CURING AGING
Bill
Andrews, Ph.D. and Jon Cornell
Since
before recorded history began, people have been searching for ways to live
longer. We all know the story of Ponce de Leon's search for the elusive
Fountain of Youth, but even two millennia earlier, emperor Qin Shi Huang of
China was sending out ships full of hundreds of men and women in search of an
Elixir of Life that would make him immortal. The desire to live forever is as
old as humanity itself.
But it has only been in the last thirty years that science has
made any real progress in understanding the fundamental question of why we age
and what can be done about it. These discoveries have not been widely
publicized-yet -and so most people are unaware of how close we are to curing
the disease of aging once and for all.
Is Aging a Disease?
References to "the
disease of aging" still make many people uncomfortable. After all, aging
is a natural process that has existed forever -so how can it be a disease? In fact, aging has not existed
forever. Approximately 4.5 billion years ago, a cell came into existence on
Earth that was the progenitor of every living organism that has since existed.
This cell had the ability to divide indefinitely. It exhibited no aging
process; it could produce a theoretically infinite number of copies of itself,
and it would not die until some environmental factor killed it. When the
ancestry of any given cell is traced back to this very first living cell, this
lineage is called the cell's germ line. Much later -perhaps three billion
years later- some cells of the germ line began to form multicellular organisms:
worms, beetles, lobsters, humans. The germ line, however, was still passed on
from one generation to the next, and remained immortal. Even with the inclusion
of multicellular organisms, the germ line itself exhibited no aging process. But, in some multicellular organisms, such as humans, certain
cells strayed from the germ line and began to exhibit signs of aging. These cells aged because
they became afflicted with a disease: their ability to reproduce themselves
indefinitely became broken. The cause of this disease is still speculative, but
many scientists are searching for cures.
The fact that a disease
has existed in the genetic code of an animal for a very long time does not mean
that it is not a disease. Thousands of diseases, from hemophilia to cystic
fibrosis, have lurked in our genes for far longer than recorded history. These
diseases should be cured, and aging is no exception.
The Cause of Aging
The root cause of aging is very straightforward: we age because
our cells age.
In 1961, Leonard Hayflick,
a researcher at the Wistar Institute in Philadelphia, discovered that there was
a limit to the number of times a human cell could divide.1 After about 70 divisions, a cell
derived from embryonic tissue enters a stage where its ability to divide slows
and eventually stops. This stage is called cellular senescence. Hayflick also
observed that the number of times a cell could divide was governed by the age
of the cells: cells from a 20-year-old could divide more times than cells from
a fifty-year-old, which in turn would divide more times than cells from a
ninety-year-old.
Hayflick discovered that,
in essence, there is a clock ticking inside every dividing cell of our body.
Our aging process isn't simply a consequence of accumulated damage: there is a
specific property of our cells that limits how long we can live. The nature of this property was proposed
independently in the early 1970s by both Soviet and American scientists.2 When a
cell divides, the genetic material inside that cell needs to be copied. This
process is called DNA replication. These scientists suggested that the
limitation on cell division is rooted in the very nature of DNA replication.
The enzymes that replicate a strand of DNA are unable to continue replicating
all the way to the end, which causes the loss of some DNA. As
an analogy, think of a DNA as a long row of bricks, and of DNA replication as a
bricklayer walking backwards on top of a brick wall laying a new layer on top
of that row. When the end of the wall is reached, the bricklayer finds himself
standing on top of the brick he's supposed to replicate. Since he can't put
down a brick where his feet are, he steps back and falls off the wall - leaving
the very end of the wall bare. As a result, the new copy of
the wall is shorter. Just like this brick wall was copied
imperfectly, our DNA is unable to perfectly copy itself; when a strand is
replicated, the new strand is shorter than the old strand. If we lost portions
of the information encoded in our DNA every time it replicated, human life
would be impossible. Our cells couldn't even divide enough times to allow us to
be born. Fortunately, we are born with long, repetitive sequences of DNA at the
end of each of our chromosomes, which later shorten during the normal DNA
replication process.
These
repetitive sequences are called "telomeres."
Telomeres,
like all DNA, are made up of units called nucleotides, arranged like beads on a
string. The nucleotides in human telomeres are arranged in the repeating
sequence TTAGGG (two thymine nucleotides, one adenine nucleotide, and three
guanine nucleotides). This
sequence is repeated hundreds of times in tandem in every telomere. Each time
our cells divide and our chromosomes replicate, our telomeres become shorter. When we are first conceived, the telomeres
in our single-cell embryos are approximately 15,000 nucleotides long.
Our cells divide rapidly in the womb, and by
the time we are born, our telomeres have decreased in length to approximately
10,000 nucleotides. They shorten throughout our lifetime, and when they reach
an average of about 5,000 nucleotides, our cells cannot divide any further, and
we die of old age.
Telomerase
Telomere
Length Therapy
So what
about us? Can we insert the telomerase gene into all of our cells and extend
our lifespan? Inserting the gene
directly into our DNA, through the use of viral vectors, is not a viable
option. The main problem with this approach is that inserting genes into
cells often causes cancer. That's because the gene gets inserted into our
chromosomes at random sites, and if the wrong site is chosen, the gene can
interrupt and disable cancer suppressor genes or turn on cancer-inducing genes.
And you only need one out of the hundred trillion cells in your body to
become cancerous in order to kill you.
Fortunately,
the telomerase gene already exists in all our cells. That's because the DNA in
every one of our cells is identical: a skin cell, muscle cell, and liver cell
all contain exactly the same genetic information. Thus, if the cells that
create our sperm and egg cells contain the code for telomerase, every other
cell must contain that code as well. The reason that most
of our cells don't express telomerase is that the gene is repressed in them. There
are one or more regions of DNA neighboring the telomerase gene that serve as
binding sites for a protein, and, if that protein is bound to them, telomerase
will not be created by the cell. However, it is possible to coax that repressor
protein off its binding site with the use of a small-molecule, drug-like
compound that binds to the repressor and prevents it from attaching to the DNA.
If we find the appropriate
compound, we can turn telomerase on in every cell in the human body.
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Compounds
such as these have very recently been discovered. One such compound is TA-65,
a nutraceutical discovered by Geron Corporation and licensed to TA Sciences.
Additionally, Sierra Sciences, using a robotically-driven high-throughput drug
screening effort, has discovered over two hundred compounds in 29 distinct drug
families that induce the expression of telomerase in normal cells. However, the perfect drug
hasn't been found yet. None of the compounds induce telomerase in
large enough quantities that are likely to stop or reverse aging; even the
strongest known compound, a synthetic chemical patented by Sierra Sciences but
not approved for human use, induces only 16% of the telomerase expression found
in some immortal cell lines. Also, many of these compounds (with the notable
exception of TA-65) are somewhat toxic to cell cultures and probably unsafe
for human consumption. Finding a more powerful drug will require more screening
and more research, and the speed of that progress is dependent almost entirely
on the level of funding that the project can achieve.
Proofs
of Principle
There
is a plan in place for inducing telomerase in all our cells. But will that plan
work? Will it cure aging? That's the trillion-dollar question, and scientists
have been trying to answer it for more than a decade. So far, all the signs
point to yes: telomerase is a very likely cure for aging. In 1997, scientists inserted the telomerase gene into normal
human skin cells grown in a Petri dish. 5 When they observed that the telomerase enzyme
was being produced in the cells, as hoped, they also observed that the skin
cells became immortal: there was no limit to the number of times these cells
could divide. When the lengths of the telomeres in these
"telomerized" cells were examined, the scientists were surprised to
see that the telomeres didn't just stop shortening: they got longer. The
critical question, then, was whether the cells were becoming younger.
A few
years later, scientists inserted the telomerase gene into human skin cells that
already had very short telomeres. These cells were then grown into skin on the
back of mice.6 As one would expect, skin from cells
that hadn't received the telomerase gene looked like old skin. It was wrinkled,
blistered easily, and had gene expression patterns indicative of old skin. The
skin grown from cells that had received the telomerase gene, on the other hand,
looked young! It
acted like young skin, and, most importantly, its gene expression patterns, as
analyzed by DNA Array Chip analysis, were almost identical to the gene
expression patterns of young skin. For the first time ever, scientists had
demonstrably reversed aging in human cells.
Would
the concept apply to living organisms? In Nov. 2008, scientists published a
paper describing how they had created cloned mice from mouse cells containing
the inserted telomerase gene, which continually produced the telomerase enzyme. 7 These mice were shown to live 50% longer
than cloned mice created from cells that didn't contain the inserted telomerase
gene. It's becoming increasingly clear that
prevention of telomere shortening might be the best way to extend human
lifespan beyond the theoretical 125-year maximum lifespan. How long this can
extend the human lifespan is anyone's guess, but living a healthy, youthful life
to 250, 500, or even 1,000 years is not outside the realm of possibility. More
research needs to be done to answer that question.
The
Cancer Question
The
ability to divide forever and never age describes our ancestral germ line, but
it also describes a much less pleasant type of cell line: cancer. A cancer begins when something goes wrong in
a cell, causing it to lose control over its growth. It begins to divide
repeatedly, ignoring chemical signals that tell it to stop. However, the
telomeres continue to shorten in these cells, and eventually, the cells reach a
stage where they can no longer divide, at which point they enter a "crisis
mode." In the vast majority of
cases, when this crisis is reached, the cells will enter senescence and stop
dividing. However, very occasionally, they will find ways to re-lengthen their
telomeres. When this happens, a cancer begins to divide not only uncontrollably
but indefinitely, and this is when cancer becomes truly dangerous. In most cases (85-95%), cancers accomplish
this indefinite cell division by turning on telomerase. For this reason,
forcing telomerase to turn offthroughout the body has been
suggested as a cure for cancer, and there are several telomerase inhibitor
drugs presently being tested in clinical trials. So, anti-aging scientists must be out of
their minds to want to turn the telomerase gene on, right?
No!
Although telomerase is necessary for cancers to extend their lifespan,
telomerase does not cause cancer. This has been repeatedly demonstrated: at
least 7 assays for cancer have been performed on telomerase-positive human
cells: the soft agar assay, the contact inhibition assay, the mouse xenograft
assay, the karyotype assay, the serum inhibition assay, the gene expression
assay, and the checkpoint analysis assay. All reported negative results. 8
As a
general rule, bad things happen when telomeres get short. As cells approach
senescence, the short telomeres may stimulate chromosome instability.9 This chromosome instability can cause
the mutations normally associated with cancer: tumor suppressor genes can be
shut off and cancer-causing genes can be turned on. If a mutation that causes telomerase
to be turned on also occurs, the result is a very dangerous cancer.
Paradoxically,
even though cells require telomerase to become dangerous cancers, turning on
telomerase may actually prevent cancer. This is not just
because the risk of chromosome rearrangements is reduced, but also because
telomerase can extend the lifespan of our immune cells, improving their ability
to seek out and destroy cancer cells. It's
fairly obvious that long telomeres in human beings are not correlated with cancer.
If that were true, young people would get cancer more often than the elderly.
Instead, we usually see cancers occurring in people at the same time they begin
to show signs of cellular senescence - that is, at the same time their immune
system begins to age and lose its ability to respond to threats. Extending the
lifespan of our immune cells could help our bodies fight cancer for much longer
than they presently can.
Objections
to Finding a Cure
There
are some who claim that a cure for aging is not a good thing, and that this is
a technology that should never be researched in the first place. Some of the
most common concerns about extending human lifespan are listed below, along
with responses to these objections.
"Won't
the Earth become overpopulated?"
It
stands to reason that extending our lifespans would increase the world
population; after all, we've seen it happen before. In just over a century, the
average life expectancy of a person living in the USA has increased from 47.3
in 1900 to 78.0 in 2008. Technologies including vaccines, antibiotics,
chemotherapy, and antioxidants, as well as social advances such as sanitation,
environmentalism, and an anti-smoking crusade have all contributed to this.
Most recently, we've made attempts to push our lifespans out even further with
technologies such as hormone replacement, caloric restriction, and
Resveratrol.
And,
indeed, these technologies have increased the size of our population. But
something interesting also happened: population growth rate began to slow.
Birthrates fell rapidly, and in less than four decades, the average number of
children in a family was more than cut in half, from 6 to 2.9. Today, most
researchers think we are headed quickly towards a stable population. Evidence
is mounting that humans will simply not reach populations larger than our
ability to sustain them: economics preclude us from doing that. As resources
become scarce, prices rise, and as prices rise, family sizes shrink. Is it a bad thing that our medical advances
have nearly doubled our life expectancy? Most would say it's a decidedly good
thing. So it's probably a safe bet that if we can drastically increase that
figure again, future generations will also look back on it as beneficial.
"Won't
Social Security be bankrupted?"
Social
Security is quickly heading toward bankruptcy right now - and the reason lies
in the very nature of aging. A typical
person today works for forty to fifty years before retiring at age 65 or
shortly thereafter. Although retirement is often framed as a reward earned by a
lifetime of hard work, the truth is that, not too long after reaching age 65,
people inevitably become too sick and weak to continue working even if they
wanted to. That's not the most desirable of rewards. The fundamental problem with Social Security
is that many of our modern medical advances have extended our lifespan, but
have not expanded our healthspan to match. In 1935, when Social Security began,
only about 57% of the population survived to age 65, and those who did only
lived an average of 13 more years. Today, nearly 80% of the population survives
to 65, and those who do typically live 17 more years.10
But
these aren't our highest-quality years of life. Extending lifespan without
improving healthspan has given us a large number of people who remain sicker
longer, putting a historically unprecedented burden on the healthy to care for
the sick. If we felt as healthy and energetic at age 65 as we do at 30, why
would we want to permanently retire? It would be far cheaper for the government
to pay for a worker to take a ten-year vacation after forty years of work than
to pay for seventeen years of decline and the staggering health care costs that
accompany it. Not only that, but ten years of vacation as a healthy, youthful
individual sounds like a much better reward for decades of hard work than
seventeen years of decline.
"Isn't
curing aging unnatural or sacrilegious?"
Certainly,
it can be argued that a cure for aging is unnatural. But it can also be argued
that a human being, in his or her most natural state, is cold and hungry,
infested with parasites, vulnerable to predators, and generally lives a life
that Hobbes famously described as "nasty, brutish, and short." In our natural state, we are susceptible to
the disease of aging, and, similarly, we are susceptible to the disease of
smallpox. Yet few among us would look back and claim that we made a horrible mistake
when we unnaturally eradicated smallpox.
Sometimes, objections to finding a cure for aging are made on religious
or philosophical grounds: some see such a cure as a defiance of natural order
or of God's will. However, there are also many people whose religions and
philosophies are exactly what drives them to seek a cure for aging. For
example, Christian writer Sylvie Van Hoek believes that the search for the cure
is not only compatible with belief, but that belief compels us to seek a cure:
The Book of Genesis speaks of God's love. The
creation stories describe the perfect world He created for us. After each
creation He confirmed that it was good. There was no death or suffering in the
Garden of Eden because it was not part of His plan. It couldn't have been
because all that God creates is good; everything that is not good is the result
of the absence of God. It was original sin that corrupted our perfect world. In
failing to resist temptation and wanting to be like God---by eating from the
forbidden tree of knowledge---man and woman turned away from God. This
transformed the beauty of our nakedness into something shameful. Shame was
impossible before the sin because nakedness meant that we enjoyed an intimate
relationship with God. It was the sin that marked the beginning of our struggle
with physical and moral suffering. Suffering is always the death of something,
so physical death is just the far extreme along that same continuum.
Critics [of anti-aging science] should read A
Theology of the Body by John Paul II (Pauline Books, Boston, 2006). The recent
pope eloquently expands on every bit of scripture concerning the body.
In fact, I view [anti-aging science] as very
much comporting to God's plan. He never wanted this for us. He created a
different world, one that we corrupted. He could have turned away from us as we
did to Him, but instead He sent the Christ to save us. He continues to
work in the world today because He wants us to be happy. You may think you're
doing something coldly scientific by fighting aging, but you're already up to
your eyeballs in the fight against evil.11
There
may be some who will always have philosophical and religious concerns about
anti-aging science. But aging can be a painful, torturous process: it seems
difficult to argue that going through the final stages of decline is an
inherently good thing, or that finding a way for all of us to remain fit and
healthy is inherently evil.
"Won't
future generations face challenges, such as long-lived dictators, that could
have been avoided?"
The
short answer is yes. But the same can be said of any technology. When humans
invented the car, we also created the problems of traffic safety and air
pollution. When we invented factories and industrialized the manufacture of
goods, we were forced to rebuild ancient economic and social structures. When
we discovered fire, we also had to learn not to get burned.
But,
looking back, we wouldn't have it any other way. Any progress comes with its
own challenges, but rejecting progress because we don't trust future
generations to deal with it is not the solution.
Other
Cures for Aging
There
are many theories on what causes aging,12 and they may all be
true - different pieces of the puzzle of why we grow old. These theories can be
looked at as multiple sticks of lit dynamite inside our cells, each stick of
dynamite representing a different cause of aging. It's only the stick of dynamite
with the shortest fuse that will kill us.13 Which theory of aging has the shortest
fuse? No one knows for sure, but given the well-established correlation between
telomere length and age, telomere shortening is a good bet. Scientists around the world are looking for
cures for aging, and control of telomere length is not the only one being
discussed. In fact, there might even be better ways.
One
approach that's receiving a lot of attention is stem cell therapy. Stem cell
therapy actually works on a principle similar to telomerase activation; the
idea is to periodically infuse the body with young cells to replace cells that
have senesced.
Some
scientists feel that curing cellular senescence is only a single piece of the
aging puzzle, and that aging must be addressed on other fronts. An example is
Aubrey de Grey's "Strategies for Engineered Negligible Senescence";
De Grey believes that a cure for aging must include therapies that address not
only cellular senescence but also cancer-causing mutations, mitochondrial
mutations, intracellular junk, extracellular junk, cell loss, and extracellular
crosslinks. There are also theoretical approaches to curing aging which appear
to be scientifically sound, but for which the technological groundwork has not
fully been laid. These include nanotechnological methods of intelligently
repairing cellular damage, where infinitesimally small robots could be programmed
to maintain the body at an optimal state of health. Another exciting concept is
"mind uploading" technology, in which the brain would be regularly
scanned into a computer to safeguard it against damage to the body. Although
it's unlikely that these technologies will come to fruition in the very short
term, they do merit further research. Ultimately,
our goal is to extend our lifespans and healthspans and live a young, healthy
life for as long as possible. Telomerase activation may or may not be the "magic
bullet" needed to achieve that end, but it's a technology that's well
within reach, and any extension of lifespan could allow us to live long enough
to see the next technology developed. To
extend our lifespans indefinitely, all we need to do is enter a period of
scientific progress where technologies that extend our lifespans more than one
year are discovered each year. Authors Ray Kurzweil and Terry Grossman have
coined a phrase to describe this strategy: "Live long enough to live
forever."
In Conclusion
People
often wonder why progress in finding a cure for aging isn't moving faster. A
common impression is that aging cures are well-funded, but the science is out
of our reach. That simply isn't true. The primary reason that aging isn't
already cured is because of lack of funding.
What is most needed in order to find ways to extend our lifespan before
that lifespan runs out on us is for the wealthy individuals that want to see
aging cured in their lifetime to get together, review all the approaches that
exist for curing aging, prioritize them, and then fund the ones on the top of
the list. Besides lengthening telomeres, some of the candidates for funding
were described in the previous section.
This
kind of patron investment is the only plausible way to lay down a path to the
cure for aging. The government doesn't support this kind of research, and
venture capital is more focused on short-term profits than long-term cures.
If aging is
cured in our lifetime, it will be because of these patrons, not because of
brilliant leaps of intuition on the part of any scientist. When it comes to
curing aging, the science is fairly straightforward; the funding is not.
1. Hayflick L. (1965). The
limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37 (3): 614-636.
2. Olovnikov AM. Principle of
marginotomy in template synthesis of polynucleotides. Doklady Akademii nauk SSSR. 1971;
201(6):1496-9. Watson, J. D. Origin of concatemeric T7 DNA. Nat New Biol. 1972; 239(94):197-201.
3. Cawthon, R. M., K. R. Smith,
et al. (2003). "Association between telomere length in blood and mortality
in people aged 60 years or older." Lancet 361(9355): 393-5.
4. Adapted from: Tsuji, A.,
A. Ishiko, et al. (2002). "Estimating age of humans based on telomere
shortening." Forensic Sci Int 126(3): 197-9.
5. Bodnar, et al. Extension
of life-span by introduction of telomerase into normal human cells. Science,
1998.
6. Funk, et al. Telomerase
Expression Restores Dermal Integrity to in Vitro-Aged Fibroblasts in a
Reconstituted Skin Model. Experimental Cell Research, 2000
7. Tomas, et al. Telomerase
Reverse Transcriptase Delays Aging in Cancer-Resistant Mice. Cell, 2008.
8. Jiang, X.-R. et al. Telomerase
expression in human somatic cells does not induce changes associated with a transformed
phenotype. Nature
Genet., 21, 111-114 (1999); Morales, C.P., et. al. Absence of
cancer-associated changes in human fibroblasts immortalized with telomerase. Nature Genet., 21, 115-118 (1999); Harley,
C. B.Telomerase is not an oncogene. Oncogene 21(4): 494-502 (2002).
9. Benn, P. A. Specific
chromosome aberrations in senescent fibroblast cell lines derived from human
embryos. Am J
Hum Genet 28(5): 465-473 (1976); Meza-Zepeda, L. A., A. Noer, et al. High-resolution
analysis of genetic stability of human adipose tissue stem cells cultured to
senescence. J Cell
Mol Med 12(2): 553-263 (2008); Boukamp, P., S. Popp, et al. (2005). Telomere-dependent
chromosomal instability. J Investig Dermatol Symp Proc 10(2): 89-94 (2005).
12. For a review of theories
of aging, see: Hayflick, Leonard (January 23, 1996). How and Why We
Age. (Reprint
ed.). Ballantine Books. ISBN 0345401557.
Google Ventures and the Search for Immortality
Bill
Maris has $425 million to invest this year, and the freedom to invest it
however he wants. He's looking for companies that will slow aging, reverse
disease, and extend life.
Katrina Brooker March 9, 2015
Ian Allen/Bloomberg Markets Google
Ventures has close to $2 billion in assets under management, with stakes in
more than 280 startups. Each year, Google gives Maris $300 million in new
capital, and this year he’ll have an extra $125 million to invest in a new
European fund. That puts Google Ventures on a financial par with Silicon
Valley’s biggest venture firms, which typically put to work $300 million to
$500 million a year. According to data compiled by CB Insights, a research firm
that tracks venture capital activity, Google Ventures was the
fourth-most-active venture firm in the U.S. last year, participating in 87
deals. A co with $66 billion in annual
revenue isn’t doing this for the money. What Google needs is entrepreneurs. “It
needs to know where the puck is heading,” says Robert Peck, an analyst at the
investment bank SunTrust Robinson Humphrey, who published a report in February
examining Google’s outside investment units, including Google Ventures. “Look
at what happened to BlackBerry when it missed the advent of smartphones. And
Yahoo! missed Facebook.”
Google puts huge
resources into looking for what’s coming next. It spends millions on projects
like Google X, the internal lab that developed Google Glass and is working on
driverless cars. In January, the company made a $900 million investment in Elon
Musk’sSpaceX.
In 2014, it started Google Capital to invest in later-stage technology
companies. Maris’s views on the intersection of technology and medicine fit in
well here: Google has spent hundreds of millions of dollars backing a research
center, called Calico, to study how to reverse aging, and Google X is
working on a pill that would insert nanoparticles into our bloodstream to
detect disease and cancer mutations.
Maris
has a peculiar position in the Googlesphere. He’s a part of it, but also free
from it. Google Ventures is set up differently than most other in-house
corporate venture funds—Intel Capital, Verizon Ventures, and the like. The firm
makes its investments independent of its parent’s corporate strategy. It can
back any company it wants, whether or not it fits with Google’s plans. The fund
also can sell its stakes to whomever it wants, including Google competitors.
Facebook and Yahoo have bought startups funded by Google Ventures. With
Google’s money and clout behind him, Maris has a huge amount of freedom. He
can, and does, go after Silicon Valley’s most-sought-after startups. Uber,
Nest, and Cloudera are among the firm’s big wins. Maris doesn’t intend to stop
pursuing these kinds of deals. But he has other ambitions, too. “There are
plenty of people, including us, that want to invest in consumer Internet, but
we can do more than that,” he says. He now has 36 percent of the fund’s assets
invested in life sciences, up from 6 percent in 2013. “There are a lot of billionaires in Silicon
Valley, but in the end, we are all heading to the same place,” Maris says. “If
given the choice between making a lot of money or finding a way to make people
live longer, what do you choose?”
Maris
is standing at
the front of Joshua Tree, Google Ventures’ large conference room. Each room at
headquarters is named after a national park. “OK, we have a lot to get through
today,” he tells his staff. The group meets here biweekly to talk about
prospects and strategy. Maris has a team
of 70, most of whom are in the room this day or patched in by phone or video.
The group includes the fund’s 17 investing partners, who are in charge of
finding startups. Among the investing partners are Joe Kraus, co-founder of
Excite; Rich Miner, co-founder of Android; and David Krane, employee No. 84 at
Google. The mood in the room is casual.
Some staffers sit cross-legged on the floor; others curl up on soft felt
couches. There are a lot of jokes. One partner starts his presentation with a slide
entitled “Secret Project”—which most people in the room already know about—and
concludes it with a doctored-up photo of Maris’s head superimposed on the body
of someone playing tambourine. It’s a jab at the boss, who married the
singer-songwriterTristan Prettyman last August and recently went on tour
with her. Everyone laughs. Maris smiles, but immediately he’s back to business.
“Time is the one thing I can’t get back and can’t give back to you,” he says,
turning to an agenda on the screen behind him.
“I know you’re all aware of the conference happening this week,” Maris
says. An hour away in San Francisco, JPMorgan Chase is hosting its annual
health-care confab, nicknamed the Super Bowl of Health Care. Thousands of
pharmaceutical executives and investors have gathered for what has become a
huge part of the industry’s dealmaking. Most of Google Ventures’ life sciences
startups are attending. One, Foundation Medicine, which
uses genetic data to create diagnostic oncology tools, is generating huge buzz
this year. In January, Roche Holding announced plans to take a majority stake
in the company, in a transaction valued at $1 billion. The stock more than
doubled the next day. Google Ventures has a 4 percent stake in the co. For
Maris, Foundation Medicine represents the beginning of a revolution. “The
analogy I use is this,” he says, holding up his iPhone 6. “Even five years ago,
this would have been unimaginable. Twenty years ago, you wouldn’t have been
able to talk to anyone on this.”
A group from Slack goes through a design sprint with the Google Ventures design team. In the orange
pants isJake Knapp, who runs the sprints.
Cody Pickens/Bloomberg Markets
Maris
spent six months researching venture capital around Silicon Valley. He traveled
up and down Sand Hill Road, home to many of the Valley’s most prestigious VC
firms, asking top investors for advice. At first, he had a hard time getting
anyone to take him seriously. During one meeting, a VC started laughing at his
idea for Google Ventures. Maris was
told his fund would never work: VCs wouldn’t want Google looking over their
shoulders. “There were some in the venture world who weren’t particularly
welcoming to Bill or Google Ventures,” recalls John Doerr, a legendary partner
at Kleiner Perkins Caufield & Byers, one of the most important
first-generation California VC firms. Doerr, who sits on Google’s corporate
board, advised Maris on setting up the venture fund. Around Silicon Valley,
corporate venture funds have a bad reputation. “There is an inherent paradox to
the notion of corporate venture,” says Bill Gurley, a general partner at the VC
firm Benchmark Capital. The conflict is, do the fund’s loyalties lie with the
startup or with the parent? Just about every independent venture capitalist in
tech has stories of being burned by corporate funds. Either the company uses
its venture investments to gather intelligence and ends up competing with the
companies it funds or company management loses interest at some point and pulls
out. Entrepreneurs were skeptical, too.
“I told him, this is never going to work,” says Joe Kraus, who, in addition to
co-founding Excite, co-founded a wiki software company called JotSpot, which
was sold to Google. Maris asked him early on to join as a partner in Google
Ventures. “From the entrepreneur’s perspective, the idea of tying myself to
Google would have been scary.” Kraus says. “The fear would be, if you raised
money from Google, would Apple hate you?”
Entrepreneurs who can get comfortable with Google Ventures gain access
to resources no amount of money can buy. To win over other VCs and
entrepreneurs, Maris and his bosses at Google established the terms under which
the fund still operates. Google has no access to details about the startups’
strategy or technology. That way, entrepreneurs can pitch without worrying
about their ideas being stolen. “We had to convince entrepreneurs they could
work with us,” says David Drummond. Those who can get comfortable with Google
Ventures gain access to resources no amount of money can buy. The firm can, and
does, introduce its startup founders to anyone at Google—experts on rankings on
Google search, for example, or user experience designers or Android mobile-app
builders. One startup was offered 1 million hours of core processing time on
the Google cloud for free. A big edge
for Google Ventures is its design
team. Maris drew top tech talent out of Google and made them
partners in the fund. One worked on Gmail; another helped redesign YouTube.
They form a sort of SWAT team for startups. In what’s known as a design sprint,
they can troubleshoot whatever is ailing a startup—a flailing app, slow Web traffic,
an uninspiring home page. (See “On the Clock,” above.)
“We didn’t need
the money,” says Ryan Caldbeck, co-founder of the crowdfunding startupCircleUp.
He picked Google Ventures as one of his backers in part to gain access to its
design talent. Twitter co-founder Ev Williams used the design team for his new
publishing platform, Medium. Stewart
Butterfield, co-founder of Flickr,
used the team for his new startup, Slack. Still, navigating the line between startups
and Google can get complicated. Last year, Google wanted to buy Nest, whose
signature product is a WiFi-connected, learning home thermostat. Google
Ventures recused itself from the negotiations, allowing the other VC firms
invested in Nest to broker a price of $3.2 billion. (It was the fourth-largest
venture exit of 2014.) In February, Bloomberg reported that Google was planning a
ride-sharing app that would be a direct competitor to Uber. Google Ventures has
had a stake in Uber since 2013. If Google and Uber go to war, Maris will be
right in the middle of it. “Google Ventures has a direct financial incentive to
ensure the companies we invest in succeed,” Maris said in an e-mail responding
to questions about potential conflicts. “Our investment decisions are made
independent of Google’s product road map.” He and the other partners are paid
carried interest based on the performance of portfolio companies. In theory, if
Google’s car app kills Uber, Google Ventures loses money. One
evening in San Francisco, a
group of young scientists and doctors are sitting down to dinner. “I remember
when Max was living with me and I opened up my fridge and saw this stuff he put
in there. I was thinking, Is this safe?” muses Blake Byers, a 30-year-old with
a Ph.D. in bioengineering from Stanford and a partner at Google Ventures. He
casts a sideways glance at Max Hodak, a 25-year-old Duke biomedical engineering
grad sitting next to him. Three years ago, Hodak started working in Byers’s garage
to build a robot-enabled laboratory. Once he stored chemicals in Byers’s
freezer. (“Blake gets a little carried away with that story,’’ says Hodak.
“There was never any danger.”) Hodak now runs Transcriptic, a co that
builds and operates robot-run labs in shipping container–sized boxes. It packs
them with enough computing power to run multiple experiments from anywhere in
the world. Theoretically, a scientist in Monrovia, Liberia, with access to a
laptop or a mobile phone could use a Transcriptic lab to test strains of Ebola.
Byers, who is the son of Brook Byers of Kleiner Perkins, has helped Hodak raise
$12.5 million from Google Ventures and others.
“We are just on the verge of what science and technology can do,’’ says
David Shaywitz, chief medical officer of DNAnexus,
who’s seated across from Byers and Hodak. His co, also backed by Google
Ventures, is building a global bank of genomic information using cloud
computing. Listening to the scientists
gathered around the table, it’s hard not to get caught up in the world they see
coming. In this vision of our future, science will be able to fix the damage
that the sun or smoking or too much wine inflicts on our DNA. Alzheimer’s,
Parkinson’s, and other scourges of aging will be repaired at the molecular
level and eradicated. In the minds of this next generation of entrepreneurs,
the possibilities are bizarre and hopeful and endless. We probably won’t live
forever, but we could live much longer, and better. These are the bets Google
Ventures is hoping will ultimately be its biggest wins. “We aren’t trying to
gain a few yards,” Maris says. “We are trying to win the game. And part of it
is that it is better to live than to die.”
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