Author Archives: Hervé Lebret

The Gene by Siddhartha Mukherjee – a Symphony of Research

Progress in science depends on new techniques, new discoveries and new ideas, probably in that order – Sydney Brenner
All science is either physics or stamp collecting – Ernest Rutherford

I did not know much about genetics, except my data here and there about biotechnology startups. But thanks to his book The Gene, Siddhartha Mukherjee makes me feel I know much more. His brilliant storytelling is like a symphony, describing the early days of genetics, with Darwin and Mendel and the latest developments of this fascinating science. There are brilliant quotes like the two above, respectively page 202 and 221. And there are marvelous portraits.

I will only give a few of them, the pictures I mean, as a quiz…

But before letting you discover the names below, here is a short extract from The Gene, a famous anecdote about how Genentech was born…

And a great analysis of what science, technology and biology are:
“Do not be lulled by that description. Do not, gentle reader, be tempted to think – “My goodness, what a complicated recipe!” – and then rest assured that someone will not learn to understand or hack or manipulate that recipe in some deliberate manner.

“When scientists underestimate complexity, they fall prey to the perils of unintended consequences. The parables of such scientific overreach are well-known: foreign animals, introduced to control pests, become pests in their own right; the raising of smokestacks, meant to alleviate urban pollution, releases particulate effluents higher in the air and exacerbates pollution; stimulating blood formation, meant to prevent heart attacks, thickens the blood and results in an increased risk of blood clots to the heart.

“But when non-scientists overestimate complexity – “No one can possibly crack this code” – they fall into the trap of unanticipated consequences. In the early 1950s, a common trope among some biologists was that the genetic code would be so context dependent – so utterly determined by a particular cell in a particular organism and so horribly convoluted – that deciphering it would prove impossible. The truth turned out to be quite the opposite: just one molecule carries the code, and just one code pervades the biological world. If we know the code, we can intentionally alter it in organisms, and ultimately in humans. Similarly, in the 1960s, many doubted that gene-cloning technologies could so easily shuttle genes between species. By 1980, making a mammalian protein in a bacterial cell, or a bacterial protein in a mammalian cell, was not just feasible; it was, in berg’s words, rather “ridiculously simple”. Species were specious. “Being natural” was “often just a pose”. [Page 408] […]

“Technology, I said before, is most powerful when it enables transitions – between linear and circular motion (the wheel), or between real and virtual space (the Internet). Science, in contrast, is most powerful when it elucidates rules of organization – laws – that act as lenses through which to view and organize the world. Technologies seek to liberate us from the constraints of our current realities through those transitions. Science defines those constraints, drawing the outer limits of the boundaries of possibility. Our greatest technological innovations thus carry names that claim our prowess over the world: the engine (from ingenium, or “ingenuity”) or the computer (from computare, or “reckoning together”). Our deepest scientific laws, in contrast, are often named after the limits of human knowledge: uncertainty, relativity, incompleteness, impossibility.

“Of all the sciences, biology is the most lawless; there are few rules to begin with, and even fewer rules that are universal. Living beings must, of course, obey the fundamental rules of physics and chemistry, but life often exists on the margins and interstices of these laws, bending them to their near-breaking limits. The universe seeks equilibriums; it prefers to disperse energy, disrupt organization, and maximize chaos. Life is designed to combat these forces. We slow down reactions, concentrate matter, and organize chemicals into compartments, “It sometimes seems as if curbing entropy is our quixotic purpose in the universe,” James Gleick wrote.” [Page 409]

And now the answer the the picture quiz:

Charles Darwin Gregor Mendel William Bateson Thomas Morgan Alfred Sturtevant
Calvin Bridges Hermann Muller Hugo de Vries Ronald Fisher Theodosius Dobjansky
Frederick Griffith Oswald Avery Max Perutz George Beadle Edward Tatum
Linus Pauling James Watson Francis Crick Rosalind Franklin Maurice Wilkins
Arthur Pardee François Jacob Jacques Monod Edward Lewis Christiane Nüsslein-Volhard
Eric Wieschaus Sydney Brenner Robert Horvitz John Sulston Paul Berg
Arthur Kornberg Janet Merz Herbert Boyer Stanley Cohen Frederick Sanger
Walter Gilbert Craig Venter Allan Wilson Luigi Luca Cavalli-Sforza Shinya Yamanaka
Jennifer Doudna Emmanuelle Charpentier

Virtual Innovations?

I had not contributed to Entreprise Romande for a while, which might be the reason of my somehow tiredness about the never ending flow of (virtual?) innovations. Here is my translation of my latest contribution…

When the editor of your favorite magazine asked me for a new contribution about innovation, offering me to write about bitcoin, artificial intelligence, data protection, GAFAs or China, I was the victim if not of a slight dizziness, at least of a certain weariness. I just had to add to this list Fake news, Trips to Mars or Replacement of Humans by Machines and my ongoing passion for startups and technological innovation turned into a light nightmare. It seems to me that the more we talk about innovation and the less we really innovate.

When I explain my slight skepticism to anybody, they usually start with the mention of replacing the cashier of the Migros (a “famous” chain of Swiss supermarkets) with a machine. I reply that it seems to me that we, buyers, have replaced the cashier. If the media relayed in 2011 Foxconn’s announcement that it wanted to install a million robots in 3 years, threatening the 1.2 million employees, an online search indicates today that it has a ability to install 10,000 robots a year, and still the same number of employees.

Silicon Valley, having been at the origin of the major innovations of the last fifty years, is scrutinized more attentively. Of course the GAFAs represent a real threat: the two A become the supermarket of the world while the G and F support them by advertisements based on data that we have kindly given them, putting them in a quasi-monopoly situation. But you read well, supermarket, advertising. And that is what is called major innovations?

And what about globalized venture capital? Softbank has announced the launch of a 100 billion fund, by far the largest ever. In the last two months, 10 internet startups (including Dropbox and Spotify) have announced their intention to go public. The figures are dizzying: they generated 10 billion in revenues and 2 billion losses in 2017, thanks to 4 billion of funds raised since their creation. Venture capital has become an infernal machine that, like China and the GAFAs, seems unstoppable. But the venture capital that financed in 1976 Genentech and Apple with a few millions today massively funds the “uberisation” of the world, new global supermarket, and less and less the “deeptech”. I see in these trends an accelerated globalization but few major innovations.

When I think of the innovations of tomorrow, I think of nuclear fusion that will solve our energy problems, research on AIDS or cancer that will rid us of these disasters as we have been able to get rid of previous diseases, I think of disruptive solutions for water, food, mobility. Tom Perkins, Silicon Valley’s big venture capitalist, thought that the innovations of our time were based on three major inventions, the steam engine, the electricity and especially the transistor that made possible all the technologies that seem to threaten us today. But where is the next invention? I recognize myself in Peter Thiel’s phrase: “We wanted flying cars; instead, we had 140 characters. ”

Do not get me wrong, the innovation flow was exceptional in the 20th century and developments continue. In biotechnology, the Crispr-CAS9 technology [1] is as promising as the genetic revolution of the 1970s. Three startups, Crispr Therapeutics, Intellia Therapeutics and Editas Medicine went public in 2016 and promise to cure 10,000 diseases. But today these three companies represent less than $70 million in revenue and more than 200 million in losses in 2017. We do not yet have gene therapy or personalized medicine. Google’s Alphago beat the best go player, but nasty voices ​​say that it’s only the largest computing power and the largest data storage of computers that has allowed such performance, and no particular invention or intelligence . In more complex contexts, the machine is not able to compete with humans. And what will really bring us the multiplication of Big Data? But the promises of some to politicians and others to their shareholders, amplified by the media, are sometimes an insult to intelligence: why parasitize the human spirit with promises of (virtual) innovations sometimes more “abracadabrantesque” one than the others and ultimately disappointing when the real world is sufficiently complex and exciting?

[1] https://www.investors.com/news/technology/crispr-gene-editing-biotech-companies/

What we cannot know

It’s the 3rd book I read by Marcus du Sautoy. After the Music of Primes and Finding Moonshine: A Mathematician’s Journey Through Symmetry, here is What we cannot know.

Seven frontiers of knowledge according to du Sautoy: Randomness and Chaos, Particle Physics and the Infinitely Small, Space and Quantum Physics, The Universe and the Infinitely Big, Time and Gravity, Consciousness, Mathematics.

To illustrate some of this, here are tww short extracts:

Du Sautoy asks, what is the B. in Benoit B. Mandelbrot and the answer is Benoit B. Mandelbrot. Nice!

And quite nice too about the “purity of fields” by xkcd.com

If you love science(s) or mathematic(s), a clear must-read!

Are Biotechnology Startups Different?

This is a research work I did recently and after trying very shortly to publish it in academic papers, I stopped trying. Maybe it is not good enough. Maybe the research world and I do not fit! It is the result of two series of research I have done for years, one about Stanford-related spin-offs and another about equity in start-ups.

I encourage you to read it if the field is of interest for you or just have a look at the tables below which I extracted from this 5-page short document.

Finally, an explosion of new IPO filings in IT

In the recent years, there had been regular filings in the biotech field, but IT had suffered. then Dropbox and Spotify filed and successfully went public. This probably gave confidence to “unicorns” and many have filed recently such as Smartsheet, DocuSign, Zuora. Carbon Black is the latest one with an interesting history. here is its S-1 filing and below my computed cap. table.

Carbon Black was founded in 2002, has raised close to $200M since inception (not counting the money raised by 4 startups is has acquired, Confer Technologies, Objective Logistics & VisiTrend). It has a royal list of VCs, including Kleiner Perkins, Sequoia, Highland, Atlas or lesser know funds such as .406 or Accomplice. I do not know who the founders were, but I could get the name of Todd Brennan who has left in 2008. Who else, help me! Finally the company is based close to Boston, not in Silicon Valley… This is just the latest of my compilations, that you may find in a previous post Equity in Startups.

Hillbilly Elegy, Powerful and Moving

Another must read about the crisis of our times. Following Piketty or others, or lesser known analysis of Small-Town America of living anywhere vs. somewhere, here is J. D. Vance’s “great insight into Trump and Brexit”.

If ethnicity is one side of the coin, then geography is the other. [Page 3]

It is unsurprising, then, that we’re a pessimistic bunch. What is more surprising is that, as surveys have found, working-class whites are the most pessimistic group in America. More pessimistic than Latino immigrants, many of whom suffer unthinkable poverty. More pessimistic than black Americans, whose material prospects continue to lag behind those of whites. While reality permits some degree of cynicism, that fact that hillbillies like me are more down about the future than many other groups – some of whom are clearly mode destitute than we are – suggests that something else is going on. [Page 4]

The scale of migration was staggering. In the 1950s, thirteen of every one hundred Kentucky residents migrated out of state. Some areas saw even greater migration: Harlan county, for example, which was brought to fame in an Academy Award-winning documentary about coal strikes, lost 30 percent of its population to migration. In 1960, of Ohios’s ten million residents, one million were born in Kentucky, West Virginia, or Tennessee. This doesn’t count the large number of migrants from elsewhere in the southern Appalachian Mountains; nor does it include the children or grandchildren of migrants who were hill people to the core. [Page 28]

Mamaw’s family participated in the migratory flow with gusto. Of her seven siblings, Pet, Paul, and Gary moved to Indiana and worked in construction. Each owned a successful business and earned considerable we lath in the process. Rose, Betty, Teaberry, and David stayed behind. All of them struggled financially, though everyone but David managed a life of relative comfort by the standards of their community. [Page 29]

Moving and powerful…

Claude Shannon, an honorable mathematician?

A Mind at Play is a very interesting book for many reasons. The subtitle “How Claude Shannon Invented the Information Age” is one reason. It is a great biography of a mathematician whose life and production are not that well-known. And what is Information? I invite you to read these 281 pages or if you are too lazy or busy, at least the Shannon page on Wikipedia.

What I prefer to focus on here is the ever going tension between mathematics and engineering, between (what people sometimes like to oppose) pure and applied mathematics. Pure mathematics would be honorable, applied mathematics would not be, if we admit there is such a thing as pure or applied maths. So let me extract some enlighting short passages.

The typical mathematician is not the sort of man to carry on an industrial project. He is a dreamer, not much interested in things or the dollars they can be sold for. He is a perfectionist, unwilling to compromise; idealizes to the point of impracticality; is so concerned with the broad horizon that he cannot keep his eye on the ball. [Page 69]

In Chapter 18, entitled, Mathematical Intentions, Honorable and Otherwise, the authors dig deeper: Above all [the mathematician] professes loyalty to the “austere and often abtruse” world of pure mathematics. If applied mathematics concerns itself with concrete questions, pure mathematics exists for its own sake. Its cardinal questions are not “How do we encrypt a telephone conversation?” but rather “Are there infinitely many twin primes?” or “Does every true mathematical statement have a proof?” The divorce between the two schools has ancient origins. Historian Carl Boyer traces it to Plato, who regarded mere computation as suitable for a merchant or a general, who “must learn the art of numbers or he will not know how to array his troops.” But the philosopher must study higher mathematics, “because he has to arise out of the sea of change and lay hold of true being.” Euclid, the father of geometry, was a touch snobbier “There is a tale told of him that when one of his students asked of what use was the study of geometry, Euclid asked his slave to gibe the student threepence, ‘since he must make gain of what he learns’.”
Closer to our times, the twentieth-century mathematician G. H. Hardy would write what became the ur-text of pure math. A Mathematicians’ Apology is a “manifesto for mathematics itself,” which pointedly borrowed its title from Socrates’ argument in the face of capital charges. For Hardy, mathematical elegance was an end in itself. “beauty is the first test,” he insisted. “There is no permanent place in the world for ugly mathematics.” A mathematician, then, is not a mere solver of practical problems. He, “like a painter or a poet, is a maker of patterns. If his patterns are more permanent than theirs, it is because they are made with ideas.” By contrast, run-of-the-mill applied mathenatics was “dull,” “ugly”. “trivial” and “elementary”
And one (famous) reader of Shannon’s paper dismissed it with a sentence that would irritate Shannon’s supporters for years: “The discussion is suggestive throughout, rather than mathematical, and it is not always clear that the author’s mathematical intentions are honorable.” [Pages 171-2]

This reminds me of another great book I read last year Mathematics without apologies with one chapter entitled “Not Merely Good, True and Beautiful”. Shannon was a tinkerer, a term I discovered when I read Noyce‘s biography, another brilliant tinkerer. He was a brilliant tinkerer and he was a brilliant mathematician. He had himself strong vues about the quality of scientific research (pure or applied – who cares really?): we must keep our own house in first class order. The subject of information theory has certainly been sold, if not oversold. We should now turn our attention to the business of research and development at the highest scientific plane we can maintain. Research rather than exposition is the keynote, and our critical thresholds should be raised. Authors should submit only their best efforts, and these only after careful criticism by themselves and their colleagues. A few first rate research papers are preferable to a large number that are poorly conceived or half-finished. The latter are no credit to their writers and a waste of time to their reader. [Page 191]

A brilliant tinkerer as the video below shows…

and it seems he designed and built the (or one of the) first computer that played chess. He was a juggler and a unicycler.

In the chapter Constructive Dissatisfaction, the topic is intelligence. It requires talent and training, but also curiosity and even dissatisfaction: not the depressive kind of dissatisfaction (of which , he did not say, he had experienced his fair share), but rather a “constructive dissatisfaction”, or “a slight irritation when things don’t look quite right.” It was a least, a refreshing unsentimental picture of genius: a genius is simply someone who is usefully irritated. He had also proposed six strategies to solving problems: simplifying, encircling, restating, analyzing, inverting and stretching. You will need to read that section pages 217-20.

He was also a good investor. In fact he was close to a few founders of startups and had a privileged access to people like Bill Harrison (Harrison Laboratories) and Henry Singleton (Teledyne) and although he used his knowledge to analyze stock markets. Here is what he has to say about investing: A lot of people look at the stock price, when they should be looking at the basics company and its earnings. There are many problems concerned with the prediction of stochastic processes, for example the earnings of companies… My general feeling is that it is easier to choose companies which are going to succeed, than to predict short term variations, things which last only weeks or months, which they worry about on Wall Street Week. There is a lot more randomness there and things happen which you cannot predict, which cause people to sell or buy a lot of stock. To the point of answering to the question of the best information theory for investment with “inside information.” [Page 241-2]

A genius, a wise man, an honorable mathematician.

Incubators are for Chickens

I could have tweeted only (and not blogged) about the picture below. Its author whom I met today authorized me to put it online. It is good to remember the fundamentals, the basics of entrepreneurship. It does not mean entrepreneurs do not need support, but not too much except if they are too fragile. In the past I had heard many similar things (incubators – incinerators?), and Wikipedia explains that incubators have various functions such as a device used to care for premature babies in a neonatal intensive-care unit, a device for maintaining the eggs of birds or reptiles to allow them to hatch. Once they are out of incubators, at least they are ready for accelerators…


“Incubators are for Chickens – In Doers We Trust.”

Sensirion prepares its IPO

Sensirion finally announces its IPO. The spin-off from ETH Zurich was founded in 1998 and many were expecting such an event from a very succesful but quite discrete company. Sensirion has disclosed some numbers and I had followed the development of the company thanks to some data from the Zurich register of commerce. So as usual here is my guess of the capitalization table. And I look forward to compare it with the data from the IPO prospectus when it will be published…


Felix Mayer and Moritz Lechner, co-founders of Sensirion

Again this is guessing only. As you might see, the early funding rounds are unknown to me. I am not sure about how many shares the founders, main investor and employees have adn I am not sure either at which price the company will be priced. I based my numbers on about twice the company sales in 2017… The company claims Knoch has 55% of the company, the founders 14% and employees 8.5%. It does not look to far…

The Sensirion IPO prospectus is not public and is confidential so I cannot publish more than I have here. I can only write I was not too far from the truth despite some discrepancy…