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".

Broken Drug Development Model

Sam Jaffe's article in Technology Review, "A Dip in Time", discusses some well known problems with the pharmaceutical industry.  Namely that it costs a ridiculous amount of money to get a drug into testing, which is just the beginning of the financial gamble because it is so hard to predict how new compounds will behave in a large and complex population.  More interesting for me is the suggestion -- within the first sentence, even -- that, "Some [are speculating] that the way new drugs are financed and brought to market will soon be overhauled".

With venture firms basically gambling that one or two in ten investments will pay for the rest, we certainly can't expect innovation from that direction.  Alas.

The article ends with a note that Millennium Pharmaceuticals is using genetic/genomic screening to choose which patients to include in drug trials.  This will certainly help with the trials, but it is rather a backwards strategy to take what you happen to have on hand and see who benefits.  That said, this is what most companies have to work with, and they are looking out for the bottom line first and foremost.  It is clear some significant effort needs to be put in to changing the whole drug discovery and testing infrastructure, so that it is a bit more rational at the front end.

Richard Meagher and Phytoremediation

Richard Meagher, at the University of Georgia, is doing some excellent work using plants to clean up toxic materials in soils, a technology otherwise known as phytoremediation.  Meagher's lab genetically modifies plants and trees so that they express a bacterial gene that helps metabolize complex mercury and arsenic compounds.  His team has achieved impressive results, some of which was described in National Geographic's Strange Days on Planet Earth.

Another biological chassis and power supply

If you want to build new widgets using biology, you need to work with cells amenable to the task.   Tom Knight, at MIT, prefers the innocuous insect commensal bacterium Mesoplasma florum as a prototype biological chassis and power supply for genetic circuits.

After reading my article on garage biology in this month's Wired, David Metzgar, at the Naval Health Research Center, sent me a paper describing another candidate organism, Acinetobacter ADP1.  The paper describes ADP1 as naturally competent for genetic transformation and that it has a "strong natural tendency towards homology-directed recombination."  That is, it likes to harvest DNA from its environment and incorporate it into its genome.  Metzgar writes that, "The close relationship between E. coli and ADP1, combined with the newly available whole genome sequence of ADP1, allows the tremendous amount of existing knowledge related to gene function and metabolism of E. coli to be applied directly to ADP1."  They ported a variety of genes directly from coli to ADP1 without modification.

Since it is common, easily grown, and poses no pathogenic threat to humans, this could be a useful bug.

Acquiring Open Source Projects

One of the issues that always arises in discussions of Open Source Biology is how anyone will make any money.  Not everyone is interested in money, of course, but molecular biology is still a bit expensive and requires capital of some sort to keep it running.  Without the possibility of a return on their investment, most investors probably won't go near open source biology.

This was an explicit objection raised by a banker/VC type at After the Genome VI, in December of 2000.  I've heard similar complaints all along the way, though the VC in question also added something like "they won't let you do it" to his oration, presumably refering to big biotech companies.  I immediately asked myself what "they" could do about it, and have pondered the question ever since.  The problem doesn't seem to be encouraging tinkerers to have at it, or that big companies might prevent them from doing so, but rather turning the fruits of tinkering into useful tools and products that most people want to use.

Products take a long time to develop to the stage where people want to actually purchase them.  Lot's of open source software in particular doesn't attract a large user base because the interface isn't as polished as that provided by commercial houses, even if the guts of the code are better.  This is as true of software and cars as it is of molecules and other biological technology.  In my experience, most biologists seem to want a box with an instruction book -- a package they can use to produce data -- and are rather less likely to put up with sorting out the intricasies of working with a tube full of molecules from some guy down the street.

On the one hand tools and skills are proliferating at a remarkable rate, democratising the technology and its applications, but on the other most new useful tools still come from "traditionally" funded and run corporations, and we want to ensure continued investment that funds that development of finished products.

One way out of this might be the aquisition of open source projects by established companies, or by start-ups funded specifically to take a project private and push the commercial applications.  It turns out this has now happened in the open source software world.  This obviously can only work if all the contributors to the open source project agree to sell their rights as developers to the company.

David Berlind describes what transpired, and explores its implications, at ZDnet:

To acquire an open source project, the acquirer must be absolutely certain that they are acquiring the copyrights to all of the code being used in the project.  Those copyrights ultimately belong to the individual contributors to the project who, up until the point of acquisition, would have been bequeathing certain rights to their code to others under whatever open source license is behind the project.  To the extent that licensing that code under an OSI-approved license is what let the code out out of the box and into the open source wild, there’s nothing that the acquirer can do to put it back in the box.  That code will always remain available under whatever open source license it was published.  But, by acquiring the copyrights and any trademarks associated with that code, the acquirer also acquires the right to modify and distribute the original code without having to make those modifications available under an open source license.  In other words, future versions of the open source software could become closed source.

The last sentence is perhaps the most interesting, particularly in the context of biology.  I can imagine open source biological technologies developed in a distributed way, or at least developed by more than one person, which are useful to those willing to master the eccentricities but which are not widely used because they may be unwieldly.  In steps a commercial endeavor to tie up all the loose ends, and then put it in a nice package with a bow on top -- complete with instruction manual, please.  As with software projects, all the details disclosed prior to aquisition would remain in the public domain, but any further work the company put into development would remain their property and contribute to the value of the final product.

This is, of course, similar to how technology is moved from universities into the private sector.  So it isn't a great stretch of the imagination to see that it might work with distributed, "amateur" development efforts.  Something to consider.

Heinz Feldmann on Marburg

Heinz Feldmann, head of the Level 4 labs at the National Microbiology Laboratory of the Public Health Agency of Canada, was in town this week to give a couple of talks on the Marburg virus.  He just returned from field work in Uige, the center of the current outbreak.

Here are a few notes:

  • There are claims that up to 80% of the highland Gorillas in the area have been felled by Ebola, but Feldmann expressed some skepticism and noted that none of the cases had been lab confirmed.  Evidently, there is  discussion of using experimental vaccines in the Gorillas to try to preserve the population.  This is more than can be done for the humans, because the vaccines have yet to undergo even safety testing.
  • Feldmann and others are working on vaccines for Marburg and Ebola, and adenovirus vectors don't work very well due to extensive seroprevalence in the population of neutralizing antibodies.
  • However, his lab is using VSV as a vector and this is working extremely well in monkeys.  When the GP protein from Marburg is included in VSV Virus Like Particles (VLPs), 100% of monkeys survive exposure with cross strain protection, including the "POP" strain thought to have been weaponized by the Soviets.  Ebola is a slightly different story, with 100% protection for any given strain, slightly less protection across strains, and zero cross species protection.

I am increasingly interested in the possibility of VLPs as the foundation of a synthetic and distributed vaccine production infrastructure.  Ralph Baric was in town a few weeks ago, and he said he was having success with VLP vaccines for Noroviruses.  So your next ocean cruise could well be diarrhea free.