Monday, August 7, 2017

Cloning the vaccinia virus genome as a bacterial artificial chromosome in Escherichia coli and recovery of infectious virus in mammalian cells

On July 6th, 2017 Science published a brief article titled "How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA." I thought it was an important thing to look at both scientifically and ethically. The general public often hears about intersting or new discoveries and advances in science but don't always fully understand the implications of such news. In the Science article, they describe how a Canadian research team, led by David Evans from the University of Alberta, were able to reconstruct a pox virus that is closely related to smallpox.

Image from http://www.sciencemag.org/news/2017/07/how-canadian-researchers-built-poxvirus-100000-using-mail-order-dna

Why aren't we looking at the primary literature? I need to first point out that this particular article is not primary literature. The scientists have discussed their findings but have not yet published the paper on it. Part of that is because it has been rejected twice - once from Science for not really adding much to the current knowledge we have and the second was by Nature Communications for unknown reasons. There is a debate as to whether or not it is ethical to even publish the data. The risk with publication is that someone can take the materials and methods and create the virus that causes smallpox for bioterror purposes.

What do I need to know before I read the article? Variola virus is the causitive agent of the disease smallpox; horsepox is closely related to variola virus. Smallpox was elimited through a worldwide vaccine program and the last cases of smallpox occured in the late 1970s. On May 8th, 1980, the world was deemed smallpox free. (For additional information on smallpox, see the Centers for Disease Control and Prevention.) Since that declaration, the vaccination of the public ceased, leaving the vast majority of the population susceptible to contracting smallpox. The majority of smallpox samples have been destroyed or are stored in Russia or the US (at the CDC). 

What did Evans et al do? According to the article, which is purposely vague, Evans et al ordered the horsepox genome in multiple sections of DNA. Each section of DNA had a section of overlap that allowed for homologous recombination. Thus, the scientists were able to stitch together a bunch of small pieces of DNA into long pieces that made up the entire horsepox genome. Evans et al then introduced the genome to cells in vitro, which were able to be infected by the naked genome and start producing viable viral particles. It is important to note that there are a number of virus genomes that can be infectious, this is not unique to poxviruses.



The technology used by Evans, et al, was based on a 2002 Proceedings of the National Academy of Science (PNAS) paper by Domi and Moss. The article, "Cloning the vaccinia virus genome as a bacterial artificial chromosome in Escherichia coli and recovery of infectious virus in mammalian cells" describes a method for reconstituting vaccinia virus in vitro. Again, this suggests that the technology isn't really novel, but a continuation of previous work. What was novel with what Evans et al did was that it was cheap. The final bill for the work was around US$100,000, making it finanically as well as technically feasible, hence the ethical issues.

The scientific community has faced such controversy previously, one example is when a group of scientists produced a pandemic-flu in the lab (see this article for more information or here for an article by the researchers). There are several things to consider when debating the ethics of such research:

  • Does the research provide useful information? In other words, what are the benefits of the research overall? For some controversial studies, the research gives insight into the evolution of deadly diseases or steps to treatments or vaccines, such as the work by Yoshihiro Kawaoka, the scientist that researched highly-virulent strains of influenza. Other work provides little new knowledge beyond the technical.
  • What are the risks to the general public? It is easy for scientists to sometimes forget that the strides they make in the lab could potentially put the public at risk. Often, their goals are to gain knowledge and insight into biological processes that can lead to helping people in the long run. The hope is that the research they are doing will lead to great strides in their fields and open doors to new treatment options, drug targets, and vaccines. In today's political climate, and post-Bacillus anthracis attacks in the US (B. anthracis is the causitive agent of the disease anthrax) scientists and government agencies need to consider the use of recreated or hypervirulent microbes for bioterror attacks. Thus, there is another layer to the risk taking in letting some knowledge out to the general public through publications where scientists who are more nefarious can take it and create bioweapons.
  • Do the pros outweigh the cons? The scientific community will always debate such controversial studies. It is often up to ethics boards and journal editors to make the tough decisions to publish or not. 
In the end the scientific community, including ethics boards and journals, look at each study on a case by case basis. The Evans et al article has been rejected twice now, it will be interesting to see if any journal will pick it up and publish it. 

Personally, I hesitate to pass judgement unless I have more knowledge of how Evans et al's work is different from previously published studies. I can speculate, but without reading/hearing about the exact experiment, it's hard to judge the level of danger to the general public. I do trust the opinions of journal editors, reviewers, and ethics panels to make the appropriate decision. What do you think? Should they publish it or not? Why? Let me know in the comments!

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