[insert generic Draco Malfoy joke here]

A bunch of folks have emailed me about this article, being heavily pimped in pop media:

Broad-Spectrum Antiviral Therapeutics

Being SciBlogs resident Debbie Downer, it was good to see Ive trained you all well. The most common comment people emailed along with the link to a pop news article: “Why is this wrong?”/”Why is this not going to work?”/etc

LOL!!

Well, this is a very very very preliminary paper– The concept itself is clever, the basic science seems fine, and they have taken it beyond ‘this works in tissue culture’ to ‘this can work in mice with a specific pathogen’. Thats more than you get from a lot of high PR papers, so good on them. Everything looks okay on the front end, but whether this approach ultimately leads to a treatment for any particular infection for humans is still up in the air.

More on the science of what they did in this paper:

If you watched my presentation last week, in the first few minutes of my talk I spoke about ‘pattern recognition’ proteins. This part of your immune system doesnt change or learn in response to pathogens– it just looks for what its supposed to look for, and if it sees what its looking for, it tells the cell and your body that something is wrong.

One example I gave was double stranded RNA. Your body should never ever ever have dsRNA floating around– You carry your genome as dsDNA. From that template you make RNA, and while RNA has a ‘structure’, its not double stranded, its single stranded with structure. And that RNA can be used for a variety of purposes, including making proteins. There are many viruses, however, that have a dsRNA stage in their life cycle. Obviously this included dsRNA viruses (rotavirus), but it also includes single-stranded RNA viruses. Thats because ssRNA viruses need to make copies of themselves, and their messenger RNA from their genome, with is an RNA template. Through that process, you get dsRNA.

Your cells have sensors that look for dsRNA, because any time dsRNA is around, its bad news. When those sensors are triggered, it sets off a chain-reaction of chemical messengers that shut down protein synthesis in a cell, tell the cell to commit suicide to protect its neighbors, and warn the neighboring cells that something has gone down. Its like a cellular phone tree :-|

Of course, viruses know about all this.

So they have evolved their own ways of interfering with this cellular phone-tree so babby viruses can be made uninhibited by cell suicide.

What they did in this paper was to partner different dsRNA sensors with different branches of the chemical messenger phone-tree, kinda cutting out the middle-men in the phone-tree that viruses can interfere with.

While thats neat, why this could work as a pharmaceutical you give someone who is sick in the hospital is that their manipulated sensors have ‘transduction domains’ on them– fancy way of saying that when cells ‘see’ these proteins floating around theyre like ‘Oh! Shiny! Do want!’ and they suck them up. Once they are in the cells, even though they are generated artificially and modified, the cells treat them like their own pattern recognition receptors.

But *all* cells will do this. So you cant just put one of these domains on something that will willy-nilly kill cells, cause youll kill ALL of them. Because these sensors only help kill cells when they see dsRNA, and cells shouldnt have dsRNA unless they are infected with a virus, YAY! You should only kill infected cells, and healthy cells that take up the proteins but are uninfected should be left alone.

But again, because *all* cells will take up these nifty proteins, the question also becomes “How do you get these proteins to the cells that need them?” I mean it would be SUPER if this turned into an anti-Hepatitis C drug… but if you inject it into someones arm and their blood vessel epithelial cells are like ‘SHINY! GIMME!’ and all the liver cells are like “Awww… I wanted some…” and your liver cells are the ones that NEED the modified protein cause theyre the ones with HCV, youre SOL.

When these proteins are injected IV, a LOT of it when to the liver (makes sense) and some got to the kidney (makes sense) and lungs (eh?). I would have liked to have seen the brain too (viral infection of the brain? damn straight we need some drugs for that).

What if you want the modified proteins in the respiratory tract? Like for flu? Well, they administered influenza intra-nasally, and their proteins intra-nasally, and YAY, it helped keep influenza in check. It would be nice for physicians to have this gun in their arsenal if we can get it to work in humans.

We will still have to figure out the best way to use this potential drug for other viruses that effect other tissues, in humans. But this is a super novel idea, and when sometimes I get down on the lack of novel ideas in my own field, its good to see them popping up anywhere.

Comments

  1. #1 Tezcatlipoca
    August 18, 2011

    Hola Abbeh! Here’s another one I’d appreciate you taking a peek at. Being a simple telecom schlub I’ve got no comment other than the link.

    http://www.fastcompany.com/1774219/koronis-pharmaceuticals-thinks-it-may-have-a-cure-for-hiv

  2. #2 Mu
    August 18, 2011

    If this works, would the effect be permanent? Or, with other words, would we be at risk of dying years later from a harmless but widespread-in-the-body virus that triggers the self destruct mechanism in a large number of cells?

  3. #3 Sigmund
    August 19, 2011

    The ‘drug’ in this case is basically an engineered protein. As such it is likely to trigger the immune response if given as a regular therapy. That’s not to suggest it is without use – it might make a good emergency treatment or even a preventative for workers likely to be exposed to a viral pathogen for a limited time period (say medical personnel responding to a viral outbreak.)
    The biggest problem is that drugs work best when the active molecule is small enough to diffuse through the body tissues. Larger molecules, like proteins or long nucleic acids, tend to be cleared up, degraded or filtered out before they can reach enough of their targets.
    It’s a nice idea though.

  4. #4 Elihphile
    August 21, 2011

    Completely off topic but I thought this might interest you (from The Observer/ Guardian Online):

    http://www.guardian.co.uk/society/2011/aug/21/chronic-fatigue-syndrome-myalgic-encephalomyelitis

  5. #5 Connor
    August 21, 2011

    What I would be worried about chronic, unknown infections that are continuously generating low levels of dsRNA, like herpesviruses etc. Administer these proteins systemically and what you could have are some nasty side-effects. Or with hepatitis, when maybe 80% of your liver is infected. With this treatment, you would lose the majority of your liver in a week.

  6. #6 Brian
    August 22, 2011

    Re: Tezcatlipoca

    Not so useful… in fact, less useful than AZT, and especially less useful than non-nucleoside reverse transcriptase analogues like efavirenz. AZT/efavirenz/etc stop the HIV reverse transcriptase in its tracks, whereas mutations are just that… mutations. It’s like hammering on the tracks of a train versus putting a concrete wall in the way.

    Re: Connor

    A definite possibility. The authors of this study, like almost everyone else using mice, used specific pathogen-free mice (except Peter Duesberg haha, who has to go to the pet shop). For most people, you might as well inject yourself with LPS (lipopolysaccharide, a strong TLR adjuvant). You’ll die within hours.

    Re: Abbie

    It’s not so much the drug going to the site (I realize that this is basically in vivo transfection). A strong IV push will drive almost everything to the liver… hence how hydrodynamic injection is used in adenoviral/etc delivery to mouse livers. But seriously, dsRNA caspase activators in people that are almost certainly infected with who knows how many herpesviruses?

  7. #7 Sigmund
    August 22, 2011

    Brian said:
    “But seriously, dsRNA caspase activators in people that are almost certainly infected with who knows how many herpesviruses?”
    It’s difficult to predict effect here. Many drugs work brilliantly in theory but not at all in practice. Likewise speculating on theoretical nasty side effects doesn’t mean they will occur in vivo. Even if it was a real possibility it wouldn’t rule out the benefits of the treatment – merely limit it to a specific subset of treatments where herpes infected neurons are not involved (for instance it might work fine as an anti-influenza nasal spray.)

  8. #8 Cindy
    September 10, 2011

    What’s a “babby virus”?