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AUTHOR COMMENTARIES - From Special Topics

Tuberculosis - January 2009
Interview Date: August 2009
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Dr. Barry holding the rare Polynesian Storm-Petrel afloat on a two week voyage through the tropical South Pacific in search of rare seabirds. The team landed on many fantastic atolls and islands throughout French and British Polynesia. Clifton E. Barry, III
From the Special Topic of Tuberculosis

In our Special Topics analysis of tuberculosis research over the past decade, the work of Dr. Clifton Barry, III, ranks at #1 by total cites, based on 53 papers cited a total of 5,178 times. His work ranks in the top 1% in the field of Microbiology in Essential Science IndicatorsSM from Thomson Reuters.

Dr. Barry is a Senior Investigator in the Laboratory of Clinical Infectious Diseases as well as Chief of the Tuberculosis Research Section at the National Institute of Allergy and Infectious Diseases in Bethesda, MD.

Below, ScienceWatch.com correspondent Gary Taubes talks with Dr. Barry about his highly cited work in tuberculosis.

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 What initially prompted your interest in tuberculosis (TB)?

My first knowledge or interest in TB had absolutely nothing to do with anything other than if you look at the bacteria with the eyes of a chemist, which I did, you see some really cool stuff, some really interesting complex natural products that decorate the surface. For a chemist, this is a very attractive organism, regardless of the importance of the disease.

 How would you describe your approach to TB, considering your chemistry background?

Well, as always in science, a lot of the things you do first on any problem are the things you're relatively comfortable doing. My formal training was in organic chemistry, but I quickly strayed from the straight chemistry approaches and more into the biology side of things. Nowadays, I'm even more on the clinical side. I actually have patients in clinical trials—when I was a graduate student studying the fine details of some enzyme, I would have thought it inconceivable that this is what I'd end up doing. It's still inconceivable.

 What prompted you do the research that led to your highly-cited 1998 Science paper, "Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid" (Mdludi K, et al., 280[5369]: 1607-10, 5 June 1998)?

Isoniazid is one of the most important TB drugs. Of the 7.8 million people who get diagnosed with TB, virtually all of them will receive isoniazid. It's a hugely important drug. We had no effort in our lab in that drug. It was an area I was only peripherally interested in. I had read a lot of stuff on it, when a paper that predated ours came out in Science from another lab. It was basically claiming to have figured out the mechanism for isoniazid resistance.

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I heard the PI of that paper give a talk on it at a meeting in Colorado, and he told a story that made absolutely no sense in the context of everything else that had happened in the field. I remember getting up to ask a question, being completely terrified at the time to do so, and asking that since there were conflicting reports dating back 20 years, how did he reconcile those reports? His answer, effectively, was that he wasn't even aware of those reports. That got me thinking about the problem quite a bit and motivated me to take on the project.

When we did, it turned out to be unbelievably complex, much more so than anybody had ever thought. In fact, there is still disagreement in the field about the details and this remains an open question. Here's one of the most important drugs used globally to control TB, and we still don't really understand what it is about this drug that makes a tuberculosis bacterium die. That topic has carried us through the last decade or so with several of other big lines of investigation, including a Science paper we just published a couple of months ago, describing another class of drugs entirely.

The underlying theme to all of these is that many of these very simple-appearing compounds are, in fact, a kind of Trojan horse, ways in which we slip something innocuous in to the bacteria and then it kills itself. We have different ways of understanding how that happens with different drugs, but basically it kills itself by acting on something completely innocuous. That 1998 Science paper was our first brush with that concept. It isn't about intelligent design of the drug. We don't pick an enzyme and make a better and better inhibitor that turns into a drug—what the pharmaceutical industry is really good at. With bacteria, we really have to get them to accept something and then kill themselves, and we don't know why they do it.

 Why do you think that paper then has been so highly cited?

In part because it was so controversial at the time, parts of it were certainly over-simplified and still seen through a lens where we wanted there to be one single target. In part also because the paper described for the first time the enzymes that biosynthesize one of the most important, genus-defining molecules in mycobacterial cells—the mycolic acids.

A lot of people still shake their heads and say we still don't understand how this drug kills bacteria. It poisons many, many processes in a cell simultaneously from what appears to be a very simple compound. As the beautiful studies from James J. Collins's group at Boston University have elegantly shown recently in other bacteria ,even for drugs with a single target, we don’t understand the molecular mechanisms involved in death in detail for simple agents, let alone complex ones like isoniazid.

 What did the paper actually conclude?

That first paper, the one the PI talked about in Colorado, pointed to one particular enzyme and said that was the target. Our paper said it's not that target; instead there was an alternative target in the same pathway that was affected by the action of that drug. Subsequent papers, some as recent as last year, have gone on to identify still other targets of the drug. In a sense, we were as wrong as everyone else; they're all clearly important and contribute to cell death. But the bug isn't a simple little machine. There are subtleties and complexities in the way its metabolism rearranges itself when something happens.

The analogy I like to use is that it's like a modern aircraft with all its redundancies and failsafes. The bacterium has encountered all these things before, so sorting out simple cause and effect is extremely difficult. It's even tricky to identify what event leads to death when they do die. It's not as if we can identify this enzyme and say if we target this, the bacteria dies. That just never appears to work.

 Another of your highly cited papers is a 2000 paper in Nature, "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis" (Stover CK, et al., 405[6789]: 962-6, 22 June 2000). What was that claiming and why was that so influential?

That paper was really the first description of a set of compounds, or a series of molecules, that have really important, dramatic effects against the bacteria. Again, I think that one is most relevant and very highly cited primarily because it's translated into drugs that are actually being tested in human beings right now. That molecule described in 2000 is currently in phase II clinical studies. Another molecule in that series is also in phase II and probably five or six behind it that are rapidly approaching phase I trials. At this point, I'm actually optimistic that we may see a new drug come out of that series. That's big news. There hasn't really been a new drug like this for TB since rifampicin was introduced 40 years ago.

Like a lot of good antibacterials, that drug came originally from a natural product isolated in the 1950s and then it went through a lot of chemical optimization, the end result of which was that 2000 Nature paper. A company named PathoGenesis in Seattle elaborated on that original compound, decorated it with different chemical groups, and came up with that molecule pa824. That paper has a lot of brand recognition, which is why it's highly cited. That paper was important because it really broke this class of drugs open. That particular molecule may or may not be a drug but something in that class will be. I'm as sure about that as that as you can be in this business.

One reason we published that paper in Nature, as opposed to some chemistry journal, is that this was the first time anybody articulated this idea that TB lesions might be hypoxic—that they may be low in oxygen, like cancer lesions. And the activity of drugs against hypoxic TB might actually be important in determining patients' outcomes. That concept represented a major breakthrough although great microbiologists, starting with Larry Wayne at the VA Hospital in Long Beach, California, had been saying this for quite some time.

 Did you get lucky with that compound or was this a well-planned assault on the bacteria?

No, that wasn't at all well planned—it was dumb luck. There are parallels to cancer here that are amazing. One of the things people do with cancer when they have a significant tumor is try to measure the oxygen tension. If that's low, the prognosis is usually very bad for the patient. You have what's called an anoxic tumor, or hypoxic tumor. So for a long time companies have tried to make things that would work under low-oxygen conditions in tumors.

Just by accident a group working at Ciba-Geigy in Hindustan was making this class of compounds, looking for better tumor radiation hyper-sensitizers and it just got entered into the corporate archive. They were screening against everything, running a TB screen, when they discovered this compound had anti-TB activity. PathoGenesis was led by a great combination of a microbiologist with sharp insight (C. Ken Stover) and chemist that wasn’t locked in to the notion that every discovery project had to have an enzyme target (Bill Baker) and they just picked up on that and took things quite a bit further chemically. That was complete dumb luck on our part and it's the story of the whole modern pharmaceutical industry—compounds made for one reason turned out to have some other activity instead.

 Did you expect these two papers to be so influential, or did it come as a surprise?

"...people are more and more terrified, as they should be, of drug-resistant TB, completely blowing out all of our decades and decades of work in TB control programs."

I'm always shocked when people actually read our stuff. In both of these cases, I remember thinking, "Well, this is almost a complete waste of time to submit it to x, to Science or Nature or something like that. It has no chance of getting in." I still feel that way when we send a paper off to Science or Nature. I still do it, though. I have this fantasy that we'll get something in, and every once in a while it happens. So, no, I'm definitely not that far-sighted to be able to tell if we've done something really that important. A lot of our real influence on the field has been because we’re a highly collaborative group and we’ve been lucky enough to team up with some of the best scientists that work in TB and drug discovery. Most of my highly cited papers represent collaborations—I’ve always been a good team player.

 It's been almost a decade since then; how has the field of TB research evolved in that time?

Well, there's been an exponential increase since then in people interested in the area. To some extent it's driven by the fact that funding has also gone exponentially higher; it's also driven by the fact that people are more and more terrified, as they should be, of drug-resistant TB, completely blowing out all of our decades and decades of work in TB control programs. Back when that paper came out, there was probably one group in the world seriously working on TB drugs. Now you couldn't count the number of groups that have some serious efforts in this.

I remember that back in 1997, I was asked by Gordon Research Conference people to put together a new Gordon conference on TB. I said I wanted to do it on TB drug development. I got a very skeptical letter back saying, "Are you sure? You have to get 90 people to come to the meeting or we won't hold it again." So I piled my entire laboratory into a van, took everybody, got all my friends to come, and barely squeaked by with 90 people. This year, the meeting is already sold out with 160 people attending and nearly 100 more on the waiting list to get in—and the meeting is still a month away. It gives you some sense how the field has grown and how thinking has evolved.

 How has your thinking about TB drug development evolved over the years?

Mine has changed dramatically. I used to think this would be pretty simple stuff, all about chemistry, and how you can sort of understand what the essential enzyme was in the bacteria and move from that to a drug. Now I've devoted much more effort to understanding how these bacteria are complex systems, and really the only way to intelligently attack this is to either give up and say it's all luck, just keep playing the lottery until you win, or try to delude yourself into thinking you actually understand what's going on and continue to apply the scientific method to it. I choose the latter; otherwise I'd just go off and watch birds for the rest of my life.

 Could you afford the bird-watching option?

No, I can't, but I'm hoping to retire early enough to have a second career as an ornithologist.

 What would you like to convey to the general public about your work?

That's easy. The biggest message is that TB is not a fixed problem. The general perception still, in the United States and Western Europe, is that TB was my grandfather's disease or their generation's and that it's fixed. Three million people a year die from TB and 10 million get infected. The way drug resistance comes about in this organism is really scary. I have seen enough people dying from this disease that I can tell you it is not your grandfather's disease.

A lot of great people work in this field now, but it still has a tiny fraction of the funding of HIV/AIDS, and it kills more people than HIV/AIDS. It's just that they're the wrong people. They're people with brown skin and black skin and they don't live here. But that doesn't mean the disease won't be here in our lifetime.

There's definitely a perception in many countries that TB is a disease of poverty, something to be ashamed of, that only beggars get it in places like India. That's absolutely not true, this disease strikes down college students and middle-class workers as efficiently as the impoverished. Way back when, it used to be a disease of aristocrats and poets and famous people—people suffering for their art were the ones who got it. Thoreau died from it, Orwell died of it, Chopin and Schrödinger died of it, Chekhov, Keats...the list is unbelievable. It was this romantic thing in the 19th century—a disease associated with aristocracy and the arts. In our century, it has this reputation as something dirty, a little secret that poor people die from. But all that can change very quickly if we don't do something about it.

Clifton E. Barry, III, Ph.D.
Tuberculosis Research Section
Laboratory of Clinical Infectious Diseases
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD, USA

Clifton E. Barry, III's current most-cited paper in Essential Science Indicators, with 187 cites:
Stover CK, et al., "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis," Nature 405(6789): 962-6, 22 June 2000. Source: Essential Science Indicators from Thomson Reuters.

KEYWORDS: TUBERCULOSIS, DRUG TREATMENTS, ISONIAZID, DRUG TARGETSNITROIMIDAZOPYRAN, CLINICAL TRIALS, HYPOXIC TB, DRUG-RESISTANT TB, POVERTY.

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Special Topics : Tuberculosis : Clifton E. Barry, III Interview - Special Topic of Tuberculosis