MIT develops new method to cure broad range of viruses
bostinnovation.com
bostinnovation.com
Put into slightly more straight forward terms, the apoptotic pathway is like a massive self destruct switch, which is triggered by a whole range of different things (viral infection, DNA damage, cancer signals etc). The body has evolved various mechanisms to detect dsRNA, as this is often a sign of viral infection. dsRNA doesn't occur naturally in mammals beyond ~10-25 nucleotides in length, while many viruses either have a dsRNA genome, or create long strands of dsRNA during their replication cycle, even if they do not have a long-term stable dsRNA genome. I’d imagine this provides a mechanism for DRACO proteins to target these non-dsRNA viruses. These DRACO proteins are simply a way to supercharge the body’s defences, increasing the cell's sensitivity to dsRNA.
My main concern would be relating to an immune response (any kind of recombinant protinaceous therapeutics is often risky), and also regarding administration and pharmacokinetics. Viruses are good at making lots of themselves, and may accumulate in different cell types, tissues or organs. Getting good, thorough coverage of the body may be a challenge. However, that said, any kind of “outside the box” therapeutics is always very welcome, especially where apoptosis is concerned, as it’s implicated in a wide range of diseases but is still relatively poorly understood.
It's like we store our genome on DVD, and some viruses use CDs. They're very similar, but it's not the "content" the DRACO proteins are looking at, but the medium. We have no way to make CDs, only viral proteins can do that, so if the DRACO proteins see CDs, there's probably a virus about.
[1] http://en.wikipedia.org/wiki/DsDNA_virus
[2] http://en.wikipedia.org/wiki/Double-stranded_RNA_viruses
DRACO works by killing cells that contain viral dsRNA, which will include cells infected by most kinds of DNA and RNA viruses, because those viruses usually have a dsRNA stage.
http://dilbertblog.typepad.com/the_dilbert_blog/2007/06/freq...
As a resident of Los Angeles, and graduate of Caltech, I'm completely sympathetic to trying to get the word out about tech innovations happening in places other than Silicon Valley.
Journal article (open access, hooray!) http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjourna...
Would it be possible to devise some sort of virus which could somehow 'checksum' a given cell's DNA, and trigger cell-death if it doesn't match?
I've no idea if that is even possible, or whether it'd require a custom virus per-person (or whether you could add some sort of 'training stage' by introducing it to clean host DNA first)
Another tricky problem would be making sure it hits every/enough cells to kill the other virus, but slowly enough that there's time for the body to replace them. And of course, that the virus checksums itself regularly and self-terminates on mutation.
I tried to find some specifics on wikipedia, but apparently the system is incredibly complicated!
There are also a host of proteins that check for DNA breaks, damage from UV or other carcinogens and just generally keep an eye on things.
By selecting and rearranging several different coding sequences from three different chromosomes, each lymphocyte develops its own antibody "design", permanently changing its own genome in the process. This is what allows us to develop immunity to a broad range of foreign antigens with a relatively small amount of genetic code. Think of it as an "immune alphabet", if you will. You certainly don't want to interfere with that!
Other rearrangements also occur, some harmful, others not so much. Even if you wanted to target just the bad ones, though, a virus really isn't the tool for it. Your cytoxic T lymphocytes already do that. In fact, what you're really describing isn't all that far off from what we already have. I think we even have mechanisms for genetic error correction and repair, but I'll have to hit the books again to double-check that.
Obviously it would be more complex than
if hash(nuclear DNA) != clean_DNA_hash) die;
A recent article on creating false-positives for a virus scanner (http://lock.cmpxchg8b.com/aids8064.html) by analysing the signatures makes me think of creating 'virus pre-images' for vaccination.
Other than the specialised cells which manipulate their own genome, would there be value in positively checksumming {D,R}NA, rather than adaptively pattern-matching for the bad ones, which is (I think) how it mostly works now?
Granted, you'd be hindering the evolutionary process by preventing mutation, but if we ever intend to start messing around inside ourselves, the first step would probably be to make sure that whatever we create, it's going to stay that way, or die.
The problem is
a) there's a LOT of DNA in a cell, and a lot of a cells, so checksumming would logistically be pretty much impossible. This is assuming there is some mechanism by which you can "scan" the DNA, which in itself has a whole host of steric/timing issues (different chromatin states, how do you deal with cell division? histone methylation and DNA accessibility, DNA binding proteins inhibiting interaction with certain regions at different times)
b) the more conceptual issue is that DNA in cells have natural variation anyway. My DNA is different to yours, but DNA in some of my cells is going to be subtly different to DNA in other parts of me.
The necessary internal variation sounds like it'd be the fatal flaw here, unless there's some way to determine 'good' changes and 'bad' changes.
As you said above, there are already repair/watchdog proteins for specific sections, so maybe that could be the basis for additional checking in other high-risk areas (Telomerase?).
You can think of it as like a "count-down timers". Every time a cell divides, the DNA gets doubled, so one cell doubles its DNA, creating two cells with identical DNA. When this happens, each of the telomeres in the new cell get a little bit shorter by a constant amount, and with this happening in a recursive way at some point they reach a critical length (Hayflick limit). At this point the cell knows it's undergone a certain number of divisions (~40 I think) meaning it's an old cell, so statistically it's likely to have picked up a few mutations. These mutations could make the cell less effective, or even worse, lead to some kind of disease (i.e. cancer), so as a precaution the cell initiates apoptosis. It's pretty clever - there may not be anything wrong, but there's a significant chance there is, the cell isn't perfect at detecting problems, so to avoid the risk to the rest of the body it kills itself.
Telomerase rebuilds telomeres, so is crucial in cells where lots of division is going on rapidly (such as embryonic cells) so cells can divide many more times by adding on the bit of teleomere that's lost. The problem is in cancer cells, telomerase is very often mutated into an “always on” position as it gives cells a way of being immortal. In normal cells telomerase isn't usually active, although it may have some other roles in pseduo-related areas. I was lucky enough to see Elizabeth Blackburn (Nobel prize winner for telomerase's discovery) speak a few years ago on this topic – it's really fascinating.
Proteins involved in DNA checking/repair are ones like ATM, Chk1, Chk2 , BRCA1, BRCA2, Rad51. There are many more, and they tend to work cooperativly together, though I can't remember the others off hand.
For more information regarding this kind of thing I'd really recommend Weinberg & Hanahan's The Hallmarks of Cancer [1]. Although published 11 years ago it's pretty much a “classic”, and gives a good overview of DNA damage and telomerase, albeit from a cancer viewpoint as opposed to generally.
[1] - http://www.weizmann.ac.il/home/fedomany/Bioinfo05/lecture6_H...
Also, are we sure that killing "a broad range of viruses" in one's body is a good idea? Killing "a broad range of bacteria" certainly is not.
and for the cases when pretty much all the cells of specific type are already infected?
Ideally a way to excise the viral code from the cell would be found. DRACO basically activates the destructor on a cell and ends the entire cell, even if it is still serving the body.
I also recall that our chromsomes contain the genomes of viruses that have been overcome over the span of our species life on this planet. Whether these fragments would get affected is something I'm curious about.
The results are largely from cell culture so any talk about a "cure for a broad range of viruses" in the press release is premature bullshit to say the least.
There were some mice studies, along with this statement in the paper: "We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza" - for which evidence are examination of harvested organs after two days, and three graphs showing separation for mortality between treatment and control (buffer) groups out 10 days or so (time plot ends at that point). Searching the paper, I finally find by looking at the morbidity graph that we're talking about 13 mice per group for one type of DRACO intraperitoneal administration, 5 per group for the other type of DRACO i.p, and 12 mice per group for intranasal administration.
In addition, as the authors themselves note, how much cell death could be tolerated in the face of chronic viral infection remains to be seen.
This is a very preliminary trial. There are years of work before this even approaches meriting mention of a "cure".
[1] http://www.newyorker.com/reporting/2007/12/03/071203fa_fact_...
What is truly unfortunate is, this doesn't always work. Some viruses are able to "hide" in their host cells, preventing them from activating the immune response, and persist idefinitely in a latent state. This is why you can't really get rid of herpes, once you have it.
What looks promising about this development is that it seems to target a form of RNA that is simply not found in healthy cells. Human cells store their genome in double-stranded DNA, and use single-stranded RNA for transcription, but make no use of double-stranded RNA. Apparently, only certain viruses do, so the presence of dsRNA in a human cell should be diagnostic for viral infection, regardless of its sequence. In other words: see dsRNA, kill it!
Would that all viruses were that easy.