Kazakh Biotech Empire

The 24 June issue of Science contains a story (subscription required) by Richard Stone describing efforts to build up biotech in Kazakhstan.  They aren't thinking small; "The government has approved plans and is now reviewing financing for a $50 million Life Science and Biotech Center of Excellence, supported in part by the World Bank."

I think this is interesting for a couple of reasons.  The first is that the article describes U.S. Department of State hopes that the endeavor will keep former bioweapons scientists engaged in less threatening activities.  The second is that the World Bank is helping finance what could be at minimum a regional biotech power.  Given a few years to build up the infrastructure, combined with the expertise developed at Stepnogorsk in manipulating and manufacturing biologicals, they could be a global technological and economic power.

The Death of Innovation, or How the NIH is Undermining Its Future

Donald Kennedy's latest editorial in Science notes that the vast majority of NIH grants are going to older investigators.  Writes Kennedy;

In 1980, despite a tightened academic job market..."new" investigators held 50% of competing new grants, and 23% of all awards were going to scientists under 35. Now, alas, that percentage has shrunk to less than 4%, with a huge corresponding increase in the proportion going to older researchers.

This despite the fact that the NIH budget has at least doubled since 1980.  (The figure is from an interesting article on how to fund science and innovation by Kei Koizumi for the AAAS.)  A rough Google search suggests 80% of PhD's in the US are held by people under 40 (does anybody have good numbers for biology?), which means that the vast majority of NIH dollars are going to investigators who have been around awhile.

Now, of course, I don't mean to imply that "older researchers" aren't innovating.  Few brand-spanking new PhD's can keep up with Sydney Brenner.  A characteristic of biology that distinguishes it from theoretical physics is that doing good biology requires the grasp of a great many facts and stories.  Whereas a the guts of a PhD in physics can be derived over a weekend (or so I was told upon arriving at Princeton -- mine took rather longer) the combination of biological lore and experimental art accumulates over time.  But if we aren't funding young scientists with new ideas then we are missing out.  New methods and tools are the key to progress in biology.

Why should young scientists from abroad bother to come here?  Why should any young scientist bother to stay here?  Yes, yes -- the US still has the biggest budget and a tremendous diversity of research.  But even Sydney seems to be spending most of his time in Europe and Asia these days.  If we fail to ensure proper funding and opportunity for young biological scientists, then the innovation is simply going to happen elsewhere. 

The Challenges of International Regulatory Regimes for Biological Technologies

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?

Synthetic Biology 1.0

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.

"Influenza Pandemic: Challenges Remain in Preparedness"

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.

Senator Bill Frist's Biological "Manhattan Project"

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.

The Economic Consequences of Chinese Pandemic Un-Preparedness

The population of China plays a significant role in the world economy.  Low cost manufacturing in China drives the larger economies of many other nations.  As a benchmark for this influence, recent reports put 80% of Walmart's manufacturing capacity in China. (Though the folks Newsweek, unsurprisingly, can't make up their minds and corrected an original report to say only 6%.)  While not every global firm relies so heavily on China, a bit of everything we buy is made there, or was made using machine tooling produced there. 

The health and productivity of workers responsible for China's manufacturing power is therefore of critical interest.  On a longer timescale, as China grows into a market on which western companies depend, the health of more than a billion consumers will also play a crucial role in the world economy.  These observations set up a series of questions about the capabilities of China’s public health system.  The answers to those questions in turn, through the role of the Chinese population as manufacturers and consumers, help determine the impact on the global economy of a pandemic Avian Flu outbreak within China.

I've just returned from a scenario planning exercise run by the GBN called "China's Choices".  I was able to ask journalists, professors, and corporate planners with experience in country about some of these issues.  The answers were not encouraging.  I will get into the details below, but there is already cause for concern.

Over at Recombinomics, Henry Niman continues to bang the drum about human cases of the Avian Flu in Asia, now citing local reports from China about a number of unexplained deaths that he asserts are due to the Flu.  He is evidently unsatisfied with the WHOs correspondence with the Chinese government in which all reports of human cases are denied.  Given Niman's language, I have to wonder if he is fanning the flames of panic.  But if there is in fact the beginnings of an outbreak in China then everyone had better pay attention right now.  However, I have a feeling that even in the event of a real outbreak it will take quite a while for anyone to figure out what is going on.  One of the things to come out of "China's Choices" is that even the central government can't trust data coming in from rural areas, and that you have to be on the ground gathering your own information.  This is primarily because China is an enormous country, and local officials are now rewarded based on what they report to be true about local conditions and production levels, rather than rewarded based upon standard metrics.  Can the Chinese government know to trust local reports of human cases of Avian Flu, let alone trust the denials?

We can at least try to get an idea of how they might handle an outbreak.  Worldwide flu vaccine production capacity is only a few hundred million doses per year, concentrated primarily in Western Europe and the U.S.  It is truly hard to dig up numbers for how much flu vaccine is produced and administered in China, but as far as I can tell, Chinese domestic flu vaccine production is no more than 10-20 million doses.  China Daily reported at the end of 2003 that demand for flu vaccines was only 15 million doses that year, growing at 15% annually.  Most of the vaccine used in the country is purchased from the US and Europe, as reported last summer in the China Chemical Industry News;

In 2003, the 13 Chinese domestic vaccine business only shared 30 per cent of the market. And the remaining 70 per cent of flu vaccine was imported from France, America and other countries. Huge technique differences exist between China vaccine manufacturers and their foreign counterparts.

Because the vast majority of humanity is immune naive for H5 viruses, the consensus seems to be that two doses of any vaccine will be required to generate an immune response.  This means there is probably only enough vaccine to take care of Beijing, or perhaps a selected population in many of the big cities.  Where does that leave the rest of the population?  At "China's Choices" last week, it was pointed out that when the rural population starts to revolt regimes tend to change in China.  Launching completely into the realm of speculation, I am led to wonder if the lack of a flu vaccine might be another tipping point.  Everything depends on the response of the government, and I don't think anyone -- inside or outside China -- is prepared to deal with a pandemic.

Keep in mind that WHO hasn't been getting samples of recent human H5N1 isolates from Asia, the vaccine takes some months to produce once samples are shipped and a strain is identified, and a vaccine based on that strain (modified, in this case, to be less lethal) may not actually confer immunity.  It is thus unlikely that China will have effective vaccine ready to go anytime soon, and they can't expect help from us because we don't have one either.

So much for setting the stage.  What happens if a flu pandemic hits China?

Inside the country, areas may be quarantined and people may stay away from populations centers to avoid infection, thereby depriving manufacturers of labor.  If the outbreak is severe, enough people may be sick that productivity is seriously impacted.

Outside the country, even if governments understand that quarantines will only marginally slow the spread of the  virus, populations will likely demand limitations on travel and trade.  Estimates of the economic costs of SARS range from USD 50 Bn (Bio-ERA) to 150 Bn (CDC) in lost trade and tourism revenues, while less than 800 people succumbed to the disease.  Thus fear of the disease caused considerably more economic damage than did the disease itself.  There is no reason to expect the response to an Avian Flu pandemic will be less severe.  Whether or not production of goods is actually slowed within China, shipping probably will be.  That is, the manufacturing capacity relied on by much of the global economy may go dark for up to several years.

While the domestic impact of a Chinese Flu pandemic depends on factors such as the availability of vaccines and anti-viral drugs, the stability of the public health system, and the willingness of the government to communicate with its citizens and the outside world, the global impact of a Chinese Flu pandemic depends on when it happens.  Aside from issues of whether the virus might escape the borders and find its way into other countries, aside from whether the Chinese government learned from the SARS outbreak and shares epidemiological information, the global impact of a pandemic confined entirely within China's borders could be severe.  If an outbreak happens soon, the consensus of folks I spoke to at the GBN meeting was that investment would move elsewhere, diversifying manufacturing capacity into India, for example.  There would be short term pain, but not that much economic damage would result.

But if the pandemic hits at point when the consumer market within China is significant, then it won't just be low cost manufactured goods that go missing; a reduction in shipping could mean the sudden loss of hundreds of millions of consumers.  We live in a globalized economy wherein goods and services are provided based on the availability of credit and upon cash flow.  If western economies start to rely on capital flow out of China, a pandemic could be far more severe than people are planning for now.

In the short term, if this system starts to break down, it just isn't clear that critical products -- gloves, surgical masks, disposable plastic lab ware -- are going to make it where they are needed.  What fraction of the medical disposables we use are manufactured in China?  If a pandemic flu outbreak occurs in China, do we have reserves or replacement capacity? 

Masks were in short supply during the SARS crisis, and I wonder if all the right people are making sure masks and similar necessities are not only stockpiled for the next crisis, but that the manufacturing and supply lines will remain open.  A flu outbreak could come in multi-month long waves, with the challenge to the global system of health care providers, critical goods manufacturers, and the overall economy lasting several years.

These questions point the way to considering how restriction in trade with China may begin to impact local economies to the point that they have difficulty mounting domestic responses to a pandemic.  I have no answers after all of this, just more questions.