Interview with Mark Fisher, Ph.D.

On February 17, 2012, we conducted an interview with Mark Fisher, Ph.D., a professor of Biochemistry and Microbiology at the University of Kansas Medical Center who has done a great amount of research on anthrax and the protein-folding of the bacteria that is responsible for the disease. He has also been published for his work with anthrax and more information on Dr Fisher can be found at http://www.kumc.edu/biochemistry/mfisher.html. Our interview is presented below:

1. Can you tell me a little bit about yourself and your background?

Dr. Fisher: I grew up in Kansas and was always interested in science from the time I was young, it thrilled me. I obtained a Bachelor's of Science from the Chemistry Department at KU and then went on to the University of Illinois where I received my Ph. D. in Biochemistry. From there I transferred to the National Institute, specifically the National Heart, Lung and Blood Institute. While I was there I first worked on oxidative modification in aging in proteins and then I formulated my own project and put that out to the world at the University of Kansas Medical Center.

At NIH I was one of the first researchers in a field that was a young field at that time and was involving the origin and the function of what they call "Heat Shock proteins" and it turns out these proteins are chaperone proteins. They help other proteins fold so they are "assistants" so to speak and they're called on when an organism is stressed. They're always around and they are a necessary component of the cell. They exist throughout life and they are absolutely essential and are involved not only in how proteins fold, they attempt to keep proteins from misfolding, but also how they disintegrate. They're pretty essential.

2. What lead you from there to specifically focusing on anthrax research with regard to proteins?

Dr. Fisher: Well one of the things that I noticed about these chaperone proteins is that they correct protein aggregation. And one of the most important aspects of bacterial toxins in particular is that these are all protein-derived toxins, from the diphtheria toxins to the botulism toxins to the tetanus toxins to even the anthrax toxins, exist in a free floating form that is soluble in water, but when they interact with cells they change their conformational state to a protein that can be inserted into the cell membrane.

And if they change their conformations outside the cell the proteins aggregate so we were interested in a) figuring out if we could capture one of these pre-aggregation forms and b) seeing if we could determine what these un-inserted forms look like. So we used the chaperone proteins initially to capture these forms that could puncture the cell membrane. And the protein that we are specifically interested in is one of the three proteins involved in toxin toxicity. It functions as a needle, it doesn't kill the cell outright but it helps to transfer the other two proteins into the cell and those two are the real cell killers. We are actually the first lab in the world to actually see a low-resolution structure of this needle protein.

3. So do you still currently work with anthrax? And what kind of research are you working on?
Dr. Fisher: Yes, I am still working with anthrax and actually we've gotten better at obtaining these images that we can now see large versions on the electron microscope. We've also been doing structural analysis, so under different pH conditions we can determine what kind of control regions are changing and if their conformation is the result of changing environmental conditions and so forth.

4. What kind of advances or progress do you hope the results of these tests will be able to lead to?
Dr. Fisher: Well these experiments will be very important in designing small molecule inhibitors that actually prevent the transition [mentioned above] from occurring. So our human health angle with this is that we need to understand how these bacterial toxins go from one form where they're non-lethal to another form where they have to unfold and refold into a new shape and insert into a cell membrane; and then those are the ones that we want to prevent from occurring. But in order to understand the transition from the one form to the other you have to capture the two pictures of the soluble and the membrane insertable form.

5. So understanding these transitions and how to prevent them is the key to fighting the toxins?
Dr. Fisher: Yes, and all of the work that we've been doing lately is involving not only being able to look at the transitions but understanding how fast these transitions occur. Which takes time obviously but we are very hopeful.

6. Evolution obviously occurs as the result of mutations in our genes so how can the theories of evolution be applied to your research with anthrax?

Dr. Fisher: Well when bacteria are confronted with something that can prevent their growth these bacteria then mutate. So you get different mutant strains of the same type of bacteria and understanding what regions can be variable and what regions aren't variable is important to understand because that's how proteins change. They change because of the genetics coding for them, the proteins themselves don't evolve it's the genes that evolve and allow the characteristics of the resulting protein be selected for.

It's important for us to understand not only the overall detailed mechanism of this but also the plasticity of these systems.  They are under genetic control and can actually evolve into a new form that is more highly infectious. An example of course is the HIV virus. You get infected with one virus but people don't die from that initial virus, it undergoes a microevolution and a person's system goes through a battle with it but cannot keep up and is eventually overwhelmed.  All of these micro-organisms, including the ones that cause HIV and anthrax, can change their "code" and as a result drugs that you've engineered so tediously can be circumvented by the viruses. 

7. And we've actually discussed in class how certain people's system are better at fighting HIV and how certain people, such as people with two copies of the CCR5 delta32 gene are basically immune to HIV; is this true of anthrax as well or does everyone's immune system pretty much equal in its resistance to it?

Dr. Fisher: Well anthrax is not as common a disease as HIV at least in humans, it's much more common in other animals, and there is variance in animals where you don't have as much of an effect of anthrax on one individual as you do on another. And these could be as subtle as just having more circulating proteins that are clipping enzymes like proteases that are clipping away at the toxins.

8. Have you ever worked with grid computing in your research?

Dr. Fisher: I know what it is very and I think it can be a very helpful tool but no I have never personally worked with it.

9. Finally, you are clearly well-versed in evolutionary processes and through your experiments have seen evidence of how organisms change; have you ever encountered someone who denied the existence of evolution and/or argued for the theory of Intelligent Design?

Dr. Fisher: Yes, I have many times and I do not avoid them, I confront them straight away. I usually approach it in the language that they're used to. The language of God, I explain, is written in a "book" of molecules not man-derived written word. This is where the ultimate aspects of God can come from because that is something that we as humans did not make. And an interesting thing about those people that believe in Intelligent Design is that they will accept microevolution in the form of bacteria and viruses evolving but they will not accept that macroscopic organisms can evolve. But evolution is the combination of numerous microscopic events which occur at the gene level all the time and I think one of the best arguments that one could make for the existence of evolution is there are virus proteins and viral genomes inserted into the human population. And the viral genes and human DNA co-evolve. Every human being on Earth has some so we are a walking history of evolution on this Earth. We are literally 3 billion years worth of information in books that are put on our genome.

And these enhanced retroviruses that insert themselves into our genome insert themselves into very precise regions of the DNA and these regions are the same for everyone across the population. And this insertion occurs at the exact same location in the genome of chimpanzees. So you can look at the "book" of the genome where the divergences and similarities occur among all organisms. So you can map evolutionary trees based on these enhanced retroviruses that have been inserted into the genome. Viruses have a huge impact on evolution and definitely affect how organisms move from one level to the next. And as I've mentioned, just like with HIV and anthrax, not all organisms are going to react to these viral proteins the same way. Some will be better at contending with them than others and that is the beauty of evolution.


Thank you so much for your time and all of these fantastic information.