Kimothy Smith is a molecular epidemiologist whose research on genetic variation in anthrax unexpectedly bought him extra work after last year’s US anthrax attacks. He was a co-author of a key paper (Science, vol 296, p 2028) which compared the detailed DNA sequence of the anthrax used in the attacks to several unidentified, virulent “Ames” strains. He helped uncover the only site at which these strains differed – a discovery that may yet help nail the perpetrator.
It seems more and more likely that the UN weapons inspectors will get the chance to find out whether Iraq is hiding biological weapons. Are you packed and ready to go?
I was placed on the roster of potential bioweapons inspectors last year, so yes, I have a bag packed. The majority of inspectors I know who work for UNMOVIC (the UN Monitoring, Verification and Inspection Commission) are what I guess you’d call ordinary scientists, with additional training and experience.
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Like many of the rest of the inspectors, this will be your first time doing anything like this. What can a bunch of biologists do to uncover Saddam’s bioweapons if he doesn’t want you to find them?
Perhaps nothing, perhaps everything. It works like this: Iraq declares its manufacturing or imports that have a legitimate use, but could also be used for illicit weapons. Then the inspectors put that declaration together with everything else they know, and visit facilities, to see if things add up. If things don’t, they follow up the discrepancies. This thorough, systematic and careful investigation – something that good scientists do very well – is likely to get the job done.
Is someone going to use serious bioweapons in the next decade?
I sincerely hope not, but I fear that they will. I’m not willing to bet that they won’t. But I think we are as ready as the current state of technology and knowledge allows, and getting better prepared every day.
You didn’t always make your living studying deadly bioweapons, did you?
No, I started as a veterinarian in Oklahoma, where I grew up. I also farmed 1000 acres of wheat and cotton, and had a couple of hundred head of cattle. But after a while, I felt like my brain was drying up. While veterinary practice and farming have their challenges, there just aren’t too many intellectual challenges in a dust-bowl Oklahoma town. But there’s family. Too much of it. I am related to nearly everyone in that three-county area.
So you fled to a PhD course at Louisiana State in Baton Rouge – but not to study anthrax?
Nope, red cockaded woodpeckers. They’re very endangered, with only a few thousand left, and the biologists trying to reintroduce them into new areas weren’t having much luck. I tried to discover why, and also what pathogens might be lurking to ruin the translocation. But the folks doing the work didn’t really want to know about pathogens, and the politics of trying to work with an endangered species were impossible – I mean, it took me a whole year to get my hands on an actual bird. Moving into anthrax research allowed me to continue working on the epidemiology of infectious disease but with more funds.
And travel…
Yeah. One day Martin Hugh-Jones, one of the professors, announced he was looking for a graduate student to collect anthrax in Kruger National Park in South Africa. And I said, where do I sign?
Why Kruger?
Kruger Park is ideal for studying anthrax in its natural state, where it is part of the ecology. It’s entirely likely that anthrax evolved in that region of southern Africa, based on the genetic analyses we’ve performed, because it’s where the most genetic diversity is, including some variants found nowhere else we know of. And there probably isn’t another place on Earth where such good records of outbreaks have been kept for so long and over so large an area, with natural hosts for anthrax, and regular epidemics. The best thing about it was being exposed to a different culture, set in such beautiful landscapes, and getting to see wildlife in the natural setting. On the other hand, one day I was walking some way in front of Valarius De Vos, the top South African anthrax expert, looking for the places you find anthrax spores – hyena dung is good. Suddenly he called out: “Kimothy, be very still.” I looked up and there were three bull elephants not ten metres from me. They checked me out, then slowly moved away. But it was scary.
What is so interesting about anthrax?
One of the coolest things about anthrax-unfortunately, it’s a bit Hannibal Lecter-ish – is that it’s one of the very few organisms that needs to kill its host to reproduce. The victim has to die and bleed for the bacteria to escape back into the soil. In fact, if you cover an elephant that died of anthrax with thorn bushes to keep the vultures off, it doesn’t bleed and the anthrax doesn’t form as many spores in the soil. It’s a risky lifestyle for a pathogen, feast or famine. But anthrax has solved the problem by lying dormant for decades, waiting for a new victim. Human beings have a long history with anthrax yet we still don’t have a good handle on everything there is to know about it. The events of the past year underscored that.
When the first victim of the anthrax mailings died in Florida, the lab where you were working got samples of the bacteria almost immediately.
We had a very powerful technique for reliably distinguishing between different genetic variants of anthrax. We were using it to study anthrax biodiversity round the world, and how anthrax evolved. But a few of us also realised how it might also be used forensically, to trace the source of a pathogen. We use variable number tandem repeats (VNTRs) which are small, repetitive DNA sequences. Some mutate slowly and some mutate very quickly, faster than the random single nucleotide changes, or SNPs, often used to track genetic variation. The more they differ between samples, the longer the bacteria have been apart. The rapidly changing VNTRs are ideal for differentiating very closely related isolates, for example in forensic investigations, because they can differ in bacteria that have been separated for relatively few generations.
What did you find?
We found a very fast-mutating string of adenines that could distinguish between several possible sources of the anthrax used in the attacks. I can’t say more than that, because I’m under a non-disclosure agreement with the FBI.
What else can you use these VNTRs for?
The more slowly changing VNTRs can trace phylogenetic relationships within the species, sometimes within the whole genus, across a region or even worldwide. VNTRs have long been used to type eukaryotic species, such as humans – as we saw in the O.J. Simpson trial. They were also used to distinguish HIV samples from different patients in the mid-1990s but, other than that, using them on microorganisms is fairly new, possibly because microbial and eukaryotic geneticists rarely cross paths. Maybe that will change now. But VNTRs can help unravel unanswered questions in the epidemiology and ecology of pathogens. For example, folks have speculated that cattle trails, like the Old Chisholm Trail, helped disperse anthrax across the US. And we are using VNTRs to try to find genetic evidence for that.
When you started studying anthrax, did you realise there was so much interest in it as a biological weapon?
Yes and no. I was aware of its history during the Second World War, and that the Soviets and the US had both done research on it. I became aware of the evidence that Iraq had investigated its use later, during my time as a graduate student in Louisiana. But the depth and breadth of its potential as a biological weapon in warfare and terrorism – no. But it wasn’t long before I learned that some of the people you meet at anthrax conferences aren’t really scientists. Once I was having a drink with two South African ladies at a scientific conference on anthrax there, when this guy literally popped up out of the bushes, tipped over the wine bottle, and put an end to our conversation. I don’t want to say much more about it, but it wasn’t an accident.
What was it like working on the anthrax case in the glare of publicity?
Distracting. Very distracting. Within a week we had TV crews parked outside the building. At one point we were about to have a lab meeting. The office door was open a crack, and the lens of a television camera actually came poking through the door. The head of the lab slammed the door, and we got the building security to escort them out.
If you had to do it over, what would you do differently? And what would you tell a scientist in a similar spot?
I’d get more sleep – and make my team get more sleep too. And I’d advise anyone facing this to make friends with your institution’s public information person. They can help protect you.
How has anthrax and pathogen research changed since 11 September and the anthrax attacks?
The cost of doing business with the “select agent” pathogens that are potential bioweapons has increased. There is more paperwork and tighter security. The regulations are changing, too, such as who can work with them. I understand the necessity for this, but it takes time away from the science and increases the financial burden. And the funding agencies are having a lot of trouble distributing all this new money. There are a lot of proposals to sift through, and they just can’t do it fast enough. The upside is that there is much more funding for research on infectious diseases, and for the public health system. The pay-off for society is a better knowledge base and early warning system for infectious diseases, including those that could be agents of terror.
Is your new lab, Lawrence Livermore National Laboratory in California, already benefiting from the increased funding?
Yes, we’re planning lots of new work. One particularly exciting area is the sequencing of human and agricultural viral pathogens for which there is little or no sequence information available. I’d rather not say which ones right now.
There’s some controversy about scientists publishing the genetic sequences of dangerous viruses, especially since one lab managed to reconstruct an infectious polio virus from scratch just by knowing its genetic sequence.
Until we’re told differently, we plan to publish our results in full. Making our results available to other researchers means scientists can make advances to safeguard against bioterrorism. We simply have to practise responsible science. What a thing to say! But good scientists are also human beings, they can make good value judgments. Scientists are not amoral just because they follow the scientific method. They can decide what science is right to do, and what science may not be.
What research do we need to do to guard against future attacks?
Everything from pathogen ecology, life history, virulence, pathogenesis and host-pathogen interactions, to new therapies and prophylaxis and detection technologies. One thing we especially need is global maps of the background genetic variation in pathogens. It feeds basic science as well as forensic investigation. For that, we need good fieldwork and international collaboration. And we could learn a lot from people’s existing collections – if they haven’t already destroyed them. Some people are doing that because they don’t want the hassle of having these agents around with all the recent attention they’ve been getting.
As you wait to find out about Iraq, military personnel are about to get the controversial anthrax vaccine. Have you had it?
Yes. I’ve been vaccinated for a number of years now. If you’re really facing exposure to anthrax, then the risk of any side effects has to be preferable to the disease. The only real side effect that I’ve suffered so far was an urge to grow my hair long and pierce my ear.