Comment by carbocation | Hacker News Reader

Comment by carbocation | Hacker News Reader

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I can nearly eliminate cholesterol in mice (well, they start out with very little to begin with) and my roommate can cure a Huntington's disease model in his lab mice. If media attention were given to every group to achieve something remarkable in mice, we would end up hearing about a lot of false starts. And false starts are a critical/inevitable part of science, so the only thing I'm really saying is that the media attention to this topic is most likely premature.

Mice are a useful model, but they are different enough from humans that we should be cautious when interpreting mouse data in a broader context.

Once repeated studies attacking the same problem from different angles in different institutions start to align, that's when my interest gets piqued. (Unless it's research within my field, in which case I feel better able to understand the strengths and limitations of early-stage studies.)

I also admit that, to a certain extent, this is akin to a "middlebrow dismissal" (though I'm not trying to dismiss their work), and I'd love to hear from an expert in their specific domain.

Finally the truth is plain to see - humans are merely the first step to the true masters of the planet - genetically engineered immortal mice. King Dangermouse will soon take his rightful place.

In all seriousness though, curing Huntingdons or cholesterol and many other research h vectors may seem old hat to you, in the industry as it were, but for the layperson you are at a cutting edge of science benefiting all of us - take some of my perspective and you should be far more proud of your work than perhaps your comment suggests

(Of course when the mice do inherit the Earth prepare to be kept as part of a slave army)

> humans are merely the first step to the true masters of the planet - genetically engineered immortal mice. King Dangermouse will soon take his rightful place.

That was actually mentioned in a Cracked.com article yesterday

http://www.cracked.com/article_20090_6-creepy-things-you-nev...

And a whole new career opens up for me - sarcastic article writer. No, wait, that is my blog !

Finally the truth is plain to see - humans are merely the first step to the true masters of the planet - genetically engineered immortal mice.

Who do you think created the earth to find the Question to the Ultimate Answer?

of course I forgot :-)

I'm going to find it hilarious when the real world goes all Assassin's Creed and our legacy to the planet is a semi-immortal, hardworking, physically ultra-tough, perfectly moral servitor race of drugged religious fanatics.

True. But a lot of studies show that enhancing telomerase activity is related to longer telomere length, which is related to lower risks of mortality and diseases. Induced in vivo gene expression is really hard to accomplish -- and you have good reason to be dubious of direct application to Homo sapiens. But one very good take away from the article is that it furthers the argument that telomerase activity is very very good for mammals. And it turns out there are some good ways of enhancing telomerase activity without inducing gene expression: exercise, stress-reduction, and a good diet.

Here's some background literature:

The Nobel Prize in 2009 was related to work in this area! http://www.nobelprize.org/nobel_prizes/medicine/laureates/20...

Good NEJM Review about Telomeres http://www.nejm.org/doi/full/10.1056/NEJMra0903373

Very nice paper from Science, "Extension of Life-Span by Introduction of Telomerase into Normal Human Cells." Similar to the article posted, but was done with cell in vitro http://www.sciencemag.org/content/279/5349/349.short

Finally, an article from PNAS "Accelerated telomere shortening in response to life stress" http://www.pnas.org/content/101/49/17312.short

Enjoy!

Unfortunately, changing telomerase activity is also rather strongly linked to cancer. Still, with the dramatic improvements in cancer treatment over the last 30 years there may be a useful tradeoff where an increased cancer risk is offset by an increased heath / lifespan on average. But, don't expect a free lunch as evolution tends to find those fairly quickly.

Did you read this part?

This study "shows that it is possible to develop a telomerase-based anti-aging gene therapy without increasing the incidence of cancer," the authors affirm.

Translation: "There was no statistically significant increase in cancer detected." However, that's less meaningful than you might think as detecting even a 2x increase in cancer among mice is a lot harder than say showing in increased population lifespan.

http://onlinelibrary.wiley.com/doi/10.1002/emmm.201200245/fu...

The real question is what was their power to detect an X-fold increase in cancer. Probably quite low, as that was not the purpose of this particular study.

Heh, I worked a floor away from Dr. Szostak the year he won the Nobel. (Purely a curio, I've never met him and his knowledge didn't osmose my way.)

Call me boring, but my opinion is that telomerase activity is good until it isn't, just like everything else. However, Yamanaka's iPS work is a good reminder that sometimes manipulating a surprisingly few substances (4 proteins, in his case, leading to induced pluripotence of previously differentiated cells) is all that is needed for profound effect.

induced pluripotence > http://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells

I've always been curious why mice were seen as a good filter for testing potential medications.

Isn't it just as likely that medications that seemed promising and would actually work in humans would be ineffective in mice, thus never making it to trials?

If, as you suggest, medications that work in mice don't usually work in humans, why should we expect the opposite to be true.

Of course I understand it may be the best we can do in some circumstances, but might it also be counterproductive to have such an unreliable signal?

Mice breed fast and die quick, which lets you run a lot of trials much faster than you could in humans or primates. They're also "close enough" that most treatments will have similar effects in both - most treatments that work in mice but not in humans usually fail due to bad side-effects, or due to having the same direct effect as in mice but that not causing the follow-on effects that are what is actually desired.

There are vastly more compounds and potential treatments that are harmful or do absolutely nothing than there are that are beneficial - being able to filter out nonworking treatments quickly is very important to actually finding the stuff that does work.

> most treatments will have similar effects in both

If so, that would answer the question and undercut what I was responding to.

> being able to filter out nonworking treatments quickly is very important to actually finding the stuff that does work.

Assuming that the filter is accurate. If not, we could close avenues that would be fruitful and open avenues that will be not, wasting decades and billions of dollars.

A filter doesn't need to be perfect to be worthwhile - just to pull some made-up numbers out of nowhere, if 1/100 options are worth investigating, and your filter gives you true positives 70% of the time and false positives 30% of the time, using that filter gives you about twice as much of a return on your investment as skipping the filter and investigating everything.

> I can nearly eliminate cholesterol in mice

"Cholesterol" is an organic compound that is essential for life. What exactly do you mean you can nearly eliminate it in mice?

Of course you're right; I'm using colloquial shorthand. I'm referring to apolipoproteins bound to lipids and cholesterol (at which point we can call them lipoproteins). What I really am talking about is VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides.

awolf's challenge is particularly relevant and on-point because extremely low levels of LDL-cholesterol from birth (hypobetalipoproteinemia or abetalipoproteinemia) is associated with neurological deficits. When caused by defective APOB, it is also associated with non-alcoholic fatty liver disease.

What is the function of LDL (bad?) cholesterol in the body?

A simple and generally correct statement: LDL particles deliver cholesterol from the liver to the cells throughout your body. Cholesterol is water insoluble, so it needs a carrier; the apolipoproteins (ApoB, which is the key protein component of VLDL and LDL) are those carriers.

>the media attention to this topic is most likely premature.

The media attention to this topic is most likely planned, not premature. The point is to get the discussion about this issue happening now, and - as you say this could possibly be a false start - but the purpose of media is to agitate the subject and motivate discussion of the issues at hand.

Its no small thing that technology to extend lifespan, who knows - 20%? - in humans, may well be within the grasp of our generation, or perhaps the next. This will be, absolutely, one of the major issues of the 21st Century if it turns out to be a real technology, applicable to the human animal.

The media are stirring this pot, and should continue to stir this pot well and truly in advance of any such achievements as giving rich, wealthy, technologically advanced societies and groups the ability to extend their life-spans, artificially ..

Just think of the consequences. Thats what the article is trying to make you do ..

Am I right in my understanding: that the reason things are easily cured in mice is that mice have "throw away" disposable soma metabolisms that don't do anywhere near as much error correction as human ones, and so there's a lot of low hanging fruit. Something badass enough to harm humans, on the other hand, has already dodged many error correction mechanisms and is intrinsically harder to fight.

To be frank, I don't know. My work with mice was rather limited so I don't have the depth of knowledge of mice as a model organism that I would need to answer this good question.

In general, toxicities are identified in humans that weren't observed in mice, the delivery mechanism may be intrinsically unsafe or unknown to be safe, the genetic architecture differs in a way that changes expression of relevant genes, or the metabolism differs in some way.

> the media attention to this topic is most likely premature

Yeah, that's true; though, I don't think there's any harm. If it piques interest in science and isn't a scam then some good comes from the attention. What better way to grab the attention of the masses than to talk about treating a fatal condition from which all humans suffer?

Isn't telomerase-based aging mechanism more or less the same in all mammals?

Out of curiosity, any observation (casual or formal) of what happens to neural health when you eliminate cholesterol?

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