synthesis tag:www.synthesis.cc,2008-11-25://1 2010-03-10T21:52:43Z Rob Carlson (Home) Book :: www.biologyistechnology.com Biodesic :: www.biodesic.com Movable Type Pro 4.21-en DIY Cleanroom tag:www.synthesis.cc,2010://1.332 2010-03-10T21:41:16Z 2010-03-10T21:52:43Z Rob Carlson Gizmodo and Make are both pointing to Bill Morris's DIY Cleanroom.  Compare it to the hoods shown in my post on Garage Biology in Silicon Valley a couple of days ago.

Morris reports that his goal is a Class 10,000 hood, a specification that is slightly more involved than I had remembered.

In any event, Morris' hood would be of great use to those doing cell culture at home.  I suspect you are going to want a better filter, for nabbing smaller contaminants, maybe higher airflow, and perhaps some way to hack up a laminar-flow set-up.

Cool.
]]> Garage Biology in Silicon Valley tag:www.synthesis.cc,2010://1.331 2010-03-08T23:45:10Z 2010-03-11T00:08:02Z Rob Carlson Carlson_CA_Assembly_February_2010.pdf), which focus on the role of small business and garage hackers in creating innovation in the Bioeconomy, and here is the agenda (PDF).  See my recent post on "Micro-Brewing the Bioeconomy" for the details of craft brewing as an example of distributed biological manufacturing.  I also did an event at the GBN for the book, and I'll post a link to the recording when it goes live.

I spent most of one Saturday hanging out at a garage biology lab in Silicon Valley.  When I walked in the door, I was impressed by the sophistication of the set-up.  The main project is screening for anti-cancer compounds (though it wasn't clear to me whether this meant small molecules or biologics), and the people involved have skillzzz and an accumulation of used/surplus equipment to accomplish whatever they want; two clean/cell-culture hoods, two biorobots (one of which is being reverse engineered), incubators, plate readers, and all the other doodads you might need.  They aren't messing around.  I didn't get into the details of the project, but the combination of equipment, pedigree, and short conversations with the participants told me all I needed to know.  That doesn't mean they will be successful, of course, just that I believe they are yet another example of what can be attempted in a garage.  This sort of effort is where new jobs, new economic growth, and, most importantly, desperately needed new technologies come from.  Garage innovation is at the heart of the way Silicon Valley works, and it is envied around the world.

IMG_0173.jpg
IMG_0174.jpgI continue to get push back from people who assert that "it is really too hard" to hack biology in a garage, or too expensive, or that garage labs just can't be up to snuff.  This sort of dissent usually comes out of National Labs, Ivy League professors, or denizens of the beltway.  All I can say to this is -- Doodz, you need to get out more.

So why am I not telling you the who and the where for the photos above?  Because, like many garage biology hackers, they are a little skittish given the way the Uncle Sam has been off his rocker for the last few years when it comes to mis-perceived biothreats (Shoot first, Google later).  The people who built the lab pictured above are pursuing a project that is technically well beyond anything discussed on the DIYBio list, and while they may be watching the DIYBio conversation they don't advertise what they are up to.  It would be better for all of us if we could rest assured that conversations about this sort of work could proceed in the open without guys showing up in biohazard suits with weapons drawn -- Youtube, at the 00:00:48 mark.  Words fail to describe this video.  Or, rather, I have plenty of choice words to describe the quality of the investigation and planning that went into an armed assault on the residence of an art professor whose many previous public shows and events included biological technologies including hacked bacteria -- and indeed I have shared those words with the appropriate individuals in DC, and will do so again -- but it won't do my blood pressure any good to go further down that road here.

While the innocuous art professor may be back at work, and while some may view this as water under the bridge, it is not my impression that Federal law enforcement officials truly understand the impact of their behavior.  (Here, I will try again: Dear Feds, You are making us less safe.)  The response to errant "enforcement"efforts (or "career enhancement", depending on your perspective) is exactly what you would expect -- people stop talking about what they are doing, making the job of sorting out potential threats all that much harder.  I recall giving a talk in DC in 2003 or so wherein I made this point to a room full of intelligence types (domestic and foreign), and only about half of them -- predominantly the younger ones -- understood that information was their only tool in this game.  The notion that you could effectively produce safety through prohibiting garage biology and related efforts is the height of folly.  See, for example, "And the Innovation Continues...Starting with Shake and Bake Meth!" for the latest on the effectiveness of domestic prohibition of methamphetamine production.  The effect is -- surprise!!! -- more innovation.  Just like it always is.  However much garage biology we wind up with, we will be much safer if practitioners are willing to discuss what they are up to without worrying about misdirected badges, search warrants, and guns. 

To be sure, I don't have reason to suspect anything but good intentions and productive work originating from the garage lab shown above.  Nor is a drug screening project likely to result in something scary.  But I certainly can't know they won't make a mistake.  I would feel more comfortable if they, in turn, didn't feel like they had to keep a low profile so that there could be open discussion of potential missteps.  This applies to individuals and governments alike: "Above all else, let us insist that this work happens in the light, subject to the scrutiny of all who choose to examine it." (PDF)  And I am waaay more concerned about what the government might get up to behind closed doors than I am about activities of individuals.  

Next week I am headed to DC for another biosecurity/bioterrorism discussion, which will be interesting in light of the recent "F" grade given to US biopreparedness by the President's Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism.  See also my earlier analysis of the report.  I mention this here because the US Government still doesn't get the role of garage biology in much needed innovation (see the slides above from the talk to the CA Assembly Committee for a list of important technical advances from small businesses and individuals -- this discussion is also in the book).  Nor has the US Government clued into the PR job they have ahead of them with students who are gaining skills and who want to practice them in the garage.  Both the FBI and the Biological Weapons Commission Convention (sorry, Piers!) had a presence at iGEM in 2009 -- as liasons to students the FBI sent Agents whose cards read "Weapons of Mass Destruction Coordinator".  !!!Calling Chiat\Day!!!

There continues to be a prominent thread of conversation in Washington DC that "biohacking" is somehow aberrant and strange.  But apparently DIYBio, you'll be happy to hear, is a group composed of the Good Guys.  Everyone should feel happy and safe, I guess.  Or maybe not so much, but not for the reasons you might think.

The creation of a false dichotomy between "DIY Biotech" (good guys) and "Biohacking" (bad guys) lends unfortunate credence to the notion that there is an easily identifiable group of well-meaning souls who embrace openness and who are eager to work with the government.  On the contrary, in my experience there are a number of people who are actively hacking biology in their garages who intentionally keep a low profile (I am not certain how many and know of no existing measure, but see discussion above).  This tally included me until a little over a year ago, though now my garage houses a boat under restoration.  These people often consider themselves "hackers", in the same vein as people who hack computers, boats (!), cars, and their own houses.  Yes, it is all hacking, or Making, or whatever you want to call it, and not only is it generally innocuous but it is also the core of technological innovation that drives our economy.  And without direct interaction, I do not believe it is practical to ascribe motivation or intent to an individual - including and especially an incorporated individual - operating in a garage.  Thus, I strongly object to the establishment of a conversation related to biosecurity in which the term "biohacker" has any pejorative connotations precisely because it perpetuates the misconception that i) this group is quantifiable; ii) that the group has any unified motivations or identifiable ethical norms (or anti-norms); iii) that it can realistically be currently addressed (or assessed) as a "group".

Hmm...with that, I have run out of steam for the moment, and have real work to do.  More later.
]]> Micro-Brewing the Bioeconomy: Beer as an Example of Distributed Biological Manufacturing tag:www.synthesis.cc,2010://1.324 2010-03-03T20:37:00Z 2010-03-09T04:26:07Z Rob Carlson an iGEM victory in that other Cambridge (congratulations again, almost-Dr. Brown and team), beer is always there.

And now it is helping me think about the future of biological manufacturing.  Not just by drinking it, though I can't say it hurts.  Yet.

Anyway, the rise of craft brewing in the US is an interesting test case, and a proof of principle, of distributed biological manufacturing successfully emerging in a market dominated by large scale industrial production.  To wit, Figure 1:

US_Brewery_Count_Biodesic.png
Figure 1.  The number of US large and small breweries over the last century.  The (official) count was forced to zero during Prohibition.  (Click on image for full-size.)

A Short, Oversimplified History of Craft Brewing

Before Prohibition, the vast majority of beer produced in the US was brewed by relatively small operations and distributed locally.  There was no refrigeration, nor were there highways and trucks, so beer had to drunk rather than produced and stored in large quantities (modulo some small amount of storage in basements, caves, etc.).  Moreover, the official count of breweries went to zero during the years 1920-1933.  After Prohibition, brewing was regulated and small scale producers were basically shut out of the market.

With the aid of refrigeration and transportation, large scale breweries took off.  Consolidation took its toll -- beer is pretty close to a commodity, after all -- and the number of breweries in the US shrank until about 1980.  In 1979, Jimmy Carter signed legislation reopening the market to small brewers.  This is an interesting and crucial point, because as far as I can tell nothing else substantive changed about the market.  Deregulation reopened the market to craft brewers and the industry blossomed through organic growth and the preferences of consumers.  (Conclusion: Emerging small scale, distributed production can compete against an installed large scale infrastructure base.)

The definition of a "craft" brewer varies a bit across the various interested organizations.  According to the Brewers Association, "An American Craft Brewer is small, independent, and traditional."  Small means less than 2 million barrels a year (at 26 Imperial gal or 30.6 standard gal per barrel); independent means less than 25% owned by a non-craft brewer; traditional means either an all malt flagship beer or 50% of total volume in malt beer.  There is a profusion of other requirements to qualify as a craft brewer, some of which depend on jurisdiction, and which are important for such practical concerns as calculating excise tax.  Wikipedia puts the barrier for a craft brewer at less than 15,000 barrels a year.  According to the Brewers Association, as of the middle of 2009 there are about 1500 craft brewers in the US, and about 20 large brewers, and about 20 "others", with brewpubs accounting for about 2/3 of the craft brewers. 

Show Me the Hops.  Or Wheat.  Or Honey (if you must).

Brewpubs and microbreweries are so common that the majority of Americans live within 10 miles of a craft brewer, and it is a good bet that there is one quite close to where you live.  The Beer Mapping Project can help you verify this fact.  Please conduct your field research on foot.

Beer generates retail revenues of about $100 billion in the US (brewery revenues are probably less than half that), contributing combined direct and indirect jobs of about 1.9 million.  But craft brewers account for only a small fraction of the total volume of beer brewed in the US.  According to the Beer Institute's "Craft Brewers Conference Statistical Update - April 2007" (PPT), three brewers now supply 50% of the world's market and 80% of the US market.  See Figure 2, below. The Brewer's Association clarifies that only 5% of the volume of beer brewed in the US is from craft brewers, who manage to pull down a disproportionate 9% of revenues. (Conclusion: Small scale producers can command a premium in a commodity marketplace.)

US_market_share_Biodesic.png
Figure 2.  US beer market share.  (Click on image for full-size.)

Here is an interesting question to which I do not have an answer: how much beer brewed by large producers is actually bottled and distributed locally?  "Lot's of beer", where I don't have any real idea of what "lot's" means, is produced via contract brewing.  It may be that "large scale production" is therefore not as centralized as it looks, but is rather the result of branding.  This makes some sense if you think about the cost of transportation.  As beer (regardless of its source) is mostly water, you are paying to ship something around that is usually plentiful at the destination.  It makes a lot of sense to manufacture locally.  But, as I say, I have yet to sort out the numbers.

Brewing as an Example of Distributed Biological Manufacturing

All of the above makes brewing an interesting test case for thinking about distributed biological production.  Craft brewers buy feedstocks like everybody else, pay for bottles and probably for bottling services, and ship their product just like everybody else.  They may be much smaller on average than Anheuser Busch, but they survive and by definition make enough money to keep their owners and employees happy.  And they keep their customers happy.  And their thirsts quenched.

Above, I identified two important conclusions about the craft brewing market relevant to this story: 1) Craft brewing emerged in the US amidst an already established large scale, industrial infrastructure for producing and distributing beer.  2) Small scale, distributed production can command a premium at the cash register.

As we look forward to future growth in the bioeconomy, more industrial production will be replaced by biofactories, or perhaps "industrial biorefineries", whatever those are supposed to be.  Recall that the genetically modified domestic product (GMDP) now contributes about 2% of total US GDP, with the largest share for industrial products.

This story becomes particularly relevant for companies like Blue Marble, which is already producing high value, drop-in replacements for petrochemicals using biological systems.  (Full disclosure: Blue Mable and Biodesic are collaborating on several projects.)  As feedstocks, Blue Marble uses local waste agricultural products, macro- and micro-algae, sewage, and -- wait for it -- spent grains from the microbrewery next door.  (How's that for closing the loop?)  Products include various solvents, flavorings, and scents.

The craft brewing story tells us that consumers are quite willing to pay a premium for locally produced, high quality products, even before they learn -- in the case of Blue Marble -- that the product is organic and petroleum-free.  It also tells us that small scale production can emerge even amidst an existing large industry. 

Can Blue Mable and other companies compete against enormous, established chemical and petroleum companies?  In my experience, the guys (and they are nearly universally guys) at the top of the oil industry don't even get this question.  "It is all about steel in the ground", they say.  In other words, they are competing based on the massive scale of their capital investments and the massive scale of their operations and they don't think anybody can touch them.

But here is the thing -- Blue Marble and similar companies are going to be producing at whatever scale makes sense.  Buildings, neighborhoods, cities, whatever.  Any technology that is based on cow digestion doesn't have to be any bigger than a cow.  Need more production?  Add more cows.  This costs rather less than adding another supertanker or another refinery.  Blue Marble just doesn't require massive infrastructure, in large part because they don't require petroleum as a feedstock and are not dependent on high temperatures for processing.  Most of the time, Blue Marble can do their processing in plastic jugs sitting on the floor, and stainless steel only comes into the picture for food-grade production lines.  This means capital costs are much, much lower.  This is a point of departure for biomanufacturing when compared to brewing.

(Update: Perusing old posts, I discovered I did a decent job last year of putting this scale argument in the context of both computers and the oil industry, here.)

Beer is close to a commodity product, and it is the small scale producers who get a better price, even though their costs will be roughly the same as large scale producers.  Blue Marble generally has substantially higher margins than petrochemical producers -- and by focusing on the high margin portion of the petroleum barrel they are going to be stealing the cream away from much larger companies -- but Blue Marble's costs are much lower.  What is the financial situation of a large petrochemical company going to look like when they lose the market for esters, which can have margins of many hundreds of dollars per liter, and are left with margins on products closer to gas and diesel at dollars per liter?  This is a different sort of play than you would see in brewing.

Now, I am not guaranteeing that distributed biological production will win in all cases.  Large beer brewers clearly still dominate their market.   It may be that biological manufacturing will look like the current beer industry; a few large players producing large volumes, and a large number of small players producing much less but at higher margins.  But craft brewing is nonetheless an existence proof that small scale, distributed production can emerge and thrive even amidst established large scale competition.  And biological manufacturing is sufficiently different from anything else we have experience with that the present market size of craft brewing may not be that relevant to other products. 
]]> GM Potatoes Approved in Europe for Industrial Starch Production tag:www.synthesis.cc,2010://1.326 2010-03-03T20:01:00Z 2010-03-03T20:02:05Z Rob Carlson Not everyone is happy in Europe today.  Evil Genetically Modified (GM) crops are on the march.  After 12 years of deliberations, the EC approved the cultivation of BASF's Amflora potato for industrial uses or animal feed.  Amflora is only the second GM crop approved for cultivation in Europe.  Before getting into this too far, I want to make clear that such decisions should be based on science, and if the science says there are safety or health concerns then we should be cautious.  But the science, all the science I am aware of, says GM crops are safe, at least from a health perspective.  Non-peer reviewed yelping doesn't count.  (Leakage of transgenes is another matter, which I get to below, lest the reader think I am wholly uncritical of GM crops.)

According to the NYT, the EC's Health Commissioner John Dalli described the decision this way:

Responsible innovation will be my guiding principle when dealing with innovative technologies. After an extensive and thorough review ... it became clear to me that there were no new scientific issues that merited further assessment. ...All scientific issues, particularly those concerning safety, had been fully addressed. Any delay would have simply been unjustified.
Digging into this a bit, I found on the European Commission's site quite a long list of GM crops that are approved for various uses in Europe.  Not cultivation, mind you, but use.  Six member states presently "prohibit the use and/or sale of the GM product on its territory". 

The primary complaint by critics appears to be that Amflora contains antibiotic resistance genes, which is not the change that makes them useful in the field, but rather an old technology used to produce the plants in the first place.  That this very old technology is now being deployed in the field is the result of the slow approval process in Europe.  No new GM crop in the US would contain antibiotic resistance genes.  Why is this important?  Because those genes may leak out of the crop into other organisms.

According to the NYT, this risk was evaluated as being very low for the Amflora potato.  Fine.  But it is a real risk in general, one that has been observed in other GM crops.  Here is the relevant passage from of my book, in the context of using GM crops as industrial feedstocks (p165 -- refs are at bottom of this post):

Leakage of genes from GM crops into their unmodified cousins is potentially a threat if herbicide-resistance genes are transferred into weeds. Gene flow into close relatives has been observed in tests plot of Kentucky bluegrass and creeping bentgrass, which provided "the first evidence for escape of transgenes into wild plant populations within the USA."[47]  A similar result has now been demonstrated for a stable and persistent transfer of an herbicide-resistance gene from the widely cultivated Brassica napus, commonly known as rape or rapeseed, to its wild relative Brassica rapa.[48]  Within the confines of a laboratory, herbicide-resistance genes can be transferred with relative ease via pollen exchange between common weed species.[49]  These demonstrations may give pause to both policy makers and commercial interests. Any gene transfer in open cultivation that results in unintentional propagation of a new herbicide-resistant weed strain has the potential to cause substantial economic and physical damage.
The resulting potential threat to agricultural systems raises significant questions about the wisdom of relying on genetically modified crops for feedstock production.
If gene leakage can be minimized, then GM crops hold sufficient promise that they should be used.  The EC appears to believe that this is the case for Amflora potatoes.  Critics in Europe aren't satisfied.  But here is the truly nutty bit about criticism from Greenpeace and Friends of the Earth -- it is through their efforts that technological progress in Europe is so damn slow.  Why would any company want to go through the pain and expense of trying to get new technology (i.e., a GM crop that doesn't contain antibiotic resistance genes) into Europe when the only test case took 12 years to make it into the field?

At any rate, the Amflora decision may indicate the mood has changed at the EC level.  Not that the floodgates are likely to open, but perhaps GM crops will now be seen in a different light in Europe.


Refs from Biology is Technology excerpt:

47.  P. G. Johnson et al., Pollen-mediated gene flow from Kentucky bluegrass under cultivated field conditions,Crop Science 46, no. 5(2006): 1990; L. S. Watrud et al., From the cover: Evidence for landscape-level, pollen-mediated gene flow from genetically modified creeping bentgrass with CP4EPSPS as a marker, PNAS 101, no. 40(2004): 14533; J. R. Reichman et al., Establishment of transgenic herbicide-resistant creeping bentgrass (Agrostis stolonifera L.) in nonagronomic habitats, Molecular Ecology 15, no. 13(2006): 4243.

48.  S. I. Warwick et al., Do escaped transgenes persist in nature? The case of an herbicide resistance transgene in a weedy Brassica rapa population, Molecular Ecology 17, no. 5(2007): 1387-1395.

49.  I. A. Zelaya, M. D. K. Owen, and M. J. VanGessel, Transfer of glyphosate resistance: Evidence of hybridization in Conyza (Asteraceae), American Journal of Botany 94, no. 4(2007): 660.
]]> Book Talks at NYC Resistor and Science House in March tag:www.synthesis.cc,2010://1.325 2010-03-02T22:48:42Z 2010-03-02T22:59:04Z I'll be giving at least two talks in NYC in mid-march.NYC Resistor March 13, 2010Time: 2 p.m. - 4p.m.87 3rd Avenue, 4th Floor Brooklyn, NY 11217Science HouseMarch 14, 2010 Time: 1 p.m. - 4 p.m. 240 E 39th St. Apt... Rob Carlson
NYC Resistor
March 13, 2010
Time: 2 p.m. - 4p.m.
87 3rd Avenue,
4th Floor
Brooklyn, NY 11217

Science House
March 14, 2010
Time: 1 p.m. - 4 p.m.
240 E 39th St. Apt 44B
New York, NY 10016

Science House is requesting that people email ahead of time, as the seats are already filling up.
]]> Biology is Technology makes Wired Magazine's Playlist for February, 2010 tag:www.synthesis.cc,2010://1.323 2010-03-01T07:46:31Z 2010-03-01T07:53:10Z Rob Carlson book hit the shelves late last week, and just in time for a little shout out from Wired in the form of the February Playlist.  Thanks, Thomas.
]]> The LavaAmp at Wired Science tag:www.synthesis.cc,2010://1.322 2010-02-19T06:35:13Z 2010-02-19T06:34:36Z Rob Carlson 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 tag:www.synthesis.cc,2010://1.321 2010-02-16T23:25:56Z 2010-02-16T23:44:42Z Rob Carlson 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? tag:www.synthesis.cc,2010://1.319 2010-02-16T23:05:00Z 2010-02-17T00:04:29Z Rob Carlson 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 tag:www.synthesis.cc,2010://1.318 2010-02-03T19:00:44Z 2010-02-03T19:57:07Z Rob Carlson 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 kit is 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 tag:www.synthesis.cc,2010://1.316 2010-02-03T01:01:00Z 2010-03-03T01:00:50Z Rob Carlson (Updated 12 Feb 2010 with cost estimates for the iPad.)

Wired's cover story this month proclaims that "In the Next 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.
]]> Here Comes the Wolf Pack tag:www.synthesis.cc,2010://1.317 2010-02-02T18:04:31Z 2010-02-02T19:10:40Z Rob Carlson NetworkWorld, and here is Gizmodo's short note.  BigDog is part of the inspiration for my thinking about Cowborgs that wander around fields munching grass and producing biofuel (see "The New Biofactories", from last year's McKinsey Quarterly special What's Next).

But there is another obvious application that has been lurking in the back of my mind.  The spec calls for the following capabilities:

  • The robot must support all manner of walking, trotting, and running/ bounding and capabilities to jump obstacles, cross ditches, recover from disturbances and other discrete mobility features. The LS3 must be able to follow a leader between 5m and 100m ahead, in dynamic, cluttered environments with other moving soldiers in close proximity.
  • It must have the ability to perceive and traverse its immediate terrain environment autonomously with simple methods of control.
  • The robot must understand simple soldier-to-LS3 interaction with minimal direct control of the platform's speed and heading (joy-sticking and tele-operating are examples of direct control). The vehicle must require minimal oversight or direct control (e.g. joystick control) from an operator.  Direct control modes should only be used for error recovery, and should not be needed more than 3 times per 24-hour operational period, for no more than 5 minutes at a time.  
With the sort of stability and mobility required to meet these specifications, there isn't any reason you couldn't mount weaponry on the LS3.  You could imagine all sorts of science fiction scenarios with Miniguns or Vulcans, which for all I know might have serious mass issues for either the armament or the ammunition, or might sport too much recoil.  But it would probably be enough to mount cartridge fed shotguns or smaller grenade launchers, or any other weapons platforms now fielded on ROVs.  The combination of autonomous terrain traversing, navigation, and operation from a distance suggest that even early versions could be directed to walk into hostile situations while troops remained out of harm's way.  The requirement to "follow a leader" could be altered to "home in on a transponder" delivered by one of the many ROVs already in the field, whether RC car or airplane.

And just as there is no reason to think the US military won't be mounting weapons on BigDog, there is no reason to think the robots won't be operated in groups.  Imagine for a moment that you are a Taliban or Al Qaeda fighter hanging out in a cave, and you probably don't have a lot of exposure to technology other than what the US military is throwing at you on a daily basis.  Into your cave walks a Wolf Pack of armored DevilDogs armed to the...teeth (?) and probably  demanding your surrender in Arabic or Pashtun.  You say no.  They open fire.  Alternate scenario: You are a militant in Afghanistan and your exquisitely planned ambush of NATO troops is interrupted by a Wolf Pack chasing you up into the hills.

I can imagine that both of these scenarios would require a serious programming effort before a BigDog becomes a DevilDog.  But if either scenario works even once, just imagine the impact on enemy morale.  And how long before the LS3 becomes an ordinance delivery platform, walking into an enemy camp with a 400 lb bomb on its back?  Powerful stuff, that, both as a tactical weapon and a morale buster.

I don't know how I feel about this.  Yes, a Wolf Pack of DevilDogs would probably keep our troops safer.  And this might be a more effective way of hunting down bad guys.  But the spectre of increasingly autonomous weapons platforms should make everyone a little uneasy.

Then again, this sort of investment will make the Cowborg happen that much sooner.  Is that worth it as a sort of "peace dividend" spin off from military spending?  Hmmm.
]]> 25% of US Grain Crop Used for Biofuel tag:www.synthesis.cc,2010://1.315 2010-01-23T01:36:11Z 2010-01-23T01:55:23Z Rob Carlson 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.
]]> Good Climate Data, Bad Climate "Data" -- Science Always Wins. tag:www.synthesis.cc,2010://1.314 2010-01-19T21:37:10Z 2010-01-19T23:48:26Z This week brings news of 1) a dramatic improvement in the estimates of how soil carbon content is related to atmospheric carbon concentration and 2) the exposure of some really crappy work on the rate of melting of Himalayan glaciers... Rob Carlson
First up, a paper from this week's PNAS by Breeker et al at UT Austin, "Atmospheric CO2 concentrations during ancient greenhouse climates were similar to those predicted for A.D. 2100".  Already from the title you can see where this is going.

The problem Breeker and colleagues address is the following: how do you correlate the carbon content of fossil soils with prevailing atmospheric carbon dioxide concentrations?  Well established methods exist for measuring the carbon content of compounds in fossil soil, but less certain were conditions under which chemical reactions produce those particular compounds.  It turns out that model used to infer atmospheric CO2 contained an error.  Breeker determined that the primary compound assayed when determining soil carbon content forms at much lower atmospheric CO2 concentrations than had been assumed.

Prior attempts to correlate soil carbon (and by proxy atmospheric CO2) with greenhouse periods in Earth's climate had concluded that warm periods experienced CO2 concentrations of much greater than ~1000 parts per million (ppm).  Therefore, one might conclude that only when average atmospheric CO2 spiked above this level would we be in danger of experiencing greenhouse gas warming that threatened glaciers.  The correction supplied by Breeker substantially lowers estimates of the average CO2 concentration that is correlated with continental glacial melting.  Eyeballing the main figure in the paper, it looks to me like we could be in real trouble above 450 ppm -- today we are at just shy of 390 ppm and there is no sign we will be slowing down anytime soon, particularly if India and China keep up their pace of development and emissions.

Looking forward to 2100, things get a touch squiffy because Breeker relies on an estimate of CO2 concentrations that come out of model of global economic activity.  So the title of the paper might be a tad alarmist, simply because 2100 is a long way out for any model to be taken too seriously.  But the correction of the paleodata is a big story because at minimum it reduces the uncertainty of atmospheric CO2 levels, and it appears to clarify the connection between CO2 levels and continental glaciation.  More work is needed on the later point, obviously, or this paper would have been on the cover of Science or Nature.

Now on to a serious screw-up at the IPCC.  Elisabeth Rosenthal at the NYT is reporting that "A much-publicized estimate from a United Nations panel about the rapid melting of Himalayan glaciers from climate change is coming under fire as a gross exaggeration."  Here is Andrew Revkin's take on DotEarth, and anyone interested in this story should read through his post.  The comments are worth perusing because some of the contributors actually seem to have additional useful knowledge, though, of course, nut jobs aplenty show up from both sides of the debate over climate change.

In a nutshell, the issue is that the most recent IPCC chapter on glaciers contained a conclusion, advertised as real analysis, that was in fact a speculation by one scientist promulgated through the popular press.  The authors of that section of the IPCC report may have been warned about the unsubstantiated claim.  Contradictory data and analysis seems to have been ignored.

So, to be frank, this is a giant, inexcusable fuck-up.  The IPCC is composed of so many factions and interest groups that this may be a case of simple blundering or of blatant politicization of science.  But here is the beautiful thing about science -- it is self-correcting.  It may take a while, but science always wins.  (See also my post of a couple of years ago, Dispelling a Climate Change Skeptic's "Deception".)  Every newspaper story I have seen about this particular IPCC screw-up notes that it was brought to light by...wait for it...a climate scientist.  It is an excellent public airing of dirty laundry by the community of science.  So while this episode demonstrates that the last official IPCC report on glacial melting in the Himalayas should not be used for any sort of scientific policy recommendation or economic forecast, you can bet that the next report will do a damn fine job on this topic. 

Finally, whether or not the IPCC gets its act together, there are plenty of good data out there on the state of the planet.  Eventually, Science -- with a capital S -- will get the right answer.  The same methodical process that has resulted in computers, airplanes, and non-stick fry pans will inevitably explain what is really going on with our climate.  And if you use computers, fly on airplanes, or eat scrambled eggs then you are implicitly acknowledging, whatever your political or religious persuasion, that you believe in science.  And you better, 'cause science always wins.
]]> Video from The Economist's World in 2010 Festival tag:www.synthesis.cc,2010://1.312 2010-01-07T19:50:37Z 2010-01-07T19:58:50Z Rob Carlson 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.
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