Nature is Full of Surprises, and We Are Totally Unprepared

The SARS coronavirus came out of nowhere.  It is an example of the speed with which a zoonotic disease can leap to the fore of international attention.  We were completely surprised.  Fortunately, the virus was not quite as virulent as first feared, and it burned itself out before causing greater havoc.  This is an important misconception about the SARS episode.  Yes, the virus was identified and sequenced in a hurry, but all our technology was of little help in responding.  We got lucky.

According to an epidemiological modeling paper published a year after the epidemic:

We conclude that the control of SARS through the use of simple public health measures was achieved because of the efficacy with which those measures were introduced and the moderate transmissibility [R0] of the pathogen coupled with its low infectiousness prior to clinical symptoms[theta].

[Fraser, et al., PNAS | April 20, 2004 | vol. 101 | no. 16 | 6146-6151]

That is, it is quite possible that the much vaunted public health measures used to battle the SARS virus were only effective because the virus wasn't actually that bad.  Not to minimize the death, disease, and the at least US$ 50 billion in economic damage, but it could well have been a lot worse.

This conclusion comes out of a modeling paper, and describes the development of a methodology similar to the one now being used to plan responses to a pandemic flu outbreak.  Unfortunately, there isn't a great deal of data to constrain the model, and as Tara O'Toole and her colleagues at the Center for Biosecurity at UPMC point out (PDF), present monitoring and quarantine policy is simply "inconsistent with available scientific understanding of the nature of person-to-person disease transmission."  There is also a distinct question as to how far we should trust the model.  Fortunately, we can look at distinct historical events to figure out whether preparations are on the right track.

Below is a time line of events starting in the fall of 2002, when the SARS coronavirus first emerged.  (Sources:  WebMD, Science, Nature, PNAS, Journal of Virology.)

34-carlson_sars_timeline_v1_3.jpg

Note that while the virus appears to have emerged in November of 2002, it wasn't until February of 2003 that Carlo Urbani saw his first patient.  The diagnosis in November is entirely forensic in nature.  That is, working backwards this seems to be when the virus first jumped to humans.  Koch's postulates, which must be met in order to conclusively link a pathogen and the disease it causes, are not met until the middle of April.  The sequence is then announced at the height of the pandemic, though it isn't published until after most deaths from the initial outbreak have already happened.  Ralph Baric's group at UNC publishes the first paper in October demonstrating control of the virus in the lab, which is a prerequisite to doing any biology, figuring out how the virus works, and developing vaccines.  (Ralph told me at a meeting last week they were ready go to with the paper a few months before it came out.  This delay was probably due to academic publishing BS, as far as I can tell, though it might have gone faster if people were still dying at that point.)  The first vaccine takes another year to test and publish (some of this interval is also due to the dynamics of academic publishing, but the point remains).

Thus the pandemic was basically over by the time we could do any biology and even start to think about vaccines.  But Ralph Baric wouldn't have been able to move as fast as he did in 2003 had he not worked out the packaging strains for the coronavirus reverse genetics system years earlier, published in November of 2000 (Yount, et al., J. Virology).  As it happened, Ralph thought the viruses were interesting, and he put in the time and effort to sort out how to work with them in the lab.  It is only through Ralph's efforts that the rest of us have the good fortune to know as much as we do now about the virus.

What about the next time?  The reverse genetics system for influenza was published in 1999, and we are still trying to figure out how the virus works.  If a flu pandemic hits we might, just maybe, be ready with useful vaccines and antivirals, particularly if the FDA's new flu vaccine licensing rules turn out to be as well thought out as has been reported.  Future flu pandemics are a near certainty, if only because we have historical examples.  Thus there is a clear motivation to get ready for the next one.  We have a choice about whether to prepare, and the flu is an understood threat.  But what about the next true surprise, the next SARS coronavirus?  And what if it is just a little bit worse than SARS? 

We have to be able to detect the threat, understand it, and respond much more rapidly than is now possible.

New Rules for Expedited Flu Vaccine Licensing

CNN is reporting that on Thursday the FDA will announce new draft rules intended to accelerate the approval of new flu vaccines.  This is excellent news.  According to the story, "Eventually, the guidelines could knock one to two years off the time it takes to develop and license a new flu vaccine."

Here is all the good stuff:

...The guidelines make clear there are a variety of approaches to creating vaccines to fight the next pandemic.

The guidelines allow for emergency approval if a completely new super-strain of flu suddenly appears. Or, manufacturers could systematically create and stockpile a library of vaccines against brewing new strains.

They even allow for the possibility of one day vaccinating people against a potential future pandemic strain at the same time they get their regular winter flu shot.

The last point is interesting, because it is an example of explicitly trying to get out in front of a pandemic strain before it appears.  The biggest reason H5N1 is a threat is that humans have never been exposed to a virus like it.  We are "immune naive", which means we have no preexisting antibodies or lymphocytes primed to respond to this particular virus.

Additional interesting policy tidbits:

In the case of a previously approved flu vaccine, manufacturers could tweak the vaccine for use against a new flu strain without having to seek a new license from the FDA, according to the draft documents.

Additionally, a manufacturer could receive "accelerated approval" for a new flu vaccine by performing studies showing that recipients experienced a surge in protective immune-system cells.

This is all good stuff, and comes not a moment too soon.  Okay, it comes a couple of years late.  We're way behind in preparing technological responses either to large outbreaks of infectious disease or to bioterror attacks.  The draft rules are putatively open for comment for 90 days -- if the rules turn out to be as well constructed as CNN is reporting, then everyone should enthusiastically support these proposed changes.

I'll post more when the official documents are released.

Avian Flu as a Harbinger of Zoonotic Diseases

As most people have heard by now, H5N1 has reached Germany and is confirmed to have killed a cat (AP via the NY Times).  I think the time scale is of interest here.  The virus has only just reached Western Europe, evidently via migrating birds, and already it has jumped to mammals.  In contrast, there appear to have been few cases in felines in Asia, despite the amount of exposure mammals have had there.  From the AP report:

In addition to the large cats infected in Thailand, three house catsnear Bangkok were found to be infected with the virus in February 2004. In that case, officials said one cat ate a dead chicken on a farm where there was a bird flu outbreak, and the virus apparently spread to the others.

I suppose its possible cat deaths are going unreported throughout Asia, but if the AP report is correct then  transmission to cats is very low probability, and I find it odd that the virus is already confirmed to have killed a cat in Germany.  It makes one wonder how the sequence is changing.

Fortunately, there are as of yet no known cases of cat-to-human transmission.  But human exposure to the virus has only just begun in Europe, and the coming months will increase this contact.

All news reports seem to agree that the virus arrived in France and Germany via migrating wild birds.  In an article focusing on the effects of the virus on the French poultry industry, Craig Smith notes in the New York Times that:

...The real threat, many experts fear, may come in the weeks ahead as pintail, garganey and shoveler ducks begin arriving from their wintering grounds in Africa, where the virus has already spread among poultry. The annual migration toward northern breeding grounds is expected to last until the end of May.

Smith also describes how migration patterns have been somewhat unusual this year due to extremely cold weather.  Thus the spread of the virus may be enhanced by changing weather patterns, increasing the likelihood of transportation into areas of the world densely populated by both humans and domesticated animals.  This sort of thing is only going to happen more often.

The AP (via the NY Times) recently picked up this thread with an article entitled, "Scientists See Growing Animal - Disease Risk."  The article begins, "Humans risk being overrun by diseases from the animal world, according to researchers who have documented 38 illnesses that have made that jump over the past 25 years," and winds up:

One explanation may be the recent and wide-scale changes in how people interact with the environment in a more densely populated world that is growing warmer and in which travel is faster and move extensive, Marano said. Those changes can ensure that pathogens no longer stay restricted to animals, she added. Examples from recent human history include HIV, Marburg, SARS and other viruses.

That prospect leaves open the question of what future threats await humans.

''It always surprises us. We think that avian flu will be the next emerging disease. My guess is something else might come out before that,'' said Alan Barrett, of the University of Texas Medical Branch at Galveston. ''It's very hard to anticipate what comes next.''

SARS, in particular, is an excellent example of surprise from nature.  It is also an example of how ill prepared we are for emerging diseases.  It is clear from recent work that if the SARS coronavirus had been just a little more virulent, and if it had spread just a little more before symptoms emerged, then the epidemic would likely not have been held in check by public health measures.  Moreover, it is only because coronaviruses caught the attention of a talented virologist several years before that the community was able to get a handle on the virus as quickly as it did.  More on this in an upcoming post.

(UPDATE, 5 March 06: Ralph Baric is the virologist mentioned above.  Here's the story.)

Here Comes China

The NatureJobs section in this week's Nature has a short news piece on science funding, education, and investment in China:

The US National Science Foundation's Science and Engineering Indicators 2006could perhaps be renamed 'Here Comes China'. The biennial report shows an increasingly international science and technology workforce, with China showing large gains in internal investment in R&D, investment by multinational corporations, and numbers of Chinese nationals earning science and engineering doctorates in the United States.

China has increased its R&D investment 24% per year over the past five years, compared with 4–5% for the United States. This growth, from US$12.4 billion in 1991 to $84.6 billion in 2003, puts the country behind only Japan and the United States. Meanwhile, investment by US-based multinationals into Asian markets outside Japan has more than doubled, from $1.5 billion in 1994 to $3.5 million in 2002, with more than $1 billion going into China alone. Finally, Chinese students earn more US science and engineering PhDs than those of any other foreign nation.

These statistics are impressive, but they tell only one side of the story. What do they mean in terms of jobs and who will get them? The United States, Europe and Japan still produce many PhDs and create a host of jobs. But China is coming on strong. One wild card is whether Chinese PhDs will stay in the United States or return home. While China's PhD production in the United States has increased, PhDs by US white males has dropped from its peak of about 8,900 in 1994 to just over 7,000 in 2003.

It would be premature to say this marks the end of US dominance in science and engineering employment, but it does show that the United States is producing less of its own scientists and may have more difficulty recruiting from abroad as other nations, particularly China, ramp up funding and infrastructure. As the report says, these trends point to a "potentially diminished US success in the increasing international competition for foreign scientists and engineers".

DNA Vaccine for Ebola

The AP (via the Washington Post) is reporting that the NIH has passed safety trials on a DNA vaccine for the Ebola virus.

From the article:

[Dr. Gary Nabel] and colleagues at the NIH's Vaccine Research Center developed a vaccine made of DNA strands that encode three Ebola proteins. They boosted that vaccine with a weakened cold-related virus, and the combination protected monkeys exposed to Ebola.

The first human testing looked just at the vaccine's DNA portion; the full combination will be tested later.

It will be interesting to see how they go about testing the effectiveness of the vaccine in humans.  There is at present no cure for Ebola, so who is going to volunteer for the test?

The vaccine was reported at a meeting last month.  I'll post additional details as they become available.

"Biowar for Dummies"

Paul Boutin has posted a story on his blog, "Biowar for Dummies,"  originally written for Wired Magazine but never published.  I'll take this opportunity to correct two small points before the story is widely read.

1.  The Molecular Sciences Institute is a non-profit research institute, not "a California biotech firm".  It was founded by Sydney Brenner in 1996.  I was a Research Fellow there from 1997 to 2002.
2.  I am most emphatically not designing, nor building, new organisms in my home.  I am, however, designing new proteins.  I would prefer local and federal authorities not get confused about this.

Here is a link to the original paper with the "Carlson Curves", "The Pace and Proliferation of Biological Technologies," published in Biosecurity and Bioterrorism in 2003.  There is more of my writing on the subject at www.synthesis.cc.

H5N1 in France, India.

Reuters (via the NY Times) is reporting that H5N1 has been confirmed in poultry and people in India, and appears to be the cause of death of ducks in France.  Check that -- the radio news just said H5N1 is confirmed in France.  No print/web confirmation yet that I see.

These results may be consistent with the notion of H5N1 being spread both through migratory birds and through domesticated poultry, presumably with poultry being transported across borders, often illegally.  This debate is ongoing at ProMED.  Some quick checking by Todd Harrington at bio-era suggests the flow of poultry from China and Turkey to Nigeria isn't as promiscuous as claimed by the recent Washington Post article, and it seems all legal poultry exports from China are now as cooked meat.  All legal exports, mind you, from a country with absurdly long borders.  All this is just more cause for concern and confusion, it seems.

Alas, even the best informed people are having trouble figuring this out.

Avian Flu in Africa May Have Arrived in Poultry

The Washington Post is reporting that, "The lethal strain of H5N1 bird flu found in Nigeria this month probably got there in poultry and not through the movement of wild birds." 

The article, by David Brown, quotes Billy Karesh of the Wildlife Conservation Society in New York, with whom I collaborate through Bio Economic Research Associates:

I would never rule out wild birds. But I think we have to look at the most probable routes, and the most probable route would be poultry. How did it skip the whole Nile Delta and get to Nigeria? That kind of bothers me. Common sense would dictate that it should be all over Egypt by now.

Though I've been skeptical about transmission via traveling poultry, I can't argue with Dr. Karesh's reasoning.  Mr. Brown also writes that:

The first Nigerian cases were found at a commercial farm with 46,000 chickens, not among backyard flocks that would have greater contact with wild birds. Nigeria imports more than a million chicks a year from countries that include Turkey, where H5N1 appeared last fall, and China, where it has circulated for a decade.

So there is at least trade in poultry from Asia towards Nigeria, and perhaps also from Asia towards Turkey, though I am still checking into the latter possibility.  But even if shipping of poultry turns out to explain the appearance of the virus in Turkey, it seems to be showing up in wild birds first in other countries, for example last week in Italy, Greece, and Bulgaria, and just this week in Germany, Austria, and Iran.

Which leads me to think we will see the virus all over Western Europe in a matter of weeks.  Of course, nobody still has any idea how this is going to turn out in the long run.

Stem Cells from Fat

Bio.com is reporting -- okay, more like carrying a press release -- that Healtheuniverse, Inc., is preparing for clinical trials of stem cells recovered from human fat tissue.  Quoting from the document in question:

Scientific protocols are being prepared for the first human clinical trials using the company's proprietary stem cell technology. This technology uses adipose tissue, or fat which can be used as an abundant source of stem cells for tissue engineering and regenerative medicine. The Company intends to sell this proprietary technology to physicians, clinicians and medical organizations through a packaged product line and licensing agreements within the worldwide regenerative medicine market which is estimated to grow to $500 billion by 2010.

First, clinical trials for regenerative medicine are just getting underway, which means that in only 4 years we are very unlikely to see a $500 billion market.  Second, Healtheuniverse?  HEALTHeUNIVERSE (Ticker: HLUN.PK), according to the website.  A stylism that bears an uncomfortable similarity to www.healthEuniverse.com, and looks like it was suggested by the namebots at Network Solutions.  Brings back nightmares from, say, circa 1999.  But then they are in Biopolis, Singapore, so perhaps I should forgive the name.

All fun derived from the name aside, the technology in general shows great promise.  Zuk, et al., published a paper in Molecular Biology of the Cell in 2002 (full text at PubMed) showing that, "Human adipose tissue is a source of multipotent stem cells."  This may be a way to generate therapeutic patient specific stem cells from adult tissue without cloning.  For example, Timper, et al,. published just last month (PubMed) an article demonstrating, "Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells."

So, promising, and still off in the future.  But I don't think a company trading on the Pink Sheets will be my first stop for stem cell therapy.