Thread by @PeterKolchinsky

SARS2 is a scary menace, but did you know that we’ve domesticated viruses? Like wolves vs dogs, we’ve tamed them, including some deadly ones, to perform many useful functions (and may help us stop SARS2). I became a virologist to understand their uses. Here are 9 examples...

1) HIV has killed millions of people, disabling a person’s immune system until it can’t defend them against common, normally mild pathogens. HIV’s special trick is to permanently integrate its genome into that of our own cells (don’t worry, SARS2 doesn’t).

We use that feature of HIV for gene therapy, eg replacing chunk of the virus’s genome w/ hemoglobin gene to insert it into bone marrow stem cells of patients w/ sickle cell anemia (who have malfunctioning hemoglobin genes). Similar therapies work for other diseases. Thanks HIV.

2) Adenoviruses typically cause mild infections, including common colds. These, too, we are trying to use for gene therapies, particularly when we just want to temporarily make a protein in cells. One company is developing such an adenovirus gene therapy for heart disease...

...to induce growth of new blood vessels when old ones are clogged. Another is using this virus to make oral vaccines that would otherwise require injection (eg flu vaccine pill). When we use a virus to deliver code for making something in cells, we call that a virus vector.

3) JNJ & Oxford/AstraZeneca are developing vaccines against SARS2 using adenoviral vectors that deliver the gene for SARS2 Spike protein into our cells, where it’s produced and trains our immune systems to attack anything covered in that protein, namely SARS2! Thanks adenovirus.

4) There’s a virus called Adeno-Associated Virus (AAV) that doesn’t encode enough instructions to replicate in cells unless that cell is also infected with Adenovirus (AAV steals some of adeno’s proteins). Bit of a moocher. We’ve figured out how...

...to gut the entire AAV genome & use its shell to deliver a useful gene into certain cells that AAV infects well (eg liver, retina, & spine. Novartis makes a gene therapy for a rare disease called Spinal Muscular Atrophy (SMA) that uses AAV. It’s transformative for kids.

Some companies are trying to use AAV to deliver genes encoding proteins that would prevent people from losing their eyesight due to aging. One such viral gene therapy is approved for a rare genetic form of blindness. Thanks AAV.

5) There are also viruses called phage that infect only bacteria. We have turned them into really cool tools for creating drugs. These phage act like a diverse set of self-replicating barcodes that encode one peptide drug candidate each.

We see which phage sticks to a protein and then grow up more of those phage in bacteria. We do several rounds of that kind of binding & replication, basically evolving a drug through natural selection, until we find the code for the peptide (which means “short protein”)...

... that sticks to the target protein so well that we can turn the peptide into a drug (either as a peptide or integrated into an antibody). There are a number of drugs on the market that were discovered using such phage-display libraries. Thanks phage.

6. For many decades, we’ve also been trying to turn phage into antibiotics. It’s kind of like using cats to get ride of mice except in this case we hope to fight off an infection caused by a bacteria by injecting phage specially selected to assassinate that bacterial species.

Phage not only don’t infect human cells, but a specific phage won’t infect a different bacteria than it evolved to infect. So a phage-based antibiotic treatment wouldn’t kill off our good bacteria (as chemical antibiotics do to varying degrees). This phage work is still ongoing.

Phage are among the most alien looking viruses, in my opinion. My firm has a collection of glass viruses made my Luke Jerram. This sculpture of the lambda phage is one of my favorites.

7. We use viruses in many other ways in laboratories. For example, we’ve got lab tests called pseudotyped virus neutralizing assays in which a defective HIV has been modified to use SARS2 Spike protein (instead of its own gp120 protein) to infect cells like SARS2 would to see...

...if vaccinated people (or animals) have antibodies that block this frankenvirus from infecting cells. If yes, vaccine is said to elicit a neutralizing antibody response (which is good) against SARS2. Don’t worry, if this lab creation escaped, it wouldn’t be able to replicate.

8. And of course, viruses that threaten us can be turned into harmless vaccines against themselves. I’ve explained before how vaccines work (see pinned tweet). Eg. Flu vaccines are made by growing up flu viruses in chicken eggs and then inactivating those viruses so...

...after we’re injected, they harmlessly train our immune system to recognize those flu strains in the future. Like showing our immune police cells a picture of what the bad guy looks like.

9. One particularly cool approach to turning a virus into a vaccine is to weaken it (ie attenuating it) instead of killing it. That’s historically been done by removing or breaking parts of its code, and then deliberately infecting people (still considered vaccination)...

...which gives immune system a chance to see virus in action, which can be better than just seeing a picture of the virus. Attenuated vaccines are typically safe but can cause disease in some people w/ weakened immune system. A novel way of creating an attenuated vaccine is to...

...recode the virus so that the instructions actually still tells the cell exactly how to make the same virus but to make the code so complex that it takes the cells a long time to read it. Like rewording “Cut this” to “Render this whole to bring about its separation into parts”.

Think of it this like the difference between evil robots that infect cells w/ easy to understand instructions for making more robots vs instructions written in legalese or Shakespearean English so that cell’s factory workers are left scratching their heads as to what it means.

They still make the robot copies as instructed, but so slowly that it prevents this kind of attenuated virus from doing much harm. In the meantime, the immune system studies it in preparation for someday encountering the fast-replicating, real bad guy.

10. Here’s what viruses don’t do. In Mission Impossible 2, writers concocted the idea of stopping a deadly virus with an “antivirus” that directly attacked the bad virus. I was in grad school studying virology when that movie came (2000) out. imdb.com/title/tt012075…

I thought it was lame that Hollywood had to dumb things down like that. You can stop a virus w/ an “antiviral” drug or an “antibody”. You can even use a viral vector to deliver the code for an antiviral antibody (how cool do all those terms sound used together!?).

But no, Hollywood had to resort to an antivirus, which is what we call a type of software for stopping computer viruses. Gratuitously inaccurate. My friends and I thought that maybe Hollywood didn’t know any actual virologists...

...who could have made that script more accurate. So I tracked down a Hollywood science advisor (who consulted on Star Trek shows). He explained that actually Hollywood had plenty of scientific advice but just didn’t care.

That wouldn’t be the first time I would discover that people who should know better sometimes intentionally misrepresent science to manipulate the public.

When Contagion came out in 2011, I saw that at least some in Hollywood saw that a scientifically accurate script about viruses & pandemics could be plenty cool enough to make a great movie (though they did develop a vaccine implausibly quickly). imdb.com/title/tt159877…

11) And finally, I’ll leave you with this nugget. The human genome is the product of hundreds of millions of years of viruses infecting animals and leaving behind scraps of code that evolution refined into all kinds of different genes.

It’s almost as if we discovered that Microsoft Windows was the product of millions of viruses infecting computers around the world for hundreds of years. (Feel free to make jokes)

In fact, there are elements of our own immune system that behave like viruses to jump around and “transpose” themselves to create a diverse library of antibodies the way that one can shuffle LEGO pieces around in countless ways to create new shapes. frontiersin.org/articles/10.33…

It’s not going too far to say that life would not have evolved as it did & we wouldn’t be here if not for viruses. They may seem to be our enemies, but they helped to “create” us and now we are harnessing them to become instruments & medicines. Maybe think of them as frenemies.

Oh, & I can’t believe I forgot this one. We’ve converted herpes virus into an oncolytic virus, meaning we inject it into tumor where it infects tumor cells, makes immune stimulating proteins, & draws immune system in to destroy the cancer. Thank you, herpes (ok, that sounds odd).