The Economist January 22nd 2022 Science & technology 71mals often caused tumours called terato
mas, in which cells turn into weird mix
tures of tissues. It has subsequently been
discovered, though, that a partial reset
avoiding this problem is possible by turn
ing the relevant genes on only briefly. This
results in a return to youthful rude health
without “unspecialising” the cells in
volved. Experiments on mice have shown
how that can stop the progression of pro
geria, a mutationinduced syndrome that
mimics rapid ageing, can promote the
healing of injured muscles, and can pro
tect the liver against damage by paraceta
mol, a widely used painkiller.
In contrast to the Yamanaka factors,
which have a clear discovery date, the idea
of an isrpathway has emerged gradually.
One of biology’s most important concepts
is homeostasis, the maintenance of a con
stant internal environment in the face of
external pressure to change. The isrdoes
this at a cellular level. If a source of cellular
stress is detected—be it external, such as
oxygen or nutrientdeprivation, or viral in
fection; or internal, such as an accumula
tion of misfolded proteins or the activation
of a potentially cancercausing gene—the
isr switches on an emergency program to
reset protein manufacturing. If this does
not clear the problem, it then presses the
selfdestruct 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 foun
ders’ 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 Cal
ifornia and San Diego. The institutes in
these will be led by Wolf Reik, Peter Walter
and Juan Carlos Izpisua Belmonte respec
tively. Each will house, in its turn, about
half a dozen research groups investigating
various aspects of the problem.
Dr Reik, plucked from the Babraham In
stitute, an independent biomedicalre
search laboratory near Cambridge, is an ex
pert in a field called epigenetic gene regu
lation. Tinkering with this process, in
which gene expression is controlled by the
way dnais packed into chromosomes, is
how the Yamanaka factors operate. Dr
Walter, until now at the University of Cali
fornia, San Francisco, studies the behav
iour of proteins inside cells. He has been
involved from the beginning in mapping
theisrpathway. 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 reju
venate without a full factory reset, with all
the potential medical consequences that
gives rise to. Previously, those seeking to
turn Yamanaka factors to medical advan
tage were looking at stemcell therapies to
regenerate tissues already in the body and
also at the idea of growing organs for trans
plant. 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 inter
ested in the question of ageing and rejuve
nation. In 2013 he was among the first re
cipients of a Breakthrough prize, an award
that Dr Milner and some likeminded Sili
con Valley bigwigs dreamed up to try to
give the Nobel Foundation a run for its
money. Though he will not run an insti
tute, he will help gather a network of col
laborators 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 lead
ing 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 pro
blem that would be unapproachable with
out ai. And the field is now starting to grap
ple 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 func
tional 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 in
cludes only one Nobel laureate, Dr Yama
naka himself ) is not thought glittering
enough, the firm’s board sports three oth
ers: David Baltimore, a biological poly
math, who won his for his work on viruses;
Jennifer Doudna, jointinventor of a gene
editing technique called crisprCas9 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 big
gest risk may be that the participants have
jumped too early. The nittygritty of what
they will be doing, at least in the firm’s sal
ad 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 com
mercial product.
Three billion dollars is a big financial
cushion, though. It gives leeway for chang
es of direction and recovery from mis
takes. It will also, as Bob Nelsen, whose
firm, archVenture Partners, is on board to
the tune of a sum north of $250m, its big
gest 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 exist
ing 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
tcell responses in the immune systems of
the elderly and dealing with badly func
tioning islet cells in the pancreases of peo
ple 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 with
out Ma Bell, then America’s telephone mo
nopoly, at their back. Bell hired bright peo
ple and let them get on with it, too. That re
sulted in the transistor and the laser. But
those were products of physics, not biolo
gy. And the Altos approach seems similar
to that taken by Calico Life Sciences, which
has not worked so well—though Hal Bar
ron, 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 bi
ology of ageing really is. Despite appear
ances, multicellular organisms do not sim
ply wear out in the ways that machines do.
Like everything else in biology, the process
of senescence is regulated by natural selec
tion. The details are debated. But an over
arching principle, called disposablesoma
theory, seems to govern what is going on.
Disposablesoma theory starts from the
premise that, for an individual, death is in
evitable. 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