Although this is obviously on my mind because of the current situation this is more of a broad question rather than a corona virus question. That’s why it’s here in GQ.
I read The Stand. I’ve seen other movies about man-made viruses. I received a small pox vaccine and an anthrax vaccine just in case they were weaponized. But I realize I don’t even have the slightest bit of knowledge to speak about the subject.
At this point in science and technology how easy is it to manipulate a virus into something else? Like a weapon.
Is it possible to do so without there being indications that the changes were man-made?
Is there a way to explain to non-science people how this kind of manipulation is made?
Back when that anthrax scare, I read that anthrax was not a good candidate to be weaponized. You need something (anthrax spores in that case) that could be made into a powder that could be widely distributed, e.g., from an airplane.
Anthrax spores were described as being sticky, and if you had a bunch of them together (like in an anthrax bomb) they would clump together into a sticky mass and not distribute well.
We can create custom DNA or RNA sequences with whatever sequence of bases we want. In principle, that would be enough… except that we can only with great difficulty analyze such a sequence and determine the properties of the organism or virus (if any) that it would code for: The most practical way to do so is to actually create the thing and see what (if anything) it does (keeping in mind that the vast, vast majority of valid DNA sequences won’t code for anything viable at all).
The reverse problem is even harder: Starting with a list of properties you want your organism or virus to have, and then coming up with a sequence that’ll produce those properties. That’s one of those sorts of problems that can in principle be solved, but doing it naively would take longer than the lifetime of the Universe.
What can sometimes be done, is to either take bits and pieces from different things that have the properties you want, and try to combine them in various ways that you hope will produce the results you want, or to start with something that’s as similar as you can find to what you want, make a whole bunch of random small alterations, and see if any of those get you any closer. But both of those methods involve a lot of trial and error, and no guarantee that you’ll ever be able to get what you want.
All of this works best when the change you want is to produce a specific protein, or a combination of a small number of them. If you already know of a protein that’ll do what you want, then you can easily find a DNA sequence that will lead to that protein, and then it’s just a matter of finding the right place in the genome to insert that sequence. But even knowing that a protein will do what you want is hard, and most often done by finding some other organism that already makes that protein and does what you want. Sometimes what a protein does is a function of its shape, but even that’s tough to work with: That’s what the folding@home project is about, using a whole lot of computational power to try to find proteins with particular shapes that we think might be useful.
Unlike most conventional, explosive weapons, biological and chemical ones are very hard to limit to the intended target. In the worst case, the release of one might backfire and cause more damage to the wrong party.
There was a government program called atomic gardening. The basic idea was to expose plants to sub-lethal doses of radiation in order to increase the rate of mutation. You didn’t have any control over the results but if you did a lot of it, you could expect some of the mutated strains to be improvements.
There were successes. Ruby grapefruits were developed by these means.
I’m not a biologist but I think a similar program would work for viruses. Just expose a bunch of existing viruses to radiation, collect the mutations, and see which ones are more lethal than their ancestors.
Researchers have been able to perform semi-automated whole genome sequencing (in effect, reading and recording the entire genetic sequence of an organism or virus) since the 1990s but techniques and technologies have made this inexpensive and quick in the the timeframe of the last decade to the point that it is now a routine thing that can be done by someone in a decently equipped lab with basic training. Sequencing a genome, however, is only the beginning of being able to modify the genome. Individual genes (which are essentially a template for producing proteins) have to be identified and the behavior of that protein in the context of the organism or environment in which it operates has to be characterized, including its interaction with other proteins and how it is expressed in that context.
For viruses, which have very simple genomes, this is relatively straightforward in theory because they do not have any kind of regulatory systems themselves; however, virion particles (the viral genome within the capsid that is the infectious object) have to enter into the cell of a living organism in order to function, and it is within the context of that cell that it actually has an effect, and it is often difficult to cultivate this in a lab in an observable way with anything more complicated than a bacteriophage. Viruses are often very picky about the cells they infest (referred to as “host tropism”) and so for viruses in complex organisms researchers have to be able to sample the virus within those tissues in various stages of attachment, penetration, hijacking of cell mechanisms or integration into the host genome, replication, and release. This is very complicated and requires a lot of inference because there is no practical way to directly observe the actions of the virus (particularly it it integrates into the host genome).
It is possible to insert genes into a genome or synthesize a gene sequence; the most common way of doing this presently is using the CRISPR/Cas9 technology. It isn’t important to understand the details of this other than it uses a specific ability of some bacteria to identify specific components of a virus that infests them (called a bacteriophage) and disable them. From the link: CRISPR-Cas9 was adapted from a naturally occurring genome editing system in bacteria. The bacteria capture snippets of DNA from invading viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to “remember” the viruses (or closely related ones). If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses’ DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.
People doing genetic engineering can do this same thing with other genetic material. However, this process is far from flawless, and it always produces transcription errors and artifacts that are evidence in a whole genome sequence. Generally, this doesn’t affect the function of the host as long as these errors fall into the so-called “nonfunctional” (e.g. don’t code for proteins) portions of the genome (which are >98% of the genome in humans and other complex animals) although unexpected effects can occur because that “nonfunctional” genetic material often serves other important regulatory functions, which is why it is considered unethical to perform genetic modification therapies on humans without extensive trials (and even then there are unknown risks). So, no, these changes cannot be made without indications of manipulation. There are also artifacts that result from genetic recombination between strains of a virus, but these look far different because what is essentially seen is a whole section of one viral genome swapped for another, and so long as virologists have sequences for both of the source viral genomes they can trace them back and even make estimates on how long ago this may have happened by looking at markers with known mutation rates.
Turning a virus into a “weapon” requires a few different qualities; first of all, the virus has to be infectious to the host; as noted, viruses tend to prefer specific tissues, and will infect different hosts in different ways. This is difficult to predict without a lot of trial and error. Second, to be a weapon the virus has to be virulent; we and every other living organism on the planet are hosts to thousands (at least) of viruses, most of which have no impact upon us and some of which may actually be beneficial. To be a weapon, a virus would have to have a detrimental effect resulting in severe morbidity or mortality. Furthermore, it would have to have severe effects on a wide swath of the population; a virus that only severely sickens or kills a few percent of people is more of an economic weapon than a practical one for reasons that should be now evident. For a weapon, you would want a very high percentage of people (>50%) to suffer significant morbidity, and you probably want a mortality in the double digit percentages unless you just want to make people really sick for some reason. Further, you would want such a pathogen to have a long enough latency period during the infectious stage that one carrier could sicken many other people; the replication number, R[SUB]0[/SUB] determines how fast and how widely the pathogen can spread before a patient can be identified and their contacts can be traced, and the higher that number is the more difficult it is to limit the spread, particularly if the patient exhibits few or no signs or symptoms. Finally, you want a vector for spreading the virus that is difficult to protect from; if the virus is aerosolized (e.g. issued from a presymptomatic carrier as a fine mist that remains suspended in air) that would be best because the only way to prevent contagion is to physically distance or use a filtering respirator, versus a virus that only passes via fomites (infectious droplets or other liquid effluvia which can be protected via hygiene and sanitation procedures).
Despite what you may read in certain, uh, press outlets, it is still beyond the state of the art to synthesize a novel virus with specific lethal properties. There is no practical way to take a completely novel virus (or a synthesized one) and predict that it will display characteristics of the above. Most attempts at weaponizing microorganisms start with taking already virulent pathogens like anthrax, smallpox, et cetera, identifying and selecting particular stains that are shown to be especially virulent and difficult to for the immune system to protect against, and then trying to enhance their infectiousness or increase the latency period.
A good, accessible-to-the-layman reference on viruses can be found in Carl Zimmer’s A Planet of Viruses. This is a short enough book–just over a hundred pages broken into ten chapters–that you can read it in a day or two. It does not answer your questions above but it will give you the basic understanding of why viruses exist, what they do, and how they fit into the context of biology as a whole which is important to understand the answers to your questions.
Anthrax spores (which are the infectious agent rather than the living bacteria themselves) can be processed to make them more freely distributable. The problem is that while anthrax is highly infectious and very virulent (in the inhaled vector), it requires the inhalation of many thousands of spores to result in a serious infection that overwhelms the body’s immune system. This requires a fairly dense distribution to reliably infect people. It also requires a lot of technical knowledge and a well-equipped lab to perform this kind of processing, and the odds of an amateur infecting himself while processing the spores is pretty high. Biological weapons in general are prone to all kinds of blowback in both production and deployment which is why major powers have eschewed them as offensive weapons.
No, this won’t work. Unlike plants (or bacteria) viruses are not living organisms and do not reproduce outside of host cells. Viral genomes are also generally very delicate because they have no mechanisms for fixing replication errors, so a viral genome damaged by radiation will just fall apart and not be viable. Viruses have their own ways of accelerating random modification called antigenitc shift and antigenetic drift. The former occur because of random errors in replication within the cell; the later are due to recombination of the viral genome with itself or other related viruses; the linked article refers specifically to HIV but all viruses have the potential for this, and the Influenza A virus is particularly prone to this. Although this only rarely produces viable new strains, viral replication is fast enough that it still happens with high frequency which is why we need a new multivalent influenza vaccine every season.
I am a a molecular biologist and I endorse Chronos’ and Stranger’s post. A few very small nitpicks however:
CRISPR is an amazing tool for editing the genome of bacteria or eukaryotes, but isn’t commonly used for editing or synthesizing anything as small as a viral genome. That used to involve a lot of copy-paste assembly using restriction enzymes, which as you say leaves a lot of small telltale artifacts:
These days there are a lot of seamless genetic engineering techniques that are pretty foolproof – look up “isothermal assembly” or “Gibson assembly” for one major flavor, or “Golden Gate” assembly for another. When I started in this field ~10 years ago these methods were somewhat exotic and expensive, but they’re now routine. The whole process still isn’t completely flawless, but with a little care and quality control can produce an artificial sequence without any errors or artifacts. For the sorts of genetic engineering I do routinely, basically it means I order one or two pieces of synthetic DNA, stitch them into together into another construct, and sequence two or three different clones to be sure I have one that has the exact sequence I want. The SARS-Cov-2 genome is about 10x larger than the things I typically construct, which is harder to assemble without errors but it’s only a matter of making and sequencing more clones.
This is certainly possible with viruses, but selecting for lethality isn’t quite as easy. Virus selected for maximum replication in cells in a dish might not actually be very infective in a whole animal. And virus selected for maximum lethality in a mouse or other animal might not have the same effect in humans. Finally, these kinds of experiments (called viral “passage”) have been done before with SARS and other coronaviruses, as a way of understanding the mechanisms of the disease. That has been enough to show that the kinds of mutations that are selected for in by “passage” experiments are not the same as the mutations seen in SARS-CoV-2:
That doesn’t completely preclude some kind of ultra secret weapons lab research using a genetically engineered manbearpig, but that kind of conspiracy theory is unfalsifiable and not worthy of additional comment.
Regarding anthrax, the Soviets had huge factories that manufactured weaponized bio and chemical weapons in violation of multiple treaties. And even with a large, determined state manufacturing the anthrax, they still had an uncontrolled release that killed ~100 people in an incident that is now known as the Sverdlovsk anthrax leak. The book The Dead Hand begins with this incident and is truly excellent at laying out the history of various weapons programs and some of the cleanup efforts that came about after the fall of the USSR.
I don’t have much to add, but during a recent flu season (H3N2 or H1N1 I believe) a computer simulation found that substituting one amino acid for a different amino acid on a protein on the viral surface could make the virus much worse.
if I can find the study I’ll post it. Computer simulations are not the same as real life, but we may be entering the age where you can do random mutations within a simulation to determine if it’ll make the virus more contagious or deadly, then use technologies like CRISPR to substitute that section of the genome.
As I understand it, the problem is not in creating a sequence of DNA, but predicting what it does (including secondary effects). It’s one thing to make a change. It’s another thing entirely to make a designer virus or bacteria, unless you start with a specific almost-the-same organism and make one or two minor changes. “I want a cold virus/flu virus, but it has to be more lethal and more easily transmissible”? If we could design genetic material that specifically, We’d have leopard-spot and tiger-stripe pussycats for sale. I’m sure there’s a couple of million waiting for the person who develops those.
Plus as mentioned - testing. How do you test a near-lethal virus for transmissibility? How many disposable human subjects do you have? How do you simulate day-to-day interactions, versus locked-in-the-same-room?
Too many what-abouts. My impression is the genetic technology for designer diseases is not yet there.
I recall old SciFi tales of manufactured pathogens or “death rays” tuned to attack certain “races” or DNA patterns, to wipe out targeted ethnicities. Has research and development of such narrow-beam weapons occurred IRL?
According to that, some expert groups consider it a possibility but I don’t know if any actual weapons have ever been developed.
A lot of those quotes are from 15-25 years ago, and biotechnology tends to advance pretty fast as a field. No idea whats possible in 2020.
Its kind of unrelated to OP, but there is a laser that can kill mosquitoes to help control malaria. However only the female of a particular species carries the malaria protozoa. So they built a laser that can identify if movement is coming from not just a mosquito, but the right species and right gender (based on things like wing flapping patterns), then it shoots it out of the air.
I’m sure something like that could easily be rigged based on obvious phenotype differences in appearance. We could have autonomous weapons designed to identify and kill anyone of a particular gender, race or who knows what other identifier.
If you can detect mosquitoes and burn them out of the air with a laser, why would you restrict it to only female Anopheles mosquitoes. Burn them all, I say …
And yes, I do understand the ecological concerns about killing vast numbers and species of mosquitoes indiscriminately. But still …
False positives could produce embarrassing results. Better include exception lists, like excluded sectors on old hard discs. Otherwise it’s, “Sorry about your wife, Senator.”
You’d starve zillions of species of insectivores. No swallows to return to Capistrano. Sad.