I am not convinced, especially when the company is hyping it to kill "virtually all" viruses. Far from the majority of viruses contain dsRNA. For example, the Ebola virus and rhinoviruses, which cause the common cold, all contain an ssRNA genome. (For this reason I am confused why somebody quoted in the article specifically uses these examples.) HPV and many other categories of virus [1] contain only DNA. It would seem that only this category [2] of viruses would be affected.
You're talking about the contents of the virus capsid.
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.
I don't believe that any DNA virus would replicate via a dsRNA intermediate, since that would be an unnecessary step and therefore anti-selective. You are correct that ssRNA viruses create a dsRNA template while replicating but I would think that this state is transient and therefore not a great target, unless this treatment can target dsRNA strands littered with replication forks.
Sorry, 'stage' was misleading. As described in the PLOS ONE article on this subject, they typically undergo symmetrical transcription. So more accurately, dsRNA & ssRNA viruses typically go through a dsRNA stage. DNA viruses typically produce dsRNA during transcription.
These DRACO proteins are (in the grand scheme of things) non-sequence (or indeed virus) specific, which is one of the reasons this is so exciting. They are specific in terms of the dsRNA binding domain they’re built with, although these domain may have a range of different sequences or secondary structures they can bind. The apoptotic response is triggered by the DRACO proteins crosslinking when two of them bind to the same fragment of dsRNA.
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.
I'm curious - I remember that over time viruses been incorporated into our DNA and rendered inert. Could these be targeted and damaged by the DRACO system? Or would they come within the ~10-25 nucleotide limit?
So the viruses incorporated into our DNA are in fact fragments of viral DNA, typically from reverse transcriptases. The DRACO proteins recognizes double stranded RNA (dsRNA), while reverse transcriptases incorporate dsDNA into our genome, and then use our own DNA replication proteins to make more of themselves! Crafty! The upshot of this, though, is that there's no dsRNA in our genome, so nothing the DRACO could detect.
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.
You have to read to the end to find out that it has only been confirmed in mice. We have cured practically every major medical condition in mice. The human part is the hard part. I'm skeptical that this mechanism wouldn't have some pretty severe side effects.
"It’s bad enough that I live in a country that ranks 37th in health care. The thing that really pisses me off is that I have worse health care than mice." - Scott Adams, "Frequently Disappointed by Mice"
I'm curious why bostinnovation.com posts get voted up so high on HN, when they're so full of hype, and so lacking in content. This one is at least intrinsically more interesting than the last one I saw, "a list of programming language designers who have driven past Boston".
jleader, I am the author of this post and the 'programming languages who have driven past Boston' article. I literally laughed out loud when I read your comment. I was surprised when that post was on Hacker News myself (I knew it wasn't my best). I promise to do better :)
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.
This is coming from a non-biological background, and hence may contain ridiculous ideas:
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.
Actually, you wouldn't want to do that. A lot of human cells actually rearrange their genome as part of their normal function. This is how lymphocytes come up with antibodies, for example.
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.
Thanks for the detailed answer, you've given me a bunch of stuff to go read about. My original idea came from something from SENS about moving mitochondrial DNA into the nucleus to take advantage of the better repair systems: http://www.sens.org/sens-research/research-themes/mitosens
Obviously it would be more complex than
if hash(nuclear DNA) != clean_DNA_hash) die;
but I wonder to what extent the immune system could be enhanced. I wonder if there are some techniques that could be adapted from the computer virus/malware detection field back into biology.
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.
One interesting thing to remember about the human immune system is that its always on - IE it spends more time correctly identifying something as NOT THREAT, than it does spending time finding THREAT. Mucking about with this could have extreme consequences, a la auto-immune diseases for example.
> 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?
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.
Mere implementation details! I shall apply for my patent forthwith. (That is, I have no idea what most of those terms mean) :p
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?).
So telomerase is slightly different - chromosomes have teleomeres at the end of each chromosome. These are just like long bits of "this-is-the-end-of-the-chromosome" DNA, like when you have a role of receipts and towards the end they have a red line through them to show the end is nigh.
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.
To a second-order approximation, you're describing an actual mechanism by which some eukaryotes fight viruses via RNAi. (I say second order because you're talking DNA while RNAi of course operates on the RNA level.) A few years earlier and you might have been in line for a Nobel ;) http://en.wikipedia.org/wiki/RNA_interference#Biological_fun...
What about a virus like Herpes which enters a nerve cell? My understanding is that nerve cells have extremely long lifespans so inducing apoptosis in them has the potential to destroy physical sensation no?
I think you have that wrong. The virus travels up the nerve into the cell body. It stays there until the nerve (or you) dies. There it hijacks the cell's DNA machinery to create more virus. These new viruses travel back down the axion to be released in the blister. A cold sore on your lip is just the herpes virus shedding new viruses. Once infected, the body develops antibody to that type of the virus so infection doesn't spread but by then it's too late. Usually the site also becomes asymptomatic over time as well, however the virus will chill out in that nerve reproducing itself forever.
>DRACO selectively induces apoptosis, or cell suicide, in cells containing any viral dsRNA [, which is RNA with two complementary strands that id the genetic material of some viruses], rapidly killing infected cells without harming uninfected cells.
and for the cases when pretty much all the cells of specific type are already infected?
Most viruses kill the host cell, or at least render it incapable of performing its normal function, so if most of the cells of a type are infected you are in trouble anyway.
Well, despite the qualifier MOST viruses, I would have to point out that some viruses end up being in your system without destroying their host cell - for example HSV.
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.
For a moment I thought it's the curing of a broad range of computer viruses, which can more likely be done than biological viruses. Reading the article cured my misconception. The technique is still impressive.
I would have a number of questions about this study, which was apparently run and written up by the "DRACO" patent holder.
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".
Unfortunately viruses may also be an agent for evolution [1]. This discovery is basically a means to kill cells that match a particular rDNA sequence. Seems like something that could become a very strange tool or a very horrible weapon.
This is what your normal immune defenses already do. While some white blood cells (neutrophils, monocytes) fight bacteria by "eating" them, viruses are too small to be directly attacked this way. Instead, they cells they infect have to be destroyed before they can release their viral burden. That's what cytotoxic T cells do. They recognize antigens on infected cells, and kill them by triggering apoptosis (programmed cell death).
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!
[1] http://en.wikipedia.org/wiki/DsDNA_virus
[2] http://en.wikipedia.org/wiki/Double-stranded_RNA_viruses