Thursday, March 19, 2015

TWO MOST important articles in HISTORY Especially Bill Maris $425 million to invest cos that will slow aging, reverse disease, extend life

Bill Andrews on Telomere Basics:
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.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.
Leonard Hayflick had discovered that there was a clock ticking in every dividing cell of our body; telomere shortening explains what makes that clock tick. The time remaining on this "telomere clock" can be measured from our blood cells. When such measurements are taken, a significant correlation is found between a person's age and the number of "ticks" remaining on the person's clock.
Telomerase
Obviously, there must be a way for our bodies to re-lengthen telomeres. Otherwise, our sperm and egg cells would contain telomeres the same length as the rest of our cells, which would yield embryos as old as we are. Because so much cell division takes place in the womb, our children would then be born much older than us. Humanity could not exist more than a generation or two if this were the case. However, our reproductive cells do not exhibit telomere shortening, and show no signs of aging. They are essentially immortal. They are our germ line - the same one that has been dividing since the beginning of life on this planet.  The reason these cells are immortal is that our reproductive cells produce an enzyme called telomerase. Telomerase acts like an assembly line inside our cells that adds nucleotides to the ends of our chromosomes, thus lengthening our telomeres. In a cell that expresses telomerase, telomeres are lengthened as soon as they shorten; it's as though every time the "telomere clock" inside our cells ticks once, telomerase pushes the hands of the clock back one tick. Telomerase works by filling the "gap" left by DNA replication. Returning to the analogy of the bricklayer that can't lay the last brick on the brick wall, telomerase would be like an angel that flies in and puts the last brick in place.
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.
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).
10. U.S. Social Security Administration: http://www.ssa.gov/history/lifeexpect.html
11. College of Saint Elizabeth, Morristown, NJ. Personal communication, 2008.
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.
13. Bowles, Jeff, personal communication.

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.              March 9, 2015
Google Ventures' Maris on Strategy, Uber Stake
 “If you ask me today, is it possible to live to be 500? The answer is yes,” Bill Maris says one January afternoon in Mountain View, California. The president and managing partner of Google Ventures just turned 40, but he looks more like a 19-year-old college kid at midterm. He’s wearing sneakers and a gray denim shirt over a T-shirt; it looks like he hasn’t shaved in a few days. Behind him, sun is streaming through a large wall of windows. Beyond is the leafy expanse of the main Google campus. Inside his office, there’s not much that gives any indication of the work Maris does here,Bloomberg Markets will report in its April 2015 issue. The room is sparse—clean white walls, a few chairs, a table. On this day, his desk has no papers, no notepads or Post-its, not even a computer.

This story appears in the April 2015 issue ofBloomberg Markets.

Here’s where you really figure out who Bill Maris is: on his bookshelf. There’s a fat text called Molecular Biotechnology: Principles and Applications of Recombinant DNA. There’s a well-read copy of Biotechnology: Applying the Genetic Revolution. And a collection of illustrations by Fritz Kahn, a German physician who was among the first to depict the human body as a machine. Wedged among these is a book that particularly stands out to anyone interested in living to 500. The Singularity Is Near: When Humans Transcend Biology, published in 2005, is the seminal work by futurist Ray Kurzweil. He famously predicted that in 2045, humankind will have its Terminator moment: The rise of computers will outpace our ability to control them. To keep up, we will radically transform our biology via nanobots and other machines that will enhance our anatomy and our DNA, changing everything about how we live and die.
“It will liberate us from our own limitations,” says Maris, who studied neuroscience at Middlebury College and once worked in a biomedical lab at Duke University. Kurzweil is a friend. Google hired him to help Maris and other Googlers understand a world in which machines surpass human biology. This might be a terrifying, dystopian future to some. To Maris, it’s business.  This is where he hopes to find, and fund, the next generation of companies that will change the world, or possibly save it. “We actually have the tools in the life sciences to achieve anything that you have the audacity to envision,” he says. “I just hope to live long enough not to die.”   Maris is an unusual guy with an unusual job. Seven years ago, Sergey Brin and Larry Page, the founders of Google, tapped him to start a venture capital fund, putting him smack between those tech titans and the sea of ambitious entrepreneurs trying to be just like them. At the time, he was a young entrepreneur himself, with limited investing experience and no clout in Silicon Valley. He’d sold his Vermont-based Web-hosting company and was working at a nonprofit, developing technology for cataract blindness in India. This made him exactly the kind of outsider Google was looking for. “Bill was ready to come at this from an entirely new perspective,” says David Drummond, who, as Google’s chief legal officer and senior vice president of corporate development, oversees Google Ventures as well as the company’s other investment vehicles.
Bill Maris in the Google Ventures offices. His firm's sole limited partner is the world's largest search co
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
When Google Ventures invested in Foundation in 2011, the company’s promise was mostly theoretical. The world was still waiting for the breakthroughs that have seemed inevitable ever since scientists first mapped the human genome in 2003. Foundation’s team included eminent geneticists, including Eric Lander, one of the leaders of the Human Genome Project. Still, the company had no viable commercial product. Technology has made huge strides since then, allowing Foundation to create products like its Interactive Cancer Explorer, which is a kind of Google for oncologists, allowing them to do research and devise treatments for their patients. “We had a lot to learn from the experts in Silicon Valley,” says Foundation’s CEO, Dr. Michael Pellini, who sought out Google Ventures as an investor for help with designing his company’s technology. “Think about Google search. We never think about all the algorithms that go behind what we see on the screen. They were able to do the same for us with genetic information.”  “20 years ago, without genomics, you could only treat cancer with a poison,” Maris says. “That’s really different from, ‘We can cure your cancer by reverse-engineering a stem cell.’ You can now legitimately invest in a co that could cure cancer.”Identifying promising life sciences companies isn’t like hunting around Silicon Valley for coders with a cool app. Biotech cos are built around complicated science. They require millions of dollars in investments, partnerships with big pharma cos, and lengthy clinical trials. To help with his hunt, Maris has brought in scientists as partners. One, Dr. Krishna Yeshwant, a Harvard- and Stanford-trained dr, still works in a clinic twice a week in Boston, where he is based. Last year, he led the firm’s biggest bet in life sciences, an investment in Flatiron Health, which is building a cloud platform to analyze cancer data.  This is just the beginning. “In 20 years,” Maris says, “chemo will seem so primitive it will be like using a telegraph.”  At the age of 22, just out of college, Maris met the friend who would lead him to Google. It was 1997: Yahoo was search, AOL was e-mail, Google was called BackRub. Maris was in NY, working at Investor AB, a Swedish investing firm. He didn’t care for Wall Street, but he did like the smart Yale grad sitting next to him. She told him about a company that was going to change the world. “I remember telling him about this new search engine my sister was working on, and he said, ‘Oh, Yahoo is good enough,’” recalls Anne Wojcicki, who would become the wife of Sergey Brin. Her sister Susan, one of Google’s earliest employees, is now CEO of YouTube. Anne Wojcicki went on to co-found 23andMe, a genetics testing co that is part of Google Ventures’ portfolio.  Maris quit Investor AB after six months and went to Burlington, Vt, to start a Web-hosting company. He was so green that he read Netscape and the World Wide Web for Dummies. He funded his co, Burlee, with his credit cards and by convincing the operators of the Lake Champlain ferry to invest. Maris sold Burlee to a company that became Web.com for an undisclosed sum in 2002. It wasn’t Google-level money, but it was enough for him to live on in Vermont with no job. He would have stayed there except that his old friend, Wojcicki, kept calling him West. Maris started visiting her and Brin, staying at their home in CA. He increasingly became drawn into their sphere. “He and Larry and Sergey would be at dinner and start talking about, I don’t know, flying cars,” recalls Wojcicki.  In 2008, Google’s chiefs tapped Maris to start a venture fund, an idea they’d been kicking around for a while. They gave him a desk at Google and instructions to figure out how he would invest Google’s money. In an only-at-Google twist, his neighbor was Kevin Systrom, who was working on a photo app called Burbn, later Instagram. (“Everyone I sit next to ends up becoming a billionaire,’’ Maris jokes.)

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.”