The LavaAmp at Wired Science

Wired is carrying a short story about personal genome sequencing that has a description and photo of the LavaAmp.

The caption describes the LavaAmp as "an experimental DNA copying machine."  I don't want to nitpick -- much -- but the instrument is certainly past being experimental.  There is data published using a very similar machine, the founders of LavaAmp have produced data using the instrument shown in the photo, and we will be shipping the v0.2 model to several Beta testers (okay, Alpha testers) as soon as the new heaters come back from the fab.  The project is moving pretty fast.

On the later point, the whole "Bits and Atoms" conversation really does deserve more attention.  As discussed in my previous post on the subject, it may be that much of the outsourced fabrication capacity available via the web is only available because of the present economic downturn.  But it is still available, and I have to say I have never had it easier in terms of shooting a design out the door and getting hardware (and plasticware) back according to my specs -- in just a few days, too.  And at really reasonable prices.

Even if the economy picks up and larger manufacturers sop up some of the extra capacity, my guess is that we are seeing the demonstration of a new market for rapid prototypes and small lots.  I doubt very much that people like me -- who are getting used to using the "send" button for emailed designs as a metaphorical "print" button for the atoms specified by those designs -- will want to give up this new capability.  And if demand for this service is maintained, or more likely increases, as the economy revives then all the more cability will be supplied via my atom-printing button.

I am still lusting after a desktop CNC mill, though.

Shell and Recent Biofuels Moves

According to the Financial Times, Shell recently entered a $12 billion deal with Cosan, the Brazilian sugar and ethanol producer.  Included in the deal are Shell's stakes in Iogen and Codexis, which together have a bunch of potent biological technologies useful for turning sugar and celluose into biofuels.  This represents a shift in strategy towards the biological production of fuels and away from industrial chemistry.  Last fall Shell sold off its stake in Choren, which had an advanced biomass-to-liquids program based on gasification of just about anything.  I met a group of executives from Choren at a meeting in Alberta about 18 months ago, and they seemed on top of the world with the partnership from Shell supporting their feedstock agnostic process.

It is interesting that Shell decided to change directions like this.  In the last couple of years I've heard many chemical engineers (including some from Shell) suggest that many of the problems plaguing process development in gasification and catalytic fuel synthesis were getting solved.  The story we told at Bio-era, and that I developed further in the book, is that industrial chemistry  would be one of many routes to biofuels, but that they might compete poorly in the long run because they require such careful tuning.  So Shell's exit might have been predicted at some point, but it came much sooner than I thought.  It appears biological technologies may appear a better bet even at this early stage.

Whither Gene Patents?

Wired and GenomeWeb (subscription only) have a bit of reporting on arguments in a case that will probably substantially affect patents on genes.  The case is Association of Molecular Pathology , et al. v. US Patent and Trademark Office, otherwise known as "the BRCA1 case", which seeks to overturn a patent held by Myriad Genetics on a genetic sequence correlated with breast cancer.

Here is a brief summary of what follows: I have never understood how naturally occurring genes can be patentable, but at present patents are the only way to stake out a property right on genes that are hacked or, dare I say it, "engineered".  So until IP law is changed to allow some other form of protection on genes, patents are it.

The ACLU is requesting a summary judgment that the patent in question be overturned without a trial.  Success in that endeavor would have immediate and enormous effect on the biotech industry as a whole, and I doubt the ACLU is going to get that in one go.  (Here is the relevant recent ACLU press release.)

However, the lawsuit explicitly addresses the broader question of whether any patents should have been granted in the first place on human genes.  This gets at the important question of whether isolating and purifying a bit of natural DNA counts as an invention.  Myriad is arguing that moving DNA out of the human genome and into a plasmid vector counts as sufficient innovation.  This has been at the core of arguments supporting patents on naturally occurring genes for decades, and it has never made sense to me for several reasons.  First, changing the context of a naturally occurring substance does not constitute an invention -- purifying oxygen and putting it in a bottle would never be patentable.  US case law is very clear on this matter.  Second, moving the gene to a new context in a plasmid or putting into a cell line for expression and culturing doesn't change its function.  In fact, the whole point of the exercise would be to maintain the function of the gene for study, which is sort of the opposite of invention.  Nonetheless, Myriad wants to maintain its monopoly.  But their arguments just aren't that strong.

GenomeWeb reports that defense attorney Brian Poissant, argued that "'women would not even know they had BRCA gene if it weren't discovered'under a system that incentivizes patents."  This is, frankly, and with all due respect, a manifestly stupid argument.  Mr. Poissant is suggesting that all of science and technology would stop without the incentive of patents.  Given that most research doesn't result in a patent, and given that most patent application are rejected, Mr. Poissant's argument is on its face inconsistent with reality.  He might have tried to argue more narrowly that developing a working diagnostic assays requires a guarantee on investment through the possession of the monopoly granted by a patent.  But he didn't do that.  To be sure, the assertion that the particular gene under debate in this case would have gone undiscovered without patents is an untestable hypothesis.  But does Mr. Poissant really want the judge to believe that scientists around the world would have let investigation into that gene and disease lie fallow without the possibility of a patent?  As I suggested above, it just isn't a strong argument.  But we can grind it further into the dust.

Mr. Poissant also argued "that if a ruling were as broadly applied here as the ACLU would like then it could 'undermine the entire biotechnology sector.'"  This is, at best, an aggressive over generalization.  As I have described several times over the past couple of years (here and here, for starters), even drugs are only a small part of the revenues from genetically modified systems.  Without digging into the undoubtedly messy details, a quick troll of Google suggests that molecular diagnostics as a whole generate only $3-4 billion a year, and at a guess DNA tests are probably a good deal less than half of this.  But more importantly, of the nearly ~2% of US GDP (~$220-250 billion) presently derived from biological technologies, the vast majority are from drugs, plants, or bacteria that have been hacked with genes that themselves are hacked.  That is, both the genes and the host organisms have been altered in a way that is demonstrably dependent on human ingenuity.  What all this means is that only a relatively small fraction of "the entire biotechnology sector" is related to naturally occurring genes in the first place.   

I perused some of the court filings (via the Wired article), and the defense needs to up its game.  Perhaps they think the weight of precedent is on their side.  I would not be as confident as they are. 

But neither is the plaintiff putting its best foot forward.  Even though I like the analysis made comparing DNA patents to attempts to patent fresh fruit, it is unclear to me that the ACLU is being sufficiently careful with both its logic and its verbiage.  In the press release, ACLU attorey Chris Hansen is quoted as saying "Allowing patents on genetic material imposes real and severe limits on scientific research, learning and the free flow of information."  GenomeWeb further quotes the ACLU's Hansen as saying "Patenting human genes is like patenting e=mc2, blood, or air."

As described above, I agree that patenting naturally occurring genes doesn't make a lot of sense.  But we need some sort of property right as an incentive for innovators.  Why should I invest in developing a new biological technology, relying on DNA sequences that have never occurred in nature, if anybody can make off with the sequence (and revenues)?  As it happens, I am not a big fan of patents -- they cost too damn much.  At present, the patent we are pursuing at Biodesic is costing about ten times as much as the capital cost of developing the actual product.  Fees paid to lawyers account for 90% of that.  If it were realistically possible to engage the patent office without a lawyer, then the filing fees would be about the same as the capital cost of development, which seems much more reasonable to me.

I go into these issues at length in the book.  Unfortunately, without Congressional action, there doesn't seem to be much hope for improvement.  And, of course, the direction of any Congressional action will be dominated by large corporations and lawyers.  So much for the little guy.

The ErrASE Synthetic Gene Error Correction kit from Novici

In December Novici Biotech started shipping a true error correction system for gene synthesis.  Novici uses the ErrASE system in house to assemble multi-kB genes from unpurified 60-mers.  This dramatically reduces costs, as anyone familiar with purchasing oligos will appreciate.  I can report that in one step the kit provides error correction equal to what one of the "big four" gene synthesis houses does via error removal.  One application of the kit reduces errors due to insertions, deletions, and substitutions by a factor of 20 or so.  I am waiting to hear what happens with two applications.  Using ErrASE essentially just involves a short incubation step.  The kitis designed to be compatible with existing manual and automated work flows.  (Full disclosure: Novici is a client of Biodesic.)

Synthetic genes are almost always assembled using single-stranded DNA, and those oligos tend to contain sequence errors.  Purification of the source oligos can improve the purity of the pool, but at the cost of throwing away ~90% of the oligos.  After assembly, the usual remedy for errors is to remove the genes that contain mistakes (for example using MutS, as I wrote about several years ago) and then sequence a number of the remaining clones to find one that has the correct sequence.

I mentioned ErrASE briefly in my commentary in Nature Biotechnology in December on "The changing economics of DNA synthesis".  It is the sort of advance that should facilitate gene assembly at ever lower costs, both because it reduces input costs through using unpurified oligos and because it reduces sequencing costs on the back end.  The combination of inexpensive oligos and ErrASE should enable DIYers to assemble synthetic genes and genetic circuits on the benchtop if they don't want to pay for the service.

Bits, Atoms, and the Future of Manufacturing

(Updated 9 Feb 2010 with new estimates of value captured by Chinese manufacturers.)
(Updated 12 Feb 2010 with cost estimates for the iPad.)

Wired's cover story this month proclaims that "In theNext Industrial Revolution, Atoms Are the New Bits".  As I address this "revolution" in the last chapter of my book, and as we are thinking hard about manufacturing issues as the LavaAmp moves forward, I have a few observations about the topic.

Chris Anderson, the Editor of Wired and author of the piece, asserts as the core of his story that

The tools of factory production, from electronics assembly to 3-D printing, are now available to individuals, in batches as small as a single unit. Anybody with an idea and a little expertise can set assembly lines in China into motion with nothing more than some keystrokes on their laptop. A few days later, a prototype will be at their door, and once it all checks out, they can push a few more buttons and be in full production, making hundreds, thousands, or more. They can become a virtual micro-factory, able to design and sell goods without any infrastructure or even inventory; products can be assembled and drop-shipped by contractors who serve hundreds of such customers simultaneously.

To summarize (and oversimplify) Anderson's article, the future is about innovators -- individuals, really -- having access to manufacturing for small runs that can be scaled up as needed.  Design will be digital, and as the appropriate machinery continues to increase in capability and fall in price, manufacturing will increasingly be digital too.

In a full snark-on mode response at Gizmodo is Joel Johnson, with a blog post entitled "Atoms Are Not Bits; Wired Is Not A Business Magazine".  The snark distracts from some otherwise interesting analysis, which you can read and which I will get to below.  The comments on the post are unusually perceptive and many were made by people who are clearly plugged in at a professional level to the atoms-and-bits manufacturing story.

The summary of Johnson's argument is that small production runs equal small money, prototyping is not manufacturing, labor is cheap in China -- so what?, and some/all of the small production available now may be the result of oversupply due to the recession.  Many of these points are probably cogent.

But even when it comes to demonstrably successful examples of bootstrapping from rapid prototyping to international sales, Johnson is skeptical.  Wired's Anderson points to Aliph, makers of the Jawbone line of headsets, as an example of a virtualized business (ie heavy on creativity and IP, but with minimal capital infrastructure) that supports his case.  Johnson shoots back with this:

It's great that hobbyists can make ever more complex items, sell them on the internet, and have a small business. But the same process used by Aliph to manufacturer Bluetooth headsets (and bear in mind it takes 80 people just to coordinate this!) is exactly the same outsourcing process used by Apple to make iPhones.

Here Johnson makes a very interesting point, but is so full of kvetch that he trips over it and misses the significance of his observation.  Of the 80 or so people working at Aliph, only 8-10 will be actually working directly on engineering or manufacturing.  At least half the full count will be in sales, marketing, and customer service, with the rest distributed in IT, administration, and support, and finally with a few (probably 5-8) executives atop the whole thing.  The interesting bit is that those 8-10 people are able to coordinate the same sort of production infrastructure used by Apple and its many hundreds (thousands?) of staff in engineering and manufacturing.  

When it comes to manufacturing labor and cost, there are a few other observations that are worth pulling into this discussion.

• First up is an article from The Economist last week about the results of recent teardowns on smartphones.  The numbers from iSuppli are interesting: of the four leading phones they took apart, the cost of components falls in a very narrow range of $170-180.
• Next is a blog post from Slashdot a couple of months ago pointing to stories about the value breakdown on the retail sale price for consumer electronics.  The post refers to some analysis by Edmund Conway at The Telegraph suggesting the value added for an iPod assembled in China is only "a couple of dollars".  On a ~$200 widget that, let's call that $2, or 1%.  That number should hold for anything resembling a smartphone, which means assembly labor plus overhead (and local profit) adds only about $2 to the phone, too.  (Update 2: iSuppli evidently already has done a teardown on the iPad, and "manufacturing costs" are about 5% of the total component costs.)
• Minimum wages in China range from ~$.4 to ~$.7 per hour, so that $2 in labor would pay for several hours total time.  This has to be an overestimate, by a long way.  I'll bet the assembly doesn't require more than a few minutes of labor per unit, with the rest going to overhead and profit.  Another issue is that Apple is probably paying Foxconn and its employees above minimum wage in order to retain trained labor, keep IP inside the company, and keep down the "fair day's wage" complaints from shareholders and critics in the US.  But that is just a guess, of course.  (Update 1: In a February 8th column at the NYT, Roger Cohen reports that a watch manufacturer in Dongguan is pulling down 5-8% of the retail price of various brands.  Wages are running $150-200 per month in that part of China.  I don't think this changes the numbers I've used above and below.)
• With so little labor involved in the assembly, what other options are available to manufacturers today?  At the US minimum wage, spending that same few minutes assembling a doodad in the States would add a few more dollars to the cost -- not so much.  I'd pay that difference to know something was made here in the States.  The overhead on the factory is another matter, though.  It could be that paying for the real estate and the rest of the capital equipment makes assembly in the US uncompetitive.  (Though it would be the construction of the factor and the initial installation of the equipment that made the difference in cost -- the material cost of the building and the equipment would be roughly the same in China.)
• That said, there is plenty of industrial land in Detroit laying fallow at the moment.  Tax breaks to build assembly plants in depressed US cities could probably bring a lot of those jobs home.  Yes, they would be minimum wage, but there are a lot of people here waiting for any job.

If you add the value of the software to the cost (say ~$30 on an iPhone), then you dilute the value of the assembly labor even more.  Thus even more of the value of the object is in bits rather than atoms and their arrangement, and the difference in wages between China and the US is diluted further still.  Even the arrangement of the atoms is really about bits, since all the sub-components of an iPhone roll off of manufacturing lines with minimal labor involved.

Around the office, we have been pondering many of these issues as they relate to biological technologies and the LavaAmp in particular.

We continue to refine the hardware design of the LavaAmp, and it looks like we have the production hardware down to 5 or 6 components, 4 of which are injection molded plastic.  The labor will only be in assembly of the final box, as all sub-assemblies should all come off automated fab lines of one kind or another.  All the real cost is in the design and tooling -- once we get up and running the per unit costs should be quite reasonable.

The reason that this is worth a larger discussion is that Biodesic is exploiting all of the trends and resources that Anderson writes about, however we are building not a consumer electronics widget but rather a tool that will facilitate the manipulation of biological systems.  As the boundary between bits and atoms blurs in one area (consumer electronics), the resulting improvements in design and manufacturing capabilities create opportunities for further blurring the boundary between bits and atoms in biology.  The LavaAmp should enable many more people to query DNA in their environment, and possibly even to play with PCR assembly of genes and genetic circuits, which is an experiment I am keen to try.  Trends like this will continue to put technologies into the hands of an ever wider range of people around the planet.

If you work with this sort of technology on a daily basis, what I wrote above comes as no surprise.  But that describes a very small minority of hardware and wetware hackers.  Many more people will come to realize it soon.  New manufacturing realities and the resulting new tools are about to contribute substantial change to our economy.

25% of US Grain Crop Used for Biofuel

The Guardian UK reported today that 2009 USDA figures show 25% of grains grown in the US were used to produce liquid biofuels.  The typical food vs fuel story follows.  And it is mostly on point, if tinted by The Guardian's usual populist tone.  Yes, all the grain could in principle be used to feed people.  No, it isn't clear that grain-based ethanol is in fact better than burning petroleum when it comes to total greenhouse gas emissions or energy content.

The story ends with a nod toward "continued innovation in ethanol product" that supposedly is increasing yields and reducing costs.  Huh.  No mention, though, of the fact that any starch crop used to make fuel starts at a major disadvantage with respect to sugar crops, nor that there is an ethanol glut in the US due to construction of too many ethanol production plants.  Neither does the story get into why ethanol isn't a very good fuel to begin with (wrong solvent properties, low energy content, water soluble).

I go into detail about this in my forthcoming book, but the upshot of the argument is that the US is investing quite a lot of money in ethanol production technology and infrastructure that will never be competitive with sugar derived fuels.  And then relatively soon we will get butanol, longer chain alcohols, and true drop-in petroleum replacements made using modified organisms.  In the meantime, I suppose we will just have to suffer through the impact of decisions made more for political reasons than for competitive or national security reasons.  But grain to ethanol isn't really good for anybody except US Senators from farm states.

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.

Can't believe it's finally here.

At long last, the printed copies of the book showed up yesterday.  Should be on shelves pretty soon.

In the News

The December issue of Nature Biotechnology contains a special focus section on synthetic biology.  Here is my commentary, "The Changing Economics of DNA Synthesis".  The PDF version appears to be available for free, at least for the moment.

My interview in the Fall 2009 issue of GBN:bulletin is now available from the Global Business Network.  The issue also contains a short interview with Stewart Brand about his new book -- it is well worth reading.

Revisiting Mood Hacking with Scents

Following on my post last spring about mood hacking, October brought more hints that behavior can be explicitly modified using scents.  A variety of news outlets picked up on a press release from BYU describing a forthcoming paper in Psychological Science that demonstrates, "that clean scents not only motivate clean behavior, but also promote virtuous behavior by increasing the tendency to reciprocate trust and to offer charitable help."  Here I am quoting from a pre-print, entitled "The Smell of Virtue", cached at the University of Toronto.  The paper describes two experiments in which citrus-scented window cleaner appeared to alter behavior.  I have to say that I found the references to Proust, saints, sinners god, and cleanliness (all that in 4 pages!) to be distractions from the main ideas, not to mention the data.

Here is the ScienceDaily reporting, and here is Time's take.

(Not everyone is happy with the methodology described in the paper, the conclusions, and the way it was written.)

What makes this interesting (to me) is that the researchers don't necessarily imply a direct biological mechanism.  The induced behavior may simply be the result of a learned association.  That is, there is no suggestion that anything about the scent that serves to flip a biological switch that leads to different behavior.  Rather the lead author, Katie Liljenquist of BYU, and her colleagues had  previously demonstrated a link between transgression and a desire for cleanliness (see "Washing Away Your Sins: Threatened Morality and Physical Cleansing", Science, 313(5792), 2006).  "Out, damned spots!" and all that.

The citrus scent may simply something that Prof. Liljenquist's test subjects (probably undergraduates at US universities) have learned to associate with cleanliness.  Would students at Asian universities have the same response to the same scent?  I suppose one way to quickly address this question is to see what sort of scents Asians prefer in their window cleaners.  Here is my point: even though there may be no innate molecular pathway exploited in this "behavior reprogramming", it may still be possible to exploit culturally defined (or perhaps "contextually constructed") neural pathways (from the receptors to the brain) for the purpose of mood hacking.

I am not particularly excited about the possibility of having my own mood hacked without my knowledge.  That this might be accomplished even in the absence of genetically identifiable response pathway should give one pause.  Any molecular pathway responsible for this effect (should it prove reproducible and engineerable) is unlikely to be well understood for many years to come.  But if the results from the citrus-scent study are to be believed, then it is already possible to manipulate behavior using scents, even though we have little idea how to defend against it other than by using more scents.  Perfume warfare.  Lovely.

Can't wait until the iGEM undergraduates get a hold of this.  They have already built bugs that smell like bananas and mint.  When will they start trying to influence the judges' decisions directly using synthetic scent pathways?