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Low Oxygen Cellular Protein Synthesis Mechanism Discovered
New submitter _prime writes "Until recently the mechanism by which cells make proteins in low-oxygen environments has been unknown. As published in Nature (paywall) this week, the discovery of the mechanism by an Ottawa-based team of researchers potentially means it could be 'very easy to kill cancer cells' without harming normal cells because cancer cells leverage the same low-oxygen protein synthesis mechanism even in the presence of normal oxygen levels."
Can't say definitively, but one of the major characteristics of cancer cells are that they evade apoptosis (cell 'suicide' in cases of damage, etc.), and if you go read up on apoptosis, you'll see that one of the common triggering effects is hypoxia (low oxygen). It's certainly conceivable that the cancer cells, in disregarding apoptosis commands, utilize this low-oxygen synthesis pathway to continue multiplying, and that preventing the cells from using that pathway would cause them to die normally - in other words, the cancer cell MAY receive the signal to die, and shut down its "normal oxygen" protein synthesis pathway, but start (or continue) using the low-oxygen pathway, instead of dying.
Very speculative, but it could very well be something that's fundamental to many broad categories of cancer cell. IF it turns out to be as effective as suggested (hoped), it would add a powerful new treatment to the chemotherapy, radiation, and surgical treatments already being used. If it doesn't, it still offers some potential insight into how cancer cells function, which could lead to development of other treatment protocols. It could also lead to better treatments of heart disease & stroke, since lack of oxygen to various cells & organs is one of the major components of damage in both of those conditions.
Wish Nature wasn't behind a paywall, the newspaper interview & writeup are interesting, but scant of detail.
Interestingly the Nature article doesn't make mention of this mechanism in cancer cells other than to show it exists in a particular brain cancer clone. As the saying goes, 'extraordinary claims require extraordinary data' - at this point we're at the mercy of the idiot PR summary and a single statement from one of the researchers.
The idea that you could wipe out cancer cells selectively (if this pathway is indeed common to malignant cells AND not required by normal cells) is nice but lets hold our breath, shall we.
I've lost count on how many times cancer has been cured according to various and sundry press releases. Of interest perhaps, is that there isn't an editorial note on the paper. Nature tends to do this for papers that they perceive to have a major result. The editorial typically gives some background and insight to the paper to allow people who aren't in the field to understand it's significance.
Faster! Faster! Faster would be better!
Of note in the Nature article is that none of the breathless claims in the PR bit are even alluded to. The abstract (which is typically available):
Protein synthesis involves the translation of ribonucleic acid information into proteins, the building blocks of life. The initial step of protein synthesis is the binding of the eukaryotic translation initiation factor 4E (eIF4E) to the 7-methylguanosine (m7-GpppG) 5cap of messenger RNAs1, 2. Low oxygen tension (hypoxia) represses cap-mediated translation by sequestering eIF4E through mammalian target of rapamycin (mTOR)-dependent mechanisms3, 4, 5, 6. Although the internal ribosome entry site is an alternative translation initiation mechanism, this pathway alone cannot account for the translational capacity of hypoxic cells7, 8. This raises a fundamental question in biology as to how proteins are synthesized in periods of oxygen scarcity and eIF4E inhibition9. Here we describe an oxygen-regulated translation initiation complex that mediates selective cap-dependent protein synthesis. We show that hypoxia stimulates the formation of a complex that includes the oxygen-regulated hypoxia-inducible factor 2 (HIF-2), the RNA-binding protein RBM4 and the cap-binding eIF4E2, an eIF4E homologue. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP)10 analysis identified an RNA hypoxia response element (rHRE) that recruits this complex to a wide array of mRNAs, including that encoding the epidermal growth factor receptor. Once assembled at the rHRE, the HIF-2–RBM4–eIF4E2 complex captures the 5cap and targets mRNAs to polysomes for active translation, thereby evading hypoxia-induced repression of protein synthesis. These findings demonstrate that cells have evolved a program by which oxygen tension switches the basic translation initiation machinery.
Is certainly consistent with your thoughts on apoptosis but there is scant discussion in TFA.
Faster! Faster! Faster would be better!
One of the main problems cancer cells have is getting enough oxygen.
Their continuous unregulated reproduction outgrows their blood supply - and while a typical tumor signals for more blood vessel growth (vascularization) into itself, the vessels themselves are organized so they can't really keep up. The result is that the bulk of a solid tumor is running on very low oxygen concentration, the main limit on its growth is its ability to obtain new vascularization, and a substantial fraction of the cancer cells may be dying off due to this oxygen shortage.
So of course having essentially every low-oxygen hack available turned on is a reasonable thing to expect of dangerous tumor types. And turning them off, even through it might not completely kill the tumor, would knock it down enormously AND the remainder would be expected to be far more vulnerable to the body's immune system.
(Of course if the tumor is a type that recognizes it should die but is evading apoptosis because that works on the normal but not the low-oxygen pathway, turning off the low-oxygen pathway means the cancer cells should just commit suicide, either completely killing the tumor or knocking it back to a miniscule number of cells with further mutations.)
Bantam Dominique roosters crow a four-note song. Once you've heard it as "Happy BIRTHday" you can't NOT hear it that way
Remarkably, not only is adaptation for low-oxygen conditions visible in the majority of malignancies (the Warburg Effect), but it's so prevalent it's actually considered one of the hallmarks of cancer. The reason this happens is easy to imagine: since the tumor has an extreme growth rate and abnormal vasculature, it may have trouble getting the amount of oxygen tha cells normally need in order to survive. It's likely that if they can actually safely target this pathway, they may have the next blockbuster cancer drug on their hands.
This kind of thinking is fantastically disconnected from reality - naive, junior-high, my-parents-don't-get-it thinking. Big pharma execs would do anything for a cancer cure; it would mean fame, money, and prestige out their eyes. And if one solitary idiot at that board meeting said something about not releasing it because of long term profits (or some other BS) he'd get laughed out of a job and be a funny story in someone's memoirs.
Now sure, they'd do what they could to milk it for profits - but they'd be damn sure it got out there before anyone else could. Hell, even if releasing it wasn't profitable at all (and it would be - obviously, obviously, obviously, obviously), they'd burn their company down if they had to.
Very, very few people would consider holding back on a cure for money; not many of those psychopaths have the personal skills to end up at the top of a big corporation, and getting a whole raft of them together would be nigh impossible. Imagining collusion across all the companies on something like this is ridiculous.
Let's not stir that bag of worms...
There's some info on texas department of public saftey's site
You need a permit to buy/possess:
(A) a condenser
(B) a distilling apparatus
(C) a vacuum drier
(D) a three-neck or distilling flask
(E) a tableting machine
(F) an encapsulating machine
(G) a filter, Buchner, or separatory funnel
(H) an Erlenmeyer, two-neck, or single-neck flask
(I) a round-bottom, Florence, thermometer, or filtering flask
(J) a Soxhlet extractor
(K) a transformer
(L) a flask heater
(M) a heating mantel or
(N) an adaptor tube
I didn't realise it was so broad. I suppose the condenser bit bans refrigeratiors and air-conditioning. 'Transformer' bans almost all electronics. Obviously it isn't enforced like this, but that's not really the point.
Apparently glassware (and chemistry in general) is only useful for making bombs and drugs, right?
Then they wonder why there is a shortage of scientists and engineers. It would be funnier if it wasn't so sad.
Sent from my PDP-11
I did think about making the (extremely obvious) remark that if one is capable of handling that question, one already has access to Nature and is well-acquainted with why there's a "paywall", and why the Ottawa Citizen is not even remotely the appropriate venue for discussing hypoxia pathways or translation initiation factors—but that does look slightly worse on one's permanent record, and it burns up the opportunity for someone else to come along and have the question answered in a more serious light.
And to be honest, Slashdot doesn't need more snarkery. One of its greatest assets is its plenitude of technically intelligent and experienced comment-posters, and that's a really wonderful resource for a community to have. Cynicism can do little but poison the site's ability to attract new users—and there have been lots of times I wish I could hit someone on the head (often myself) for unnecessary posturing, taking up a position of authority obviously beyond the extent of his or her knowledge, or responding to sloppy critique with an outright attack. Being unexpectedly kind can get jerkwads to shut up, too—and it's more likely to make the impressionable newbie or lurker contribute positively in the future, rather than emulating (limp-wristedly) the venom of others.
Bio questions? Ask me to start a Q&A journal. Computer analogies available for most topics!
Mod parent up. I just signed up for an account to say exactly the same thing.
To add to this, the major thing about Warburg metabolism is that not only does it allow cancer cells to survive in low-oxygen conditions; it actually produces the raw materials for making the protein needed to grow new cancer cells, so it allows cancer cells to grow faster than if they were using normal aerobic respiration. Here's James Watson talking about it in the NYT. So the low-oxygen conditions in a tumour are an evolutionary selection pressure for tumours to evolve towards dealing with low-oxygen conditions, but probably also for them to evolve towards growing faster and being more malignant too.
In the study in the OP they already knew the normal gubbins that engages the services of the protein-making machinery doesn't work in low-oxygen conditions, so they went looking for something that does work under these conditions and found it. It normally exists in cells so that they can make proteins when starved of oxygen. What's not clear from the Nature abstract, and what will probably need more work to study, is whether this pathway is massively boosted in cancer cells. My guess is that it will be. The Warburg effect is interesting and unique to cancer cells, but it's difficult to turn into a treatment as it's a perversion of a pathway that's essential in all cells - if you drug the pathway itself you'll likely kill the patient. This study is different as it's a pathway that's specific to oxygen-starved cells, so it may well (in about 20 years) provide some exciting new 'universal' drug targets for solid tumours, that may not kill them dead but might at least slow them down. Don't take up smoking yet though...
This kind of thinking is fantastically disconnected from reality - naive, junior-high, my-parents-don't-get-it thinking. Big pharma execs would do anything for a cancer cure; it would mean fame, money, and prestige out their eyes. And if one solitary idiot at that board meeting said something about not releasing it because of long term profits (or some other BS) he'd get laughed out of a job and be a funny story in someone's memoirs.
Now sure, they'd do what they could to milk it for profits - but they'd be damn sure it got out there before anyone else could. Hell, even if releasing it wasn't profitable at all (and it would be - obviously, obviously, obviously, obviously), they'd burn their company down if they had to.
Very, very few people would consider holding back on a cure for money; not many of those psychopaths have the personal skills to end up at the top of a big corporation, and getting a whole raft of them together would be nigh impossible. Imagining collusion across all the companies on something like this is ridiculous.
What exactly is a psychopath?
"Superficially charming, psychopaths tend to make a good first impression on others and often strike observers as remarkably normal. Yet they are self-centered, dishonest and undependable, and at times they engage in irresponsible behavior for no apparent reason other than the sheer fun of it. Largely devoid of guilt, empathy and love, they have casual and callous interpersonal and romantic relationships. Psychopaths routinely offer excuses for their reckless and often outrageous actions, placing blame on others instead. They rarely learn from their mistakes or benefit from negative feedback, and they have difficulty inhibiting their impulses."
Replace the word "fun" with "profit", and the word "romantic" with "economic", and you have the DEFINITION of any large publicly traded company
There has been at least one documentary showing that all corporations engage in psychopathic and sociopathic behaviors on a regular basis, especially in thier callous disregard for human life, the union carbide disaster is a great example of this.
if one solitary idiot at that board meeting said something about not releasing it because of long term profits (or some other BS) he'd get laughed out of a job
What if that "one solitary idiot" is the single largest shareholder (directly representing himself)? what are they going to do, laugh at him till he sells his share of the company? You assume that board members can be fired, but the majority of board members either personally own significant stock in the company, or they represent someone who does. The CEO (and CFO, CTO, etc) are the only ones who can be fired, because they are employees of the company, not shareholder representatives.