June 2005 Archives

Arriving in my mailbox this morning was a story from the Washington Times Post (Thanks, Oliver), dated 18 June 05, "Bird Flu Drug Rendered Useless: Chinese Chickens Given Medication Made for Humans", by Alan Sipress.  Chinese farmers, encouraged by the government, have since the late 1990's been feeding the antiviral drug amantadine to chickens infected with H5N1.  (Update: Recent news stories in Science and Nature carry claims from the Chinese gov't that this usage was most certainly not officially sanctioned or  encouraged.)  The story notes that this usage is in violation of international agreements on the treatment of livestock with drugs, and that the resulting long term selective pressure is the reason amantadine is no longer effective in treating the influenza strain currently causing concerns about a pandemic.  This sets up China (and due to growing economic interdependence, the rest of the industrialized world) for serious woe, amplified by the fact that the most populous country on the planet is not prepared for a pandemic. 

In summary, an important tool in dealing with a potential pandemic outbreak in humans has been rendered useless despite an international agreement aimed specifically at preventing that sort of occurrence.  Writes Sipress;

The Chinese Agriculture Ministry approved the production and sale of the drug for use in chickens, according to officials from the Chinese pharmaceutical industry and the government, although such use is barred in the United States and many other countries. Local government veterinary stations instructed Chinese farmers on how to use the drug and at times supplied it, animal health experts said.

Amantadine is one of two types of medication for treating human influenza. But researchers determined last year that the H5N1 bird flu strain circulating in Vietnam and Thailand, the two countries hardest hit by the virus, had become resistant, leaving only an alternative drug that is difficult to produce in large amounts and much less affordable, especially for developing countries in Southeast Asia.

The scientific evidence that using antivirals in poultry is a bad idea has been around for quite some time, and international policies regarding veterinary application of the drugs is based on clear evidence: "In 1987, researchers at a U.S. Department of Agriculture laboratory demonstrated that bird flu viruses developed drug resistance within a matter of days when infected chickens received amantadine."

So we have a situation where scientific, technical, and policy components were all directed towards a particular regulatory goal, and all were ignored.  There is one more key piece to this story, and that is the number of years it has taken to confirm the information.  Sipress, again;

Health experts outside China previously said they suspected the virus's resistance to the medicine was linked to drug use at poultry farms but were unable to confirm the practice inside the country. Influenza researchers at the U.S. Centers for Disease Control and Prevention, in particular, have collected information about amantadine use from Chinese Web sites but have been frustrated in their efforts to learn more on the ground.

This is truly the crux of our challenge over the coming decades.  Despite efforts determine the extent of veterinary use of amantadine within China, even widespread government sanctioned (recommended, according to the story!) use that violated explicit international agreements continued unabated.  Even if the relevant intelligence had been confirmed, it isn't clear that the Chinese government would have changed its policies.  Regulation failed in this case, and because information was hard to come by our response to the problem is further impaired.  (Update:  Regardless of the involvement of the government, my point about the importance of good information stands.)

This is why I have been arguing so strenuously that open and distributed networks of people using and developing biological technologies are strongly preferable to closed ones. In my recent essay "Synthetic Biology 1.0", I discussed the effect of regulation on preparedness for natural and artificial biological threats, in part with conditions in China in mind.  Though many states and organizations will be pushing biological technologies in the coming years, China is front and center because of its growing economic might and educated population.  It is clear they are going their own way, developing and, more importantly, using technology as they see fit.

In the year 2000, Jiang Zhemin, the former President (Premier? I can never remember which) of China, said in no uncertain terms that in order to deal with their health care crisis they would use all tools at their disposal.  He specifically mentioned genetically engineering the population (this story is now finally on the record in Gerald Epstein's recent report from CSIS, "Global Evolution of Dual-Use Biotechnology").  Such efforts will explicitly require sophisticated biological technologies, in particular those related to DNA synthesis and sequencing.  Countries throughout Asia are already pushing the technology without much, if any, concern for what we decide to do here in the states.  Creating and enforcing regulatory regimes for this sort of thing would require an international effort that historically doesn't work so very well for just about anything else.  Witness the amantadine problem.

Then there is the problem that the technology and skills do not respect borders.  Synthetic genes can be ordered from companies in Seattle, San Francisco, throughout western Europe and Russia, Dalian, Tehran; the list goes on.  How do we monitor the flow of Epindorf tubes full of lyophilized DNA around the globe?  Used synthesis instruments are not only available worldwide, but the parts for a new 192 channel instrument (styled after ABI or Gene Machines) can be had for about $10,000.  The plans and process specs were published long ago.  Yes, it requires some skill to assemble the instrument, and yes, it requires some skill to write the software, but most people with undergraduate degrees in engineering or physics have this skill or can fumble their way to it in a relatively short period of time.  Reagents are available worldwide, and I don't understand how we can track those reagents any better than we do it now for industrial chemicals or drugs.  The grey and black markets for everything from drugs to fluorocarbon coolants are thriving around the world.  I don't understand how reagents, short oligos, genes, or even synthetic genomes can be controlled any better.

This raises two main issues.  The first is that I suspect regulation will only slow down scientific and technological progress here in the US.  Other countries (and organizations) are likely to explore the relevant fields a their own pace.  This resulting technology gap constitutes the second issue, which is that we will be unprepared for surprises.  Given the history of technology from the last century, I do not believe we can control the pace of development of biological technologies.  If we, here in the US, are not in the lead, somebody else is.  And we will thus experience surprise on a regular basis.  Our choices about developing biological technologies will determine whether we are willing to let potential adversaries be in the lead.

The above arguments are primarily directed at our physical security, but I am equally concerned about our economic security.  It is clear that China and India are pushing ahead with biological technology.  The sheer numbers of talented and smart students in these countries is to me mind boggling.  I am not sure that we can maintain our economic vitality even if we keep going at the current rate, but I am certain we will lose out if we decide to slow down.  We absolutely require increased government investment in technology and increased numbers of skilled people.  If you don't believe me, then the interviews Bio-ERA has been doing for our DOE-funded Synthetic Biology project clearly indicate that our global competitiveness is already at risk.  There is absolutely no reason European or Asian scientists and businesses should order synthetic genes from the US.  More specifically, my experience at a Global Business Network meeting a few weeks ago indicates that even though China is likely to experience some internal disruption over the coming decade or two, they are pushing hard not just to be competitive, but to take the lead.  In everything.

In summary, given my historical study of other technologies and my experience developing new biological technologies, I do not believe that regulation will result in improved security.  On the contrary, I believe it will impair our preparedness, reduce our security, and reduce our economic competitiveness.  Independently from these issues, I do not see how international regulatory regimes for biological technologies are workable, even if agreements are reached and are implemented -- by no means trivial efforts in themselves.

Finally, I would observe that no regulatory regime is perfect, and regulation is in actuality more a problem of managing barriers (to entry and use) that are inherently leaky.  Implementation of regulations always seeds resistance.  Given the power of biological technologies how many surprises can afford?

I have a new essay, "Synthetic Biology 1.0", just published on Future Brief.  Here are the first few 'graphs:

Open development of biological technology is crucial to US domestic security and to the health of our economy.

Misuse of this technology in bioterrorism is a clear threat. Our first response to recent domestic bioterror attacks, and to evidence of bioweapon programs abroad, has been to pursue safety in regulation. However, it is already clear that action to limit domestic access to materials and methods will produce only illusory safety. Reagents required for genetic manipulation are available from manufacturers outside the U.S. Synthetic genes can be ordered with equal ease from fabrication labs in Seattle and Tehran .

Beyond access to the infrastructure of sequencing and synthesis, which enables attempts at state-of-the-art genetic manipulation, the practical knowledge required to assemble objects and processes in cellular and molecular systems is proliferating globally. Moreover, biological technologies are being developed globally, and they will be as useful worldwide in developing new crops, drugs, and industrial products as they will be in producing weapons. These factors considerably expand the scope of our security problem.

Ensuring domestic physical security and economic competitiveness requires a long-term plan to integrate public and private sector interests. Serious consideration should be given to the role of government in establishing the design and production infrastructure for biological engineering. In particular, investing in engineering tools as a goal of federal research policy will enable safer and more rapid progress in all areas of biology...

Follow the link to Future Brief for a PDF.  The link only just went live today, and there is already some nice commentary over at WorldChanging.

On 26 May, 2005, Marcia Crosse, Director of Health Care at the Government Accountability Office(GAO), testified (PDF) before the Subcommittee on Health, and the Committee on Energy and Commerce of the U.S. House of Representatives on pandemic preparedness in the US.  The news is not good.

Some of the choicer comments:

Challenges regarding the nation’s preparedness for and response to an influenza pandemic remain. Specifically, our prior work has found that although CDC participated in an interagency working group that developed the U.S. plan for pandemic preparedness that was posted for public comment in August 2004, as of May 23, 2005, the plan had not been finalized. Further, we found that the draft plan does not address certain critical issues, including how vaccine for an influenza pandemic will be purchased, distributed, and administered; how population groups will be prioritized for vaccination; what quarantine authorities or travel restrictions may need to be invoked; and how federal resources should be deployed. At the state level, we found that most hospitals across the country lack the capacity to respond to large-scale infectious disease outbreaks.

...The draft plan delegates to the states responsibility for distribution of vaccine. The lack of a clearly defined federal role in distribution complicates pandemic planning for the states. Furthermore, among the current state pandemic influenza plans, there is no consistency in terms of their procurement and distribution of vaccine and the relative role of the federal government. Approximately half of the states handle procurement and distribution of the annual influenza vaccine through the state health agency. The remainder either operate through a third-party contractor for distribution to providers or use a combination of these two approaches.

Most annual influenza vaccine distribution and administration are accomplished within the private sector, with relatively small amounts of vaccine purchased and distributed by CDC or by state and local health departments. In the United States, 85 percent of vaccine doses are purchased by the private sector, such as private physicians and pharmacies. HHS has not yet determined how influenza vaccine will be distributed and administered during an influenza pandemic.

There are many issues surrounding the production of influenza vaccine, which will only become exacerbated during an influenza pandemic. Vaccines, which are considered the first line of defense to prevent or reduce influenza-related illness and death, may be unavailable or in short supply. Producing the vaccine is a complex process that involves growing viruses in millions of fertilized chicken eggs. Experience has shown that the vaccine production cycle takes at least 6 to 8 months after a virus strain has been identified, and vaccines for some influenza strains have been difficult to mass-produce, causing further delay. The lengthy process for developing a vaccine may mean that a vaccine would not be available during the initial stages of a pandemic.

Here is a wee bit of good news, namely that the US Government is spending money to guarantee purchase of vaccine so that manufacturers will maintain more production infrastructure:

...The agency’s fiscal year 2006 budget request includes an increase of $30 million for CDC to enter into guaranteed purchase contracts with vaccine manufacturers to ensure the production of bulk monovalent influenza vaccine. If supplies fall short, this bulk product can be turned into a finished trivalent influenza vaccine product for annual distribution. If supplies are sufficient, the bulk vaccine
can be held until the following year’s influenza season and developed into vaccines if the circulating strains remain the same. In addition, according to CDC, this guarantee will help to expand the influenza market by providing an incentive to manufacturers to expand capacity and possibly
encourage additional manufacturers to enter the market. In addition, the fiscal year 2006 budget request includes an increase of $20 million to support influenza vaccine purchase activities.

But, of course, the testimony basically ends on a downer:

Even if sufficient quantities of the vaccine are produced in time, vaccines against various strains differ in their ability to produce the immune response necessary to provide effective protection against the disease. Studies show that it is uncertain how effective a vaccine will be in preventing or controlling the spread of a pandemic influenza virus.

At least with this testimony, and the remarks  of Senate Majority Leader Dr. Frist at Harvard Med School last week, it seems the right noises are being made in Washington DC.

Here are a couple of pages at the NAIAD describing the use of reverse genetics to "build" new flu vaccines.

Reverse Genetics: Building Flu Vaccines Piece by Piece

Illustrations: Reassortment Vs. Reverse Genetics

Senate Majority Leader Bill Frist has joined the call for a major program to advance scientific and technical capabilities in biology.

In remarks at Harvard Medical School on 1 June, 2005, he called for a new Manhattan Project(PDF).  This isn't the best analogy to make, given the connection to secret weapons programs, but the right sentiment is there nonetheless.  I strongly prefer the Apollo Program as an analogy, particularly if you re-frame the cold war competition angle as a race against pandemics and bioterrorism.

UPDATE (5 June 05): Here is what I wrote in 2003 about the Manhattan and Apollo Project as analogies for a big biological program;

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.

Anyway, Frist's comments constitute, by my reading, a major domestic and foreign policy speech.  A speech to frame a political career, you might say.

A few paragraphs:

"I propose an unprecedented effort – a “Manhattan Project for the 21st Century” – not with the goal of creating a destructive new weapon, but to defend against destruction wreaked by infectious disease and biological weapons.  I speak of substantial increases in support for fundamental research, medical education, emergency capacity and public health infrastructure; I speak of an unleashing of the private sector and unprecedented collaboration between
government and industry and academia; I speak of the creation of secure stores of treatments and vaccines and vast networks of distribution; I speak of action, without excuses, without exceptions; with the goal of protecting every American and the capability to help protect the people of the world.

I call for the creation of the ability to detect, identify, and model any emerging or newly emerging infection, present or future, natural or otherwise; for the ability to engineer the immunization and cure, and to manufacture, distribute, and administer what we need to get it done and to get it done in time. For some years to come, this should be a chief work of the nation, for the good reason that failing to make it so could risk the life of the nation and other
nations the world over.

This is a bold vision.  But it is the kind of thing that, once accomplished, is done. And it is the kind of thing that calls out to be done, and that, if not done, will indict us forever in the eyes of history. In diverting a portion of our resources to protect nothing less than our lives, the lives of our children, and the life of our civilization, many benefits other than survival would follow in train, not least the satisfaction of having done right.  If the process of scientific
discovery proceeds as usually it does, we will come to understand diseases that we do not now understand and find the cures for diseases that we cannot now cure. And, as always, disciplined and decisive action in facing an emergency can, even in the short run, compensate for its costs – by adding to the economy both a potent principle of organization and a stimulus like war but war’s opposite in effect.  This would power the productive life of the country into new fields, helping transform the information age with unexpected rapidity into the biotechnical age that is to come.  All this, if the nation can be properly inspired in its own defense and protection, perhaps just in time.

We have built great cities, dams, and aqueducts. We have built the interstate highway system, bridges, canals, fleets, armies, a world of structures. We have decided upon going to the moon and then done so in a few short years. Can we not, then, build this thing, and take these steps, to protect our lives and the lives of our children, to evade mass death and suffering, that would strike at all classes, all races, all ages? We must open our eyes to face the single greatest threat to our safety and security today, but also to seize our single greatest opportunity.
 
I am aware of the difficulties. But the United States is as blessed today as it has been since its beginnings. We are the wealthiest, freest, and most scientifically advanced of all societies, the first republican democracy, the first modern state. And although we have suffered criticism of late, we have been willing since our Founding and are willing still to pursue certain ideals. Though not infrequently condemned from the precincts of cynicism, America has mostly left cynics in its wake, sometimes after saving them from floods that they themselves have unleashed."

I can't say I agree with the notion that the vision, "once accomplished, is done."  We might be successful in creating an infrastructure that provides a response capability for both natural and artificial threats, but the work to maintain vigilance and update the technology will never be done.  Nonetheless, we need to get moving.  Right now.