How to synthesize smallpox virus

Instructions for a terrorist

Daria Spasskaya, N+1

In January, the journal PLOS One published an article by Canadian researchers devoted to the reconstruction of the equine smallpox virus in the laboratory – the same one on the basis of which Edward Jenner made the world's first vaccine in the XVIII century (Noyce et al., Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments). Despite the fact that the experiments were carried out several years ago, the article was accepted for publication only now. In fact, the article demonstrated that with relatively affordable technologies, a virus that does not currently exist in nature can be easily synthesized and recreated in the laboratory.

In this regard, the scientific community has split into two camps: critics ask why it was necessary to do this at all and why the journal published the article? What if terrorists want to use it to recreate the deadly smallpox virus? Supporters of the authors, on the contrary, say that the article had to be published necessarily and that it should become an occasion for the formation of new ethical and legislative norms concerning synthetic biology.

Epidemics of natural, or black, smallpox almost continuously raged in Asia in The Middle Ages and regularly broke out in Europe in Modern times until the invention at the end of the XVIII century by the English doctor Jenner of a vaccine against it. According to legend, Jenner noticed that cows and horses suffer from a special form of smallpox, and people working with them almost never get infected with smallpox. The doctor suggested that if a person is infected with cowpox, it will protect him from developing a more severe form of the disease. Jenner successfully tested his assumption on a boy named James Phipps. After that, vaccination with a safe form of smallpox became common practice and smallpox epidemics in Europe stopped, but the disease continued to take the lives of people in Asia and Africa.

Cowpox (Wellcome Images)

In the XX century, researchers found out that the causative agent of smallpox is a DNA virus from the Poxviridae family. On the basis of human-safe relatives of smallpox from the same family, vaccines were developed that helped to finally defeat smallpox on the planet. The last case of infection was registered in 1977, and in 1980 the WHO Assembly officially announced the eradication of the disease. Currently, samples of the deadly virus are stored only in two institutes in Atlanta and in Novosibirsk.

A few years ago, the head of the Canadian pharmaceutical company Tonix, Seth Lederman, became interested in the smallpox virus, which Jenner used for vaccination. As the researcher found out, contrary to popular legend, the pathogen that Jenner isolated was most likely a horse pox virus, not cowpox. At least, the ancestral genome of the very virus with which smallpox was eradicated in Europe turned out to be most similar to the HPXV virus circulating among horses and found 40 years ago in Mongolia.

Since then, the equine smallpox virus has also been forgotten, and probably the last sample of it was stored in the United States at the Center for Control of Infectious Diseases (CDC). Lederman turned there to investigate the possibilities of the virus as a vaccine. According to the biotechnologist, viral vaccines that were common in the 20th century (VACV) have gone far from their ancestor and accumulated unwanted mutations that enhanced their ability to reproduce in human cells. In this regard, vaccination in rare cases can cause serious side effects, such as damage to the heart muscle. Using the original virus should be safer.

Despite the good goals declared by Lederman, the virus was not given to him. Then he turned to virologist David H. Evans for help, and the researchers independently recreated the virus in the laboratory. In order to obtain the genome of the virus, which consists of 212 thousand base pairs, the researchers simply ordered the synthesis of several DNA fragments from a company providing appropriate services. The scientists then assembled the virus from parts in cells infected with a related rabbit poxvirus. Genome sequencing confirmed that the HPXV virus was successfully recreated. The researchers also infected mice with it and showed that, compared to VACV, it is more easily tolerated by animals and indeed provides immunity against a high dose of VACV.

Despite some practical and academic value of the article, it was rejected in two journals. In mid-2017, Lederman sent a press release to the magazine Science, thanks to which this story was first made public. The article itself was published in 2018 in the journal PLOS One, and although the editorial staff said they saw no reason to reject the article, the publication caused concern to the scientific community and biosafety experts.

Smallpox virus (CDC) particles.

The fact is that smallpox, as a vaccination against which the Jenner vaccine was used, is considered as a potential biological weapon. Since since the beginning of the 80s of the XX century people stopped being vaccinated against smallpox as unnecessary, the modern population is not protected from a sudden outbreak of the disease. "What if the terrorists want to recreate the smallpox virus in the laboratory? Now they have precise instructions on how to do this, in the form of a publication by Evans and Lederman," critics of the article are concerned. Of course, manipulations with the smallpox virus are prohibited by the World Health Organization, but it is unlikely that terrorists will look back at the prohibitions if they want to do it.

Another argument of critics is the uselessness of such a vaccine based on a recreated virus. In addition to VACV, other, safer options have been developed that are devoid of side effects. In addition, experts generally do not understand why businessman Lederman needs a new vaccine – it is obvious that there is no market for it now.

In reality, judging by some facts about Lederman, he was not motivated by commercial interest. The researcher is a big fan of Jenner and is writing his biography. Perhaps the re-creation of the original "vaccination", with which the famous doctor saved Europe, was fueled by Lederman's ardent interest in everything related to his idol. For this, he did not even spare a hundred thousand dollars spent from the budget of Tonix on the synthesis of the genome of the equine pox virus.

I must say that, despite the attention that this publication attracted, the possibility of recreating the smallpox virus was demonstrated back in 2002, when researchers cloned the VACV genome in bacteria. The engineering of pathogenic viruses in general is also not uncommon in laboratories – for example, we recently talked about a modified influenza virus that was also collected in order to create a vaccine. Moreover, a revealing story occurred in 2011, when two articles on the H5N1 avian influenza virus were banned from publication as a result of the threat of bioterrorism. In these articles, modifications of the virus were described, thanks to which it became able to infect not only birds, but also mammals. The appearance of such articles led to a moratorium on avian influenza virus research, which was canceled only when the scientific community managed to agree that the benefits of such research outweighed the harm. 

Therefore, many scientists support the "reconstructors" of the equine pox virus. Such publications demonstrate the possibilities of synthetic biology and outline a new range of problems facing regulatory organizations. Even if studies with rather vague negative consequences, such as experiments with human embryos, are legally limited, the synthesis of viruses in the laboratory, capable of causing much more tangible harm, should be brought under control. "Someone had to do it sooner or later," say supporters of Evans and Lederman.

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