Epigenetics

It is not surprising that we share 98.9% of our genome with chimpanzees.  It is challenging to consider that we have about the same number of genes as mice and fish; but we have far fewer genes than plants.  It is a high school science experiment to extract DNA from strawberries. Rather than a double helix, their DNA is wrapped in a quadruple helix. Obviously, the chromosomes and genes are only part of the picture.

“Every time we see two things which are genetically identical, but which aren't the same, we're seeing epigenetics in action.” – Nessa Carey.

Epigenetics is often presented as a new frontier in biology. In fact, the word originated in the 1940s; and the first book came out a decade later. Following Crick and Watson, science was focused on the chromosomes, and then on the genes.  The Human Genome Project was declared to be successful and the equivalent of Project Apollo, both for the complexity of the task and for its promise for our future.  Enter into your Web browser the phrase “scientists find gene for” and it would seem that we are living on the Moon.

• The Epigenetics of Birds by C. H. Waddington (Cambridge University Press, 1952), reviewed by: J. T. Marshall in Bios, Vol. 24, No. 1 (Mar., 1953), p. 59.
• Epigenetics. A Treatise on Theoretical Biology by Soren Lovtrup (Wiley, 1974), reviewed by Clifford Grobstein in The Quarterly Review of Biology, Vol. 50, No. 4 (Dec., 1975), p. 439.

Ghost in Your Genes: PBS Nova (BBC 2006; WGBH 2007, 2008) delivers graphic evidence that genetics is not heredity.  Identical twins raised in the same home diverge, one developing autism.  Twin sisters discover that one has cancer, but the other does not.  The town of Överkalix in northern Sweden provided a paradigmatic story of the effects of environment on heredity as grandparents who had suffered starvation passed the consequences not to their children, but to their grandchildren – depending on the sex of the ancestor and the sex of the descendant. 

The same differentiation was shown in the twins Jenna and Bridget. Bridget’s autism is associated with a genetic deletion in Chromosome 15 - the ubiquitin-protein ligase E3A (UBE3A) gene (Mayo Clinic here).  It is called Angelman Syndrome. However, the same deletion is also associated with Prader-Willi Syndrome, a form of obesity.  The outcome depends on whether the X-chromosome carrying it is inherited from the mother or from the father.  The chromosomes and genes themselves are identical in both cases; the expressions are markedly different.

“The route from genes to morphological characters is convoluted and, in many aspects, still escapes us. This is the reason why we have no hypothesis or model yet of the sequential steps of the development of an organ. There is no evidence that any part of the genome (a gene or a number of genes) codes or determines steps for developing a brain, a heart, or even a strand of hair. It is true that genes or genetic networks are involved or responsible for developing such characters, but their involvement is not linear: a number of different types of cells have to be differentiated and arranged in specific spatial patterns in order to form the organ. But both cell differentiation (Christopher and Helin, 2010) and dedifferentiation (return of cells to pluripotency) (Takahashi and Yamanaka, 2006), as well as activation of gene regulatory networks (Cabej, 2010, pp. 23-24, 39-80), are epigenetically rather than genetically determined. -  Building the Most Complex Structure on Earth: An Epigenetic Narrative of Development and Evolution of Animals by Nelson R. Cabej (Elsevier, 2013, pg 67.)

As depicted in the PBS Nova production, the Överkalix study revealed an array of distinctions laid over the chromosomal inheritances.  Diabetes, early death, or longer life in the descendants depended on whether the affected ancestor was male or female. Whether the ancestor was within the womb or out also effected contrasting outcomes. Exactly when during gestation the event occurred also effected a different result.  

Wikipedia has a bit more to say. “The Överkalix study was a study conducted on the physiological effects of various environmental factors on transgenerational epigenetic inheritance. The study was conducted utilizing historical records, including harvests and food prices, in Överkalix, a small isolated municipality in northeast Sweden. The study was of 303 probands, 164 men and 139 women, born in 1890, 1905, or 1920, and their 1,818 parents and grandparents. 44 were still alive in 1995 when mortality follow-up stopped. Mortality risk ratios (RR) on children and grandchildren were determined based on available food supply, as indicated by historical data. Among the sex-specific effects noted; a greater body mass index (BMI) at 9 years in sons, but not daughters, of fathers who began smoking early. The paternal grandfather's food supply was only linked to the mortality RR of grandsons and not granddaughters. The paternal grandmother's food supply was only associated with the granddaughters' mortality risk ratio.  … The father's poor food supply and the mother's good food supply were associated with a lower risk of cardiovascular death.”

In The Epigenetics Revolution (Columbia University Press, 2012), virologist Nessa Carey tells a similar story from the Dutch Hunger Winter of 1945.  “If a mother was well-fed around the time of conception and malnourished only for the last few months of the pregnancy, her baby was likely to be born small. If, on the other hand, the mother suffered malnutrition for the first three months of the pregnancy only (because the baby was conceived towards the end of this terrible episode), but then was well-fed, she was likely to have a baby with normal body weight. … The babies who were born small stayed small all their lives, with lower obesity rates than the general population. For forty or more years, these people had access to as much food as they wanted, and yet their bodies never got over the early period of malnutrition. …  Even more unexpectedly, the children whose mothers had been malnourished only early in the pregnancy had higher obesity rates than normal.” (pp 3-4). And this tendency to overweight was inherited in the grandchildren (pg. 102).

Nessa Carey has a virology PhD from the University of Edinburgh. She worked for five years at the Metropolitan Police Forensic Science Lab in London. (Her website is here.) In this book, she carries the analogy of a Shakespeare play. The text of Romeo and Juliet is the same for everyone. Almost every cell of your body has exactly the same chromosomes. (Red blood cells and sex cells are exceptions.)  But you do not grow teeth in your eyes. The director’s comments, distributed with the script, provide more information. Methylation and histone deacetylations change the expressions of genes. Moreover, actors write notes in pencil or attach Post-its.  We smoke cigarettes, drink alcohol, and ingest insecticides and herbicides. They affect us, of course, but it seems likely that they also affect our grandchildren.

These facts, should have been the clues to scientists that the chromosomes, the genes, DNA and RNA must be directed by other agents. Otherwise, as Carey says several times, you would grow teeth in your eyes.  By analogy to the exploration of space, a series of giant steps over centuries allowed us to plot the orbits of the planets correctly.  The work of Darwin, Mendel, Crick and Watson, the human genome project, all provided the shoulders of giants for today's research. Epigenetic medicine may be the equivalent of the Lunar colony.

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Biopunks Hack the Software of Life

Austin Biobash 2012

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Fertile Hybrids Challenge Darwin

Bob Swanson and Genentech

Disruptive Diagnostics and the Business of Science

Bob Swanson and Genentech

Money is a culture medium for growing viable enterprises into self-sustaining engines of creation. 

Bob Swanson was 29 when he provided the money for Prof. Herbert Boyer to start Genentech.  Like all overnight successes, the real story is more complicated, with deep roots.  Bright, accomplished, and motivated, Swanson had obvious potential – and a string of failures to show for it.  In the documentary, Something Ventured (see below), Thomas J. Perkins said that his firm, Kleiner Perkins Venture Capital, brought on Bob Swanson, but “there was not much for him to do.”  Swanson said that he would look into biotechnology.  Perkins replied that if something was there, they would be interested, otherwise… And at that point, Perkins trailed off into a gesture and face.  Clues are always little things.

“So we hired Bob Swanson, whom Eugene Kleiner had known through venture capital circles. Bob had worked for Citibank in their venture capital operation and he and Eugene had been involved in a failed deal. Eugene had been impressed with Swanson's ability to think straight and get things done. So when Bob was looking for a new position, we hired him. That would have been about late 1974. We were in Embarcadero Center Two then, on the top floor.[…]  Bob worked on various deals for us. And, I have to say, not very successfully. Eugene, in particular, was increasingly unhappy with Bob. He didn't think much was going to be happening.” – Thomas Perkins [Source 5]

Robert A. Swanson was born in Brooklyn, New York, November 29 1947.  When he was still an infant, his family moved to Florida where his father worked for Eastern Airlines.  He attended MIT and completed his bachelor’s in chemistry in 1969 and followed that in 1970 with an MBA at the Sloan School of Management.  [Source 1] (Wikipedia gives 1970 as the year of both degrees.) 

Immediately after completing his MBA, he was hired by Citicorp Venture Capital.  Within three years, they were impressed enough with him that he was sent to San Francisco to open a Citicorp Venture Capital Office there.  In 1975, he joined Kleiner, Perkins, Caufield & Byers.  (Perkins recalled that as “late 1974.”) [Source 5]

Swanson had read about the research in recombinant DNA and gene splicing.  He sought out Dr. Boyer and asked for 10 minutes.  The two men spent three hours in a tavern.  Swanson’s knowledge of chemistry served him well, as he could understand the nuances in the different techniques being pursued by different researchers.  Swanson saw the market for Boyer’s work.  They launched Genentech on April 7, 1976. [Source 2]

In 1977, Genentech started with human growth hormone by contracting for production with City of Hope Hospital in Los Angeles and with the University of California at San Francisco. That allowed Genentech to move up to cloned human insulin in 1978.  They followed that with other successes: alpha interferon, gamma interferon, a hepatitis B vaccine, and thrombolytic (clot-producing) agents for hemophiliacs, and then tissue plasminogen activator (TPA) to dissolve blood clots associated with heart attacks.

America’s bilateral East Coast / West Coast dichotomies are easy to cite, especially in technology.  (In Hackers: Heroes of the Computer Revolution, Steven Levy pointed out that the Spacewars video game came from MIT, whereas Stanford gave us Adventure, based on Lord of the Rings.)  But Robert Swanson understood the importance of social capital, built with strong employee bonds.   His scientists could publish their work, something most big drug companies were reluctant to allow.  Also typical of the West Coast, Genentech held Friday parties known as ho-hos.  As Genentech researchers remembered it: 

“The Ho-Ho tradition began simply with refreshments for employees every Friday afternoon. At the end of one particularly hectic work week, a manufacturing VP said, "Oh, another Friday afternoon, ho, ho, ho, ho." And the name stuck. …
The Ho-Ho was an occasion for play and absurdity. One time Swanson and Boyer came dressed up as Tweedledee and Tweedledum… But from the start, Ho-Hos were more than just fun. To Swanson, the Ho-Ho was “a wonderful idea, because you need a place where people at all levels of the organization, from the president on down, can get together in their shirtsleeves and talk about the issues, as equals... One of the things you worry about, as you get higher in an organization, is whether people are comfortable telling you the truth about the way they see the needs of the company - where are we screwing up as a company?” 

The firm posted a profit in 1979 and went public in 1980. That public offering came at some human cost for the venture capitalists.  Perkins and Swanson disagreed on the timing, with Swanson being opposed to going public.  Eventually, Swanson saw Perkins’s point, but their strained relationship was worse off for it.  Still, Bob Swanson worked as CEO of Genentech through its steepest growth curve through 1990.  Tom Perkins was chairman of the board.  Then, from 1990-96 Swanson served as chairman.  In 1990, Genentech and Roche Holding Ltd. completed a $2.1 billion merger. Initially Hoffman-LaRoche bought a majority interest in Genentech. Then in 2009, LaRoche bought the rest of the stock, but turned around and sold off blocks of it in to the public.

After leaving Genentech Bob Swanson formed a private investment management firm (K & E Management), and served as chairman of Tularik, Inc., a firm researching gene expressions that can be harnessed to produced therapeutics. He also volunteered his time to civic organizations and to his daughters’ soccer teams.

In the book, 1,000 Years, 1,000 People: Ranking the Men and Women Who Shaped the Millennium, (New York :, Kodansha International, 1998) the authors ranked Bob Swanson number 612 for launching the biotechnology revolution.

After a year of battling brain cancer via surgery and chemotherapy Bob Swanson passed away on Monday, December 6, 1999, at his home in Hillsborough, California. (The Guardian gave it as November 30.)  He was 52.

Sources:

1. http://web.mit.edu/newsoffice/1999/swanson-1208.html (Obituary)

2. http://www.gene.com/about-us/leadership/our-founders (Tribute)

3. http://www.nytimes.com/1999/12/07/business/robert-a-swanson-52-co-founder-of-genentech.html (Obituary)

4. http://www.guardian.co.uk/science/1999/dec/10/obituaries.genetics (Biography)

5. http://content.cdlib.org/view?docId=kt1p3010dc (Program in the History of the Biological Sciences and Biotechnology: Kleiner Perkins, Venture Capital, and the Chairmanship of Genentech, 1976-1995; interviews conducted by Glenn E. Bugos, Ph.D.)

6. "The Origins of Biotechnology: A Genentech Perspective"

http://blog.zymergi.com/2013/01/origins-biotech-genentech.html

(Personal recollections and images of artifacts including company newsletters.)

ALSO ON NECESSARY FACTS

Venture Capital

Disruptive Diagnostics and the Business of Science
Epigenetics

Austin Biobash November 2012

Austin Biobash February 2013

Biohackers

Venture Capital

“Writing the check is the easy part.” Genentech, Apple, Intel, Cisco, Oracle, … none of them would exist, nor would a hundred others that created billions of dollars worth of new wealth by delivering new inventions.  More than the money – though there was that – venture capitalists brought expertise in management and marketing, guiding start-ups, connecting people with each other, sometimes even making the most difficult of all decisions, to fire the founder CEO for the good of the company.

 

Everyone knows Steve Jobs and Steve Wozniak; many recognize Nolan Bushnell, Gordon Moore, and Mike Markkula.  Fewer have heard of Arthur Rock, Tom Perkins, or Don Valentine.  Something Ventured (website here) is their story, the viewpoint of the venture capitalist.  They are a humble lot.  At the end of the movie, they admit that writing the check is the easy part. Without the inventors, the creators, the innovators, the visionaries, the venture capitalists would have nothing in which to invest.  But, invest they did – and do. 

 “They saw opportunity where others only saw risk.”

Arthur Rock was working as an investment banker when his firm received a letter from a group of engineers and scientists who were unhappy working for Nobel laureate William Shockley and were looking for an employer to take them all as a group.  Rock convinced them to start their own company.  Rock approach thirty-five companies – Chrysler, National Cash Register, Curtiss Wright, Borg Warner, Ford, Champion, Motorola, Magnavox, … - and no one wanted to invest.  Then, Arthur Rock met Sherman Fairchild.

Fairchild Semiconductor led to the “Fairchildren” the entrepreneurs within the “Traitorous Eight” of Shockley’s lab who would go on to form their own firms with other venture capitalists backing them. 

“I do not know how to write a business plan. I only know how to read them. We start at the back; and if the numbers are big we read the front to see what kind of business it is.”  (Tom Perkins investor in Genetech, AOL, Compaq, and Amazon).

When Dr. Tom Kodadek spoke to the post-doctoral biological student association at the University of Texas (see Disruptive Diagnotics here), he touted “angel funding” and warned against venture capitalists who take 30% of your firm.  Like a good scientist, he admitted that his narrative was a personal story.  Thirty percent is much less than the half that others have been willing to trade for $1 million or $2 million in start-up funding for an idea that might be (at best) three pages badly written.  Venture capitalists have vision.

“We turned down Jobs and Wozniak.” (Don Valentine) “What are you going to do with a computer in your home? Put recipes on it?” (Pitch Johnson)  “I sent my partner down to look at it and he said, the guy kept me waiting for an hour and he’s very arrogant, and of course that was Steve Jobs!” (Bill Draper)  “They offered me a third of Apple Computer for $50,000 and I said, ‘Gee I don’t think so… … but I said, ‘Call Don Valentine.’ (Nolan Bushnell)

“… and Steve asked me, What do I have to do to have you finance me and I said, you need someone who knows marketing and distribution and he said, Fine, send me three people and one did not like him and one he did not like and the third was Mike Markkula. Mike Markkula worked with me at Fairchild before he worked at Intel.” – Don Valentine. 

Mike Markkula wrote the check for Apple and his first order of business as CEO was to build a board of trustees and his first call was to Arthur Rock.  “Arthur said, ‘I want to put some money in that company,’ and I said, ‘Then you have to come on the board.’ His expertise was in marketing and distribution and how to choose people.”

“I was 32. I was retired from Intel, but that’s what I did on Mondays: I helped people write business plans, just because I liked meeting bright people with fire in their belly. ... The business plan said that with $142,000 we could be cash flow positive in nine months.” – Mike Markkula about Apple.  

• Mike Markkula -- $142,000 

• Arthur Rock -- $57,000  

• Don Valentine -- $150,000  

• Apple's 2010 Market Value: $220 billion

The Austrian School of Economics advocates consistent laissez faire.  They are different from the Chicago School, made famous by Milton Friedman.  The Chicago school argues macro-economic policies with its Keynesian rivals.  The Austrians focus on individuals.  Israel Kirzner, Frank Knight, Peter Klein, and others have attempted to understand and formalize—and continue to investigate – entrepreneurship.  However, as individualists, they argue what the word means, not how to produce more of the same by some cookie-cutter process.  That cannot be done.

The "Traitorous Eight" of Shockley Semiconductor
Who Formed Fairchild Semiconductor

Arthur Rock grew up clerking in his father’s candy store from the time he was six or seven.  Don Valentine’s father was a union organizer and once he understood what a union was, they fought constantly.  Dennis Kramlich was about twelve or thirteen when he bought half a freight car of light bulbs from Sylvania and sold them from his wagon.  “I called it the Bright Boy Lightbulb Company.”  Tom Perkins earned a degree in electrical engineering from MIT and found the work incredibly boring. He then went to Harvard Business School where his professor, George Doriot, taught a unique class in entrepreneurship.  (Doriot’s own company, American Research and Development, made only one insightful commitment, to Ken Olsen’s Digital Equipment Corporation.) Doriot’s students included Perkins, Kramlich, Pitch Johnson, and Bill Draper. 

"These were companies with a lot of things missing.  And our approach was always, ‘Is our Rolodex strong enough to help these people?’”  -- Don Valentine.

This film glorifies the essential individualism of investment capital and entrepreneurship. No formula exists. No formula can exist. Each of the venture capitalists in this documentary has a unique narrative. In every case it reduces to the same primary: “I thought that it was a good idea.” Not everything turns a profit. Ultimately, something does, some ventures do. 

“At the time we started Genentech, there was no such thing as genetic engineering. The risks were enormous.” 

A quarter million invested in Genentech in 1976 became $47billion when sold to La Roche in 2009.  Five million invested in Intel became $90 million.  $1.4 million invested in Tandem Computers in 1974 became $3 billion when Compaq bought the company in 1997.

I was told by a guy at Salomon Brothers, "We’ve heard the pitch, but you did not go to Harvard Business School.”  -- Don Valentine, founder of Sequoia Capital, investors in Apple, Cisco, Oracle, Electronic Arts and LSI Logic. 

• “There are no firm rules in the venture capital business, except that there are no firm rules.”  Reid Dennis
• “I would trust him with my life, but not with my money.”  Eugene Kleiner.
•  "You gotta get money from strong people because weak people don’t invest in tough times, but that is when most of the big winners are created. ”Jimmy Treybig, co-founder Tandem Computers.  
• “I am not interested in entrepreneurs who want to do things our way. I am not interested in entrepreneurs who come with a dress code. I am interested in entrepreneurs who want to something new that preferably becomes big.” -- Don Valentine

 For all of its individualism – and Donald Valentine is a supporter of the Ayn Rand Institute – capitalism depends on the bourgeois virtues of community. (See the works of Dierdre McCloskey.)  To fund Atari, Sequoia found Fidelity Ventures and the Mayfield Fund to share the burden of risk in return for the opportunity of profit.

PowerPoint was like the Night of the Living Dead, a company that never failed, but just sucked a lot of life out of other people…. until it was sold to Microsoft…

Something Ventured movie website here.

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Entrepreneurship
Atlas Shrugged's John Aglialoro
Capitalist Culture: Cairo 1600

Tribute to Steve Jobs

The One Percent are the Atlases 

Biohackers

For most of the history of life sciences, major discoveries were made in labs less sophisticated than today’s kitchens … Laser meat thermometers. Handheld blenders. Microwave ovens. Ziploc bags. A steady supply of electricity, clean water, and refrigeration.

Biopunk: DIY Scientists Hack the Software of Life by Marcus Wohlsen (Current Penguin, 2011) does for the next generation of homebrew science what Steven Levy’s Hacker’s Heroes of the Computer Revolution did for the previous transformation from a world based on industrial manufacturing to one dependent on information services.  The next revolution will transform our inherited legacies into self-made potentials.

Each of us is an individual.  Individualism is not an abstract political idea.  It is a biological fact.  

"In his apologia for chemistry, The Same and Not the Same, (Columbia University Press, 1995) Nobel laureate Roald Hoffmann asserts that no two hemoglobin molecules are identical. So-called “identical twins” are not. Individualism is objectively real: both empirically knowable and rationally explainable." (From this blog post.)

The consequences of genetic individualism serve as one large motivator for many of the innovators and inventors spotlighted in this book.  Many of the biohackers who build labs in kitchens, closets, and garages, seek to get beyond the medicines for mass populations, to discover the origins of individual problems and find the one exactly right solution for that person. 

A point not made explicitly by Wohsen or Levy but fundamental to them both – and in reply to Pres. Barack Obama and Prof. Elizabeth Warren on the question of who built what: invention comes from individuals. Even with Wikipedia and Google, we do not share a collective mind.  Someone had to invent the shovel before “we” could build roads.  Not everyone employed in a government laboratory – or for a pharmaceutical firm – innovates, invents, creates, or discovers.  As both Wohlsen and Levy demonstrate, those new ideas and processes come from outside the norm, beyond the expected, without approval or permission – or even funding. 

Biohacker Kay Aull’s father was found to have hemochromatosis: his body absorbs too much iron. It is a genetic defect. She carries the gene, also.  Kay Aull verified this by building her own laboratory test in her kitchen for under $100. 

Like the replication and mutation of DNA itself, Wohlsen tells essentially the same story about very different people working in their own ways on problems they find interesting.  They hack processes on the cheap to replicate that for which industry and government laboratories pay catalog prices in the hundreds of thousands of dollars. Meredith Patterson built her own “LavaAmp” thermocycler for polymerase chain reactions. J. Chris Anderson, Raymond McCauley, Anne Wojcicki, Linda Avery, Aubrey deGrey, Guido Nuñez-Mujica, and a dozen others have their own hacks, their own missions.

And they rely on commercial labs as needed. In fact, the wet lab as a marketable service is one aspect of this new revolution. In addition, the biohackers have conferences and meet-ups of their own, while they also attend mainstream events. Many have advanced university degrees; some dropped out of college to pursue biohacking. Many of them know each other, just as Bill Gates and Steve Jobs crossed paths in Albuquerque. 

This is a global phenomenon. Wohlsen tells of the cotton farmers of the Gujarat state of India who arguably captured and then remarketed a Monsanto product, Bt Cotton, now known variously as BesT Cotton, Navbharat 151, etc. Moore’s Law for computers found a generation every 18 months. Biology trims a few months off of that. 

Biohackers also eschew the secrecy that surrounds genetics research. Billions of dollars are at stake. Competition is fierce. Corporations have every incentive to keep their knowledge base proprietary, secret, and then when announced, locked in patents. But this retards progress.  Despite the claim that patents “promote the Progress of Science and the useful Arts” (Art. I. sec. 8. of the Constitution), the historical evidence is that openness works much better.  Biohackers share information.

You cannot have heroes without villains. The bad guys hang out in the halls of Congress. Bart Stupak represented northern Michigan which is still Paul Bunyan country; he is now retired and working as a lobbyist. Stupak called frontline genetic research "snake oil."  Henry Waxman still speaks for Beverely Hills. They led and lead the gang that would crush biohacking with new federal laws. Those laws would prevent you from resequencing your own DNA to fix your own problems. 

Unfortunately – something of modern trend in books like this – the notes are in the back; and lack direct references such as numbers or asterisks in text, but are listed by page number and key phrase. 

This book is an excellent introduction to the open community of biopunks and gene hackers.  Wohlsen provides websites, citations, and other supporting documentation. If you are looking for a biohacker conference or website, or want to join a meet-up, this is a good overview of the culture, its arts and industries.

ALSO ON NECESSARY FACTS
Epigenetics
Disruptive Diagnostics and the Business of Science
Austin Biobash November 2012
Austin Biobash February 2013
Bob Swanson and Genentech
Fertile Hybrids Challenge Darwin