway has emerged gradually. One of biology’s most important concepts is homeostasis, the maintenance of a constant internal environment in the face of external pressure to change. The ISR does this at a cellular level. If a source of cellular stress is detected—be it external, such as oxygen or nutrient-deprivation, or viral infection; or internal, such as an accumulation of misfolded proteins or the activation of a potentially cancer-causing gene—the ISR switches on an emergency program to reset protein manufacturing. If this does not clear the problem, it then presses the self-destruct button, blowing up the cell it is in, in a process called apoptosis, to stop it becoming a locus of disease.


These two discoveries offer, in the founders’ view, ways to bring sick cells back to health by resetting malfunctioning ISR pathways, and to give healthy cells that are getting on a bit in years a tonic. The initial plan is to look into this at three campuses, in Cambridge, England, the Bay Area of California and San Diego. The institutes in these will be led by Wolf Reik, Peter Walter and Juan Carlos Izpisua Belmonte respectively. Each will house, in its turn, about half a dozen research groups investigating various aspects of the problem.

Dr Reik, plucked from the Babraham Institute, an independent biomedical-research laboratory near Cambridge, is an expert in a field called epigenetic gene regulation. Tinkering with this process, in which gene expression is controlled by the way DNA is packed into chromosomes, is how the Yamanaka factors operate. Dr Walter, until now at the University of California, San Francisco, studies the behaviour of proteins inside cells. He has been involved from the beginning in mapping the ISR pathway. And Dr Izpisua Belmonte, who ran the Gene Expression Laboratory at the Salk Institute, in San Diego’s northern suburb of La Jolla, is also deeply embroiled in studying the Yamanaka factors. Indeed, it was he who spotted their potential to rejuvenate without a full factory reset, with all the potential medical consequences that gives rise to. Previously, those seeking to turn Yamanaka factors to medical advantage were looking at stem-cell therapies to regenerate tissues already in the body and also at the idea of growing organs for transplant. Dr Izpisua Belmonte opened the third avenue of rejuvenative possibility that Altos seeks to exploit.

Dr Yamanaka, too, has volunteered—literally (he will not be paid). Indeed, it was through him that Dr Milner became interested in the question of ageing and rejuvenation. In 2013 he was among the first recipients of a Breakthrough prize, an award that Dr Milner and some like-minded Silicon Valley bigwigs dreamed up to try to give the Nobel Foundation a run for its money. Though he will not run an institute, he will help gather a network of collaborators in his native country.

The last piece of the scientific jigsaw—almost inevitable these days—is artificial intelligence (AI). This is the purview of Thore Graepel, until now one of the leading lights in Google DeepMind. Modelling what is going on inside cells, which are composed of millions of molecules of thousands of varieties, is the sort of problem that would be unapproachable without AI. And the field is now starting to grapple with it, as shown by the recent success of DeepMind’s AlphaFold program, which is able to predict from a protein’s chemical structure how it will fold up into a functional shape. Dr Graepel’s software will try to make sense of the outpourings of data from the firm’s investigators.

Moreover, in case this list (which includes only one Nobel laureate, Dr Yamanaka himself) is not thought glittering enough, the firm’s board sports three others: David Baltimore, a biological polymath, who won his for his work on viruses; Jennifer Doudna, joint-inventor of a gene-editing technique called CRISPR-Cas9 that has boosted biotechnology; and Frances Arnold, who won her prize for work on directing the evolution of enzymes.

How, then, will it all play out? The biggest risk may be that the participants have jumped too early. The nitty-gritty of what they will be doing, at least in the firm’s salad days, is pretty much what they would have been doing anyway, in their old jobs, except with bigger budgets. The flip side of this is that there is nothing immediately to hand that might be developed into a commercial product.

Three billion dollars is a big financial cushion, though. It gives leeway for changes of direction and recovery from mistakes. It will also, as Bob Nelsen, whose firm, ARCH Venture Partners, is on board to the tune of a sum north of $250m, its biggest ever investment, observes, allow Altos to build its own development arm, and not have to rely, as lesser startups often do, on selling its intellectual property to an existing pharmaceutical company.

Not having a clear product from the get-go does not, then, seem to be a problem—though Mr Nelsen does mention boosting T-cell responses in the immune systems of the elderly and dealing with badly functioning islet cells in the pancreases of people with diabetes as early possibilities. Everyone involved seems confident that salable products will emerge.

Re-record, don’t fade away

Altos’s founders are thus imitating old-fashioned corporate laboratories of the sort epitomised by Bell Labs, except without Ma Bell, then America’s telephone monopoly, at their back. Bell hired bright people and let them get on with it, too. That resulted in the transistor and the laser. But those were products of physics, not biology. And the Altos approach seems similar to that taken by Calico Life Sciences, which has not worked so well—though Hal Barron, appointed as Altos’s chief executive, was once Calico’s head of research, and might have ideas why not.

More fundamentally, there are doubts about how controllable the underlying biology of ageing really is. Despite appearances, multicellular organisms do not simply wear out in the ways that machines do. Like everything else in biology, the process of senescence is regulated by natural selection. The details are debated. But an overarching principle, called disposable-soma theory, seems to govern what is going on.

Disposable-soma theory starts from the premise that, for an individual, death is inevitable. Accident, infection, a predator or a rival will get you in the end. It therefore makes sense for evolution to care more about individuals when they are young than when they are old, since by then they may have died or been killed anyway.

Lots of things about ageing make sense from this perspective. Genes can have bad effects in old age as long as they have good ones during youth. Repairs need not be perfect—just good enough to keep the show on the road. Anti-cancer mechanisms need to be tip-top for the first decades of life, but can get slacker with time. As can the immune system. Though they will, no doubt, build outward from their starting point, Altos’s researchers will surely have to incorporate more aspects of molecular biology than those they are beginning with, in order to cover these bases.

The counterargument, put by Dr Klausner and his colleagues, is that resetting the clock is a natural process. It happens every generation. The reproductive cells which create these new generations get a fresh start each time. They really do return to factory settings. And if the clock can be reset for those cells, why not others? Whether Dr Milner, Mr Nelsen and the others who have backed the firm see a return on their investment will depend, above all, on the answer to that question. But it will be fascinating to see it asked.

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