Dr. Paula Sundstrom, Geisel School of Medicine at Dartmouth College. Sundstrom recieved her Ph.D. in 1986 from the University of Washingston and joined the Dartmouth Faculty in the Fall of 2003.
What has been the focus of your research at Dartmouth?
I study a fungal pathogen called Candida albicans. I’ve been studying how this fungus interacts with host cells, how it attaches, invades, and manipulates the host epithelium to cause disease.
What kinds of investigations do you conduct?
I incubate the fungus with oral epithelial cells, I study how the epithelial cells react to the fungus, and I study the gene expression changes of the oral epithelial cells. My reason for doing this is to develop therapeutic strategies to prevent thrush, which causes white patches on the oral cavity and is often seen in immunosuppressed patient as masses of fungi and keratinocytes. And so in patients that are immunocompromised or immunosuppressed, the fungus is actually able to invade and create a sort of biofilm on the surface. I’m trying to figure out how the keratinocytes respond to the fungus and what is damaging the keratinocytes. I would like to ultimately be able to find a pathway that Candida is manipulating to damage the keratinocytes and then try to find pharmaceutical agents that could help protect the keratinocytes. There is a lot of gene expression and analysis using software to try to understand which keratinocyte pathways are being manipulated by Candida.
I also do standard molecular biology. I’ve been working with this fungus for a very long time. I actually had an amazing discovery when I identified a gene that encodes a protein that can attach covalently to our oral epithelial cells. Most microbes attach via electrostatic bonds, and the covalent bond is ten times stronger than any other kinds of bonds. This allows the fungus to attach very tightly to the mucosal surfaces and not be very easily washed away by swallowing and saliva. This is a very exciting discovery, and to make this discovery, I used genetics. I discovered the gene using an immunoscreening approach, and then I knocked out the gene in Candida and showed that they didn’t pair this way. I used biochemical approaches to prove that the protein was functioning in this covalent cross-linking.
Is it very rare that these sorts of proteins attach covalently?
Actually, this protein is very interesting. It’s like a hybrid of a fungal protein and a mammalian protein, because covalently attaching proteins are actually found in mammalian cells. The enzyme involved in this category of covalent attachment is called the transglutaminase, and it uses side chains of glutamine residues to cross-link one protein to another, so that a side chain of glutamine residues will attach to a lysine residues on another protein, and so you get an isodipeptide bond between the side chains of these two amino acids. The N-terminus of this protein is very much like mammalian substrates of this transglutaminase, in terms of the amino acid sequence, in terms of being a repeated protein, and in terms of having the glutamine amino acid repeat. It’s the type of protein that the host enzyme likes to use as a substrate for cross-linking. The carboxy-terminal end of the protein of the fungal protein is very rich in hydroxy amino acids like serine or threonine and gets heavily glycosylated, and at the C-terminus it is covalently linked to the backbone of the fungal cell wall, so this protein has one end linked into the fungus and the other end is cross-linked to a host. It’s a very special type of protein, and in evolutionary time, it’s a relatively new protein. It’s a protein that has evolved to allow Candida to attach very tightly to the places where it causes disease.
How large of a time commitment does your research require? How do you feel about balancing research and undergraduate teaching?
Research takes a lot of time, but the undergraduate teaching I do here is my favorite thing that I do, because I have the opportunity to introduce research to undergraduates. It’s what I do in my class [Biology 67: Biology of Fungi and Parasites that Cause Disease]. We do it by reading papers—primary research papers coming from labs like mine that are making active contributions to biology.
When we read scientific papers, we try to read them fast. It’s very complicated, and we don’t have time to see whether the abstracts and conclusions are supported by the data. The question we address is, “Can we look at this and really see what’s going on?” By doing that, the students get an introduction to research. We talk about the journals that publish the research and what their goals are, the researchers and authors of the paper, the senior author and why they’re doing this research. We talk about the data and what the data means, whether they have good controls, whether they’re supporting their conclusions in more than one way, and in the end, we evaluate the papers in terms of whether it could lead to even more interesting research that will one day help patients, and we eventually start to see what research is about. We see good papers that bring out new ideas and exhibit different types of experiments done in different ways. We can predict that if certain conclusions are true, we can do one experiment and have it come out one way, and we can do another experiment and have it come out another way. We see how rigorous, how good, and how solid the data is. And I can see the light bulbs turning on, and it’s very fun for me. Students are often intimidated at the beginning of the course. I ask questions about the data and the paper, and they struggle to find the answers, but then after a while, they get used to it, and they start to really come up with same questions themselves. It’s amazing the insights they manage to find after their minds become attuned to looking at the data and applying what they have learned in their classes to real research.
It’s such a big step from textbook learning.
It is a very big step; I always get questions at the beginning of class, “What are the textbooks, I want to start reading ahead,” but I rarely use the same papers from one year to the next. It’s very nice for me because I read some papers very carefully that I may otherwise gloss over, but the closest thing we use to a textbook are review articles written by people who are actually generating the primary research. These review articles introduce the background and show how the new data fits into the accepted canon of research. They are very exciting to read, since these are the people who are doing the research, and they have the most interesting questions, and they write about it really well, more than what you would see in a textbook. For each major research paper we read, we usually read a review by the same person, and we discuss the review and have questions, and by the time we read the research paper, the students are ready to go. They have a story already and can see how this new paper adds to the story. It’s quite a bit different, and the students aren’t used to that. And they come into class and see the assignments involving paper X and “explain this” and “what does that show”—very specific questions. And we split up the labor too; Student A talks about this paper, Student B talks about another. The students work in teams to talk about the questions. They have quite a bit of preparation to do for each class; it’s not just me sitting there telling them what to write down in their notes for a few hours. And the sooner that the students start really covering the class material themselves, the sooner they start learning really well. In the last part of the class, the students start giving presentations. They choose their own papers based on the criteria detailed in class, and they have to do an oral presentation and a written paper about their oral presentations. They give a background, they really go into the data, and they really evaluate their papers and see whether it holds up to what the authors are actually saying. They determine whether the paper is actually a good paper. And we have consultants for each presentation that come with prepared questions and generate class discussion. It’s pretty intense for the students; they work very hard to get these presentations together.
What prompted you to teach this class this way?
I started teaching this sort of material when I was at Ohio State University (OSU). I was at OSU for about ten years, and I started co-teaching a class. When we went over papers, it didn’t sit very well with me about the teaching. Later, I followed my own instincts in terms of creating a class that really goes into the primary literature and involves the students. And so I did, and as the years go by, I do change the class in format and material, but I continue to follow my own instincts about teaching. Oftentimes you see graduate students in Ph.D. exams who don’t really know what they’re talking about, they’re in a lab and someone has told them what they’re doing, and they can kind of fill in the blanks but they’re not thinking about it themselves. In this class, I’m trying to develop these skills for thinking critically about data. We talk about the next experiments that can stem from the new data, then they start to think about putting themselves in the driver’s seats for doing these experiments and taking responsibility for what happens in the lab. That’s a big part of why I teach my class this way; I want my students to take ownership of the science.
Do you think more classes should be taught this way?
I don’t like to presume; there are so many other outstanding ways to teach. I’ve heard other professors say that they simply don’t have time to do this. I take the papers and come up with questions to get the students to think, and it does take time to do that. It takes time to get the paper ready. I wouldn’t like to impose that one anyone. I do think that it really works well, and there are many benefits to doing classes this way for the students and for me. We get to really know each other well over the course of the class—I’m able to write pretty good letters for medical schools and other professional pursuits following graduation. When I grade, I usually write the better part of a page to each student covering each part of the grade—class participation, the exams, the presentations—and so after doing that for each student, it’s not difficult to write a letter of each student. That’s a very good benefit of my class. It’s usually a very small class—nine now—but I think we have a system that works very well.
What advice would you have for those who want to get started in scientific research?
It takes a certain sort of mindset; research is thinking logically, and you have to find out whether that’s you. Certain people may have never considered doing research, and they take my class and suddenly know what they want to do, but sometimes it’s hard to know. Researchers are in the lab a lot. The best thing to do is just to go into a lab and work with a grad student or a postdoc and just do something simple at first. It may be just doing an assay for someone, and it may be kind of repetitive, but it’s something you can take a small amount of time to learn and how it fits into the big research picture. And if you like what’s going on in the lab, you can get more involved with an independent project. I know a lot of people do it this way; it’s harder not to have lab savvy before starting your own lab project. You can do this in the right lab with the right support, but this is an easier way in. Also, if you ease into things, you might find out that you like what’s happening in another lab more than swhat is in your current lab; you can make more intelligent choices for what’s right for you.
Switching gears, what do you have to say about public perception of fungi?
Most people don’t know much about fungi; it’s taught as a pretty small part of high school biology. The public perception, I’m not quite sure about, but when something comes out in the news about meningitis, say, people will become very fearful. Fungi are interesting and important on so many levels, though. In terms of death and decay, they’re huge players in the decomposition of organic matter. They have specialized enzymes for doing so, and they can then adsorb these for growth. They help recycle waste and dead stuff all around. They have special ways of growing that allow them to do that; they have threadlike structures called hyphae that allow them to spread and degrade in different areas. Without decay, we’d just be living in piles of stuff! There are lots of positive interactions between fungi and plant roots; they intertwine. Also, fungi are used in industry to make drugs like cyclosporine and penicillin; they’re also used in the food industry to make wine, beer, and cheese. People make a lot of money off of fungi. However, fungi can also be pathogens and pests in taking down crops; their spores can spread through the air. Public perception can depend on what you do; farmers probably have a different perception of fungi than most people. They play a large part in life, but we’re not always aware of what they do.