A History of Silicon Valley

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These are excerpts from Piero Scaruffi's book
"A History of Silicon Valley"

(Copyright © 2016 Piero Scaruffi)

The Selfies (2011-16)

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In 2000 the University of California had started a program called "California Institute for Quantitative Biosciences", or QB3, to help Berkeley, San Francisco and Santa Cruz researchers become entrepreneurs. The program became particularly successful in the life sciences. At the same time, pioneered at UC Berkeley by Jennifer Doudna's laboratory and at Emmanuelle Charpentier's laboratory in Sweden, in 2012 a new technique to edit genomes stole the limelight in biotechnology. Discovered as an adaptive immune system in bacteria for protection against invading viruses, CRISPR-cas9 was seen by Jennifer Doudna's group as a way to target and edit a genome. CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats) are sections of DNA that are often associated with genes that code for proteins (the genes are then called Cas, short for "CRISPR-associated"). These CRISPR-Cas systems offer a faster and cheaper way to edit genomes than the ZFN (Zinc Finger Nuclease) method, pretty much exclusively owned by Sangamo Biosciences, and the TALEN method invented in 2011 by Dan Voytas of the University of Minnesota and by Adam Bogdanove of Iowa State Univ (and owned since 2011 by the French company Cellectis and Minnesota-based Recombinetics, co-founded by Voytas). CRISPR-Cas9 startups, offering "genome-editing platforms", started popping up everywhere. The first one, in 2011, was Rachel Haurwitz's and Martin Jinek's Caribou Biosciences, a spinoff of Doudna's lab at UC Berkeley, but within a few years similar startups spread from London (CRISPR Therapeutics, founded in 2013) to Boston (Editas Medicine, a 2013 spin-off of the Broad Institute, and Intellia Therapeutics, founded in 2014 by Caribou itself). CRISPR represented the fourth generation of genetic "cut and paste" technology after recombinant DNA, ZFN and TALEN.

The CRISPR technique made it a lot easier, faster and cheaper for scientists to change, delete and replace genes (i.e. rewrite the genomes) in any form of life, including humans. The first results, though, were limited to plant biology, and mostly came from Asia. In 2014 Gao Caixia in China created a strain of wheat that was fully resistant to powdery mildew. This experiment was followed by genetic engineering of tomatoes, soybeans, rice and potatoes. In 2015 Moritoshi Sato discovered a light-sensitive Cas9 nuclease that further improved the CRISPR technique, making it more precise and reliable. In 2015 Josiah Zayner, founder of the Open Discovery Institute in Burlingame, launched a crowdfunding campaign to fund a DIY CRISPR kit for hobbyists.

Corvus Pharmaceuticals was founded in 2014 in Burlingame by biopharmaceutical veterans Richard Miller and Joseph Buggy to make oral drugs that would help the immune system fight cancer. This was the beginning of the age of gene therapy. Audentes Therapeutics was founded in 2012 in San Francisco (by health-care industry veterans Matt Patterson and Thomas Schuetz) to make gene-therapy products for patients who suffer from life-threatening diseases which are probably caused by genetic defects (in 2015 it also acquired Cardiogen, founded in 2014 by Louis Lange, which specifically focused on inherited cardiac arrhythmias via a technique developed in Italy by Silvia Priori).

In 2016 (according to AngelList) the Bay Area had more biotech startups than the rest of the USA combined, which basically meant about 30% of the world's startups. The history of biotech repeated the script of computer technology: the technology was invented somewhere else, and an industry dominated by European and East Coast multinationals ended up migrating to the Bay Area. The double-helical structure of DNA was discovered in Britain (by Francis Crick and James Watson), and the Human Genome Project was largely an East Coast enterprise. The big pharmaceutical companies were mostly in Europe (Novartis and Roche in Switzerland, GlaxoSmithKline and AstraZeneca in Britain, Bayer in Germany) or on the East Coast (Pfizer and Bristol-Myers Squibb in New York, and Merck, Johnson & Johnson, Wyeth, Sanofi and Organon in New Jersey). When in 1973 Stanford University's Stanley Cohen and UC San Francisco's Herbert Boyer discovered how to make "recombinant DNA" (DNA made in a lab), the scientific community viewed it as an exciting experiment, but not many understood that it would create a whole new industry. In 1976 a young venture capitalist, Robert Swanson, convinced Herbert Boyer to form Genentech, and the rest is history: On the East Coast, the MIT began spawning Boston-based startups like Integrated Genetics, also founded in 1981. The other success story of the 1980s was Amgen in Los Angeles, founded in 1980. The pharmaceutical corporations were based around New Jersey and New York, and MIT and Harvard were world-class institutions in chemistry, engineering and biology; but nonetheless the biotech industry boomed in California. Obviously the spirit of risk-taking and "think different" was more important than money and number of scientists. Big companies were very good at marketing a biomedical product, but not very good at coming up with new ideas in a new technology. Genentech also set an important precedent: it created a new idea, but then partnered with a giant corporation to market that idea to the world. To be fair, there were many startups in the Boston area. George Church alone (the director of Harvard's Personal Genome Project) co-founded Knome, Alacris, AbVitro, Pathogenica, Veritas Genetics, Joule, Gen9, Editas, Egenesis, enEvolv, WarpDrive...

In the 1990s another Bay Area startup, Gilead Sciences, succeeded quietly thanks to a different model. Riordan switched business in 1991 to the development of antiviral drugs, realizing the enormous potential of the field. Gilead lost money until 2003, but in 1999 Roche started selling the anti-influenza drug Tamiflu (Oseltamivir), a Gilead invention, and in 2005 the US government requested emergency funding to fight an influenza pandemic and 15% of these funds were spent to buy Tamiflu. It probably helped that Gilean's board included politicians who were close to the Bush administration, and that in 2005 Gilead's former chairman Donald Rumsfeld was a minister in the US government. A second Gilead success was Tenofovir (better known as Viread), an anti-AIDS drug that the FDA approved in 2001. Gilead was blessed with relatively quick approval of its drugs by the government during that period, but there had been business genius in focusing on fighting viruses (harder than fighting bacteria) to treat chronic and global diseases (AIDS, hepatitis C and the flu). In 2009 Gilead was ranked one of the fastest growing companies by Fortune magazine, and in 2013 Gilead hit the market with another hit, Sovaldi (Sofosbuvir), for the treatment of hepatitis C, one of the most expensive drugs of all times. In 2015 Gilead was the largest biotech company, with a market value of $150 billion, larger than more established "big pharma" multinationals such as GlaxoSmithKline, AstraZeneca and Bristol-Myers Squibb.

By the 2010s biotech was one of the most funded businesses in the Bay Area, and several incubators were born. Besides QB3, there were Berkeley Biolabs (founded in 2014 by Jayaranjan Anthonypillai), IndieBio (an emanation of SOSVentures launched in 2014 in Ireland), as well as one of Bayer's CoLaborators and one of Johnson & Johnson's JLabs. The main Bay Area centers for biotech were South San Francisco (where Genentech was born in 1976), Emeryville (between Oakland and Berkeley, a natural location for UC Berkeley spinoffs), the Mission Bay district of San Francisco (where a new medical campus of UC San Francisco opened in 2003), and Silicon Valley (notably Affymetrix, the startup that invented the "DNA chip", and 23andMe, the startup that bootstrapped the genomics industry).

In the first half of 2015 the Bay Area witnessed the biggest bubble in biotech since the 1990s, with a record influx of venture capital for biotech startups. But it wasn't only the Bay Area. The biotech bubble was all over the USA. Among the star attractions of 2015 were Denali Therapeutics (San Francisco, neurodegenerative diseases), Melinta Therapeutics (New Haven, antibiotics discovery), CytomX Therapeutics (Santa Barbara, tumor-targeting antibodies), Regenexbio (Maryland, gene therapy), Dimension Therapeutics (Boston) and Voyager Therapeutics (Boston). The year 2015 was also a record year for mergers and acquisitions in biotech, just like the previous year had been a record year for IPOs (74 IPOs in one year).

The biotech boom was fueled by a simple statistical data: in the USA there were 80 million "baby boomers" about to retire over the next 20 years, presumably causing a boom in health care. There was also a general level of enthusiasm for the "miracle drugs" being developed or introduced by big pharmaceutical companies: drugs to reduce cholesterol, for cancer treatment, to improve the cognitive skills of elderly people afflicted by dementia, etc (e.g. the cholesterol-lowering drug Lipitor, introduced in 1996 by Pfizer, which in 2012 was accounting for more revenues than the GDP of Tanzania). However, biotech was a completely different business than information technology. First of all, a biotech startup needed much closer ties to the scientific community. While software was mostly about finding an app that went viral, and hardware was mostly about packing more transistors on a chip, biotech was still very much about productizing scientific discoveries. While software startups were being founded by younger and younger engineers, biotech was still such a complex business that typical startups were founded by more experienced people, and it was not unusual to see a partnership between an academic researcher and a venture capitalist. Thousands of new software apps and gadgets were launched every year, but instead very few new drugs were approved every year by the FDA, way less than 100. A biotech venture was a complex project that required skills in chemistry, biology, engineering, marketing, and even skills in dealing with the government agency that approved drugs (the FDA) and with the big pharmaceutical companies that had the power to market new drugs worldwide. Compared with software, the cost to develop a new biotech "product" was colossal. The clinical study alone could easily cost ten times more than the development of a software application, and last many years before receiving government approval. In general, the risk for the biotech industry was much higher than the risk for the computer industry. But the payback could be astronomical: a new drug could generate billions of dollars of revenues for a long time.

Personal genomics was still riding high. The Human Genome Project had cost an estimated $2.7 billion over a decade. In 2009 the cost of Illumina's genome sequencing was $48,000 and by the end of that year only about 100 human genomes had been sequenced. By 2015 the four big genome-sequencing services, namely 23andMe, Generations Network's AncestryDNA (launched in October 2007), National Geographic's Genographic Project (launched in 2005) and Family Tree DNA (that had acquired the technology from the German company DNA-Fingerprint), had already genotyped millions of people. 23andMe genotyped its first customer in November of 2007, and genotyped its millionth customer in June 2015. 23andme's service was now costing only $200. By then the gene-sequencing market was dominated by three companies: San Diego-based Illumina (that owned about 70% of the market), Silicon Valley-based Applied Biosystems (acquired in 2014 by Thermo Fisher Scientific), and 454 Corporation (founded by Jonathan Rothberg in 1999 in Connecticut and acquired by Roche in 2007).

As their machines got cheaper, the product sold to the customers also get cheaper. However, the results of those DNA tests rarely included comprehensive reports. Only a few of these "personal-genomic" startups generated reports that a health-care specialist could use to make real predictions and prescriptions. The leader in "actionable" reports was still Boston-base Knome (acquired by Utah-based Tute Genomics), that had been the first startup to introduce a commercial human genome sequencing in 2007, followed by Illumina itself, but they charged more than $10,000 for the "actionable" reports. In 2015 Maryland-based Veritas Genetics, founded in 2014 by George Church, the director of Harvard's Personal Genome Project, announced a package that included both "sequencing" and "interpretation" of the genome at an affordable price. In 2016 Las Vegas-based Sure Genomics, founded in 2014 by people who had no background in biological sciences, announced a method for its customers to perform the tests at home with a single saliva test and receive in the mail an actionable report. Helix, a 2015 San Francisco-based Illumina spinoff, was working on the first "app store" for genetic information, so that customers of a gene sequencing service could find useful "apps" to analyze their DNA report (a model that mimics Apple's App Store). Oxford Nanopore (founded in 2005 by a professor of Chemical Biology at the University of Oxford, Hagan Bayley) also began testing the first portable gene-sequencer, called Minion, although it worked only for small genomes (e.g., the ebola virus).

The goal of genomics was, ultimately, to extend human life, i.e. longevity. In 2013 Google funded Calico (which got nicknamed "Google's longevity lab" in Silicon Valley) and hired Arthur Levinson, a former Genentech executive to run it. Levinson 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), and Shelley Buffenstein, a specialist at the University of Texas in animals with exceptionally long lifespans. Calico's first project was a joint venture with pharmaceutical firm AbbVie to focus on diseases that affect the elderly.

Longevity became officially a business in the 2010s. Ambrosia, a startup in Monterey founded by Jesse Karmazin, began experimental transfusions of younger blood to older people after 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. This and other studies generated enthusiasm in 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. In 2011 Jan Van Deursen's team at the Mayo Clinic found a way to remove senescent cells from mice and Van Deursen immediately co-founded Unity Biotechnology in San Francisco to commercialize this idea with investors such as billionaires Jeff Bezos (of Amazon fame) and Peter Thiel (of PayPal fame). In 2014 Tony Wyss-Coray himself co-founded Alkahest in Redwood City.

The Human Genome Project had been a big success and had delivered a "blueprint" of how the human software works; but we are all different: there are genetic variations between person and person. Those genetic variations can make the difference between living a long and healthy life and dying at a young age of a fatal disease. The way to study "genetic variation" was to collect genetic data about as many people as possible, compare their genes, and compare genetic variations with health. For this purpose a number of universities and agencies set up programs that mixed big data, crowd-sourcing and biotech : the Personal Genome Project (launched in 2005 by George Church at Harvard), UK Biobank (launched in 2006 in Britain), the 1000Genomes project (launched in 2008 by David Altshuler of the Broad Institute in Boston), and DNA.land (launched in 2015 by Yaniv Erlich at the New York Genome Center). The crowdsourcing experiment then migrated to the West Coast, where people started talking about the "Internet of DNA" or "Internet of Living Beings". In 2013 David Haussler at the University of California in Santa Cruz partnered with David Altshuler to create to set up the Global Alliance for Genomics and Health, a peer-to-peer network of scientists and volunteers to work together on understanding genetic variations. In 2014 Google's Life Sciences division (later renamed Verily) launched Baseline, a project to provide a definition of what "healthy" means in genetic terms.

Genomics had been getting cheaper thanks to quantum leaps in laboratory automation: Affymax (later renamed Affymetrix) had introduced the first "DNA chip" in 1994 and Wilhelm Ansorge had squeezed the whole human genome on a microarray in 2002. In the mid-2010s cloud-based biotech was attempting to completely eliminate the laboratory for the customer. Transcriptic, founded by Duke University graduate Max Hodak in 2012 in Palo Alto, conducted laboratory tests using robots on behalf of customers who could be located anywhere in the world.

Meanwhile, DNA synthesis (i.e. "printing" DNA) was being revolutionized by the combined forces of miniaturization, automation and software. Scientists needed raw materials called oligonucleotides in order to perform "rapid prototyping" in polymerase chain reaction (PCR) or gene sequencing. Twist Bioscience, founded in 2013 in San Francisco by Agilent's veteran Emily Leproust, by Complete Genomics's hardware engineer Bill Banyai and by Bill Peck (who had worked at both Complete Genomics and Agilent), aimed at producing synthetic DNA on a massive scale using a silicon-based method to make oligos. In 2016 Twist acquired Israel's Genome Compiler and their technology to design genes in order to allow customers to design genes and then print DNA on demand.

These new biotechnologies were even used to create new materials. Refactored Materials (later renamed Bolt Threads), a 2009 spinoff of UC San Francisco (scientists Dan Widmaier, David Breslauer and Ethan Mirsky) manipulated bacteria to manufacture spider silk, stronger than steel but very light, that could be used for making clothes. Zymergen, founded in 2013 in Emeryville by two Amyris alumni, Jed Dean and Zach Serber, had discovered a way to insert DNA into bacteria, and to create microbes that could create new materials.

Ginkgo Bioworks, founded in 2008 in Boston by MIT's synthetic biology pioneer (and iGem co-founder) Tom Knight with other MIT alumni (Jason Kelly, Reshma Shetty, Barry Canton, and Austin Che), called itself "the world's first organism-engineering foundry". A foundry is usually a place where semiconductor chips are manufactured on behalf of companies like Intel. Ginkgo Bioworks opened a "foundry" to make living organisms: the customer sent the design, and Ginkgo delivered the organism (to make, for example, synthetic perfumes, cosmetics and foods). Both Zymergen and Ginkgo aim at becoming biotech factories for manufacturers of all sorts of consumer goods.

What was still needed was the equivalent of Computer-Aided Design (CAD) for synthetic biology. In 2010 Chris Anderson at UC Berkeley delivered Clotho, an open-source "bioCAD" platform to design organisms, and in 2014 Autodesk launched Project Cyborg, a cloud-based platform of design tools for DNA designers.

DNA is a natural substance for computing because it uses the genetic code, a code that obeys strict rules of logic. In 1994 Leonard Adleman at the University of Southern California (the same scientist who had coined the expression "computer virus" and whose student Fred Cohen had unleashed the world's first computer virus) had found a way to encode a string of data in the sequence of nucleotides and then used the chemical properties of DNA to perform a calculation. In other words, he had built a "DNA computer". In 1995 Richard Lipton at Princeton University had proved that a DNA computer could solve some mathematical problems faster than electronic computers. In fact, a few months later two of Lipton's students, Dan Boneh and Chris Dunworth, had shown that a DNA computer could break the data encryption system developed by the National Security Agency (NSA) of the USA. The first practical DNA computer was unveiled in 2002 and used for gene analysis by Olympus in Japan (a collaboration with Akira Suyama's team of the University of Tokyo), but not much progress was achieved in the following years until in 2013 Drew Endy at Stanford unveiled a biocomputer operating inside a living cell. This computer could only answer "true/false", but the question was important: it could detect a disease that could not be detected with ordinary medical equipment. A biocomputer is slow but it can operated in places where electronics cannot be deployed: anywhere inside the human body.

Another biotechnology became popular in the 2010s. Living beings are self-assembling structures. They are not built in a factory: they assemble themselves, cell by cell. DNA is an excellent "construction material" because it constructs billions of living organisms every single day. Nadrian Seeman of New York University (who had written about constructing 3D structures from DNA since the 1980s) and Paul Rothemund of CalTech (who proved that DNA can be programmed to form larger DNA structures) were the pioneers of what came to be called "DNA origami". Biologists started using DNA to "design" robots in the same way that architects use software to design objects. In 2012 two of George Church's students at Harvard University, Shawn Douglas and Ido Bachelet, developed nanorobots made of DNA with the intention that they could be programmed to target specific cells in the body, for example to seek out cancer cells and program them to self-destruct. Douglas moved to UC San Francisco in 2012 and Bachelet to Bar-Ilan University in Israel, founding two important schools of DNA origami.

In 2012 George Church encoded his latest book into DNA. In 2013 Ewan Birney's team at the European Bioinformatics Institute encoded all 154 of Shakespeare's sonnets, an audio recording of Martin Luther King's famous speech "I Have a Dream", and a picture of their office in a string of DNA (a total of 739 kilobytes). In 2015 Sri Kosuri, a member of the Harvard team that had encoded Church's book into DNA, encoded a rock song by the band OK Go into DNA, the first music to be released on DNA. The storage ability of DNA is impressive: everything that human civilization has produced in writing (50 billion megabytes of text) can be stored in the DNA of the palm of your hand.

Biotech used fermentation, an ancient technique, for making chemicals out of genetically-manipulated organisms. In the 2010s a new technique, cell-free biotech, was tested by startups such as Synvitrobio (founded in 2015 in Berkeley by Zachary Sun and Richard Murray of Caltech and George Church of Harvard) and Sutro Biopharma (originally founded in 2003 as Fundamental Applied Biology in South San Francisco). In 2017, for example, Sutro created STRO-001, an antibody that inhibits tumour growth, using cell-free biotech.

click here for the other sections of the chapter "The Selfies (2011-16)"
(Copyright © 2016 Piero Scaruffi)

Table of Contents | Timeline of Silicon Valley | A photographic tour | History pages | Editor | Correspondence