Humankind 2.0

a book in progress...
Meditations on the future of technology and society...
...to be published in China in 2016

These are raw notes taken during and after conversations between piero scaruffi and Jinxia Niu of Shezhang Magazine (Hangzhou, China). Jinxia will publish the full interviews in Chinese in her magazine. I thought of posting on my website the English notes that, while incomplete, contain most of the ideas that we discussed.
(Copyright © 2016 Piero Scaruffi | Terms of use )

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Longevity Research

(An excerpt of the chapter on Biotech)

The goal of genomics is, of course, longevity. We want to prevent diseases, and we want to figure out which genes make some people live to a very old age. In 2013 Google funded Calico (which is nicknamed "Google's longevity lab" in Silicon Valley) and hired Arthur Levinson, a former Genentech executive to run it. He was Genentech's chief scientist and from 1995 its CEO until Roche acquired the company in 2009. Levinson hired others from Genentech, notably David Botstein, a geneticist from Princeton University and former vicepresident at Genentech. He hired Cynthia Kenyon, the UC San Francisco biologist who in 1993 discovered that removing a gene doubled the lifespan of worms and that injections of sugar shortened their lifespan. He hired Shelley Buffenstein, a specialist at the University of Texas in animals with exceptionally long lifespans. Calico also acquired access to Ancestry's massive datasets.

Craig Venter founded Human Longevity Inc in San Diego in 2013, a company that has been studied genetic data and already found some correlations between genetic variations and longevity. Ambrosia, a startup in Monterey founded by Jesse Karmazin, has begun experimental transfusions of younger blood to older people because Stanford's scientist Tony Wyss-Coray discovered that rats live longer when given the blood of younger rats. This research was a continuation of studies originally published in 2005 by Thomas Rando's laboratory at Stanford ("Rejuvenation of Aged Progenitor Cells by Exposure to a Young Systemic Environment", 2005).

For me the science of longevity really begins in 1993. In 1993 Cynthia Kenyon at UC San Franisco discovered that partially disabling a gene called Daf-2 can double the life of a worm (to one month instead of two weeks). This became known as the sugar problem because eating sugar basically is equivalent to activating (instead of disabling) Daf-2, and in fact sugar shortens the life of the worm (Kenyon famously warned that "sugar is the new tobacco"). After that experiment many other experiments focused on genes and chemicals of all types that seem to affect the lifespan of animals and plants.

A few years later (1999) Leonard Guarente at the MIT found a gene that increased the lifespan of yeast, SIR2. SIRT1 is the equivalent gene in mammals and the family of these genes, "sirtuin", became known as "the anti-aging gene". Guarente and Cynthia Kenyon founded Elixir Pharmaceuticals in 1999 to make anti-aging products. In 2003 Fritz Muller's team at the University of Fribourg in Switzerland discovered that suppressing an enzyme called TOR (Target of Rapamycin) increased the lifespan of worms. Zelton Dave Sharp at the University of Texas proved that the same is true in mice: give them rapamycin (the inhibitor of TOR) and they live longer lives. In 2007 Guarente's pupil David Sinclair showed that the two substances (sirtuin and rapamycin) target the same "longevity pathway". Biologists started searching for "sirtuin activators" and "TOR inhibitors". There was one obvious TOR inhibitor, rapamycin, but no obvious sirtuin activator. In 2003 Sinclair had proposed resveratrol as sirtuin activator, a substance that is found in red wine, and had founded Sirtris in 2004 to make anti-aging drugs based on resveratrol. In 2008 GlaxoSmithKline bought Sirtris, but now the scientific consensus is that resveratrol doesn't work, especially after a study conducted in 2014 by Richard Semba's team of Johns Hopkins University. On the other hand, rapamycin (known as "rapamune" by pharmacies around the world) definitely works on mice. It was confirmed by another study in 2009 led by Richard Miller of the University of Michigan but conducted by three separate teams in three different universities.

Soon the enthusiasm spread to Silicon Valley. Aubrey de Grey, a former Artificial Intelligence scientist, published the book "Ending Aging" (2007) and founded the SENS (Strategies for Engineered Negligible Senescence) Research Foundation in 2009 in Mountain View.

These studies are interesting but we should never forget that dying is not really a disease. What happens to everybody is not a disease: it is the norm. Everybody dies, so that is not a disease in the sense that diabetes or malaria are diseases. When we look for a drug to cure malaria, we are looking for a drug to turn malaria victims into normal people. When we look for a drug to make us immortal, we are looking for a drug to turn people into something else, not people anymore.

The search for longevity, and possibly even immortality, has led scientists to a tiny polyp, the hydra. This is the only animal that does not age and therefore does not die of old age. It would be immortal if no predator killed it. What makes the hydra "immortal" is that its stem-cells keep proliferating. In 2012 Thomas Bosch at Kiel University discovered that this property of the hydra is due to the so-called FoxO gene, which all animals have but only in some individuals it works overtime. Scientists have long suspected that this gene is important for longevity because a 2008 study by David Curb's team (mainly Bradley Willcox) at the University of Hawaii showed that this gene seems to be particularly active in centenarians. Some day with a bit of genetic manipulation it may be someday possible for humans to regenerate stem-cells and increase longevity. (Bad news for tall people: in 2014 a study by the same team showed that FoxO3 was "inversely associated with height", i.e. the taller you are the shorter your life expectancy. But good news for tea drinkers: the same team showed that drinking tea helps activate FoxO gene expression, i.e. live longer lives. But, don't panic, all these studies are very preliminary).

Another interesting animal for the study of longevity is the jellyfish called "turritopsis". It is the only known animal that can reverse its life cycle and rejuvinate. This animal is not immortal (it does die) but for brief periods it can get younger, and that's certainly something that many elderly people would like to do.

A chemical called NRF-2 became famous when in 2010 Rochelle Buffenstein at the University of Texas showed that it is a key actor in the aging process while protecting the body from diseases. In 2016 Linda Partridge of University College London lithium prolongs the life of fruit flies because (as known since 1996 thanks to the thesis at the University of Toronto by Jim Woodget's student Vuk Stambolic) it blocks a chemical called GSK-3 (that is suspected of being involved in the aging process) while at the same time stimulating that famous NRF-2. In 2016 Manfred Kayser in the Netherlands discovered that a gene called MC1R is responsible for "looking older".

In 2011 Jan VanDeursen's team at the Mayo Clinic published found a way to remove senescent cells from mice. These senescent cells are almost literally rotting, secreting a toxin called SASP (Senescence-Associated Secretory Phenotype) that contaminates nearby cells spreads senescence throughout the body. Van Deursen immediately co-founded Unity Biotechnology in San Francisco to commercialize this idea (together with Judith Campisi of the Buck Institute for Research on Aging and serial biotech entrepreneur Nathaniel David). Their investors have included billionaires like Jeff Bezos and Peter Thiel.

Potentially, this is big business, so no surprise that Craig Venter opened Human Longevity Inc (in San Diego in 2013) and Jesse Karmazin started Ambrosia (in Monterey in 2016) to investigate the finding by Tony Wyss-Coray at Stanford University that a transfusion of younger blood makes old mice live longer. In 2014 Tony Wyss-Coray himself co-founded Alkahest in Redwood City.

In 2011 Jean-Marc Lemaitre's lab in France took cells from centenarians and reprogrammed them in the lab to "rejuvinate" them ("Rejuvenating Senescent and Centenarian Human Cells by Reprogramming through the Pluripotent State", 2011). That opened the door to another line of research: artificially inducing the "Yamanaka factors" (Oct4, Sox2, C-myc and Klf4) to reset the aging clock. Based on studies by Rando and Howard Chang at Stanford ("Aging, Rejuvenation, and Epigenetic Reprogramming", 2012), suggesting how the aging clock could be reversed, in 2016 Juan-Carlos Izpisua-Belmonte at the Salk Institute in San Diego succeeded in reprogramming cells in mice to express the four Yamanaka factors. These mice lived more than 30% longer.

Other startups in the field of "extended longevity" are resTORbio, which is a Novartis spinoff, Insilico Medicine, Mount Tam Biotechnologies, and Gero in Russia.

Anti-aging treatments are offered by hundreds of clinics but here are all unregulated therapies. Meanwhile the record of longevity still belongs to Jeanne Calment, who died in 1997 at the age of 122. Nobody has managed to live longer.

(This is an excerpt of the chapter on Biotech)


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