Video from The Economist's World in 2010 Festival

The Economist has posted video from the World in 2010 Festival, held in Washington DC in early December.  The Innovation panel is below, with me (Biodesic), Dean Kamen (DEKA Research), Dwayne Spradlin (Innocentive), and Kai Huang (Guitar Hero), moderated by Mathew Bishop (The Economist).  (Here is a link to video selections from the rest of the event.)  I was chatting with a reporter a few days ago who observed that everyone else on the panel is quite wealthy -- hopefully that bodes well for me in 2010.  But maybe I am destined always to be the odd man out.  C-Span is re-running the video periodically on cable if you want to watch it on a bigger screen, but I can't seem to find an actual schedule.  (Here is their web version: Innovation in 2010.)


I have a couple of general thoughts about the event, colored by another meeting full of economists, bankers, and traders that I attended in the last week of December.  I met a number of fantastically accomplished and interesting people in just a few hours, many of whom I hope will remain lifelong friends. 

First, I have to extend my thanks to The Economist -- they have been very good to me over the last 10 years, beginning in 2000 by co-sponsoring (with Shell) the inaugural World in 2050 writing competition.  (Here is my essay from the competition (PDF).  It seems to be holding up pretty well, these 10 years later, save the part about building a heart.  But at least I wasn't the only one who got that wrong.)

Here is a paraphrased conversation over drinks between myself and Daniel Franklin, the Executive Editor of the newspaper.

Me:  I wanted to thank you for including me.  The Economist has been very kind to me over the past decade.
Franklin: Well, keep doing interesting things.
Me:  Umm, right.  (And then to myself: Shit, I have a lot of work to do.)

On to the World in 2010 Festival.  The professional economists and journalists present all seem to agree that we have seen the worst of the downturn, that the stimulus package clipped the bottom off of whatever we were falling into, and that employment gains going forward could be a long time in coming.  Unsurprisingly, the Democratic politicians and operatives who turned up crowed about the effects of the stimulus, while the Republicans who spoke poo-pooed any potential bright spots in, well, just about everything.

At the other meeting I attended, last week in Charleston, SC, one panel of 10 people, composed Federal reserve and private bankers, traders, and journalists couldn't agree on anything.  The recovery would be V shaped.  No, no, W shaped.  No, no, no, reverse square root shaped (which was the consensus at The World in 2010 Festival).  No, no, no, no, L shaped.  But even those who agreed on the shape did not agree on anything else, such as the availability of credit, employment, etc.

Basically, as far as I can tell, nobody has the slightest idea what the future of the US economy looks like.  And I certainly don't have anything to add to that.  Except, of course, that the future is biology.

Here is John Oliver's opening monologue from the Festival.  He was absolutely hilarious.  Unfortunately you can't hear the audience cracking up continuously.  I nearly pissed myself.  Several times.  (Maybe the cocktails earlier in the evening contributed to both reactions.)

Back to Innovation in 2010.  Dean Kamen had this nice bit in response to a question about whether the imperative to invent and innovate has increased in recent years (see 36:20 in the C-Span video): "7 billion people can't be recipients, they have to be part of the solution.  And that is going to require advanced technologies to be properly developed and properly deployed more rapidly than ever before."

To this I can only add that we are now seeing more power to innovate put into the hands of individuals than has ever occurred in the history of humanity.  Let's hope we don't screw up.

WWF Endorses Industrial Biotech for Climate Solutions

A fortnight ago the World Wildlife Fund released a report pushing industrial biotech as a way to increase efficiency and reduce carbon emissions.  Interesting.  Of course, industrial biotech doesn't necessarily require direct genetic modification, but the WWF must know that is an inevitable consequence of heading down this road.  More on this after I get a chance to read the report.

And the Innovation Continues...Starting with Shake and Bake Meth!

My first published effort at tracking the pace and proliferation of biological technologies (PDF) was published in 2003.  In that paper, I started following the efforts of the DEA and the DOJ to restrict production and use of methamphetamine, and also started following the response to those efforts as an example of proliferation and innovation driven by proscription.

The story started circa 2002 with 95% of meth production in Mom and Pop operations that made less than 5 kg per year.  Then the US Government decided to restrict access to the precursor chemicals and also to crack down on domestic production.  As I described in 2008, these enforcement actions did sharply reduce the number of "clandestine laboratory incidents" in the US, but those actions also resulted in a proliferation of production across the US border, and a consequently greater flow of drugs across the border.  Domestic consumption continued to increase.  The DEA acknowledged that its efforts contributed to the development of a drug production and distribution infrastructure that is, "[M]ore difficult for local law enforcement agencies to identify, investigate, and dismantle because[it is] typically much more organized and experienced than local independent producers and distributors."  The meth market thus became both bigger and blacker.

Now it turns out that the production infrastructure for meth has been reduced to a 2-liter soda bottle.  As reported by the AP in the last few days, "The do-it-yourself method creates just enough meth for a few hits, allowing users to make their own doses instead of buying mass-produced drugs from a dealer."  The AP reporters found that meth-related busts are on the increase in 2/3 of the states examined.  So we are back to distributed meth production -- using methods that are even harder to track and crack than bathtub labs -- thanks to innovation driven by attempts to restrict/regulate/proscribe access to a technology.

And in Other News...3D Printers for All

Priya Ganapati recently covered the latest in 3D printing for Wired.  The Makerbot looks to cost about a grand, depending on what you order, and how much of it you build yourself.  It prints all sorts of interesting plastics.  According to the wiki, the "plastruder" print head accepts 3mm plastic filament, so presumably the smallest voxel is 3mm on a side.  Alas this is quite macroscopic, but even if I can't yet print microfluidic components I can imagine all sorts of other interesting applications.  The Makerbot is related to the Reprap, which can now (mostly) print itself.  Combine the two, and you can print a pretty impressive -- and always growing -- list of plastic and metal objects (see the Thingiverse and the Reprap Object Library).

How does 3D printing tie into drug proscription?  Oh, just tangentially, I suppose.  I make more of this in the book.  More power to create in more creative people's hands.  Good luck trying to ban anything in the future.

Another Step Toward DIYStemCells

(18 June 2009: Lightly edited for clarity.)

The June 5 issue of Cell Stem Cells has a brief report describing the use of four proteins to reprogram human fibroblasts into induced pluripotent stem cells (iPSCs).  I think this is a pretty important paper, as it dispenses with any sort of genetic manipulation of the target cells or any use of plasmids to insert new "control circuitry", or any chemical manipulation whatsoever.

As expected, it is getting easier to produce iPSCs, and the authors of the paper ("Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins") note that their work demonstrates the elimination of "the potential risks associated with the use of viruses, DNA transfection, and potentially harmful chemicals and in the future could potentially provide a safe source of patient-specific cells for regenerative medicine".

Kim et al used four recombinant human proteins to turn human newborn fibroblast cells (purchased from ATCC -- see the Supplemental Data) into iPSCs, where each of the proteins was fused to a nine amino acid long "cell-penetrating peptide" (CPP) that facilitated the importation of the proteins across the cell membrane.  The procedure was not particularly efficient, but after multiple treatments the authors produced cells that could differentiate into many different kinds of human tissues.

Here are a couple of thoughts about the paper.  Note that in what follows I have only had a few sips of my first cup of coffee today, and my brain is still quite fuzzy, but I think I am mostly coherent.  You can be the judge.

First, the authors did not use mature cells from adults, so don't expect this paper to lead to replacement organs and tissues tomorrow.  The use of cells from newborns makes a great deal of sense for a first go at getting protein-based reprogramming to work, as those cells have already been demonstrated to be relatively easy to reprogram.  The published procedure required many weeks of effort to produce iPSCs, and authors note that they have quite a ways to go before they can produce stem cells at the same efficiency as other techniques.

Nonetheless, it works.

Second, the paper describes PCR-based cloning of human genes to add the CPP sequences, along with a fair amount of bench manipulation to generate cells that made each of the four reprogramming proteins.  All the sequences for those proteins are online, as are the sequences for the CPPs, so generating the corresponding genes by synthesis rather than cloning would now cost less than $10K, with delivery in 2-4 weeks.  In another year, it will probably cost no more than $5K.  (How long will it be before these proteins show up in the Registry of Standard Biology Parts?)

Third, the authors did not use purified reprogramming proteins to generate iPSCs, but rather used whole cell extracts from cells that produced those proteins.  Thus the concentrations of the reprogramming proteins were limited to whatever was in the cell extract.  This might critically affect the efficiency of the reprogramming.  Presumably, the authors are already working on generating cultured cell lines to produced the reprogramming proteins in larger quantities.  But if you wanted to do it yourself, it looks like you might "simply" have to order the appropriate sequences from Blue Heron already cloned into the human expression plasmid pCDNA3.1/myc-His A, which is available from Invitrogen.  This would add a couple of hundred dollars to the cost because Blue Heron would have to play around with a proprietary plasmid instead of the public domain plasmids they usually use to ship genes.  You would then follow the recipe from the Supplementary Data to transform a protein production cell line to make those proteins.  Or perhaps you have a favorite recipe of your own.  Here is something I don't get -- it looks like that particular expression plasmid adds a His tag to the end of the gene, so I don't understand why Kim et al didn't try a purification step, but maybe that is underway.

Fourth, if you wanted to do this at home, you could.  You should expect to fail many times.  And then you should expect to fail some more.  And then, assuming your human cell culture technique is up to snuff, you should expect to eventually succeed.  You might want to wait until the inevitable paper showing how to do this with adult differentiated skin cells is published.

And then what?

You will have an autologous stem cell line that you can use to produce tissues that are, immunologically speaking, identical to those in your body.  What should you do with them?  I would suggest you show them off at cocktail parties, brag about them on Facebook, and then destroy them with bleach and an autoclave.  In lieu of an autoclave a microwave would probably do just fine.

But I expect that at least some of you will try to follow a recipe to generate some sort of human tissue, or even to simply inject those cells in your own bodies, which will result in all kinds of crazy teratomas and other tumors.  To quote Harold Ramus, "that would be bad".  So don't do that.  Just because DIYStemCells are cool doesn't mean you should actually use them yourself.  But I know some of you will anyway.  That is the future of biological technologies, for better or worse.

The Economist Debate on the Fuel of the Future for Cars

Last week The Economist ran an online debate considering the motion "Biofuels, not electricity, will power the car of the future".  I was privileged to be invited as a guest contributor along with Tim Searchinger of Princeton University.  The two primary "speakers" were Alan Shaw of Codexis and Sidney Goodman of Automotive Alliances.  Here is my contribution to the debate, in which I basically rejected the false dichotomy of the motion (the first two 'graphs follow):

The future of transportation power sources will not be restricted to "either/or". Rather, over the coming decades, the nature of transportation fuel will be characterised by a growing diversity. The power sources for the cars of the future will be determined by the needs those cars address.

Those needs will be set for the market by a wide range of factors. Political and economic pressures are likely to require reducing greenhouse gas emissions and overall energy use per trip. Individuals behind the wheel will seek to minimise costs. But there is no single fuel that simultaneously satisfies the requirements of carbon neutrality, rapid refuelling, high-energy density for medium- to long-range driving and low cost.

I find it interesting that the voting came down so heavily in favor of electricity as the "fuel" of the future.  I suppose the feasibility of widespread electric cars depends on what you mean by "future".  Two substantial technology shifts will have to occur before electric cars displace those running on liquid fuels, both of which will require decades and trillions.

First, for the next several decades, no country, including the US, is likely to have sufficient electricity generating resources and power distribution infrustructure to convert large numbers of automobiles to electric power.  We need to install all kinds of new transmission lines around the country to pull this off.  And if we want the electricity to be carbon neutral, we need to install vast amounts of wind and solar generating capacity.  I know Stewart Brand is now arguing for nuclear power as "clean energy", but that still doesn't make sense to me for basic economic reasons. (Aside: at a party a few months ago, I got Lowell Wood to admit that nuclear power can't be economically viable unless the original funders go bankrupt and you can buy the physical plant on the cheap after all the initial investment has been wiped out.  Sweet business model.)

Second, the energy density of batteries is far below that of liquid hydrocarbons.  (See the Ragone chart included in my contribution to The Economist debate.)  Batteries are likely to close the gap over the coming years, but long distance driving will be the domain of liquid fuels for many years to come.  Yes, battery changing stations are an interesting option (as demonstrated by Better Place), but it will take vast investment to build a network of such stations sufficient to replace (or even compete with) liquid fuels.  Plugging in to the existing grid will require many hours to charge the batteries, if only because running sufficient current through most existing wires (and the cars themselves) to recharge car batteries rapidly would melt those wires.  Yes, yes -- nanothis and nanothat promise to enable rapid recharging of batteries.  Someday.  'Til then, don't bother me with science fiction.  And even if those batteries do show up in the proverbial "3 to 5 year" time frame, charging them rapidly would still melt most household power systems.

In the long run, I expect that electric cars will eventually replace those powered by liquid fuels.  But in the mean time, liquid fuels will continue to dominate our economy.

More on the genetics of the H1N1 virus

Effect Measure has a nice post on the origin of genes in the present H1N1 strain making the rounds, and it adds some subtlety to the story I relayed a couple of days ago.

In short, the genome appears to be composed of pieces that have all be circulating in pigs for many years, yet some of those genes may have originally come from human and avian viruses.

I took a few minutes last night to add tags to most of my old posts about SARS, H5N1, vaccines, influenza, and infectious disease.  I also fixed a few links still broken from the ISP switch last year, including the SARS outbreak timeline in "Nature is Full of Surprises, and We Are Totally Unprepared".

Update:  Here is another good 2009 H1N1 Flu Outbreak map from Google.

A few notes from Nature Biotech

I am catching up on past issues of Nature Biotech.  Here are a few things that caught my eye:

(Feb 09) Cuba is launching a domestically produced GM corn.  The strain (which looks from the name to contain Bt) is to be used in animal feed.  Another sign that developing countries view biotech as important national initiatives, and that they can push the technology on their own.

(Feb 09) Researchers in Belgium got fed up with efforts to get their field trial for GM poplars approved in country, and are taking the trial to the Netherlands.  So much for uniformly applying laws on planting GM crops in Europe.  (Mar 09) Local environment ministers voted to overturn the European Commission's initiative to force member states to lift national bans.

(April 09) Malaysia has dropped several billions of dollars on biotech as part of their stimulus package.  More on this when I dig into it.

The Origin of Moore's Law and What it May (Not) Teach Us About Biological Technologies

While writing a proposal for a new project, I've had occasion to dig back into Moore's Law and its origins.  I wonder, now, whether I peeled back enough of the layers of the phenomenon in my book.  We so often hear about how more powerful computers are changing everything.  Usually the progress demonstrated by the semiconductor industry (and now, more generally, IT) is described as the result of some sort of technological determinism instead of as the result of a bunch of choices -- by people -- that produce the world we live in.  This is on my mind as I continue to ponder the recent failure of Codon Devices as a commercial enterprise.  In any event, here are a few notes and resources that I found compelling as I went back to reexamine Moore's Law.

What is Moore's Law?

First up is a 2003 article from Ars Technica that does a very nice job of explaining the why's and wherefore's: "Understanding Moore's Law".  The crispest statement within the original 1965 paper is "The number of transistors per chip that yields the minimum cost per transistor has increased at a rate of roughly a factor of two per year."  At it's very origins, Moore's Law emerged from a statement about cost, and economics, rather than strictly about technology.

I like this summary from the Ars Technica piece quite a lot:

Ultimately, the number of transistors per chip that makes up the low point of any year's curve is a combination of a few major factors (in order of decreasing impact):

  1. The maximum number of transistors per square inch, (or, alternately put, the size of the smallest transistor that our equipment can etch),
  2. The size of the wafer
  3. The average number of defects per square inch,
  4. The costs associated with producing multiple components (i.e. packaging costs, the costs of integrating multiple components onto a PCB, etc.)

In other words, it's complicated.  Notably, the article does not touch on any market-associated factors, such as demand and the financing of new fabs.

The Wiki on Moore's Law has some good information, but isn't very nuanced.

Next, here an excerpt from an interview Moore did with Charlie Rose in 2005:

Charlie Rose:     ...It is said, and tell me if it's right, that this was part of the assumptions built into the way Intel made it's projections. And therefore, because Intel did that, everybody else in the Silicon Valley, everybody else in the business did the same thing. So it achieved a power that was pervasive.

Gordon Moore:   That's true. It happened fairly gradually. It was generally recognized that these things were growing exponentially like that. Even the Semiconductor Industry Association put out a roadmap for the technology for the industry that took into account these exponential growths to see what research had to be done to make sure we could stay on that curve. So it's kind of become a self-fulfilling prophecy.

Semiconductor technology has the peculiar characteristic that the next generation always makes things higher performance and cheaper - both. So if you're a generation behind the leading edge technology, you have both a cost disadvantage and a performance disadvantage. So it's a very non-competitive situation. So the companies all recognize they have to stay on this curve or get a little ahead of it.

Keeping up with 'the Law' is as much about the business model of the semiconductor industry as about anything else.  Growth for the sake of growth is an axiom of western capitalism, but it is actually a fundamental requirement for chipmakers.  Because the cost per transistor is expected to fall exponentially over time, you have to produce exponentially more transistors to maintain your margins and satisfy your investors.  Therefore, Intel set growth as a primary goal early on.  Everyone else had to follow, or be left by the wayside.  The following is from the recent Briefing in The Economist on the semiconductor industry:

...Even the biggest chipmakers must keep expanding. Intel todayaccounts for 82% of global microprocessor revenue and has annual revenues of $37.6 billion because it understood this long ago. In the early 1980s, when Intel was a $700m company--pretty big for the time--Andy Grove, once Intel's boss, notorious for his paranoia, was not satisfied. "He would run around and tell everybody that we have to get to $1 billion," recalls Andy Bryant, the firm's chief administrative officer. "He knew that you had to have a certain size to stay in business."

Grow, grow, grow

Intel still appears to stick to this mantra, and is using the crisis to outgrow its competitors. In February Paul Otellini, its chief executive, said it would speed up plans to move many of its fabs to a new, 32-nanometre process at a cost of $7 billion over the next two years. This, he said, would preserve about 7,000 high-wage jobs in America. The investment (as well as Nehalem, Intel's new superfast chip for servers, which was released on March 30th) will also make life even harder for AMD, Intel's biggest remaining rival in the market for PC-type processors.

AMD got out of the atoms business earlier this year by selling its fab operations to a sovereign wealth fund run by Abu Dhabi.  We shall see how they fare as a bits-only design firm, having sacrificed their ability to themselves push (and rely on) scale.

Where is Moore's Law Taking Us?

Here are a few other tidbits I found interesting:

Re the oft-forecast end of Moore's Law, here is Michael Kanellos at CNET grinning through his prose: "In a bit of magazine performance art, Red Herring ran a cover story on the death of Moore's Law in February--and subsequently went out of business."

And here is somebody's term paper (no disrespect there -- it is actually quite good, and is archived at Microsoft Research) quoting an interview with Carver Mead:

Carver Mead (now Gordon and Betty Moore Professor of Engineering and Applied Science at Caltech) states that Moore's Law "is really about people's belief system, it's not a law of physics, it's about human belief, and when people believe in something, they'll put energy behind it to make it come to pass." Mead offers a retrospective, yet philosophical explanation of how Moore's Law has been reinforced within the semiconductor community through "living it":

After it's [Moore's Law] happened long enough, people begin to talk about it in retrospect, and in retrospect it's really a curve that goes through some points and so it looks like a physical law and people talk about it that way. But actually if you're living it, which I am, then it doesn't feel like a physical law. It's really a thing about human activity, it's about vision, it's about what you're allowed to believe. Because people are really limited by their beliefs, they limit themselves by what they allow themselves to believe what is possible. So here's an example where Gordon [Moore], when he made this observation early on, he really gave us permission to believe that it would keep going. And so some of us went off and did some calculations about it and said, 'Yes, it can keep going'. And that then gave other people permission to believe it could keep going. And [after believing it] for the last two or three generations, 'maybe I can believe it for a couple more, even though I can't see how to get there'. . . The wonderful thing about [Moore's Law] is that it is not a static law, it forces everyone to live in a dynamic, evolving world.

So the actual pace of Moore's Law is about expectations, human behavior, and, not least, economics, but has relatively little to do with the cutting edge of technology or with technological limits.  Moore's Law as encapsulated by The Economist is about the scale necessary to stay alive in the semiconductor manufacturing business.  To bring this back to biological technologies, what does Moore's Law teach us about playing with DNA and proteins?  Peeling back the veneer of technological determinism enables us (forces us?) to examine how we got where we are today. 

A Few Meandering Thoughts About Biology

Intel makes chips because customers buy chips.  According to The Economist, a new chip fab now costs north of $6 billion.  Similarly, companies make stuff out of, and using, biology because people buy that stuff.  But nothing in biology, and certainly not a manufacturing plant, costs $6 billion.

Even a blockbuster drug, which could bring revenues in the range of $50-100 billion during its commercial lifetime, costs less than $1 billion to develop.  Scale wins in drug manufacturing because drugs require lots of testing, and require verifiable quality control during manufacturing, which costs serious money.

Scale wins in farming because you need...a farm.  Okay, that one is pretty obvious.  Commodities have low margins, and unless you can hitch your wagon to "eat local" or "organic" labels, you need scale (volume) to compete and survive.

But otherwise, it isn't obvious that there are substantial barriers to participating in the bio-economy.  Recalling that this is a hypothesis rather than an assertion, I'll venture back into biofuels to make more progress here.

Scale wins in the oil business because petroleum costs serious money to extract from the ground, because the costs of transporting that oil are reduced by playing a surface-to-volume game, and because thermodynamics dictates that big refineries are more efficient refineries.  It's all about "steel in the ground", as the oil executives say -- and in the deserts of the Middle East, and in the Straights of Malacca, etc.  But here is something interesting to ponder: oil production may have maxed out at about 90 million barrels a day (see this 2007 article in the FT, "Total chief warns on oil output").  There may be lots of oil in the ground around the world, but our ability to move it to market may be limited.  Last year's report from Bio-era, "The Big Squeeze", observed that since about 2006, the petroleum market has in fact relied on biofuels to supply volumes above the ~90 million per day mark.  This leads to an important consequence for distributed biofuel production that only recently penetrated my thick skull.

Below the 90 million barrel threshold, oil prices fall because supply will generally exceed demand (modulo games played by OPEC, Hugo Chavez, and speculators).  In that environment, biofuels have to compete against the scale of the petroleum markets, and margins on biofuels get squeezed as the price of oil falls.  However, above the 90 million per day threshold, prices start to rise rapidly (perhaps contributing to the recent spike, in addition to the actions of speculators).  In that environment, biofuels are competing not with petroleum, but with other biofuels.  What I mean is that large-scale biofuels operations may have an advantage when oil prices are low because large-scale producers -- particularly those making first-generation biofuels, like corn-based ethanol, that require lots of energy input -- can eke out a bit more margin through surface to volume issues and thermodynamics.  But as prices rise, both the energy to make those fuels and the energy to move those fuels to market get more expensive.  When the price of oil is high, smaller scale producers -- particularly those with lower capital requirements, as might come with direct production of fuels in microbes -- gain an advantage because they can be more flexible and have lower transportation costs (being closer to the consumer).  In this price-volume regime, petroleum production is maxed out and small scale biofuels producers are competing against other biofuels producers since they are the only source of additional supply (for materials, as well as fuels).

This is getting a bit far from Moore's Law -- the section heading does contain the phrase "meandering thoughts" -- I'll try to bring it back.  Whatever the origin of the trends, biological technologies appear to be the same sort of exponential driver for the economy as are semiconductors.  Chips, software, DNA sequencing and synthesis: all are infrastructure that contribute to increases in productivity and capability further along the value chain in the economy.  The cost of production for chips (especially the capital required for a fab) is rising.  The cost of production for biology is falling (even if that progress is uneven, as I observed in the post about Codon Devices).&nb sp; It is generally becoming harder to participate in the chip business, and it is generally becoming easier to participate in the biology business.  Paraphrasing Carver Mead, Moore's Law became an organizing principal of an industry, and a driver of our economy, through human behavior rather than through technological predestination.  Biology, too, will only become a truly powerful and influential technology through human choices to develop and deploy that technology.  But access to both design tools and working systems will be much more distributed in biology than in hardware.  It is another matter whether we can learn to use synthetic biological systems to improve the human condition to the extent we have through relying on Moore's Law.