Jon Clardy

Clardy JonFirst of all, congratulations on your election to the American Academy of Microbiology! I took a peek at your CV, and your background is in organic chemistry. Do you consider yourself a microbiologist at this point?


Um, not really! I don’t consider myself a chemist that much either. I think the difference is symptomatic of the differences between the two disciplines. To a microbiologist, it would look like I’m just doing a hodgepodge of things – that is, the study of biofilms, chemical communication, discovery of new antibiotics – and it just doesn’t make sense to a traditionally trained microbiologist. To me, it makes perfect sense because I’m always dealing with molecules. So I feel that I’m always dealing with the same kinds of things. And of course there are differences between the kinds of organic molecules I’m dealing with, but everything I do depends on small molecules. That’s the distinction - I think I’m more of a microbiologist than a chemist because everything we do (or at least most of the things that we do) begins with a biological question rather than a chemical question. Then we attempt to understand the underlying chemistry that might be responsible for the biology.


Your group looks for “natural products” made by bacteria in the soil – sort of like archaeologists with a microscope. What kinds of “natural products” are you looking for and how do you search for them?


The answer depends on who is asking the question. [laughs] If NIH is asking, we’re looking for novel antibiotics. But I don’t think that’s much different at heart than asking questions such as: “how do bacteria sense their environment and how do they respond to it?” which is a much more fundamental question. But the answers to that can lead to useful molecules. At the end of the day, I, like most people in the business of science, would like to discover something that turns out to be useful.


Why is the soil such a rich environment for novel chemical discoveries?


Well I don’t think it’s just the soil. It’s true in the ocean, and it’s probably true wherever you look – even probably true inside of us. There are so many different species out there, competing with each other and trying to cooperate with each other, and the way that bacteria deal with the world is through small molecules. If there are a lot of things going on, you need to be able to sense a lot of molecules and might need to be able to respond to a lot of molecules.


Can you speculate as to why some bacteria (such as Pantoea and Pseudomonas) are so adept at producing a vast diversity of natural products?

Partly it’s an accident of what we’ve been looking for. As more and more bacterial genomes are discovered, we’re beginning to find out that organisms, which initially seemed uninteresting chemically, really have the potential to do much more than we ever realized. That said, I think that the bacteria that seem to be very productive most often are found in a bunch of different niches and can also be highly symbiotic in that they’re often found in close association with something else. For example, Pseudomonas fluorescens is almost always associated with plants, requiring them to communicate both with the plants and any other organisms nearby.


Your work very nicely bridges the gap between applied and basic research. Which research leads excite you more – finding potential therapeutic applications of a novel compound or uncovering the natural role of compound in its environment?


The latter! What’s so special about naturally occurring compounds? Why are they so useful in medicine as compared to all the synthetic compounds we can make? The answer is that they have an evolutionary history but it’s an evolutionary history that we know almost nothing about. Everyone has heard of [the antibiotic] erythromycin and if you said to them, “Great – we use it as an antibiotic. What do you think the bug that makes it really does with erythromycin? Why does it make it? Does it want to kill bacteria, or keep other bacteria away? And what are those bacteria? Where does erythromycin come from and how did it evolve? What came before erythromycin and what came before that?” These are all very interesting questions that we don’t know the answers to, and the types of questions we’re trying to work on.


Do you ever feel like you’re discovering more chemicals than you know what to do with?


There are times like that. The truth is that it’s relatively easy to find new chemicals, but it’s very hard to find function for those chemicals. Since what biologists really care about is function, I think that’s the harder job.


How, then, do you prioritize the multitude of projects going on in your lab?


We’re trying to follow a strict logic where we say ok: here is a behavior, a phenotype, some biological phenomenon, and ask: what’s causing that? It might look like there’s something diffusing from one colony that’s affecting another colony – that sounds like chemistry. So instead of trying to … grow an organism up and see if it makes something new, we try to start the other way around and say, “Here’s [a phenotype] … that looks like it’s caused by chemistry through small molecules. Let’s figure out what that small molecule is and then we’ll know its function before we’ve even discovered it.” Once you start prioritizing things that way, it simplifies your life greatly.


In addition to screening for novel compounds from the soil, your group is also looking for new anti-malaria targets. What is your approach and how is it different from what’s been done before?


First, this is a highly collaborative project. We decided to focus on the liver stage of malaria, and we did that because in the liver stage, which is the first stage of malaria, the number of parasites is very low. If you look for agents to block that stage of the malaria parasite’s life cycle, you would cut down the chances of developing resistance just because the number of parasites is so much smaller and therefore the genetic diversity is reduced. There were a lot of challenges, especially for a chemist, in trying to set up the assay. But we did set up a high-throughput assay to find compounds associated with liver stage activity. Now we’re trying to figure out how they work. Down the road, the modest goal is to come up with a better therapeutic or prophylactic agent for malaria that people could take before they had symptoms. But the much more ambitious goal (which I think should be the goal for all infectious disease) is trying to eradicate the parasite. What we’re doing now is waiting until symptoms appear and then trying to wipe out the parasite from the body or trying to kill all of the mosquitos. But I think we’ll need liver stage active compounds for an eradication campaign, if that ever becomes a priority.


Where do you see your field in ten years? What questions do you most want the answers to?


I’d actually like to see the field becoming much more systematic. For example, if you ask the question: what’s the most common way for bacteria to sense what’s going on, all microbiologists would answer “two component regulatory systems”. The next question is, how many two component systems does Bacillus subtilis have? Or Pseudomonas aeruginosa? Genetics has provided answers to that; it’s very systematic in that we can count the number of two component systems in a certain bacterium. The next thing to come (and it will take a while) will be to unravel the signals involved in all of those two component systems and determine what they regulate. What’s the external signal and what do the systems do internally? We really don’t know the answers to those questions for any organism. Microbiology is getting more in touch with its molecular side, which got down-played in our enthusiasm for genetics, and will become more systematic in the future. Through genetics we’ve learned that there are a finite number of things and now our task is figure out what they all do.


What’s your favorite science book?


No question – Microbe Hunters by Paul de Kruif. The other one that I would say was almost as interesting is called Eleven Blue Men by Berton Roueche. It’s a collection of medical mystery stories but, again, it had the flavor of things that I liked to do. It would describe some strange phenomenon such as “11 men turned blue and died”, and go through what happened and you learned a lot of science as you read the stories. What I liked about both of those books is that you could imagine, even as an elementary school or junior high school student, that solving scientific mysteries would be a cool thing to do for the rest of your life.


What’s something that your science colleagues might be surprised to learn about you?


Now that the kids are gone, I’ve become very excited about gardening and ferns in particular. I’m slowly turning the garden behind our house in Boston into a huge Darwinian experiment to see what ferns I can keep alive.