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Science & technologyJan 22nd 2022 edition

Biotechnology
A $3bn bet on finding the fountain of youth

Can an instant unicorn crack cellular rejuvenation?

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Jan 22nd 2022

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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.

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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 life spans. 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.

Pick'n'mix

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
ability 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.

[20220122_s]

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 successful 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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This article appeared in the Science & technology section of the
print edition under the headline "Backwards ran the sands of time"

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