Photo Credit: James Gathany, Public Domain. Dr. Terrence Tumpey examines a reconstructed version of the 1918 flu.

With the rapid pace of shiny new discoveries in the biotechnology sector, it’s easy to lose sight of the fact that there are some pretty incredible technologies which have been around for quite some time now but have fallen off the public’s collective radar. One example is something I have done hundreds of times in my career but still seems impossible to those outside of the field: creating a flu virus from scratch. Not mutating an existing virus to make a new strain, but creating an infectious virus from whole cloth using nothing but common, commercially-available laboratory materials. And not just any strain, but the equal ability to make a harmless laboratory strain or reconstitute the 1918 “Spanish” flu.

And this technique is not just limited to the influenza virus: to date, the ability to reconstitute infectious virus from common, innocuous, non-infectious materials – known in the business as “reverse genetics” – exists for dozens of different types of viruses, including (but certainly not limited to) influenza, poliovirus, HIV, hepatitis B and C, SARS, rabies, measles, Ebola, Dengue, West Nile, and on and on. The ability to artificially create a virus is a powerful tool for researchers, as it allows us to create new variants and see what effects a targeted mutation may have, as well as being able to design new strains with more favorable properties for use as vaccines.

However, the ability to construct pandemic viruses whole cloth with no need for any sample of the original virus also poses some powerful threats to public health and safety. So let’s take a look at how this process works and what the implications of this technology are.

Back to Basics: How Is This Even Possible?

The key point to remember about viruses is that they are not only obligate, intracellular parasites, but indeed are not really functioning organisms at all. At the most fundamental level, a virus is just a small amount of genetic material which encodes enough information to a) Hijack a host cell’s synthetic machinery, b) Replicate its own genetic material, and c) Get the host cell to produce a physical package that can bring that genome to a new host cell and insert it into that cell. So while we might conceive of a virus as similar to a bacteria — in the sense of being a small infectious particle that lodges in our body and replicates — viruses are really just genomes that are dependent on everything else they need from the cells they infect.

This crucial fact is what allows us to create a virus from scratch. Genetic material (confusingly, viruses use both DNA, RNA, and DNA/RNA hybrids as their genomes, whereas all other living organisms only use DNA) is inherently easy to create artificially and to manipulate in the lab. With only four bases which assemble into linear chains, DNA is the perfect biochemical building block to work with in a laboratory setting.

Thus, the theoretical steps in creating a virus from scratch are: a) Find the sequence of the virus you want to create, b) Create a synthetic DNA/RNA construct with this sequence, c) Introduce this genetic construct into a cell culture in a Petri dish, and d) you’ve got a virus!

Reconstituting the 1918 Spanish Flu

In a breakthrough which was widely publicized at the time, a group of researchers at the CDC and the Mt. Sinai School of Medicine in New York reconstituted the pandemic 1918 “Spanish” influenza virus in the early-to-mid 2000s. The most technically difficult challenge was actually obtaining the sequence of a virus which had not infected humans in over 80 years. This was overcome by painstakingly isolating segments of viral RNA from several corpses which had been buried in Alaskan permafrost, as well as using several lung biopsies from deceased soldiers which had been preserved in paraffin. Because these specimens were so old, most of the viral RNA had degraded, so the researchers were forced to sequence millions of small fragments – in total, much more than the actual genome length of about 10,000 nucleotides – in order to obtain 100% coverage.

Once this sequence had been confirmed and entered into the database, it was then time to create a new, full-length, intact copy of that genome which could be inserted into a cell culture. This was a fairly straightforward task using machines which automatically synthesize DNA. However, because these machines can only create chains of DNA, but the influenza virus (like many other viruses) actually have genomes consisting of RNA, a few molecular biology tricks are available to convert the synthetic DNA into the RNA form which can then hijack the host cell. This is typically achieved by embedding the DNA version of the genome into a larger DNA backbone which is taken up by cultured cells and contains extra genetic elements which direct cellular enzymes to create an RNA copy of the synthetic DNA which is identical to an actual viral genome. In other words, for our own convenience, we are also tricking the host cell into creating a viral RNA genome out of a piece of artificial DNA – and once the cell creates that viral RNA genome, it immediately sets about hijacking the host cell into producing virus, both by creating new copies of itself and by creating the proteins which will then form the viral particle encapsulating the RNA.

From the standpoint of the biologist, this is an incredibly simple process. Designing and manipulating the DNA may have been slightly tricky, but once we have that DNA, it’s literally a matter of sprinkling it (in dissolved form) onto a Petri dish full of mammalian-derived cells. Put the cells back into the incubator, wait 24 hours, and the medium on top of the cells is chock full of your virus. Incredible!

Indeed, this procedure is so simple that many research laboratories (including the ones I have worked in) create dozens of new strains of the flu virus on a weekly basis. Find a specific locus you want to study more, introduce a mutation into that locus, create your virus, and run tests with it (in cell cultures, lab animals, etc.) to see what new properties it has.

The Bad News

As you might be guessing (if you’re still reading this far), this process could easily be manipulated for nefarious reasons. So let’s address the obvious question: Could terrorists conceivably recreate the 1918 Spanish flu (or another pandemic virus) on their own?

The answer is a definitive “yes.” As a PhD-level virologist, I wager I could set up a lab using commercial, off-the-shelf technology that would be capable of creating influenza viruses (including the 1918 virus) for between $1-2 million over a time frame of about 1-2 years, given one PhD-trained virologist and a team of three or four capable biological technical assistants. And keep in mind that there are several thousand of us around the world with this experience, and it is very simple for a talented student from a Middle Eastern country to obtain a scholarship for graduate school at a European or American university where he could learn these skills.

What’s more, the techniques are simple enough that nearly any PhD-trained scientist (or laboratory technician with enough experience and resourcefulness) could teach themselves these techniques in about 1-2 years. Thus, it is easily conceivable that a terrorist cell could recruit a Western-trained PhD biologist to lead such a project for a reasonable fee and time span, without necessarily raising any red flags.

The Good News

Before anyone starts building an airtight bubble in their basement, keep in mind how much hype we have heard over the last decade about looming viral pandemics, and how few of them have actually panned out. From SARS, to bird flu, to swine flu, to Ebola, all were sold as the coming apocalypse, yet all were fairly easily manageable (obviously the jury is still out on Zika).

The truth is that we have gotten the worst viruses under pretty good control, be it through vaccination, drugs, or other preventative measures. We have very efficient infrastructure for vaccinating against the flu, polio, measles, or any other virus which could be manufactured in the lab and spread through the air. What’s more, a number of recent studies suggest that we may still be quite immune to the 1918 Spanish Flu, and there is also quite a bit of immunity to polio virus from previous vaccination campaigns.

What about SciFi’s recurring scenario of a rogue syndicate which designs a new “killer” virus in the lab? Here there also seems to be reason not to worry. As mentioned above, research laboratories are constantly creating new variants of many of deadly viruses to observe the effects of those changes. And intriguingly, most of the new variants which are more potent in vitro are duds in actual animal models. Indeed, it’s fiercely difficult to engineer a virus which is more virulent than the strains found in nature while also being resilient enough to get efficiently passed from one person to another.

In other words, there’s a good chance that the viruses we’re exposed to in nature are already the worst that evolution can come up with – that they’ve already reached their optimum. Because of their incredibly small size, every nucleotide of a virus’ genome is multifunctional – and it appears that enhancing a virus’s capability in one aspect leads to a trade-off in some other aspect of its replicative cycle. So, considering how well we’ve managed to neutralize the threat from natural viruses, we probably don’t need to worry much about man made ones, either.

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