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[ChairmanPoo]

Yeah. I've not seen anyone start crying in the streets "WARFARIN IS POISON! WARFARIN IS POISON!". Despite the fact that dicoumarins WERE originally conceived as rat poison, and are indeed still used like that. Yet for some reason chemotherapy gets people all worked up.

By the way, if we're still on the nitpick train: Any treatment using chemical compounds technically rates as chemotherapy, and indeed you see this terminology from time to time applied to antibiotics, if not very often. 

Once again it's not my intention to diss the technology. I'm a big fan and highly hopeful of advanced biotechnology. I'm a big fan of immunotherapy too, although in that regard I'm more interested in engineered lymphocyte TCRs and CARs, which are very promising (but once again, not without their side effects, and not instantly wiping out previous oncological and haemato-oncological therapies).

Case in point: Anti-CD19 CAR-T cells are very effective against acute lymphoblastic leukemia (well, B acute lymphoblastic leukemia, obviously), but it has been shown that nonetheless it's benefitial to perform a HSCT afterwards as consolidation therapy. Maybe over time we'll have better CAR-T-Cells with multiple targets that can obviate it altogether, but nonetheless the takehome message is that this is widening the arsenal (and therefore improving results, often dramatically), not wiping the slate of what has been done before.

Another, possibly more relevant (because more time has passed) case in point: Chronic myeloid leukemia has a very effective treatment in tyrosin-kinase inhibitors, and this changed the prognosis of the disease dramatically, with the gold standard for treatment jumping from allo-HSCT to everyone that could stand it (before), to taking a pill everyday (after).  Nevertheless HSCT is still done from time to time for CML, as some people do need to undergo transplantation for a variety of reasons.

[scrdest]

I am baffled why you seem to be fixating on the MAbs here. MAbs aren't important here. The interaction and the inhibition thereof is.

I am delineating the difference between straight-up poisons and high-dosage toxicity. Yes, everything, even water, is toxic if you dose someone with enough of them. But something like warfarin, or indeed even aspirin, is harmful in a 'too much of a good thing' way - granted, a number of downright classical toxins like atropine are as well, just with a lower dose.

But the mechanism of action of warfarin is relatively innocuous; it's not that you as a healthy person particularly want something to interfere with your vitamin K metabolism, but still.

Cytotoxic therapy agents are, surprisingly, cytotoxic. You might not have enough contact with them for them to kill you, but it's not for lack of trying. They wouldn't be terribly good at their job if they weren't.

You seem to be operating under the notion I'm against chemo - I am not, by no means! But I am emphatically for developing something better, because there has to be a more optimal primary approach to eliminating neoplasms than 'kill them all and let proliferation rates sort them out'. Especially since cancer cells are pretty damn good at dodging those and coming back in force.

'Course, that means if the immune response is shot for some reason,

and there are plenty of reasons why this might be a thing in an oncological patient, both treatment related and disease-related.

And I admitted so much.

you won't accomplish much, but we're not burning down the labs and recipes for chemotherapeuticals on launch day either.

You're not burning them at all because it doesn't work like that.

I was being light-hearted here. Point being that if that is indeed the case that we have a patient we cannot use immunotherapy or some other novel treatment, we always have chemo as a fallback. And for the majority of patients, the data is fairly striking...

Spoiler: This shit works. And it works better than chemo. (click to show/hide)

(Full disclosure, second from top is a source from the manufacturer.)

[Reelya]

http://www.bbc.com/news/science-environment-38737693

This is going to cheer those hippies up: e coli with non-standard genetic base pairs (they have a 6 letter code instead of 4 letters). This might be as close to "creating life" as any scientist could claim:

Previous research had shown that an "unnatural base pair" (UBP), consisting of two synthetic letters called X and Y, could be incorporated into the DNA of Escherichia coli bacteria.

But the resulting bugs grew slowly, and the UBP was expunged after several rounds of cell division.

Now, Prof Floyd Romesberg, from The Scripps Research Institute in La Jolla, California, and colleagues, have shown that their single-celled organism can hold on indefinitely to the synthetic base pair as it divides.

"We've made this semisynthetic organism more life-like," said Prof Romesberg, senior author of the new study.

"Your genome isn't just stable for a day," said Prof Romesberg. "Your genome has to be stable for the scale of your lifetime. If the semisynthetic organism is going to really be an organism, it has to be able to stably maintain that information."

Key to the advance was a modification to a molecular transporter, which helps the E. coli bugs import the UBP.

Next, the researchers optimised their previous version of Y so that it could be better recognised by the enzymes that synthesise DNA molecules during replication.

Finally, the researchers set up a "spell check" system for the organism using the CRISPR-Cas9 genome editing tool.

They were able to take advantage of the tool to ensure that any cells that dropped X and Y would be marked for destruction.

Their semisynthetic organism was thus able to keep X and Y in its genome after dividing 60 times, leading the researchers to believe it can hold on to the base pair indefinitely.

[wierd]

I will be much more impressed when they can make X-Y bases actually encode a useful RNA and protein chain.

However, even with it non-encoding, it could be useful for use as an error correcting code. (Think something similar to the simple parity bit used in computer memory to catch simple memory storage errors)  This would be useful in say, assisting an organism to better catch when it has become cancerous.

[ChairmanPoo]

I am baffled why you seem to be fixating on the MAbs here. MAbs aren't important here. The interaction and the inhibition thereof is.

I don't even understand what you mean here

Cytotoxic therapy agents are, surprisingly, cytotoxic. You might not have enough contact with them for them to kill you, but it's not for lack of trying. They wouldn't be terribly good at their job if they weren't.

Once again, *everything* is toxic in the right amounts. You're making a difference where there is none. If you're killed by the side effects it matters little whether we are talking about a monoclonal antibody, a cytotoxic agent of whatever sort (because it's not like they're a homogeneous class), or whatever else.

You seem to be operating under the notion I'm against chemo - I am not, by no means! But I am emphatically for developing something better, because there has to be a more optimal primary approach to eliminating neoplasms than 'kill them all and let proliferation rates sort them out'. Especially since cancer cells are pretty damn good at dodging those and coming back in force.

Once again, the matter is far more complex than mabs being "better" than chemotherapy. You are fixated in "less side effects = better", which isn't necessarily true (and it's not necessarily true that they have less side effects either. Have you checked nivolumab's tech profile? It's pretty nasty. Likely less nasty than taxanes, true, but it's not something that you can casually say "oh, it's not toxic" either)

Hell, it's not like this isn't an ongoing debate with nivolumab right now : http://www.esmo.org/Conferences/ESMO-2016-Congress/Press-Media/Greater-Patient-Selection-May-be-Needed-for-First-Line-Nivolumab-to-Improve-Progression-free-Survival-in-Advanced-Lung-Cancer

Spoiler: This shit works. And it works better than chemo. (click to show/hide)

(Full disclosure, second from top is a source from the manufacturer.)

Well shit, science advances. New treatments appear that have better results. Who would have known?

Except that STILL doesn't mean that standard chemotherapy is out of the picture with the appaerance of mabs. What that trial says is that in relapsed NSCLC nivolumab is superior to docetaxel in monotherapy.  (worth noting that in both cases it's still fairly lousy. As you might expect from a refractory tumor, on the other hand)

But if you check what's going on currently with nivolumab, you find that, surprise surprise, current trials are testing it in combination with other mAbs or with chemotherapy:

https://clinicaltrials.gov/ct2/show/NCT02477826

http://www.ascopost.com/issues/july-10-2016/combination-of-nivolumab-and-ipilimumab-moves-forward-in-nsclc/


So, no, I'm not denying the effectiveness of new therapies. I'm denying a fact that you seem to be persistently oblivious to: They don't debunk conventional, and a good deal of work is underway to combine them with conventional therapies.

It's not like there's no precedent. There are quite a few mAbs that have been in the market for years (most notably rituximab), and for the most part they're used in combination therapy.


By the way, there's a solid, known, biological reason for this. Monoclonal antibodies, as the name suggests, have one single target. Therefore you're selecting for clones that don't express said target, thus encountering eventual resistance if used in monotherapy. Now, I'm guessing this occurs faster in haematological tumors because of them having (for the most part) a higher Ki67, but common sense (and a fast check on the literature) suggests that the same principle applies.

[scrdest]

You clearly didn't bother to check what's the underlying concept, or for that matter what I'm arguing (granted, that's traditionally mostly on me to make clear) and you're being hostile now. I don't have time for this shit.

[ChairmanPoo]

You clearly didn't bother to check what's the underlying concept, or for that matter what I'm arguing (granted, that's traditionally mostly on me to make clear) and you're being hostile now. I don't have time for this shit.

  sure. You realize I actually make a living prescribing this kind of stuff right.

You're right in one thing though: I can't figure out if you are excited about immunomodulation (which is not specially new either, also works better in conjunction with other approaches), monoclonal antibodies, or both. TBH you've been rather obscure about your point

[TheBiggerFish]

http://www.bbc.com/news/science-environment-38737693

This is going to cheer those hippies up: e coli with non-standard genetic base pairs (they have a 6 letter code instead of 4 letters). This might be as close to "creating life" as any scientist could claim:

Previous research had shown that an "unnatural base pair" (UBP), consisting of two synthetic letters called X and Y, could be incorporated into the DNA of Escherichia coli bacteria.

But the resulting bugs grew slowly, and the UBP was expunged after several rounds of cell division.

Now, Prof Floyd Romesberg, from The Scripps Research Institute in La Jolla, California, and colleagues, have shown that their single-celled organism can hold on indefinitely to the synthetic base pair as it divides.

"We've made this semisynthetic organism more life-like," said Prof Romesberg, senior author of the new study.

"Your genome isn't just stable for a day," said Prof Romesberg. "Your genome has to be stable for the scale of your lifetime. If the semisynthetic organism is going to really be an organism, it has to be able to stably maintain that information."

Key to the advance was a modification to a molecular transporter, which helps the E. coli bugs import the UBP.

Next, the researchers optimised their previous version of Y so that it could be better recognised by the enzymes that synthesise DNA molecules during replication.

Finally, the researchers set up a "spell check" system for the organism using the CRISPR-Cas9 genome editing tool.

They were able to take advantage of the tool to ensure that any cells that dropped X and Y would be marked for destruction.

Their semisynthetic organism was thus able to keep X and Y in its genome after dividing 60 times, leading the researchers to believe it can hold on to the base pair indefinitely.

HEY GUYS LOOK AT THIS

Seriously though.  Keep it cool.

[wierd]

Essentially, they have forced the organism to retain the new base pair (that does nothing, as it does not encode any RNAs), by adding a lethal consequence to deletion, which it naturally wants to do, because retaining it is metabolically expensive.

If the base pair did something USEFUL, like encode a unique RNA for a unique protein, or was part of the non-coding region and used cleverly to help assure that non-useful repeat sequences are prevented, it would be a lot more interesting.

[Sheb]

Hey, Baby step. Next, create a tRNA with that UBP somewhere in there.

[wierd]

Wouldnt you need high specificity for a unique amino acid, and strong specific interaction with a ribisome for the tRNA to actually be useful?

[Reelya]

Essentially, they have forced the organism to retain the new base pair (that does nothing, as it does not encode any RNAs), by adding a lethal consequence to deletion, which it naturally wants to do, because retaining it is metabolically expensive.

If the base pair did something USEFUL, like encode a unique RNA for a unique protein, or was part of the non-coding region and used cleverly to help assure that non-useful repeat sequences are prevented, it would be a lot more interesting.

To be honest, we don't know exactly what it does or could do. Life has a way of exploiting whatever systems you give it. If you're adding new base pairs, that's going to be a detriment to survival, but life will adjust to compensate, so you get new behavior you haven't seen before.

[Sheb]

Essentially, they have forced the organism to retain the new base pair (that does nothing, as it does not encode any RNAs), by adding a lethal consequence to deletion, which it naturally wants to do, because retaining it is metabolically expensive.

If the base pair did something USEFUL, like encode a unique RNA for a unique protein, or was part of the non-coding region and used cleverly to help assure that non-useful repeat sequences are prevented, it would be a lot more interesting.

To be honest, we don't know exactly what it does or could do. Life has a way of exploiting whatever systems you give it. If you're adding new base pairs, that's going to be a detriment to survival, but life will adjust to compensate, so you get new behavior you haven't seen before.

Well, yeah, if you let it evolve for some millions years in an environment where those new bases are available. And if you can force the organism to keep this base in its genome. And give it the tools to actually read that base.

wierd: Well, yeah, a tRNA is just one part of the translation machinery, but it should be easy enough to grab an existing one, modify one or two base pair of its anticodon to include an unatural nucleotide and see if you can decode the codons with UBP. There is already a whole bunch of tRNA/amino-acyl tRNA synthetase that have been created for a bunch of unnatural amino acids, so the second step would be incorporating artificial amino acids using codons with the UBP. Then see how specific and efficient it is with several pairs of tRNA/AARS.

[Reelya]

Not millions of years, you're really thinking of multicellular life. With bacteria a new generation can be 20 minutes. With enough resources, each 20 minutes you're doubling the population and trying out that many different mutants. So for each hour you let the population expand you're trying out 2^3h more than you started with. If you were able to let the population expand for an entire day, then it would have doubled 72 times, or be about 4 sextillion times as many cells as you started with, which is close to the estimate for the number of grains of sand in the world. So the only limit on how many new cells you can try out per day is the resources that you have at your disposal.

An e. coli weights about 1×10⁻¹⁵ kg. So if you can keep alive 1 kilo of bacteria, and they breed a new generation every 20 minutes, you can try out 10^15/20 per minute, or about 1 trillion new cell configurations per second.

[wierd]

Too optimistic. Mutation rate is not that high, and most of the mutations would not be directed toward ubp integration.  Would be significantly lower than those values, and would need sustained environmental pressure to select mutants favorable to the desired outcome.

ecoli is one of the bacteria that passes a plasmid though, right? that could have interesting amplification effects.