Microsoft Supports Biobricks

Last weekend at the 2006 International Genetically Engineered Machines Competition (iGEM 2006), Microsoft announced a Request For Proposals related to Synthetic Biology.  According to the RFP page:

Microsoft invites proposals to identify and address computational challenges in two areas of synthetic biology. The first relates to the re-engineering of natural biological pathways to produce interoperable, composable, standard biological parts. Examples of research topics include, but are not limited to, the specification, simulation, construction, and dissemination of biological components or systems of interacting components. The second area for proposals focuses on tools and information repositories relating to the use of DNA in the fabrication of nanostructures and nanodevices. In both cases, proposals combining computational methods with biological experimentation are seen as particularly valuable.

The total amount to be awarded is $500,000. 

"Smallpox Law Needs Fix"

ScienceNOW Daily News is carrying a short piece on the recommendation by the National Science Advisory Board on Biosecurity (NSABB) to repeal a law that criminalizes synthesis of genomes 85% similar to smallpox.

The original law, which surprised everyone I have ever talked to about this topic, was passed in late 2004 and wasn't written about by the scientific press until March of '05:

The new provision, part of the Intelligence Reform and Terrorism Prevention Act that President George W. Bush signed into law on 17 December 2004, had gone unnoticed even by many bioweapons experts. "It's a fascinating development," says smallpox expert Jonathan Tucker of the Monterey Institute's Center for Nonproliferation Studies in Washington, D.C.

...Virologists zooming in on the bill's small print, meanwhile, cannot agree on what exactly it outlaws. The text defines variola as "a virus that can cause human smallpox or any derivative of the variola major virus that contains more than 85 percent of the gene sequence" of variola major or minor, the two types of smallpox virus. Many poxviruses, including a vaccine strain called vaccinia, have genomes more than 85% identical to variola major, notes Peter Jahrling, who worked with variola at the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland; an overzealous interpretation "would put a lot of poxvirologists in jail," he says.

According to the news report at ScienceNOW:

Stanford biologist David Relman, who heads NSABB's working group on synthetic genomics, told the board that "the language of the [amendment] allows for multiple interpretations of what is actually covered" and that the 85% sequence stipulation is "arbitrary." Therefore, he said, "we recommend repealing" the amendment.

Relman's group also recommended that the government revamp its select agents list in light of advances in synthetic genomics. These advances make it possible to engineer biological agents that are functionally lethal but genomically different from pathogens on the list. The group's recommendations, which were approved unanimously by the board, are among several that the board will pass on to the U.S. government to help develop policies for the conduct and oversight of biological research that could potentially be misused by terrorists.

DNA Vaccines Update and Avian Flu Tidbits

There has been serious progress recently in developing DNA vaccines for pandemic influenza.  First, Vical just announced (again by press release and conference presentation, rather than peer reviewed publication) single dose protection of mice and ferrets against a lethal challenge with H5N1 using a trivalent DNA vaccine.  Ferrets are seen by many as the best model for rapid testing of vaccines destined for use in humans.  According to the press release:

"We are excited by the recent advances in our pandemic flu vaccinedevelopment program," said Vijay B. Samant, President and Chief Executive Officer of Vical. "Earlier this week, we presented data from mouse studies demonstrating the dose-sparing ability of our Vaxfectin(TM) adjuvant when used with conventional flu vaccines. Today we presented data from ferret studies demonstrating the ability to provide complete protection with a single dose of our Vaxfectin(TM)-formulated avian flu DNA vaccine. Our goal is to advance into human testing with this program as quickly as possible, both to provide a potential defense against a pandemic outbreak and to explore the potential for a seasonal flu vaccine using a similar approach."

Mr. Samant will be attending the bio-era H5N1 Executive Round table in Cambridge in a few weeks, along with Dr. David Nabarro, the Senior UN System Coordinator for Avian and Human Influenza.  I'm looking forward to finally meeting these gentlemen in person.

Powdermed is in early human clinical trials for its annual and pandemic flu DNA vaccines in the U.K. and the U.S., and has recently been acquired by Pfizer.  This should provide needed cash for trials, technical development, and perhaps even for building a manufacturing facility for large scale production of their proprietary needle free injection system.  I think it is interesting that a large pharmaceutical company -- a specialty chemicals company, in essence -- has acquired technology that is essentially a chemical vaccine.  I wonder if Pfizer can lend expertise to packaging and DNA synthesis.

Despite progress in the lab and greater funding, there are still significant challenges in getting these vaccines into the clinic.  Here is the DNA Vaccine Development: Practical Regulatory Aspects slide presentation from the NAIAD.  Obviously, lots of work to do there.  And as I have written about previously, it doesn't appear that the FDA is really interested in allowing new technologies to fairly compete, even if they are the best option for rapid manufacture and deployment as countermeasures for pandemic flu.

In other DNA vaccine news, a recent paper in PNAS demonstrated, "Protective immunity to lethal challenge of the 1918 pandemic influenza virus by vaccination."  Kong, et al., showed that, "Immunization with plasmid expression vectors encoding hemagglutinin (HA) elicited potent CD4 and CD8 cellular responses as well as neutralizing antibodies."  Here is more coverage from Effect Measure, which notes that the paper is primarily interesting as a study of the mechanism of DNA immunization in mice against the 1918 virus.

However, if I understand the paper correctly, the authors developed a means to directly correlate the effect of  immunization with antibody production and thereby, "define [the vaccine's] mechanism of action".  This appears to be a significant step forward in understanding how DNA vaccines work.  I interviewed Vijay Samant of Vical by phone a few months ago, and he noted that because animal studies demonstrate complete protection even though traditional measures of immunity do not predict that result, he has a hunch that "tools for measuring immunogenicity for DNA will need to be different than for measuring protein immunogenicity."  Perhaps the results of Kong, et al., point the way to just such a new tool.

An upcoming Nature paper by Micheal Katze, just down the hill here in the UW Medical School, elucidates some of the mechanisms behind the extraordinary lethality of the 1918 virus in mice.  Writing in Nature, Kash, et al., show that:

...In a comprehensive analysis of the global host response induced by the 1918 influenza virus, that mice infected with the reconstructed 1918 influenza virus displayed an increased and accelerated activation of host immune response genes associated with severe pulmonary pathology.  We found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until death on day 5.

In other words, the immune response to infection with the 1918 virus contributed to mortality.  Moreover, "These results indicated a cooperative interaction between the 1918 influenza genes and show that study of the virulence of the 1918 influenza requires the use of the fully reconstructed virus."  That is, you have to be able to play with the entire reconstructed bug in order to figure out why it is so deadly.  And this result gives an interesting context to the recent paper of Maines, et al., demonstrating that reassortant viruses of the present H5N1 and lesser strains are not as fearsome as the complete H5N1 genome (which I wrote about a few weeks ago).  This latter observation has been interpreted in the press as evidence that H5N1 is "not set for pandemic", even though H5N1 is demonstrably changing in nature primarily by mutation rather than by swapping genes.  H5N1 is quite deadly, and it may simply be that the particular combination of evolving genes in H5N1 gives it that special something.

Finally, an upcoming paper in J. Virology demonstrates an entirely new antiviral strategy based on peptides that bind to HA proteins in vivo and thereby prevent viral binding to host cells.  "Inhibition of influenza virus infection by a novel antiviral peptide," by Jones, et al., at the University of Wisconsin, appears to still be in pre-press.

In the abstract the authors state:

A 20-amino acid peptide (EB) derived from the signal sequence of fibroblast growth factor-4 exhibits broad-spectrum antiviral activity against influenza viruses including the H5N1 subtype in vitro. The EB peptide was protective in vivo even when administered post-infection. Mechanistically, the EB peptide inhibits the attachment to the cellular receptor preventing infection. Further studies demonstrated that the EB peptide specifically binds to the viral hemagglutinin (HA) protein. This novel peptide has potential value as a reagent to study virus attachment and as a future therapeutic.

This is just an initial demonstration, but it is extremely interesting nonetheless.  However, because it is a protein based drug, it risks generating an immune response against the drug itself.  It will have to be administered in a way that preserves function in vivo in humans and doesn't spook the immune system.  The last thing you want to do is generate antibodies against a protein vital for human health.

Yet, precisely because it is a fragment of a human protein, it might mean there is a lower risk of generating that immune response, especially if it can be produced in a way that has all the right post-translational modifications (glycosylation, etc).  Though I wonder about variation in the population: various alleles and SNPs.  What if you are given a version of the peptide that differs in sequence from the one you are carrying around?  Would this generate an immune response against the drug even though it is closely related to something you carry naturally, and if so would those antibodies also pick out your allele?  Definitely the potential for bad juju there.  Another example of where personalized medicine, and having your genome sequence in your file, might be handy.  Alternatively, I suppose you could just use your own sequence for the peptide, and have the thing synthesized in vitro for use as a personalized drug.  Sequence --> DNA synthesis --> in vitro expression --> injection.  Hmmm...you could probably already stuff all that technology in a single box...

However it is used, this advance is probably a very long way from the clinic.  It might go faster if they use the peptide as inspiration for a non-protein drug, which, incidentally, the authors suggest near the end of the paper.  Definitely a high-tech solution, either way, but probably the wave of the future.

Daily Outbreak Forecast

A few days ago, Wired News carried a story by Sean Captain about the Healthmap project, a mash-up of Google Maps and various disease reporting services:

The new Healthmap website digestsinformation from a variety of sources ranging from the World Health Organization to Google News and plots the spread of about 50 diseases on a continually updated global map. It was developed as a side project by two staffers at the Children's Hospital Informatics Program in Boston -- physician John Brownstein and software developer Clark Freifeld.

This follows on Declan Butler's Avian Flu Mashup.  Both efforts encountered significant issues with data formats and parsing the trustworthiness of various data sources.

The Wired News story starts out with this lead: "Web-based maps are handy for keeping tabs on weather and traffic, so why not for disease outbreaks, too?"  And the title is "Get Your Daily Plague Forecast," which. because it is a tad trite, I find rather ironic because a recent PNAS paper demonstrates that, "Plague dynamics are driven by climate variation."

Stenseth, et al., studied the prevalence of Yersinia pestis in the primary host animal, gerbils, as a function of average temperature over 45 years in Central Asia.  They find that ,"A 1°C increase in spring is predicted to lead to a >50% increase in prevalence."  The virus causes bubonic plague in humans, and transmission from rodents to humans is thought to be the main route into the human population.  The authors note in the abstract that:

Climatic conditions favoring plague apparently existed in this region at the onset of the Black Death as well as when the most recent plague pandemic arose in the same region, and they are expected to continue or become more favorable as a result of climate change. Threats of outbreaks may thus be increasing where humans live in close contact with rodents and fleas (or other wildlife) harboring endemic plague.

And as a cheery final note, they conclude that:

Our analyses are in agreement with the hypothesis that the Medieval Black Death and the mid-19th-century plague pandemic might have been triggered by favorable climatic conditions in Central Asia.  Such climatic conditions have recently become more common and whereas regional scenarios suggest a decrease in annual precipitation but with increasing variance, mean spring temperatures are predicted to continue increasing.  Indeed, during the period from the 1940s, plague prevalence has been high in its host-reservoir in Kazakhstan. Effective surveillance and control during the Soviet period resulted in few human cases. But recent changes in the public health systems, linked to a period of political transition in Central Asia, combined with increased plague prevalence in its natural reservoir in the region, forewarn a future of increased risk of human infections.

The combination of climate influences on the prevalence of infectious disease, documented climate change over the last few decades, and the rise of megacities is something we definitely need to watch.

And all this time I was so worried about the flu...

Oh Goody -- Prizes for Genomes!

But seriously folks...it's good news that prizes are being posted for biological technologies.  A couple of weeks ago, the X Prize Foundation announced a $10 million prize for demonstration of "technology that can successfully map 100 human genomes in 10 days."  This is not the first such offer; Nicholas Wade notes in the New York Times that Craig Venter set up a $500,000 prize in 2003 for achieving the Thousand Dollar Genome.  Venter is now on the board of the X Prize Foundation and it appears his original prize has been expanded into the subject of the current announcement.  We definitely need new ways to fund development of biological technologies.

Here's more coverage, by Antonio Regalado in the Wall Street Journal.  It will be interesting to see if anyone can come up with a way to make a profit on the $10 million prize.

The prize requires sequencing roughly 500 billion bases in 10 days.  It isn't possible to directly compare the prize specs with my published numbers since there is no specification on the number of people involved in the project.  If you throw a million lab monkeys running a million low tech sequencers at the problem, you're set.  Except, of course, for all the repeats, inversions, and rearrangements that require expertise to map and sort out.

According to a news story by Erika Check in Nature, the performance numbers cited by 454 Life Sciences appear to be encouraging: "Using the 454 technique, one person using one machine could easily sequence the 3 billion base pairs in the human genome in a hundred days, [Founder and CEO Jonathan Rothberg] says," which is about 3.75 million bases per person per day.  And he is optimistic about progress in reducing costs:  "As the process gets faster, it gets less expensive. "It's clear that we'll be able to do this much cheaper," predicts Rothberg, who says that in the next few years scientists will be able to assemble a human genome for US$10,000."  At the present pace of improvement, this looks to be about 2015, though new technology could always get there sooner.

There seems to be some divergence of expert opinion about where a winning technology will come from.  Writing in Science, Elizabeth Pennisi, notes:

Charles Cantor, chief scientific officer of SEQUENOM Inc. in San Diego, California, predicts only groups already versed in sequencing DNA will have a chance at the prize. Others disagree. "I think it is unlikely" that the winner will come from the genome-sequencing community, says Leroy Hood, who invented the first automated DNA sequencer. And Venter predicts that the chance that someone will come out of the woodwork to scoop up the $10 million is "close to 100%." The starting gun has sounded. 

Indeed.  I had sworn off thinking about new sequencing technologies, but the prize has got even me to thinking...

Avian Flu Catchup, 20 Sept 06.

Here are some comments about the GSK adjuvant announcement, the expansion of vaccine candidates by the WHO, H5N1 evolution in the lab and in the wild, and sequence data sharing.

GlaxoSmithKline announced recently that through the use of a proprietary adjuvant they have dramatically reduced the amount of egg-grown vaccine required to produce a decent antibody response in humans. 

A news story at CIDRAP explains that, "The GSK vaccine was made from an inactivated H5N1 virus collected in Vietnam in 2004, according to Jennifer Armstrong, a GSK spokeswoman in Philadelphia," and then notes that, "It is uncertain, however, how effective the vaccine would be against H5N1 strains other than the one it was made from. [Albert Osterhaus of Erasmus Unversity in the Netherlands] told the AP, "This vaccine will only give protection against this particular H5N1 strain and possibly other strains.""

This last statement may be true, but in my view it may also give false hope.  Aside from criticisms others have raised about GSK announcing science by press release, instead of waiting until a publication is ready, or alternatively just releasing the data, we already know that there are H5N1 variants in the wild that kill humans but don't cross prime immune systems.

In response to this development, the WHO recently advised work begin on vaccines based on clade 2 isolates from Indonesia.  (Here is CIDRAP's take, and here is the original WHO announcement.)  Note that this does not mean we will immediately have vaccines in production against these isolates; as far as I know the reference vaccine is still solely based on the original Vietnamese isolate.

As is fairly widely understood at this point, it is not at all clear that vaccines made from either the Vietnamese or Indonesian isolates will protect humans against potential pandemic strains that arise in nature.  Some effort at discerning the threat from certain potential strains was reported in PNAS in early August.  A news story in Nature describes the results with the headline, "Bird flu not set for pandemic, says US team" (subscription req.).

I find that headline very confusing, because the work in question has very little to do with whether H5N1 is "set for [a] pandemic."  Instead, the research explored the effects on ferrets of a exposure to a small number of recombinant viruses consisting of components from H5N1 and H3N2.  The text following the headline is clearer: "The scientists who conducted the work, at the [CDC], say it suggests that the H5N1 virus will require a complex series of genetic changes to evolve into a pandemic strain...  The study [does not] address whether H5N1 could evolve into a pandemic strain by accumulating mutations."

In fact, only very limited conclusions can be drawn from the paper in question, "Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model" (Mains, et al., PNAS, vol 103, no 32).  The first and last paragraphs of the discussion section show the authors are relatively circumspect in interpreting the data:

If H5N1 viruses acquire the ability to undergo efficient and sustained transmission among humans, a pandemic would be inevitable. An understanding of the molecular and biologic requirements for efficient transmissibility is critical for the early identification of a potential H5N1 pandemic virus and the application of optimal control measures. The results of this study demonstrate, that unlike human H3N2 viruses, avian H5N1 viruses isolated from humans in 1997, 2003, or 2005 lack the ability to transmit efficiently in the ferret model. Furthermore, reassortant viruses bearing 1997 avian H5N1 surface glycoproteins with four or six human virus internal protein genes do not transmit efficiently in ferrets and thus lack the key property that predicts pandemic spread.

Although these findings do not identify the precise genetic determinants responsible for influenza virus transmissibility, they provide an assessment of the risk of an H5N1 pandemic strain emerging through reassortment with a human influenza virus. Our results indicate that, within the context of the viruses used in this study, H5N1 avian-human reassortant viruses did not exhibit properties that would initiate a pandemic. Nevertheless, H5N1 viruses continue to spread geographically, infect a variety of mammals, and evolve rapidly. Therefore, further evaluation of the efficiency of replication and transmissibility of reassortants between contemporary H5N1 viruses and circulating human influenza viruses is an ongoing public health need. The ferret transmission model serves as a valuable tool for this purpose and the identification of molecular and biologic correlates of efficient transmissibility that may be used for early detection of a novel virus with pandemic capability.

It is certainly true that this sort of work is vital for figuring out how influenza works, and in particular vital for trying to sort out how reassortant viruses arise, how they change during passage between animals, and how they kill mammals.  Reassortment was historically important in some flu pandemics.  However, the genetic changes seen in nature in the present H5N1 outbreak appear to be solely due to mutation.  In particular, a cluster of cases in Indonesia in April and May -- the first clear example of human-to-human transmission of H5N1, according to the WHO -- allows tracking sequence changes between viruses that infected eight family members.

In "Family tragedy spotlights flu mutations" (subscription req.), Declan Butler writes that;

Viruses from five of the cases had between one and four mutations each compared with the sequence shared by most of the strains. In the case of the father who is thought to have caught the virus from his son -- a second-generation spread -- there were twenty-one mutations across seven of the eight flu genes. This suggests that the virus was evolving rapidly as it spread from person to person.

[While] many of the genetic changes did not result in the use of different amino acids by the virus...experts say they cannot conclude that the changes aren't significant. "It is interesting that we saw all these mutations in viruses that had gone human-to-human," says one scientist who was present at the Jakarta meeting but did not wish to be named because he was commenting on confidential data. "But I don't think anyone knows enough about the H5N1 genome to say how significant that is."

So there is considerable mutation occurring, even between viruses present in different family members, and we don't yet know enough about H5N1 in humans to say whether this is significant with respect to evolving into a pandemic strain.  But even more interesting, there are so many differences between the viruses that they look like different clades.  Again, from Dr. Butler:

Elodie Ghedin, a genome scientist at the University of Pittsburgh School of Medicine in Pennsylvania, says she's surprised that the virus from the father had so many mutations compared with others in the cluster, apparently arising in just a few days. "I have a hard time believing that the father acquired the virus from his son," she says, adding that the nine mutations in one gene in the father's virus are almost identical to those in viruses isolated from human cases in Thailand and Vietnam in 2004.

One possibility is that the father simply caught a different strain of virus from birds, although other mutations in his virus are similar to those in the strain isolated from his son. Or perhaps the virus from the son reassorted with another flu strain circulating in his father at the time, Ghedin says.

Perhaps, but it would seem that if the father was also carrying a virus from Thailand or Vietnam that there should be signs in birds or other humans.  I was unable to find out whether the father was in a position to pick up a virus from another clade, which would be a good check on the likelihood of reassortment.

Dr. Butler goes on to note that a simple lack of information is a significant factor in the slow progress:

Part of the reason the picture is so unclear, say virologists contacted by Nature, is that the continued withholding of genetic data is hampering study of the virus. None of the sequence data from the Indonesian cluster has been deposited in public databases -- access is restricted to a small network of researchers linked to the WHO and the US Centers for Disease Control and Prevention in Atlanta, Georgia.

Fortunately, this has changed and the Global Initiative on Sharing Avian Influenza Data (GISAID) is now in place.  I'll have something more later on the sharing plan after I digest all the information.  It looks like a nice step forward, but, as always, we'll have to see what comes of it.

Vaccine Development as Foreign Policy

I was fortunate to attend Sci Foo Camp last month, run by O'reilly and Nature, at the Googleplex in Santa Clara.  The camp was full of remarkable people; I definitely felt like a small fish.  (I have a brief contribution to the Nature Podcast from Sci Foo; text, mp3.)  There were a great many big, new ideas floating around during the weekend.  Alas, because the meeting was held under the Chatham House Rule, I cannot share all the cool conversations I had.

However, at the airport on the way to San Jose I bumped into Greg Bear, who also attended Sci Foo, and our chat reminded me of an idea I've been meaning to write about.

In an essay published last year, Synthetic Biology 1.0, I touched briefly on the economic costs of disease as a motivation for developing cheaper drugs.  Building synthetic biological systems to produce those drugs is an excellent example of the potential rewards of improved biological technologies.

But a drug is a response to disease, whereas vaccines are far and away recognized as "the most effective medical intervention" for preventing disease and reducing the cost and impacts of pathogens.  While an inexpensive drug for a disease like malaria would, of course, be a boon to affected countries, drugs do not provide lasting protection.  In contrast, immunization requires less contact with the population to suppress a disease.  Inexpensive and effective vaccines, therefore, would provide even greater human and economic benefit.

How much benefit?  It is extremely hard to measure this sort of thing, because to calculate the economic effect of a disease on any given country you have to find a similar country free of the disease to use as a control.  A report released in 2000 by Harvard and the WHO found that, "malaria slows economic growth in Africa by up to 1.3% each year."  The cumulative effect of that hit to GDP growth is mind-blowing:

...Sub-Saharan Africa's GDP would be up to 32% greater this year if malaria had been eliminated 35 years ago. This would represent up to $100 billion added to sub-Saharan Africa's current GDP of $300 billion. This extra $100 billion would be, by comparison, nearly five times greater than all development aid provided to Africa last year.

The last sentence tells us all we need to know about the value of a malaria vaccine; it could advance the state of the population and economy so far as to swamp the effects of existing foreign aid.  And it would provide a lasting improvement to be built upon by future generations of healthy children.

The economic valuation of vaccines is fraught with uncertainty, but Rappuoli, et al., suggest in Science that if, "policymakers were to include in the calculation the appropriate factors for avoiding disease altogether, the value currently attributed to vaccines would be seen to underestimate their contribution by a factor of 10 to 100."  This is, admittedly, a big uncertainty, but it all lies on the side of underestimation.  And the point is that there is some $20 Billion annually spent on aid, where a fraction of it might be better directed towards western vaccine manufacturers to produce long term solutions.

Vaccine incentives are usually discussed in terms of guaranteeing a certain purchase volume (PDF warning for a long paper here discussing the relevant economics).  But I wonder if we shouldn't re-think government sponsored prizes.  This strategy was recently used in the private sector to great effect and publicity for the X-Prize, and its success had led to considering other applications of the prize incentive structure.

Alas, this isn't generally considered the best way to incentivize vaccine manufacturers.  The Wikipedia entry for "Vaccine" makes only passing reference to prizes for vaccine development.  A 2001 paper in the Bulletin of the World Health Organization, for which a number of experts and pharmaceutical companies were interviewed about ways to improve AIDS vaccine development, concluded, "It was felt that a prize for the development of an AIDS vaccine would have little impact. Pharmaceutical firms were in business to develop and sell products, not to win prizes."

But perhaps the problem is not that prizes are the wrong way to entice Big Pharma, but rather that Big Pharma may not be the right way develop vaccines.  Perhaps we should find a way to encourage a business model that aims to produce a working, safe vaccine at a cost that maximizes profit given the prize value.

So how much would developing a vaccine cost?  According to a recent short article in Nature, funds devoted to developing a malaria vaccine amounted to a whopping measly $65 million in 2003.  The authors go on to to note that, "At current levels, however, if a candidate in phase II clinical trials demonstrated sufficient efficacy, there would be insufficient funding available to proceed to phase III trials."

It may be that The Gates Foundation, a major funder of the malaria work, would step in to provide sufficient funds, but this dependency doesn't strike me as a viable long-term strategy for developing vaccines.  (The Gates Foundation may not be around forever, but we can be certain that infectious disease will.)  Instead, governments, and perhaps large foundations like The Gates, should set aside funds to be paid as a prize.  What size prize?  Of the ~$1-1.5 Billion it supposedly costs to develop a new drug, ~$250 million goes to marketing.  Eliminating the need for marketing with a prize value of $1.5 Billion would provide a reasonable one time windfall, with continued sales providing more profit down the road.

Setting aside as much as $200 million a year would be a small fraction of the U.S. foreign aid budget and would rapidly accumulate into a large cash payout.  Alternatively, we could set it up as a yearly payment to the winning organization.  Spread the $200 million over multiple governments (Europe, Japan, perhaps China), and suddenly it doesn't look so expensive.  In any event, we're talking about a big payoff in both saving lives and improving general quality of life, so a sizable prize is warranted.  I expect $2 Billion is probably the minimum to get international collaborations to seriously compete for the prize.

The foreign policy aspects of this strategy fit perfectly with the goals of the U.S. Department of State to improve national security by reducing poverty abroad.  Here is Gen. Colin Powell, reprinted from Foreign Policy Magazine in 2005 ("No Country Left Behind"):

We see development, democracy, and security as inextricably linked. We recognize that poverty alleviation cannot succeed without sustained economic growth, which requires that policymakers take seriously the challenge of good governance. At the same time, new and often fragile democracies cannot be reliably sustained, and democratic values cannot be spread further, unless we work hard and wisely at economic development. And no nation, no matter how powerful, can assure the safety of its people as long as economic desperation and injustice can mingle with tyranny and fanaticism.

Development is not a "soft" policy issue, but a core national security issue. [emphasis added]  Although we see a link between terrorism and poverty, we do not believe that poverty directly causes terrorism. Few terrorists are poor. The leaders of the September 11 group were all well-educated men, far from the bottom rungs of their societies. Poverty breeds frustration and resentment, which ideological entrepreneurs can turn into support for--or acquiescence to--terrorism, particularly in those countries in which poverty is coupled with a lack of political rights and basic freedoms.

Dr. Condoleezza Rice, in opening remarks to the Senate Foreign Relations Committee (PDF warning) during her confirmation hearings, plainly stated, "...We will strengthen the community of democracies to fight the threats to our common security and alleviate the hopelessness that feeds terror."

Over any time period you might care to examine, it will probably cost vastly less to produce a working malaria vaccine than to continue dribbling out foreign aid.  Even just promoting the prize would bolster the U.S. image abroad in exactly those countries where we are hurting the most, and successful development would have profound consequences for national security through the elimination of human suffering.  Seems like a good bargain.  The longer we wait, the worse it gets.

Geoplasma, Plasma Reformation, and Nearly Perfect Recycling

So much for trash.  Plasma conversion is finally coming to the US, according to a story in USA Today.  Why is this worth noting?  Plasma conversion is as close toperfect recycling as we are going to get, at least for the time being.

I looked into this topic extensively a few years ago while working for a consulting firm.  One of our clients was a major auto manufacturer -- to remain nameless -- and I tried to convince the company that their future business model was not exclusively in producing autos, but rather, because of the complexity of introducing new technology and new fuels, in providing "transportation solutions", including hydrogen fuel.  They preferred to keep building petro-powered SUVs.  Perhaps it's time to reconsider that decision.

There's no magic in plasma conversion -- municipal garbage is obviously high in energy.  It is burned rather than stored in many locations.  But plasma reformation is much cleaner than simple incineration.  Trash goes in, and, depending on its composition and energy content, electricity, refined metals, and purified gases come out.  There's no snake oil here; the physics and chemistry work.  The only waste product from reformation consists of silicates, which so far can only be used for building roads and as abrasives for grinding wheels.  The volume of waste, including CO2,  is also much smaller compared to incineration since all the good stuff is reused.

As far as I can tell from the USA Today story, with its limited technical information and references to plasma conversion facilities up and running in Japan, Geoplasma is licensing technology from Startech Environmental Corp for a plant to be built in St. Lucie County, Florida.  Just guessing, though.  Presently, the Geoplasma website consists only of a long video clip that I didn't bother to watch.

(UPDATE - 22 Sept 06 :: Crinu Baila, a Senior VP at Geoplasma, wrote to tell me the following:

Westinghouse Plasma Corporation (WPC) plasma arc technology will be utilized in the Florida project.

WPC’s plasma arc units are reliable, rugged and have amassed close to 500,000 hours of operation in industrial environments.

In addition WPC has coupled the plasma arc units with a robust Plasma Gasification Vessel (PGV) that has the proven capability to process a wide variety of waste materials.

The combined plasma units/PGVs have been used in three commercial applications in Japan.

I don't know if the recycling capabilities I mention in this post are as easy with the WPC units as with the Startech plasma converters, but getting this technology into the market is progress, nonetheless.)

They economics of plasma conversion are compelling.  Getting rid of trash is expensive.  New York City spends somewhere in the neighborhood of $500 million a year exporting its garbage, depending on how you count it up.  The combination of plasma conversion and hydrogen production is especially interesting if you consider the applications to distributed hydrogen production to fuel vehicles.  Here are tidbits from a report I wrote some years ago:

Hydrogen fuel cell powered automobiles are expected to enter production by 2010.  While engineering and production issues associated with the new technology will by definition be solved by the date of introduction, hydrogen fuel itself may not be easy to come by, perhaps limiting sales.  Development of a centralized hydrogen production and distribution capability analogous to today’s petroleum infrastructure would no doubt be extraordinarily expensive, but this investment may not be necessary.   Hydrogen locked up in municipal waste streams can be locally harvested in a distributed system for both stationary and automotive fuel cell use.

A Plasma Converter and gas purifier system from Startech Environmental can produce ~43 liters of hydrogen for each kilogram of municipal trash with a net surplus of energy.  New York City exports ~5.5 million kg (12,000 tons) of trash a day at an annual cost approaching $500 million dollars.  Three years worth of this export cost could be used to purchase sufficient plasma conversion infrastructure to fuel several hundred thousand cars per day from NYC’s trash.  Introduction of this technology could be aided by focusing on fleet operation such as taxicabs, police vehicles, buses, or the military.  Similar opportunities are present in other metropolitan areas, and markets, beyond NYC and will provide a short cut to providing hydrogen for fuel cell powered automobiles.

Yeah, yeah -- I know, switching over to the hydrogen economy is going to be expensive and take forever.  But not if you pick your battles:

There is a popular argument among detractors of hydrogen as a fuel that the expense of developing infrastructure for the hydrogen economy is prohibitive.  They insist that because hydrogen production and pumping stations will cost many billions of dollars to build, whatever the actual need, the realization of a hydrogen economy is far in the future.  So far in the future, so the argument goes, that we need not plan for such an eventuality at all.

The most significant error in this argument is its root premise, that a hydrogen economy is somehow foreign, unfamiliar, and ultimately too expensive.  Quite the contrary, we do not need to develop a hydrogen economy because we already have one.  The challenge is not to build a hydrogen infrastructure from scratch but to better harvest widely distributed energy and hydrogen that we now treat as waste.

A majority of industrial processes in the current economy work by shuttling hydrogen atoms amongst other molecules.  The most obvious of these processes is the burning of hydrocarbons, either for transportation or for the manufacture of other goods, where energy stored in the hydrocarbons is essentially transferred to the finished article or substance.  As a result, many manufactured products contain high energy chemical bonds, and many of those products are thrown out as whole objects.  The stored energy is thus also thrown away.  This trash is highly distributed and its conversion from valued good to waste is most concentrated near population centers.  Considerable further resources are then expended in transporting the waste elsewhere.

According to the New York City municipal budget, for example, the City spends ~$300 million per year to transport ~12,500 tons (5.7 million kg) of municipal waste a day to distant sites (this is in addition to the cost of local waste collection and transfer).  The City’s businesses generate an equivalent daily amount, which is collected by private companies.  This brings the total daily trash output of NYC to approximately 25,000 tons.  The City spends another ~$20 million a year for local “landfill monitoring and leachate control.”  The Economist estimates the total cost of exporting the City’s trash at closer to half a billion dollars a year.  There is clearly an economic opportunity if alternative disposal means can be found.

Even if you ignore the sale of recycled metals and gases, there is significant opportunity in providing fleet vehicles and hydrogen fuel for those vehicles;

“Plasma Conversion” is a process developed by Startech Environmental, of Wilton CT, in which plasma at 30,000° F is used to degrade waste, chemical weapons, etc.  The plasma provides an excess of electrons that chemically reduce complex compounds to their constituent elements.  In effect, a Plasma Converter runs backward the chemical reactions that produced the material in the waste.

Municipal waste is sufficiently energy dense to produce more chemical and electrical energy than is used to “convert” the waste.  Thus some of the recovered energy can be used to run the Plasma Converter.  More relevant for the purposes of this report, Startech has refined the process, with the aid of a ceramic filter, to produce ~7 ft3 of hydrogen gas at 99.999% purity from each pound of garbage (~43 L of hydrogen for each kg of trash).  The volume of trash produced by NYC public services could thus be processed to provide ~235 million L of hydrogen a day.  Adding the privately collected waste would double this amount.  Processing municipal waste from other metropolitan areas could reasonably be expected to produce hydrogen volumes in proportion to their population.

Startech is currently advertising units that process between 5 and 100 tons per day, which cost between $2.5 million and $12.5 million respectively.  Thus for the cost of 4 years worth of trash export fees, ~$1.3 billion, the infrastructure could be assembled to process all of New York City’s municipal trash into raw materials.  Pure hydrogen could be separated for use in fuel cells, and other materials sold to industry.  Trash is currently trucked from local pick-up points to several waste transfer stations.  Trash is then packed in sealed trucks for export.  The export step could be eliminated by locating plasma converters at waste transfer stations.  The one time infrastructure cost could be paid up front or amortized, and the operational costs would certainly be less than continuing trash export fees and would be offset by sales of hydrogen and raw materials.  A single technician can run a plasma converter, and with so many units in one place automation could enable one person to shepherd several units.

The utility of this recovered hydrogen can be estimated by calculating how many vehicles it can power.  The 2002 Hydrogen Fuel Cell powered Ford Focus test bed runs at ~100km/hr for approximately 400 km on 1244 L of hydrogen.  Assuming slightly larger average vehicles and consequent lower efficiency, a very conservative estimate is that the daily trash output of NYC could fuel more than 300,000 vehicles a day traveling several hundred kilometers each.  For example, all of the City’s taxicabs and Police cruisers could be run on each day’s supply of hydrogen produced from municipal trash.

If the numbers are so compelling, even just for arbitraging the inefficiency of exporting and caching trash, why isn't this technology popping up all over the U.S.,?  Back in 2003 or so, I had a chat with the CEO of Startech, and their biggest problem was investment in existing infrastructure.  That is, waste management companies, cities, and counties in the U.S., all h ave huge capital investments in garbage gathering, distribution, and disposal, and most of it has yet to be completely amortized.  In order to get into the market, you have to wait for the investment cycle to tick around to the point that equipment and facilities are being replaced.

So, in the end, a battle lost for me.  But only temporarily.  We'll all be mining garbage dumps relatively soon.

Bedroom Biology in The Economist

I have yet to see the print version, but evidently I make an appearance in tomorrow's Economist in a Special Report on Synthetic Biology.  (Thanks for the heads-up, Bill.)  I wasn't actually interviewed for the piece, but I've no objections to the text.  There is an accompanying piece that forecasts the coming "Bedroom Biotech", a phrase they seem to prefer to "Garage Biology".  Personally, I prefer to keep my DNA bashing to the garage rather than the bedroom.  Well, okay, most but not all of my DNA bashing.

The story contains a figure showing data from 2002 on productivity changes in DNA sequencing and synthesis, redrawn from my 2003 paper, "The Pace and Proliferation of Biological Technologies", labeling them "Carlson Curves" once again.  Oh well.  The original paper was published in the journal Biosecurity and Bioterrorism (PDF from TMSI, html version at Kurzweilai.net).  It isn't so much that I disavow the name "Carlson Curve" as I want to assert that quantitatively predicting the course of biological technologies is a questionable thing to do.  As Moore made clear in his paper, what became his law is driven by the financing of expensive chip fabs -- banks require a certain payment schedule before they will loan another billion dollars for a new fab -- whereas biology is cheap and progress is much more likely to be governed by basic science and the total number of people participating in the endeavor.

Newer versions of figures from the 2003 paper, as well as additional metrics of progress in biological technologies, will be available in December with the release of "Genome Synthesis & Design Futures: Implications for the US Economy", written with my colleagues at Bio Economic Research Associates (bio-era), and funded by bio-era and the Department of Energy.

To close the circle, I should explain that the "Carlson Curves" were an attempt to figure out how fast biology is changing, an effort prompted by an essay I wrote for the inaugural Shell/Economist Writing Prize, "The World in 2050."  (Here is a PDF of the original essay, which was published in 2001 as "Open Source Biology and its Impact on Industry.")  I received a silver prize, rather than gold, and was always slightly miffed that The Economist only published the first place essay, but I suppose I can't complain about the outcome.