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.

WHO doesn't have recent flu strains.

Catching up on Avian Flu news of the past week, I find that Nature is reporting (subscription required), "it is nearly eight months since the World Health Organization (WHO) last saw data on isolates from infected poultry in Asia".  And worse, "From the dozens of patients who caught the deadly H5N1 strain this year, the WHO has managed to obtain just six samples.  Affected countries are failing, or refusing, to share their human samples with the WHO's influenza programme in Geneva".

And this just when "trends suggest that the virus is becoming less virulent and more infectious -- two characteristics typical of pandemic flu strains".  Lovely.

The report continues, "The WHO's flu programme was last given access to a sample in October 2004, so it has no idea how the virus is changing in birds."

The upshot of the story is that countries wherein the virus is present are concerned about "losing control over information", want to develop their own vaccines, and are worried about intellectual property issues.  These points in particular are remarkable given that none of the countries affected is in much of a position to produce significant quantities of vaccine, which means that in order to protect their populations they will need outside assistance anyway.  Not to mention the affects on the rest of the world should an outbreak spread because local authorities were unprepared to deal with it. 

Evidently, "Some countries have provided samples but stipulated that the information can't be shared with the wider community".  Hmmm.  Excellent time to feel nationalistic.

Here are questions this story prompts me to ask:

Is anyone comparing the sequences of strains from human cases?  The answer would seem to be "no", which means we can't know whether more than one strain able to survive in humans is emerging, nor how those strains are changing over time at the molecular level.

How in the hell can anyone expect to prepare a vaccine against a bug we aren't getting samples of?  Who (WHO?) thinks we are actually prepared for any kind of widespread emerging infectious disease, let alone one as obvious a threat as H5N1?

The report ends by suggesting that discussions are underway to remedy the lack of cooperation and material transfer.  Somehow this doesn't make me feel any more comfortable.

"Preparing for the Next Pandemic"

Michael Osterholm, director of CIDRAP, has an excellent perspective piece in last week's New England Journal of Medicine, "Preparing for the Next Pandemic".

Here are some notes and highlights:

•    Typical annual US domestic death toll from flu is 30,000 to 50,000, with global toll 20-30 times higher.
•    “Today, making the 300 million doses of influenza vaccine needed annually worldwide requires more than 350 million chicken eggs and six or more months.”
•    Even if we develop a more capable, faster alternative, we must assure the production capacity for sufficient doses for a global population.
•    If a pandemic hit tomorrow, vaccine production in the following six months would be limited to at most one billion monovalent doses.  Because effective vaccination often requires two doses, we could thus protect at most only 500 million people.
•    Just in time economics also used to plan critical care facilities and equipment.  We do not have sufficient numbers of ventilators, for example, to handle a surge of flu victims.
•    “We have no detailed plans for staffing the temporary hospitals that would have to be set up in high school gymnasiums and community centers – and that might need to remain in operation for one or two years.  Health care workers would become ill and die at rates similar to, or even higher than, those in the general public.  Judging by our experience with [SARS], some health care workers would not show up for duty.  How would communities train and use volunteers?  If the pandemic wave were spreading slowly enough, could immune survivers of an early wave, particularly health care workers, become the primary response corps?”
•    No significant planning about use of antiviral agents.  (From my work with Bio-ERA, it is clear that there are even contradictions in the way US and Canada are stockpiling Tamiflu and vaccine.  The US has minimal stockpiles of the antiviral drug, but has already ordered large numbers of vaccine doses, while Canada has stockpiled lots of Tamiflu but is waiting on the vaccine.  I have to wonder how this might affect epidemiolgical dynamics across the border.)
•    “The current system of producing and distributing influenza vaccine is broken, both technically and financially.  The belief that we can greatly advance manufacturing technology and expand capacity in the normal course of increasing our annual vaccination coverage is flawed.  At our current pace, it will take generations for meaningful advances to be made.”
•    Osterholm argues for cell culture based vaccine production.
•    Notes that in 1968, during most recent pandemic, China’s population of humans was only 760 million, of pigs only 5.2 million, and of poultry only 12.3 million.  Current populations are humans 1.3 billion; pigs 508 million; and poultry 13 billion.  “Similar changes have occurred in the human and animal populations of other Asian countries, creating an incredible mixing vessel for viruses."

Well done, Dr. Osterholm.

Evidence That GM Crops and Cloned Cattle are Safe

Two papers in the last week contribute data to the discussion about whether GM crops and cloned cows are safe.  The answer is affirmative.  Sorry, Greenpeace; science trumps ideology, at least in this case.  Fortunately, Toto, this isn't Kansas.

"Insect-Resistant GM Rice in Farmer's Fields: Assessing Productivity and Health Effects in China", by Huang et al in last week's Science, describes a controlled study of a field trial that shows clear evidence for a reduction in use of pesticides, higher crop yields, and improved health of the farmers.  Receipt of GM and non-GM strains for planting was randomized amongst participating farmers, facilitating analysis of the effects of genetic modification.  The results speak for themselves:

This study provides evidence that there are positive impacts of the insect-resistant GM rice on productivity and farmer health.  Insect resistant GM rice yields were 6 to 9% higher than conventional varieties, with an 80% reduction in pesticide usage and a reduction in their adverse health effects.  Such high potential benefits suggest that produces from China's plant biotechnology industry could be an effective way to increase both competitiveness internationally and rural economies domestically.  The benefits are only magnified if the health benefits are added.

There has been considerable discussion about the health and economic impacts of GM food crops, with neither side having much data on their side.  This is particularly important for China, because they want to commercialize both strains studied in the field trial, which makes any uncertainty a threat to success in the market.  Now, however, the evidence indicates GM food crops are both safe and economically superior.

And it isn't just biotech plants that are proving safe.  In a paper in last week's PNAS, Tian et al studied the composition of milk and beef from cloned cattle.  Milk from the cloned cattle was virtually identical to control animals as determined by measuring fat content, lactose content, and protein composition.  The beef cattle were cloned from a bull chosen because of a high fat marbling score; unsurprisingly the clones demonstrated a high fat content as well.

The authors note that while only small number of animals were studied in this pilot project, "most parameters of the composition of the meat and milk from somatic animal clones were not significantly different from those of their genetically matched comparators or industry beef comparators, and that all parameters examined in this study were within the normal range of beef and dairy products approved for human consumption".