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Current research interests:
Our main research interests are: to understand and characterize bacterial heme/hemoglobin (Hb) acquisition systems, determine their role in bacterial pathogenicity and to exploit the understanding of these systems for a rational design of new antibacterial agents and procedures that would help the fight against pathogenic microorganisms.
What's the big deal with antibiotic-resistant bacteria?
This is really a big threat, a serious threat. Resistant bacteria are a serious problem in hospitals worldwide, not only here but also in third-world countries. Many pharmaceutical companies have basically stopped working on antibiotics, because the profit margins were not good enough, I guess. Of course now they're back in business, but of course it takes ten or fifteen years to develop a good antibiotic. So in those intervening ten or fifteen years, you can't really have any new ones. It's a big problem.
This is just a side project, but possible antibiotics are one of the things we're trying to address with our research. We are studying heme and hemoglobin receptors in gram-negative bacteria. There are two types of bacteria, gram negative and gram positive, and both types of bacteria are causing problems with antibiotic resistance worldwide.
The problem with gram-negative bacteria is that they have this very tight membrane around them, and all antibiotic has to penetrate the membrane in order to reach inter-cellular targets. Gram-negative bacteria have two membranes, whereas gram-positive bacteria have only one. The heme receptors which we are studying are expressed in this outer membrane, and they bring in heme, which is very important for a bacteria.
So what we are trying to do is develop antibiotics which will hitchhike, which will use these heme receptors to enter the cell. That's our approach. Some other groups are doing similar things, but basically we try to use these highly efficient bacterial transporters to transport novel antibiotics, or to perhaps use old, obsolete antibiotics, fuse them to heme, and then they can go together across the membrane. So that's our small niche in this field.
But we are more concentrated on the structure of these receptors, and this would be just one of the aspects of our research. Bacterial resistance is a huge problem, it's here right now today, and we do have novel compounds to combat it, but it's one thing to discover something in laboratory, and quite another to translate that into real life. That's a huge difference. So what we can say now that we have these antibacterial compounds which are active against many gram negative and gram positive bacteria. But the question is, are they going to be protected in vivo, how toxic are they, and it's a long way to go before we solve those problems. We've made the first steps- we've found compounds that can enter through these heme receptors, but, again, if the question is, 'Is this going to be something I can buy in a drugstore some day,' the answer is 'I don't know'- it's a long way off.
But all science is like that. It takes 10 or 15 years to develop something new. You cannot even go after medication directly. You can't be someone who says: 'OK, I'm going to be the guy who is going to discover a new antibiotic, and everything I do is going to be very applicable.' That's difficult.
How would you explain your research to the layperson?
We are studying mechanisms by which bacteria assimilate or obtain iron. You and me and every other creature all need iron. If we don't have iron, we are anemic, and it's a serious health problem. We get it through our food. The same thing occurs in bacteria- they have to get iron in order to multiply and to cause infections. The problem in the body is that all available iron is tightly bound to different proteins, and bacteria, when they invade you, have to solve the problem of availability.
One way they obtain it is through heme- heme is the most abundant source of iron in the body. We have hemoglobin in red blood cells, and hemoglobin is full of heme, and heme has iron in the center so many bacteria go after it. Some other bacteria have other means of obtaining iron. We are studying the role of the genes and proteins which enable a bacteria to do this, and the role of these genes and proteins in virulence.
So, to put it simply, if you inactivate that gene for heme assimilation, are bacteria still virulent? Can they still cause disease? Or maybe they are attenuated, meaning that they cannot cause disease because they cannot multiply. So in short, we are studying mechanisms of iron assimilation genes, and what's the role of these genes in virulence.
If you find the gene or protein which is so essential, then you know one factor that makes it virulent in vivo. So then, perhaps, we can propose a vaccine based on that virulence factor. Because if your antibodies will recognize that virulence factor, that will perhaps prevent infection.
Why did you choose research as a career?
It wasn't an accident- I always like research. I was studying for an M.D. When I finished, there simply weren't any openings for what I was interested in, and somehow I got into research. I was always interested in research, but life is unpredictable- you want to go one way and you end up going the other way. So I went to Germany for a short postdoctoral fellowship, and that got me into research, and I decided to stay with it. Then I went and got a Ph.D. in bacterial genetics, and that's what decided my career. It was all coincidence- the love for research and science was always there, but it's not that I was following that from a young age, it just happened that way.
I got my M.D. in Croatia.
I wanted to do a residency in infectious diseases. It was socialized medicine in Croatia in those days, and there were only a limited number of slots for, say, infectious diseases or any other specialty. General Practitioners were the ones that socialized medicine wanted the most- and that's even happening in the U.S., many medical students are becoming GP's instead of going into specialties, because they don't know, in the long run, whether or not they're even going to have enough patients.
In those days, you couldn't really get into a residency program for certain specialties very easily, and that was the case with me. I had very good grades, but it was difficult.
Then I went by chance into research, and I stayed in research.
When did you leave Croatia?
I left croatia in 1991 for a postdoctoral fellowship in Germany. Then, in 1993, I came to the U.S., to Portland, Oregon. I did research in salmonella and lyseria.
Was that difficult?
Looking back, yeah. Now I realize it was difficult. It was a big decision. But I always wanted to do good research, and you have to understand that doing good research means having money to do research, and having a good environment. Two things were missing in croatia- money, and a good scientific environment; critical mass, so to speak.
So you must have money and critical mass for research, and that's what we haven't had in Croatia. It's a small country, five million people, and you can't expect that everybody knows everything. Those are the two main reasons why I left, although me leaving somehow coincided with the war. (links) So, it helped. But I wanted to go because of the research, and somehow I just left seven days after the war broke out. That didn't really play a big role, because I made all the decisions earlier.
I still visit.
What do you currently teach?
I teach mainly Physician Assistants and some medical students, medical microbiology. I also have some graduate courses for some first and second year graduate students.
Is it different teaching in a lab versus a classroom?
It's very different because you teach them very practical things. And usually they don't have much exposure to practical lab work, or if they have it's not sufficient. It takes lots of time and effort and nerves, also, to keep repeating the same thing over and over again, very simple, basic things. But students really pick things up very fast, and after two or three weeks they are on their own and they can do their experiments slowly by themselves. Of course they are making mistakes, no question about it, but research is basically about what's the percentage of failure. In the beginning, it's obvious that a majority of those experiments are going to fail. But as you get more experience, you increase your ratio, good versus bad, which means that you're getting results.
What do you teach in the lab?
You need a certain level of knowledge to be able to think about something, so students first have to get the basic facts. Every profession has its own language, so they first have to learn to speak. Then, maybe, applying all this knowledge to a certain problem, you can try to teach them how to think and how to use it. It's difficult to teach them that- they have to have that sparkle in their eyes.
You cannot really define teaching in the lab. They have to have the knowledge, the scientific language, and they have to understand the problem, other than that, I don't know. It's an art, I think.
It's difficult to define- but you have certain students who you can't really get motivated, and you can see that very easily. They may even know the language, and they may even know what the research problem is all about, but they are not motivated, they are not interested in that, and then basically we stop there. But there are other students who, as they learn the language, as they learn the problem, their horizons expand, and you can see that in their eyes. Then things just progress on their own; they start thinking about the problem, and you interact together and come up with the right questions and try to answer them.
You cannot teach someone to be a scientist. You can teach them the language and you can teach them the knowledge, but that which makes you a scientist cannot be taught by anybody.
What are the seminal moments of your career?
That's a tough question, because this is a job. And you have to do your research, and you have to get publications out. This routine I think is killing, a little bit, science and the fun of this job. But the fun is that you have freedom, that you still can do whatever you want to do, even though you have very focused grants and research projects. Still, you can do something on the side which really interests you, perhaps some questions you'd like to answer. This freedom to explore something on my own I think is the most gratifying part.
Of course it's nice when you find something and other people say, 'oh, that's cool' or 'we like that.' So when you talk with other scientists and they respect your work and they find your work interesting, that's also gratifying. So freedom to explore, and recognition that somebody sees that as interesting just as you do, those are the best parts. But this is still a job, this is just a job. It's not 9 to 5, it's 9 to 9, and it's not five days a week, it's seven days a week, it's still a job. As one gets older, this routine of science is more and more, but I think you always have this feeling of freedom and joy of doing this.
Do you think this routine you speak of, or the grant-writing treadmill, is a detriment to science?
It's not a detriment. It has to be. You have to have a system, for science or art or whatever. So you have to produce something in order to get the money to produce something else. The problem is that these days the competition is so hard that it's difficult to get the money- in order to get the money next time you really have to work 125% in order to get your grants. So that freedom I was telling you about, those small side projects I was telling you about- those usually suffer. So you become very focused on what your narrow niche is. And is this good or bad? I don't know. It has to be there, otherwise taxpayers would say, 'I don't want to support your boring science- you are not doing anything.'
I think funding will change because people will try to get more applicable things from us. Your first question was about antibiotics, and that's very normal. 99% of people will ask: 'Do you have that stuff we can use to cure our diseases?'
But science works different than that. There are maybe one hundred of us who are working on, say, ion transport. There's going to be one other guy who will say, 'Oh, we can exploit that for antibiotics.' And then, down the road 10 or 15 years, you'll look back, and it took maybe 100, 150 scientists to come up with these basic things, but ten or five new scientists to come up with a solution. So you cannot expect science to be applicable- you can only expect us to do science.
Do you think demanding immediate applicability of research is harmful?
I think you have to have both. You have companies which want to produce or sell something- and they can be the applied part. And here we are in universities, where we can do both basic research and perhaps something applicable. I don't think necessarily that focus on application will hurt science, but we do have to separate those things. We do have a need for basic science, and of course you don't have to emphasize the need for application, but you have to have basic science so that I don't have to find a new antibiotic in order to get tenure. That would be silly. One antibiotic takes 10 or 20 years to develop. So you cannot expect one person to go from scratch to a new antibiotic. You can expect from me solid work so that somebody else or even me if I'm lucky enough or smart enough, can find a way to exploit bacterial weaknesses.
What's the most exciting thing going on in your lab now?
These bacteria are very smart beasts. They're not bags of enzymes- they can see the environment and they can respond to it. What we are studying now is that it looks like these heme receptors can be switched on and off. Not only can these bacterial receptors be switched on and off, but many other genes can switch on and off. This is known as phase variation: they can vary the expression of their genes.
For a long time researchers knew about this phase variation, but they thought that bacteria could only vary it to a certain degree. They thought that maybe one in one thousand bacteria will have it switched on or off, depending on what it was first- so 10^-3 was thought to be the frequency of variation. So what we have found now is that basically that's really not true. There are bacteria which can switch these receptors much faster, and bacteria which can switch them much slower. So we call them slow and fast switchers.
So what does it mean? Big deal, right. But these receptors are what allow bacteria to grow in the presence of hemoglobin. So if bacteria want to be more virulent, they can regulate this switching, and become fast switchers. On the other hand, if they want to hide and say 'we don't want to rock the boat,' they can turn off everything which affects the virulence, so they don't kill the host. So bacteria can regulate the level of their virulence by regulating the phase on and phase off switching.
So one strain can be much more virulent, or it can become less virulent, depending on the frequency of switching of these genes. So this means that bacteria are evolving now, in real-time. In five years we can have completely different pathogens because they are evolving all the time. They can evolve in one direction or the other, and are probably evolving in both- there will be some strains which are more virulent, and some which are more attenuated, but these will perhaps be transmitted more often.
Tell me about your education up to this point.
We have the European system, so you go to medical school after high school. But our high school is much more difficult than American high school- it's something intermediate between high school and college. So we have very good basic, general knowledge, from history to philosophy. Medical school is six years- five years of courses and one year of internship. Medical school was helpful, and I still remember a great deal from it. It was different from here, though, in that American doctors are much more focused on the patient, while we were more focused on diseases. So that was a problem in medical school in Croatia, I think. The Ph.D. was comparable, but in America you have many more scientists around you, you have critical mass. It's more difficult in Croatia because it's a small country.
I have an M.D. perspective and I have a Ph.D. perspective- on the other hand, it took too long.
Do you have any interests outside your research?
I don't really have too much time to work on my interests.
Sport. Chess. Music.
What advice would you give to students?
If I see a good student, I tell them, 'just go for it.' If he wants to go to graduate school or whatever. I tell them, 'you're excellent, you're good, you're going to succeed one way or another. They will always need people at universities to teach, to do research. I don't know what the future is going to bring you. If you see an excellent student, you say go for it. On the other hand, if you're giving advice to a whole class, that's more difficult. I would say that a career in academia is not an easy road. They should really like that. They should see themselves in that position- that would make the work much easier.
For excellent students, there's no secret. They should just do it and not be afraid. But for the average student, that's tough. I would say 'If you're not 120% sure you want to go there, don't go there- in academia.' My way is maybe different from others'- mine was longer, ten years of school, five years of post-doc; that's plenty.
But for young guys that are really excellent, I just say 'go.'
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