How important is strain choice in virus/microbiology research?
Does it differ with certain aspects of research, like pathogenesis versus structural studies?
How far do we discount studies done on less 'wild-type' viruses?
How come people are happy working with these viruses?
We microbiologists uncover the secrets of how microbes interact with their hosts in order to better understand the infection process. We can use this knowledge to allow us to develop antiviral treatments, preventative vaccines and important applications for these molecular parasites, such as anti-cancer therapies.
All of this requires that we are studying what is real and what is actually going on in the world around us. This is all the more important when peoples lives depend on our work and when we are dependent on tax payers money to fund the research. Generally, this seems very obvious but you would be surprised about how much work is done on by far less-than-perfect viruses. This is because there a number of hurdles in the path of us understanding what is real-life.
Here's the problem:
Much of virology - and other sciences - use experimental models to understand what happens during a real-life infection. For example, much virus research is dependent on a mouse infection system where we inoculate the small mammal with large amounts of virus so that we can know what happens when a human comes into contact with the virus. This can obviously lead to a number of experimental artifacts. After all, mice are definitely not humans. And, so goes the old caveat: mice lie and monkeys exaggerate. This can also be extended to the avian influenza work that is recently in the news that documents the generation of a virus that can spread from one ferret (a good influenza model) to another. What happens in ferrets may not happen in humans.
Another example of this is from the point of the virus: not all viruses are alike. Many strains of a particular virus exist, some are naturally occurring variants that exist out there and are a result of normal evolutionary processes, while some have never existed outside of the virus lab. In general these viruses are very hard to get access to experimentally as the major method of virus isolation and growth is tissue culture and may itself alter how the virus behaves. This occurs through allowing the rapidly mutating virus to adapt to life in a test-tube, i.e to life in one particular cell type (which may not even be the natural host) and to life without a proper immune response. If we are keen to study something real we should therefore be very careful not to accidentally work on some laboratory curiosity.
To take one recent example (there are however, many, many more of these):
This paper, published a few weeks ago in PLoS ONE, seeks to understand how the human respiratory syncytial virus - an extremely important pathogen - affects the expression of specific small regulatory RNA molecules. They are particularly interested in how virus infection of the respiratory tract alters one specific protein involved in control of apoptosis. This work, funded in part by the US NIH may go on to form the basis of a pharmacological treatment to inhibit RSV infection and disease. It may also go on to influence a number of other groups researching the same area. This is generally a well done piece of work - and there is a lot of work done but the one problem of this (a major one in my mind) is what I talked about above, these guys used of a very bad experimental model of RSV.
This group - and many others - use a strain called RSV-A2, which is a well known laboratory adapted strain that has been grown too many times to count on cells that aren't natural (I think it was something like 52 replications on a cow cell line). This has resulted in a viral lab curiosity (see a differential pathogenesis paper here) yet it is still used in so much RSV research, even in a recent paper documenting the first non-human primate trials of an anti-RSV vaccine. This is all very important research which is neglecting real life. Although, much research is now being carried out exploring these differences and using more clinically-relevant viruses.
The same kind of problems plagued the measles virus field for years following the first identification of its receptor molecule, CD46. It turned out that after nearly a decade of research done, this receptor was only used by vaccine (lab-adapted) strains and not wild isolates.
What can we do about it:
This is only one example but I am sure that every kind of virus research is inflicted with these problems, where we can never be sure how to interpret results that are based on these viruses. Many times it is a trade-off over ease of experimenting versus applications of the results, as many times clinical isolates of viruses just do not grow as well or as fast as their lab-adapted cousins. In some fields of research, such as: structural work this is generally not much of a problem I don't think but in the likes of pathogenesis work where we rely on the 'real' virus we must concentrate on making sure what we are using in real.
To stem these problems we could at least back up your results with as clinically relevant (or if they don't cause disease, fully wild-type) viruses as possible. We could at most develop the reagents: a recombinant wild-type virus bearing the exact sequence of wild isolates or a collection of low passage viruses with same sequence as the wild viruses.