Microbiology can be dirty

Students are starting to repopulate the campus and the relaxed pace of the summer is being quickly replaced by frenzied preparation for the start of the semester. This semester, I will be teaching the intro to microbiology course that I have taught every year. In the lab, we do some bioinformatics analysis of metagenomic data from a Winogradsky column. A Winogradsky column is a clear cylinder full of pond mud that is used as an enrichment culture to grow bacteria that cant be grown under normal laboratory conditions. To make a Winogradsky column, you collect mud from a pond or riverbank. (For those of us that are used to the cleanliness of working in a sterile hood, that means you have to take off your lab coat, get down on your hands and knees, and scoop up handfuls of goopy stinky slimy stuff from the the edge of a pond. I wear latex gloves.) You then add it to a plexiglass cylinder along with a source of cellulose (I use leaf litter) and additional sulfate to promote enrichment for microorganisms involved in the sulfur cycle. Over a period of months, layers of microorganisms requiring a range of environmental conditions develop in distinct niches with distinct populations participating in diverse metabolic activities. As various metabolites in the column are used, byproducts are produced, and the environment in the column changes. As a result of changing concentrations of oxygen, hydrogen sulfide, and variations in metabolites, different microbes will thrive and create their own niche.

Although you can see some changes occurring in the first few days, it takes several weeks or months for it to develop so I always set it up before the semester starts. This year, I had the help of my daughter (age 5) who was eager to get her hands into the gooey muck. We took the mud from the edge of Vassar Lake, a pond on campus. In the pictures you can see the changes that take place over time. The column starts out as grey silt, while the column on the left is 1 year old. The patches of colours are the different communities of bacteria.

(OK, so there is no virology in this post but it sure would be interesting to analyze the viral population of the column in addition to the bacterial population. What is the role of bacteriophages in the community dynamics and nutrient cycling in the Winogradsky column?)

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Broad Spectrum Antiviral is an Effective Inhibitor of Viruses but Not Media Hype

There have been a few important successes in antiviral drug development, but for the most part it is extremely difficult to find drugs to treat viral infections. Viruses are highly effective hijackers of cellular processes, and since drugs that target cellular processes are likely to be toxic, that leaves only a few potential virus specific targets. Further, because of the diversity of viruses most antiviral drugs are very specific for their target virus and are not effective against others. The holy grail of antiviral drugs would be something that inhibits replication of many viruses – a broad spectrum antiviral.

A new paper in PLOS One describes a creative approach to the problem of broadly targeting viral infections. The approach uses a recombinant protein that combines the properties of two natural antiviral response pathways in the cell. Almost all viruses generate long double stranded RNA (dsRNA) at some point in their replication cycle. But long dsRNA is not found in normal, healthy cells. So the presence of dsRNA triggers a response in the cell that shuts down gene expression, which can effectively shut down viral replication. Another response is apoptosis: an infected cell can trigger a cellular suicide pathway, destroying the infected cell and the virus along with it. In this new study, researchers fused parts of proteins from key mediators of both pathways to generate a new protein called DRACO that triggers apoptosis when it binds to dsRNA.

In cell culture, DRACOs induce apoptosis in cells only when dsRNA is present. The study goes on to test whether DRACOs can protect cells from infection. Cells pre-treated with DRACOs survive viral infection, while untreated cells don’t. And it protects against a large variety of different viruses; viruses from 7 different families were tested and DRACOs appear to be effective against all of them. But for an antiviral to be useful it has to also work in vivo, and DRACOs show some promise here too. 60-70% of mice pre-treated with DRACOs survive influenza virus challenge, while only 10% of untreated mice survive.

The results of this study are exciting and show promise but we must be cautious about over-extending the findings. It is a long and challenging process to go from an early stage development like this one to a clinically useful anti-viral drug. There will be some very significant hurdles to overcome to develop this further. In all the experiments, the cells (or animals) are pre-treated with DRACOs, but its not known if there is any post-exposure protection. The animal studies show that interperitoneal injection can protect animals, but the distribution of the drug in different tissues varies and in some tissues disappears before 24 hours, which could be a problem if it can’t reach the required concentrations in the target tissues. Also, being a protein, there will be challenges for effective delivery (since interperitoneal injection is not likely to be a favored route!). Many years of further testing, development, and clinical trials (if it gets that far) are needed. Despite the many challenges that lay ahead for further development of this broad spectrum anti-viral, it appears promising and worth pursuing.

As usual though, news reports describing this as a major breakthrough have missed the point that this is an interesting new development but that it is very much in its infancy. Since nearly every discovery is hailed as a breakthrough, the public gets a distorted idea of the way science proceeds. Media reports have also been misleading, including promoting it as a potential treatment for HIV or Hepatitis, which weren’t even among the viruses tested, or touting it as a possible cure for nearly all viral infections. Slow down a little, folks. There is a long way to go before those claims can be made. Perhaps someone can develop a treatment for the disease that makes headline writers distort information.

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Variola virus evolution

Why do some people get severely ill with an infection while others catch the same virus but don’t get sick? There are many factors that can influence the progression and outcome of disease, but they can be lumped into four basic categories: host, agent, transmission and environment. For example, infection with Variola virus results in smallpox, but case fatality rates in different outbreaks range from very low to as high as 30%. Its likely that many factors contribute to this variability, but it’s likely that differences in viral strains is one of them.

Summers are quiet here at Vassar. There are no summer classes but we do have a program to support undergraduate research (“URSI”) so that students can gain some research experience and professors can get cheap labor. This summer I had a student working with me who is a Biochemistry major and Computer Science minor (called a “correlate” here). She can write code and I cant, so I had her working on a bioinformatics project. We were interested in investigating the difference between poxviruses that cause high mortality rates in humans (like some strains of Monkeypox virus and most strains of Variola virus) and those that dont. I recently published a paper along with another undergraduate student showing that certain genes in poxviruses are under Darwinian selective pressure. We wanted to test the hypothesis that the selective pressure differs between virulent and avirulent strains. She used several approaches involving analysis of synonymous and non-synonymous mutation rates to see if amino acid altering mutations were fixed at different rates in virulent and avirulent viruses.

As she crunched away at code writing and data analysis and discovered one of the joys(?) of science: failing to support your hypothesis. We could not find evidence that selective pressure differed between virulent and avirulent strains. Although no Vassar student wants to fail, failing to support a hypothesis is not actually failure. Rather, its an integral part of the scientific process, something that comes from the successful execution of an experiment that tests your hypothesis. The scientific method is actually quite humbling: you set up experiments that will tell you if you are wrong, and as a scientist, you have to get used to proving yourself wrong.

So now we must ask a new question: since some poxvirus genes show evidence of selective pressure, and that selection is not related to virulence, what is the cause of that pressure?

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Virology Research and Teaching in the Liberal Arts

I work at a small liberal arts college, where I teach and do research. The balance can be difficult; the teaching is quite demanding so getting research done is challenging. During the school year my efforts are focused on teaching and the summers are when I can get more research done. With any job there are always things that could be better, but I have enjoyed being at Vassar since I got here in 2007. I just spent several days at the ASV (American Society for Virology) meeting in Minneapolis, where I reunited with several friends, met new people, and gained a greater appreciation for the great job that I have!

First, just having a job is good, let alone one that is exactly what I wanted. I met many post docs seeking and failing to find positions. I met researchers that want to teach but can’t due to the lack of opportunities at their institutions, or simply aren’t allowed to. I met researchers who are completely dependent on grant money for the continued existence of their position. With the current state of funding, that is certainly not a position I would want to find myself in.

The nature of my position is very different from most other virologists. I imagine there are other virologists at liberal arts colleges but I only met one at ASV. In addition to posts on cool things in virology, and posts by students, I will start adding posts on my experiences doing virology research and teaching at a liberal arts college

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