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

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

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

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

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

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

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

Stem_Cells@Home or DIYStemCells?

I'm in Cambridge, UK, and mostly on local time.  Mostly.  Spring is very pleasant here.

Here are a couple of interesting things that I've come across recently.

The FDA is considering regulating autologous stem cells as prescription drugs.  These cells are removed from a patient, multiplied in culture, and then reintroduced at a site of injury.  The culture step, reportedly, gets the FDA all in a lather with the desire for control.  According to the author of a story at h+ magazine, this could drastically slow down adoption and use, and potentially relegate the the technology to large corporate interests.  The story, and an accompanying interview with a physician, argues that self-regulation of stem cell treatments as a medical practice (which the FDA is not chartered to regulate) is a far better choice.

If the FDA does go the route of asserting (or, rather, attempting to assert) its might, it suggests to me that once again the powers that be are not sufficiently in tune with the progress of technology.  To wit: here is Attila Chordash's homebrew procedure from MAKE for isolating placental stem cells (I met Attila a few years ago at SciFoo and have participated with him in some IFTF activities -- smart fellow).  News this past year has been full of various ways to produce induced pluripotent stem (iPS) cells, ranging from retroviral reprogramming, to drug-controlled lentiviruses, to plasmid-mediated reprogramming. Skin cells were turned into iPSs early in 2008 (here is an earlier summary at Nature Reports Stem Cells).  Last November, a paper in PNAS showed a single synthetic prophage containing 4 genes was sufficient to turn a mouse fibroblast into an iPS cell, and showed that the method could be used to generate human iPS cells from human keratinocytes.  Each of these steps is said to demonstrate an increase the controllability of the reprogramming, increase the uniformity of the resulting population of cells, and decrease the difficulty.

This is not to say that any step in the reprogramming is simple.  From personal experience I can testify that culturing even "stable" human cell lines can be challenging at times.  But, by definition, as published methods to reprogram cells are repeated and refined this will demonstrate a progression from iPS cell production as an art into a technology.  The plasmid-mediated programming, in particular, strikes me as a promising route to a widespread technology because it does not depend upon, or result in, integration of the plasmid into the host chromosome.  Moreover, it will be trivial to synthesize new genes for use in the plasmid as better recipes come along.  So how long before these cells will be used in therapies?

A recent review in Science by Gurdon and Melton identifies some interesting challenges:

The future value of reprogrammed cells is of two kinds. One is to create long-lasting cell lines from patients with genetic diseases, in order to test potentially useful drugs or other treatments. The other is to provide replacement cells for patients. To be therapeutically beneficial, replacement cells will probably need (i) to be provided in sufficient numbers; (ii) to carry out their function, even though they are not normally integrated into host tissues; and (iii) to be able to produce the correct amount of their product.

A human adult has about 10¹⁵ cells, and the liver contains about 10¹⁴ cells. To create this number of cells starting from a 10^-4 success rate of deriving iPS cells from skin would require an enormous number of cell divisions in culture, although the prolonged culture of ES-like cells provides a valuable amplification step. However, many parts of the human body need a far smaller number of cells to improve function. An example is the human eye retina, in which only 10⁵ cells could be of therapeutic benefit.

Will introduced cells be useful even if not "properly" integrated into the host? Most organs consist of a complex arrangement of several different cell types. The pancreas, for example, contains exocrine (acinar) cells, ductal cells, and at least four kinds of hormone-secreting cells in the endocrine islet. Replacement endocrine cells can provide useful therapeutic benefit even if not incorporated into the normal complex pancreas cell configuration. In some cases, introduced cells can have functionally beneficial effects, even if indirectly. It is not yet clear whether introduced cells will be correctly regulated to produce the desired amount of product.

There is obviously a great deal of science to do before iPS cells are used on a regular basis to produce therapies. Nonetheless, therapy is already beginning around the world.  Medical tourism to China for stem cell treatments is increasingly common, even for children.

Clearly, the technology is so promising that families are willing to go to considerable sacrifice to obtain treatment.  Which brings us back to the FDA and regulation.  I have to wonder what the Feds are thinking.  I would certainly agree with anyone who suggests that stem cells are a powerful technology, and that treatments should be safe.  But any regulatory or policy step that reduces access and slows progress in the US is simply going to send people overseas for treatment.  Then, as the technology becomes ever simpler to learn and use, a back-room market will open up in the States.  
 
So, I wonder, as the technology matures, how long before we get DIYStemCells, Stem_Cells@Home, or HomebrewStemCells?  As methods are published to harvest candidate cells and turn them into autologous iPS cells, how long will it be before athletes looking for an edge, the curious, and the truly ill, all start trying this for themselves?  I am by no means arguing that this is a good idea, and I strongly suspect that the better course is to ensure that people have access to the technology through physicians who know what they are doing.  But without that access, a black market, with all of the shadows and horrors envisioned by William Gibson and others, is inevitable.

Wouldn't it be simpler, and vastly safer, to make sure that everyone has access to skills and materials?  This seems like another arena in which pushing for an Open Biology makes a great deal more sense than the alternative.

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.

On the Threat of the 1918 Flu

What do you do when a vanquished but still quite deadly foe reappears?  To further complicate the situation, what if the only way to combat not just that particular foe, but also fearsome cousins who show up every once in a while, is to invite them into your house so as to get to know them better?  Chat.  Suss out their strengths and weaknesses.  Sort out the best way to survive an inevitable onslaught.  This is our situation with the 1918 Influenza virus and and its contemporary Avian relatives

Over the last couple of weeks, several academic papers have been published containing the genomic sequence of the 1918 "Spanish" Flu.  These reports also contained some description of the mechanism behind that flu's remarkable pathogenicity.  (Here is the 1918 Influenza Pandemic focus site at Nature, and here is the Tumpey, et al., paper in Science.)  In response, several high visibility editorials and Op-Ed pieces have questioned the wisdom of releasing the sequence into the public domain.

Notably, Charles Krauthammer's 14 October column in The Washington Post, entitled "A Flu Hope, Or Horror?", suggests:

Biological knowledge is far easier to acquire for Osama bin Laden and friends than nuclear knowledge. And if you can't make this stuff yourself, you can simply order up DNA sequences from commercial laboratories around the world that will make it and ship it to you on demand. Taubenberger himself admits that "the technology is available."

I certainly won't debate the point that biological skills and knowledge are highly distributed (PDF), nor that access to DNA fabrication is widely distributed.  However, while I am sure that Dr. Taubenberger is familiar with the ubiquity of DNA synthesis, I seriously doubt he suggested to anyone that it is easy to take synthetic DNA and from it create live, infectious negative strand RNA viruses such as influenza.  I've written to him, and others, for clarification, just to make sure I've got that part of the story correct.

Krauthammer also asserts that, "Anybody, bad guys included, can now create it," and that, "We might have just given it to our enemies."  These statements border on being inflammatory.  They are certainly inaccurate.  The technology to manipulate flu viruses in the lab has been around for quite a few years, but not many research groups have managed to pull it off, which suggests there is considerable technical expertise required.  (I will clarify this point in my blog as I hear back from those involved in the work.)

The other commentary of note appeared in the 17 October New York Times, "Recipe for Destruction", an Op-Ed written by Ray Kurzweil and Bill Joy.  They call publication of the sequence "extremely foolish":

The genome is essentially the design of a weapon of mass destruction. No responsible scientist would advocate publishing precise designs for an atomic bomb, and in two ways revealing the sequence for the flu virus is even more dangerous.

First, it would be easier to create and release this highly destructive virus from the genetic data than it would be to build and detonate an atomic bomb given only its design, as you don't need rare raw materials like plutonium or enriched uranium. Synthesizing the virus from scratch would be difficult, but far from impossible. An easier approach would be to modify a conventional flu virus with the eight unique and now published genes of the 1918 killer virus.

Second, release of the virus would be far worse than an atomic bomb. Analyses have shown that the detonation of an atomic bomb in an American city could kill as many as one million people. Release of a highly communicable and deadly biological virus could kill tens of millions, with some estimates in the hundreds of millions.

These passages are rife with technical misunderstanding and overheated rhetoric.  My response to Joy and Kurzweil arrived late at the Times, but on the same day a number of other letters made points similar to mine.  For the record, here is my letter:

The Op-Ed by Ray Kurzweil and Bill Joy, celebrated inventors and commentators, is misleading and alarmist.
    The authors overstate the ease of producing a live RNA virus, such as influenza, based on genomic information.  Moreover, their assertion that publishing the viral genome is potentially more dangerous than publishing instructions to build nuclear weapons is simply melodramatic.
    The technology to manipulate and synthesize influenza has been in the public domain for many years.  Yet despite copious U.S. government funds available for such work, only a few highly skilled research groups have demonstrated the capability.  Restricting access to information will only impede progress towards understanding and combating the flu.  Obscuring information to achieve security makes even less sense in biology than in software development or telecommunications, fields Kurzweil and Joy are more familiar with.
    Dealing with emerging biological threats will require better communication and technical ability than we now possess.  Open discussion and research are crucial tools to create a safer world.

Dr. Rob Carlson, Senior Scientist, Department of Electrical Engineering, University of Washington, and Senior Associate, Bio-Economic Research Associates

I was, of course, tempted to go on, but alas the Times limits letters to 150 words.  ("Alas" or "fortunately", depending on your perspective.  Of course, I've no such restriction here.)  Kurzweil and Joy commit the same error as Krauthammer of confounding access to DNA synthesis with producing live RNA virus in the lab.  Fundamentally, however, both the opinion pieces are confused about the threat from a modern release of the 1918 Flu virus.  In a Special Report, Nature described the work by Terrence Tumpey at the CDC to recreate and test the virus:

[Terrence Tumpey] adds that even if the virus did escape, it wouldn't have the same consequences as the 1918 pandemic. Most people now have some immunity to the 1918 virus because subsequent human flu viruses are in part derived from it. And, in mice, regular flu vaccines and drugs are at least partly effective against an infection with reconstructed viruses that contain some of the genes from 1918 flu.

Thus, without minimizing any illness that would inevitably result from release of the original flu virus, the suggestion that any such event would be as deadly as the first go round is inaccurate.  To further clarify the threat, I asked Brad Smith, at the Center for Biosecurity and the University of Pittsburgh Medical Center for some assistance.  He returned, via email, with a story less comforting than that in Nature:

Rob,
       
After speaking with my colleagues DA Henderson and Eric Toner, here are my thoughts on this:
       
The 1918 flu was an H1N1 strain.  The most prevalent seasonal flu strain for the last several decades has been based on H3N2.  Note that there are many flavors of any given H and N type, the hemaglutinin and neauraminidase are constantly mutating and each has a series of antigenic sites.  For example, while the recent predominant seasonal flu has been H3N2, each season it is a slightly different H3N2.  We do retain some residual immunity from last year's H3N2, so we do get sick, but only the weakest that are infected die.  This is the difference between common antigenic drift, and the less common antigenic shift to an entirely new H and N that results in a new pandemic flu strain. (You already know this, but I'm just trying to lay it all out.)
   
H1N1 variants had been major annual strains until the 1957 H2N2 pandemic strain emerged, and has continued as a minor annual strain.  (The H3N2 strain emerged as the 1968 pandemic strain.)  It is accurate that a version of H1N1 is a component of the annual trivalent flu vaccine that we use today and some of the internal proteins of H3N2 strains are derived from H1N1 through reassortment.
       
However, most people in the US born after 1957 have never been exposed to H1N1 in the "wild" and most people do not get flu shots either (in the US or worldwide) - so they would not have been exposed to the H1N1 variant in the vaccine.
       
So, I am not completely sanguine that a reintroduction of the 1918 flu virus into today's relatively naive population would be tempered by some degree of residual immunity.  If there is residual immunity, or some effectiveness of today's vaccine and anti-virals, what would that translate into with respect to a decrease in the numbers of people sick and dying?  1918 flu caused 500,000 deaths in the US and perhaps 50 million deaths worldwide over an amazingly short 18 months.  So, even if only a few percent (relative to what happened in 1918) of the people who are infected by an escaped 1918 flu virus died, the toll would be in the millions.
   
This does not mean that the cost/benefit of studying 1918 flu means it shouldn't be studied, but it certainly isn't as de-fanged as one might hope.

-Brad

Truth be told, the diversity of opinions amongst people well educated on the details means we can't really estimate what would happen if the original virus were released.  So what do we do about the this and other threats?  One answer is to spin up a well-funded effort to improve our technical capabilities.

Echoing Senate Majority Leader Bill Frist, Joy and Kurzweil go on call in their Op-Ed for "a new Manhattan Project to develop specific defenses against new biological viral threats, natural or human made."  This is fine and all, but the Manhattan Project is decidedly the wrong model for an effort to increase biological security.  Far better as a metaphor is the Apollo Program; massive and effective but relatively open to public scrutiny.  Quoting briefly from my 2003 paper on how to improve security amidst the proliferation of biological technologies:

Previous governmental efforts to rapidly develop technology, such as the Manhattan and Apollo Projects, were predominantly closed, arguably with good reason at the time. But we live in a different era and should consider an open effort that takes advantage of preexisting research and development networks. This strategy may result in more robust, sustainable, distributed security and economic benefits.  Note also that though both were closed and centrally coordinated, the Manhattan and Apollo Projects were very different in structure. The Apollo Project took place in the public eye, with failures plainly writ in smoke and debris in the sky. The Manhattan Project, on the other hand, took place behind barbed wire and was so secret that very few people within the US government and military knew of its existence. This is not the ideal model for research that is explicitly aimed at understanding how to modify biological systems. Above all else, let us insist that this work happens in the light, subject to the scrutiny of all who choose to examine it.

Which, I think, is quite enough said on this issue (for now).