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Telomere lengthening via gene therapy in a human individual (neuroscientistnews.com)
287 points by mkagenius on Apr 24, 2016 | hide | past | web | favorite | 102 comments



I've gotten about 60 messages about Liz Parrish's outfit and the test on herself to lengthen her telomeres.

I don't think there's any substance to any of her claims and life extension.

A few very critical questions:

1/ What if anything does telomere lengthening have to do with life extension? (It's multi-factorial) Correlation is not causation.. See: https://www.ncbi.nlm.nih.gov/pubmed/25862531

2/ Why did she use a lab that's on quackwatch to do the tests? (http://www.quackwatch.org/01QuackeryRela…/…/nonstandard.html)

3/ Haven't we already proven telomere lengthening and muscle hacks in animal models?

4/ What type of AAV is she using to transfect her cells with telomerase? (Take a look at the animal studies: http://www.nature.com/mt/journal/v18/n3/full/mt2009286a.html, http://virologyj.biomedcentral.com/…/10.1186/1743-422X-10-74)

5/ How many cells had their telomeres lengthened? (I bet you it was a petty amount.....100 to 1 says they're not all that good at actually delivering genes)

There's actual chemists/biologists busting their ass at places like genentech and top research universities to solve missing mendelian inheritance the long difficult way.

They're true pioneers staring down the barrel of a gun loaded with the world's most difficult NP-Hard problems. This Parrish outfit steals their thunder.

Aging isn't something you can simply disrupt with a silicon valley mindset.

I've met organic chemists who have spent upwards of 30 years developing drugs and haven't put a single drug on the market. Their work was still super valuable.


I'm trained as a biologist and in complete agreement, this is a press stunt with no substance.

A couple further questions -

In a longitudinal study testing telomere length in a large human cohort, 44% of people had longer telomeres than when they were 10 years younger (and 10 years is a lot of aging!) http://journals.plos.org/plosgenetics/article?id=10.1371/jou... ...So even if her telomeres did get longer, how confident can we be that is at all related to the gene therapy?

Instrument / sample variability in SpectraCell measurements. Is there any data on this? How significant is a change from 6.71kb to 7.33kb anyways?


So let's say this isn't a bunch of bullshit, what benefit does she stand to receive from having her telemeters becoming longer again?


Aging is a medical condition. The present approaches to dealing with it are expensive and terrible, which is to say therapies that are nothing more than patches or meddling with late-stage disease state without addressing root causes, and research that is focused on creating a full understanding of those disease states by working backwards. There are other approaches that look like they could be cheap and effective, which is to say repairing the consensus root causes of aging after the SENS model, the forms of change and damage found in old tissues and that are caused by normal operation of metabolism, not by some other form of damage.

Disruption is absolutely possible in this scenario. Replace the bad old expensive approach with the much better approach, while the old guard tell you how wrong you are all the way until their positions become untenable.

It wasn't so many years ago that people were claiming SENS was nonsense. Now everyone agrees that, for example, senescent cell clearance, a part of SENS right from the outside, is great and extends life in mice, and human therapies should be developed to produce rejuvenation as a result of clearing these unwanted, damaging cells.

There are startups right now working on SENS and SENS-like approaches to repairing the damage that causes aging, technologies that can be realized for a fraction of the cost spent so far on mapping the biochemistry and genetics of metabolism and aging. That looks a lot like disruption under way to me.


The notion that Aging is a medical condition or disease seems murky enough. We should really wait on the Metformin trials to be completed before making such bold statements.

"Barzilai and other researchers plan to test that notion in a clinical trial called Targeting Aging with Metformin, or TAME. They will give the drug metformin to thousands of people who already have one or two of three conditions — cancer, heart disease or cognitive impairment — or are at risk of them. People with type 2 diabetes cannot be enrolled because metformin is already used to treat that disease. The participants will then be monitored to see whether the medication forestalls the illnesses they do not already have, as well as diabetes and death. On 24 June, researchers will try to convince FDA officials that if the trial succeeds, they will have proved that a drug can delay ageing. That would set a precedent that ageing is a disorder that can be treated with medicines, and perhaps spur progress and funding for ageing research. During a meeting on 27 May at the US National Institute on Aging (NIA) in Bethesda, Maryland, Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, indicated that the agency is open to the idea." Source: http://www.nature.com/news/anti-ageing-pill-pushed-as-bona-f...

Disruption is not possible in drug development. Why?

"Some of that perspective is welcome – the idea that there are always huge opportunities out there waiting for someone with enough speed and nerve to go after them, for one. That’s very Silicon Valley (and it’s also very American) and I think it’s great. But if along the way you pick up the idea that the world of apps, code, and processor speed is the default setting for the world, you can start to see everything that doesn’t advance that way as defective. That’s the Andy Grove fallacy, as I’ve called it (referenced in those links above), the idea that understanding human disease and its treatments should be pretty much like designing a new chip or writing a new app.

There’s another problem that’s not unique to the Valley, although it does tend to give people a bad case of it. That’s the “Clearly I’m smart and successful, so clearly I have something to offer in this other field over here” one. We all succumb to that one now and then; it’s human nature. You can watch Mark Cuban display it here, with respect to medical testing. But here are a couple of recent examples of the more localized problem. Iwrote last year about Emerald Therapeutics, an outsourced-lab-assay company backed by Peter Thiel (who may also be interested in their antiviral therapy ideas). Here’s another article on them, and it asks, in so many words, “Why is new drug development so comparatively torpid when app development is so torrid?”. I couldn’t provide a more succinct version of the Silicon Valley/biopharma disconnect if I tried."

Source: http://blogs.sciencemag.org/pipeline/archives/2015/04/02/sil...

"How is it possible that the technologies that most people think are important for drug discovery have become hundreds, thousands, or billions of times cheaper, while the cost of R&D, per drug discovered, increased roughly 100 fold between 1950 and 2010?" - Jack Scannell

Missing Mendelian Inheritance was the Pandora's Box of problems that we now face after the Human Genome Project. Sure we have an idea of which proteins are created by which genes, kind of, but figuring out how proteins work has been a complicated problem that can't be brute forced.

In the last 50 years, speed improvements:

1000x faster xray-crystallography protein mapping.....

300x larger protein databases....

10x cost reduction in High throughput testing...

800x number of compounds...combinatorial chemistry...


Nah, it's all good. These random people have their place. I think the problem isn't so much Liz and her friends but rather that people take them too seriously.

I think for the most part, they're doing great work and the world would be less of a place without them. Just we shouldn't expect so much.

It's like VC. Only about 1 in 100 actually go somewhere big.


You should read the last book of Maria Blasco [0], arguably the best (or at least in the top 3 researchers in the telomeres/telomerase field), and main author of the science that has inspired BioViva's work. The book is titled: "Morir joven, a los 140" (english: "Dying young, at 140") [1]

I'm going to take the time to paste here a brief excerpt translated into english:

"Is aging mandatory? Until recently, serious science did not deal with that question. After all, having ailments is normal over the years. However, what is normal today, may not be tomorrow. Mankind has grown accumulating victories against natural and normal phenomena, like high infant mortality. Fact is that more and more scientists say that not only aging can be combated, but we also must: prolonging youth could be the way to prevent cancer, Alzheimer's, and age diseases as a whole."

> Aging isn't something you can simply disrupt with a silicon valley mindset.

Usually I listen to people like Maria, who's been at it for 30+ years (not to random people in the internets with marketing and sales background). It's inspiring reading works of scientists and people so open minded, which is IMHO the essence of Silicon Valley.

> I've met organic chemists who have spent upwards of 30 years developing drugs and haven't put a single drug on the market.

Maybe because it costs a minimum of 1 billion and 10+ years of approval (plus the consent of the gatekeepers)?

[0] https://www.google.es/search?num=100&q=maria+blasco+telomera...

[1] https://www.amazon.es/Morir-Joven-Los-Maria-Blasco/dp/844933...


I should read the book.

That's fine, listen to Maria, but don't criticize me for asking valid questions, albeit somewhat bias.

It does not cost a minimum of 1 billion and 10 years of approval. The cost deconstruction of pharma trials is complicated.

As well, there's more to the dark/light side of pharma industry than generics companies. If you'd like to talk shop about it, email me.

I can share deep insights after talking to over 100+ people in the pharma industry, visiting labs, and much more.


> [...] don't criticize me for asking valid questions

Your questions are misplaced and have been probably answered before [0]. I'm just astonished by the fact that you are dismissing decades of research by some of the best and most awarded oncologists in Europe. You can't just say that "Manipulating telomeres to investigate aging sounds like a joke", when evidence (98% of the research in the field) points to the contrary.

Maybe you don't not agree with Bioviva's highly dangerous and non-standard methods for circumventing slow and expensive trials (I do not either), but that's another whole issue.

> I can share deep insights after talking to over 100+ people in the pharma industry, visiting labs, and much more.

Thanks but I have a well formed opinion about what happens inside the industry. I've also worked in the space for some years.

> It does not cost a minimum of 1 billion [...]

Current average seems to be $2.6B. Could you share your sources?

http://www.forbes.com/sites/matthewherper/2013/08/11/how-the...

http://www.forbes.com/sites/matthewherper/2012/02/10/the-tru...

http://www.nytimes.com/2014/11/19/upshot/calculating-the-rea...

https://www.bostonglobe.com/business/2014/11/18/cost-bringin...

http://www.patentdocs.org/2015/03/guest-post-26-billion-per-...

[0] https://www.reddit.com/r/Futurology/comments/3ocsbi/ama_my_n...


Was I dismissive of Maria's research?

It's fine to form an opinion, I was offering a deeper connection because I'm always open to learning from others.

My objections to crowdsourcing and aggregating information about drug development costs: http://blogs.sciencemag.org/pipeline/archives/2015/10/14/jac...

I don't fundamentally agree with any of the claims Bioviva is making around the data they've collected to consumers at large.


#3 actually seems positive.


#1 - we already know that telomere lengthening is required for life extension, but it's definitely not the only factor. The effects of short telomeres are rather bad:

http://www.ncbi.nlm.nih.gov/pubmed/23127607


> I've met organic chemists who have spent upwards of 30 years developing drugs and haven't put a single drug on the market.

You've met some bad chemists. Which is not unusual, as medicinal chemistry is basically a lost discipline at this point.


My molecular biologist friend's comment on this is pretty on-point, so I though it was worth sharing:

This is one of the first gene therapy studies I've seen that didn't end with "but we accidentally gave our subjects aggressive leukemias, whoops".

Extending telomeres is interesting! And there's a lot of good data that critically short telomeres can lead to and cause cellular senescence and death. But telomeres are just end-caps of entire chromosomes worth of DNA. They are interesting with regards to aging partly just because they are measurable and quantifiable, but aging is so much more complicated and multifactorial than just telomere length, that manipulating telomere length and saying this solves aging is an overstatement. Cancers can express telomerase and immortalize themselves just fine, for example.

Manipulating telomeres to investigate aging reminds me of this classic joke.

A cop pulls up late at night to a biologist slowly walking a spiral around a streetlight, staring at the ground intently.

"Uh, sir," says the cop, "what are you doing?"

"Looking for my keys," replies the biologist. "I dropped them somewhere on this street.

"I see," says the cop. "But why are you just looking around this light?"

"Light's better here", he replies.


> My molecular biologist friend's comment on this [...] Manipulating telomeres to investigate aging reminds me of this classic joke [...]

What's your friend speciality? Any link to his telomeres/telomerase papers, or any chance you can point him to Maria Blasco's [0] work (top researcher in the field with 200+ papers [1]) for comments?:

It'd be interesting to see science-backed rebuttals.

[0] https://en.wikipedia.org/wiki/Mar%C3%ADa_Blasco_Marhuenda

[1] https://scholar.google.es/scholar?q=MA+blasco&hl=en&as_sdt=0


I'd be suspicious of an article written by a Company about a study the Company conducted about a miracle cure developed by the Company and tested by the CEO of the Company.

http://bioviva-science.com/2016/04/21/first-gene-therapy-suc...


Hats off to brave Elizabeth Parrish who put her life at risk to push humanity forward. People were dismissing her as a lunatic at the time of treatment administration. Now independently verified results speak for themselves.


If it is true what is written in this pr articel, she is an even bigger lunatic then previously thought. You do not treat someone with two experimental treatments at the same time, that is unscientific to the power of five. How would you determine which treatment was successfull and which was not (well, Phase I is about side effects, but you still need to distinguish)? Highly controversal.


You have a sample size of one, and no control group. The patient dies. Are either of the drugs safe individually? Can't tell. Maybe one caused death and the other was fine. Maybe the two interacted in the human body somehow.

Okay, now consider the scenario where the patient lives. Are either of the drugs safe individually? Can't tell. Again, maybe the two interacted in the human body in such a way that a potentially lethal treatment was rendered ineffective at curing or killing.


Nope, Bayes makes the second situation (and to a lesser extent the first) informative since the probability of a life-saving second-order interaction between otherwise dangerous drugs is small compared to the probability of the toxicity having a more or less cumulative effect.

Now, do I expect regulatory recognition of that fact in proportion to what you would get from a proper phase 0/1 trial? Probably not, and I'm OK with that because of the moral hazard involved, but it strikes me as more than a little ungrateful to pretend that the experiment was scientifically worthless. Someone put their life on the line for all of us, we should thank them and move on.


> but it strikes me as more than a little ungrateful to pretend that the experiment was scientifically worthless.

For better or worse, the amount of information you could extract from an experiment through Bayesian analysis is much larger than what would be allowed as "kosher" science. Regular scientific process is safer because it plays safe - but that's also the reason why you aren't organizing double-blind studies when your application crashes. You can move faster by careful inference and in case you get stuck or it leads you wrong, you can always revert to a "by the books" scientific method.


Again, no. Just because the result turned out okay, the way how it was done does not become good (or scientific). There is no reason why it could not have been done in two persons.

And btw: applying it to herself is a PR stunt. Just like politicians drinking water from Flint or Fukushima. Though iIt may even be that she had to do it because she would not get FDA permission. If not, still I would not thank her. She put a life (or health) unneccessary at risk, if it is hers or someoneelses does barely matter at that point.


She put a life (or health) unneccessary at risk, if it is hers or someoneelses does barely matter at that point.

In my view, every person has the right to do whatever they want with their own life as long as they are in full use of their mental faculties, act wilfully and don't harm others. And risking life for a good cause (advancing human knowledge) is admirable. And of course, very different from risking other people's lives...


No one is claiming the result is scientific or in any way equivalent to a proper study. But that doesn't make it worthless either. It demonstrates that it is at least possible to do this successfully in one human subject, which lends substantial credibility to the pursuit of the endeavor.

An enormous amount of science has been built on scientists testing things on themselves. Here's another excellent example:

http://discovermagazine.com/2010/mar/07-dr-drank-broth-gave-...


If she is successful with all this, she won't be able to sell it in an FDA approved manner, but she will have an extended life/health span which is its own reward. Not everything is about money.


>applying it to herself is a PR stunt. Just like politicians drinking water from Flint or Fukushima. Though iIt may even be that she had to do it because she would not get FDA permission.

Medicine has a long history of self-experimentation:

https://en.wikipedia.org/wiki/Self-experimentation_in_medici...


It doesn't matter how many hypotheses you test at one time, as long as they are all orthogonal. The problem arises when attempting to test multiple hypotheses that have some co-linearity in the solution.


No. Pharmaceutical research does not and cannot work this way. Over the last few years, there has been much reasearch on molecular interactions. The current consensus is that everthing interacts with pretty much everthing at some point, it is just the degree of these interaction that varies. Molecular pathways become more and more vague (which does not mean that they disappear, its just very complex). For example, we do not even know how many existing drugs interact with each other, because who would fund that? Some reasearch hospital now do it but it is tedious when you have hundreds of potential interacting partners.

For clinical trials, this leads to very strict guidelines. One of my university professors once told us about a drug they had to test in dogs for some side effects. Nothing happend to the dogs but afterwards they would have been eutanized because it was regulated that these exact dogs cannot enter another study. They finally adopted them, but still. Similar, people entering clinical trials are usually not allowed to take certain drugs, may need to abstinent from alcohol etc.

Keep in mind. This is not an experiment, this is a clinical trial in a human.


You're completely missing the point. Those two things are not comparable. Yes, it's not a controlled study. But it still has enormous value.

If I tell you I invented a cure for cancer, you should be highly skeptical of me. But if I tell you I have a cure for cancer, prove to you that I have cancer, then cure my own cancer - you shouldn't give that treatment FDA approval, but you should sure as hell start the clinical trials process. Whereas if I do not treat myself or anyone else, you should just write me off as a crank.

That is the difference between the world before and after this self-experiment. It upgrades the probability in everyone's mind that this is a real thing and it can really work. It doesn't mean we should all go blindly get the treatment done, but it does mean we should take this research much more seriously. That is its value.


Except in this case, the proof that you've cured cancer (and that you had cancer in the first place) comes from a non-reputable lab (SpectraCell), doing a telomere length test which has not been documented in the literature. It's even on Quackwatch's list of labs doing "Dubious diagnostics tests".


Giving a drug to one person to see what happens is definitely an experiment.


> Keep in mind. This is not an experiment, this is a clinical trial in a human.

(Note: I have one drug in clinical trials, for which I designed the phase I and phase II protocols, and have appeared before the FDA in support of clinical trials of new medications.)

Actually this is not a trial, it is considered an experiment. Trials are controlled (not always blinded or tasted against placebo, as many people think). Strictly speaking you cannot give an unlicensed medication without getting in trouble -- in fact permission to do a trial is actually agreement by the FDA that they won't prosecute you for breaking this law, basically because you followed one of the procedures spelled out in the law and the FDA agreed with your proposal.

You are completely right on interactions. And yes, the animals are pretty much always sac'ed at the end of the experiment, even those in placebo arms :-(

There are a few quasi-informal exceptions to the no unapproved administration. One is if you develop the drug yourself -- hard to prosecute. In a modern corporation however you can't really do that -- if you're a research scientist developing a drug, lawyers could claim that you were forced into it by your boss (another example is that the FDA requires that QC be an independent function). So in practice the only person who can try such a drug is the CEO.

In my case I was both the CEO as well as one of the developers so was confident that the in vivo data we had showed that I would be fine. As a result I was a pincushion (these were true experiments in PK, diffusion etc -- I didn't have the indication we were treating for). The drug hasn't yet gone for approval, but if it does, somewhere in the approval application there will be a description under "previous human experience".

You can do other experiments and trials someplace not subject to the FDA (i.e. other countries). Unless they are also formally part of your FDA process you can't use them in support of approval -- but if you paid for them you have to include them as previous human experience as well.

And there are also various "compassionate use" cases though they are also somewhat-formalized now because some people try to stretch them into trial territory. By definition they are not adequately powered.

There are amusing examples of previous human experience. My favorite is someone who shall go nameless who argued in support of an erectile disfunction treatment in front of his board by dropping his trousers and injecting his penis in front of them. I have only heard of this second hand but I bet there was quite a reaction!

NB for anyone else in pharma: yes I glossed a few terms like calling the NDA an "approval application" in the interest of clarity for those not in the industry.


> My favorite is someone who shall go nameless who argued in support of an erectile disfunction treatment in front of his board by dropping his trousers and injecting his penis in front of them. I have only heard of this second hand but I bet there was quite a reaction!

That was Brindley's (in)famous lecture on papaverine: "How (not) to communicate new scientific information: a memoir of the famous Brindley lecture" http://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2005.... The reaction was just as you suppose and everyone here might enjoy reading Klotz's recollection of witnessing it.


Please submit that, it's delightful :)


It's been submitted before: https://news.ycombinator.com/item?id=3478971


Orthogonality and biology aren't friends.


In this case, I guess that they aim to make a whole cocktail of therapies to counteract age related effects, so in that light it kind of makes sense, at least as a PR trick although not as a scientific study.

Anyway, it reminds me that someone (that I have forgot) said that the first human that will never die is already born.


Aubrey de Grey has stated that the first human to reach 1000 years old is born today. He has also stated that most won't reach those livespans even with available treatments and methods due to the suboptimal behaviour we primates engage in.


Ray Kurzweil has stated (as recently as 2008) that in eleven years (in 2028), all of mankind's energy needs will be supplied by solar power. This will obviously not be true. Predictions are difficult, especially about the future.

As for Aubrey de Grey, he can state whatever he wants to, but that doesn't make it true.

It is, however, noteworthy that a scientific article published in the fairly prestigious EMBO Reports [1] concluded that "In his writings, de Grey fails to mention that none of these approaches has ever been shown to extend the lifespan of any organism, let alone humans."

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1371037/#__ffn_...


I was only sourcing the quote, not advocating it's veracity.


Unless a drunkard drive over him on in a lonely area.


But you don't know that going in do you? If you knew exactly what was going to happen you wouldn't need to experiment in the first place.


And it's not always possible to tell which hypotheses are orthogonal; if you test two hypotheses at once that you believe to be orthogonal, but it turns out that there is some underlying connection between them, you will get bogus results.


Here the co-linearity is that of them being applied to the same body. Now, I think it is still useful. At the first you always have N of one, and obviously there is no control. We at least know you don't die right away when your WBCs are upgraded.


The link between telomere shortening and age was proved just a typical correlation recently; in fact telomere can expand naturally as well. Might not be as useful as she thought...

By the way, is there any attempt for a programming language of human body on biochemical level? Programming protein/DNA/RNA interactions as a form of language? Currently all our efforts seem to be like hacking by shooting blanks, or as if you changed/inserted/deleted a few lines of code randomly and observed what that does (typically on animals).


We don't really understand the "hardware" enough to create a legit programming language for life yet.

We're basically reverse engineering biology and that's pretty hard.

Believe it or not DNA/RNA knowledge is just the tip of the iceberg in how life works.

There's so many other factors that influence DNA expression like DNA folding/compaction, enzyme up/down regulation, the genes environment, all in a vary complex interacting system that creates life as we know it.

If you want to skip the DNA and jump straight to proteins and just start assembling amino acids then you run into an NP hard problem that the most advanced supercomputers and GPU clusters can't decipher.

So that's a brief summary into the challenges that are faced.

If we ever do reverse engineer life I think we would become what historic literature classifies as "Gods".


Actually, protein design is fairly routine now. We used Exacycle, an idle-cycle computer at Google, to show that given reasonable amounts of computer time, design of proteins is a straightforward process. You don't need advanced supercomputers or even GPUs to solve this problem- just classic clusters- although GPUs (not supercomputers) speed up the rate significantly.

The important reason why this works is that while "protein folding is an NP-hard problem" is technically true for computer scientists, the more important fact is "we have approximations to the NP-hard problem that are good enough to finish in hours if you have a 600Kcores working on it".


Sure, it's tough. But nevertheless, I am interested if there are at least some efforts I can look into? Like what you see in robotics, using pneumatic tubes attached to endoskeleton simulating biarticulate muscles allowing us to study kinematics of human body by some approximation (and being useful for orthopaedics), I am curious if there are some domain-specific languages for individual biological processes. I understand having a language covering all processes is an insane level of difficulty, but some initial localized approximations of languages should be possible and useful as well. Obviously, we all know F@H and other physical simulations, but I am not aware of something generative, language-style like (besides L-systems).

What I want to see instead of scientific hypothesis->experiment->observing result->conclusion if we could instead think: "What do I need to do in order for this system to behave this way?" given some building blocks, like when we are creating an algorithm. So instead we can try to figure out some basic blocks, test hypotheses that these blocks are actually effective and figure out interactions that work (even if only probabilistically). Initially we will all laugh at results as being "stupid", but over time we can get to cover pretty complex systems (like going from wireframe 3D graphics to photo-realistic rendering).


Yep, and most interactions are non-deterministic. I think we can safely say it won't happen in our lifetime.

On the bright side, we have a lot to learn and learning is life :)


Yellow Fluorescent Proteins are a great example of this. Very loosely speaking, there is this open ended barrel structure that 'hides' the fluorescent part in the center. The fluorescent part in the center will glow yellow when you hit it with blue-shifted light (Stoke's Shift). You send light in, and you get less energetic light out. What makes the florescent part glow yellow in color is an interaction between neighboring molecules. How do those parts interact, like the real guts of the interaction? Quantum Mechanics. Resonance energy transfer and all that jazz, oh you know, elementary graduate level quantum classes (/sarcasm).

So when we say that the process is non-deterministic, maybe that is not quite right. Some of the processes are deterministic, in the sense that quantum mechanics is deterministic in the sense of probability density functions. Which is to say, who knows.

Yeah, molecular biology is right on the edge of being total random noise and actually making things happen. Where any one part of a spaghetti mess of interactions falls on that edge in a given temperature, ph, or salinity level, well, we could use more funding.


You're sure in for a surprise then.


> By the way, is there any attempt for a programming language of human body on biochemical level?

Not quite, but there are languages that allow you to create organisms using known proteins, etc. https://moleculamaxima.com/ for example.


Programming protein interaction is probably very very hard. Comlexity akin to exploiting buffer overflows or writing quines.

Thus each new protein will need to be designed separately.

We can make a programming language governing (turing-complete?) gene expression - suppressing or promoting genes which may suppress or promote genes based on conditions. But in the end we need to control some bio-active proteins, which are much harder to invent.


> The link between telomere shortening and age was proved just a typical correlation recently

Rosedale made a brilliant case (though maybe not proper proof) for this back in 2012: http://www.marksdailyapple.com/the-tall-tail-of-telomeres/


> By the way, is there any attempt for a programming language of human body on biochemical level?

I guess we need to better understand the various biological pathways first. Otherwise, you are just generating proteins (albeit perhaps conditionally), but you don't know what their effect may be.


The article isn't terribly clear if they are targeting the telomeres or use it just as a marker to see if whatever they tried to do actually did something.


There was something posted on April 1st about a DNA programming language. I don't know if it was ever declared to be an April Fools joke or not.


Thanks to mkagenius for using a reasonable title. Sadly, the actual article went with the tabloid-style "First Gene Therapy Successful Against Human Aging."


"... Successful Against Aging in White Cells in a Human" would be more accurate while also preserving the informative aspect. Most people don't know that Telomeres directly connect to human aging.


"Most people don't know that Telomeres directly connect to human aging."

As far as I know, it isn't entirely settled that they do ...which is why the title is misleading. I guess it will be hard to argue against if Elizabeth Parish pulls a Benjamin Button.


Not sure about that with the HN audience. I have only the most passing interest in biology and aging research but I automatically made the association.


Anyone that watched Gundam Seed Destiny does. :)


> Telomeres are short segments of DNA which cap the ends of every chromosome, acting as 'buffers' against wear and tear. They shorten with every cell division, eventually getting too short to protect the chromosome, causing the cell to malfunction and the body to age.

Can anyone explain what happens to telomere length when a new human is born? Presumably the telomere length is reset? Is there a beneficial reason for telomeres shortening with time?


Indeed, in gametes (sperm and egg cells) the cells use enzymes that rebuild telomeres.

Telomeres "shorten" when DNA is copied for cell replication; the benefit of this is that it means telomeres quickly whittle down to nothing, and kill the resulting cells, when a rogue cell line has started replicating an unnecessary number of times- e.g., in cancer.


However, people die of cancer (especially if untreated...)

So does this mean that without this shortening of the telomeres, the incidence of cancer would be much larger? That the cancers that actually manifest are a small fraction of the potential cancers aborted by this defense mechanism?


Absolutely. You have 'rogue' cells that go on independent replication programs all the time. But there are a few checkpoints which are no-go if a cell passes them - they are immediately forced to die. These include, short telomeres, lack of proper DNA repair, and ability to respond to induced-suicide signals. In order for an otherwise 'cancerous' cells to be a problem, it really has to have developed processes that ignore ALL of these (few) checkpoints. The chance that the particular mutation in that cell includes a mutation to overcome ALL of those hurdles simultaneously in a single cell is the chance you develop (a harmful) cancer. A change to nearly any other gene will cause one of those checkpoints to kick in and force the cell to die.

The DNA damage checkpoint is interesting all the way through public health policy in 2 cases: 1) The BRCA gene is a DNA repair protein. Women with a mutated brca gene are missing one of those 3 checkpoints. 2) HPV (for which we have a complete vaccine) is of a type of virus that is generally destroyed by your DNA-repair machinery. However HPV, being evolutionary wily, has a specific mechanism to shut down your own DNA repair machinery that would otherwise catch the foreign invader. Hence, HPV 'causes cancer' by deliberately disabling one of those checkpoints.


I can't name the research on this topic off of the top of my head, but yes to both questions. Cancer is a common occurence in all mammals and we have evolved many self defense mechanisms, including telomeres, to fight it as animals started living longer and longer. One of the most promising areas of oncology research is immunotherapy, for example, which guides your immune system to attack cancer cells that havent been recognized as targets.


Indeed- and there's many other, separate defence mechanisms that also quash cancers before they become a problem. If a tumour has grown enough to threaten, it has evolved workarounds to at least several of these.


I think that before we have immortality, we need to understand and cure cancer.


"I think that before we have immortality, we need to understand and cure cancer."

I'd be happy with toenail fungus. Or mild eczema. Or, really, any medical condition whatsoever.

You realize people are still arguing over why your joints make a "pop" sound when you crack them, right ? Like, they've sort of settled on the air bubbles rapidly escaping the joint, but ... there's still a debate.


Yes, but you will die of cancer. If we somehow can stop aging, people will die of cancer anyway.

I think we also need to figure out how to stop noses and ears from growing.


cancer is like the halting problem. there is no way to tell 100% if a program is going to halt or not. telomeres may be a way to help reduce cancer.


I assume that this is far from unique to humans, but not quite universal. I wonder whether the "immortal jellyfish" turritopsis dohrnii has some telomere rebuilding mechanism for all cells that provide its age-defying abilities.

I also wonder whether there is a second advantage to telomere depletion; reducing the instances of organisms from different generations carrying the same genes competing for resources. After all, we're here for the benefit of our genes, not the other way round.


We do know that smaller (shorter lived) mammals at least have significantly shorter telomeres than humans.

Here's a paper comparing max life span (MLS) against body temperature, body mass, and telomere length. [1]

[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680702/figure/F...


> Indeed, in gametes (sperm and egg cells) the cells use enzymes that rebuild telomeres.

Is it practical to harness this somehow to extend life then?


Some scientists consider ageing to be a disease. They're trying to rebuild telomere length to keep us young, so this sounds like a step towards that goal.


That's probably exactly what the article was talking about- though its very short on details, aside from that the treatment was a form of "gene therapy." But my guess would be that the therapy involved the addition of a gene for this very enzyme (telomerase) in a form that it would become active in adult somatic cells.

Of course whether this would actually meaningfully extend life is uncertain- aging is complicated.


If someone had the secret to eternal life would they break it on hacker news?


Early in the process of embryonic development all sorts of radical restoration of damage takes place, things that couldn't happen in an adult organism without severe disruption. Telomere lengthening via telomerase is just one of them. E.g.:

http://phys.org/news/2011-09-body.html

Early embyros have a lot in common with negligibly senescent lower species like hydra in that they are in a state of always-on regeneration. Repair everything, all the time. That state of being was lost somewhere along the way to organisms that have complex nervous systems made up of long-lived cells and structures that have to record state. An adult human couldn't operate like a hydra and live.

The setup for most species is that adults have small groups of stem cells with telomerase and unlimited self-renewal, but the bulk of tissue is made up of somatic cells without telomerase, or with much less telomerase activity, that have a limited number of divisions before self-destruction or clearance by the immune system. Stem cells produce in a small number of new somatic cells as needed, and are the only tiny set of cells with the unlimited replication privilege. Telomere length is a part of the countdown mechanism that limits divisions in somatic cells - see the Hayflick Limit - because of the end replication problem in that a little of the length is lost with each cell division. This situation is shaped by the existence of cancer. The whole arrangement looks very much like something that came into being to fend off cancer, with ever more checks and balances arising to prevent uncontrolled replication, while still incorporating the mechanisms needed for embryonic growth and later regeneration.


Telomeres shorten because we have linear chromosomes and it is physically impossible to replicate them without losing a bit off the ends (because in order to extend strand 1, you need to template off strand 2, so the end of strand 2 can't be copied).

The telomere is a solution to this problem; you just pad the ends of your chromosomes with useless repetitive sequence so if you do lose a bit while replicating it doesn't matter. Any anti tumor properties of this system are an ancillary benefit.


> Telomeres shorten because we have linear chromosomes and it is physically impossible to replicate them without losing a bit off the ends

If that were true though wouldn't successive newborns have shorter and shorter telomeres?


No, there is a specialized enzyme called telomerase which is responsible for lengthening telomeres. It is active in germline cells and most stem cells, allowing those cells to safely and indefinitely replicate. The enzyme is basically a piece of RNA template that you can slap onto the ragged end of the chromosome and hold in place to allow extension.


> Is there a beneficial reason for telomeres shortening with time?

So that people die instead of reproducing when they're old


It is also the final defense against unrestrained cell divison; a natural protection against diseases such as cancer.


There were cultures where the oldest men in the tribe got exclusivity over the teenage girls to reproduce with. Also, since men can reproduce in old age, that sounds questionable to me.


So that people die when they're no longer reproductively viable / relevant, rather than using up valuable resources. Wouldn't telomere shortening have some selection-pressure advantage?


I'm no biologist, but as I recall newborns have long DNA strands. As it says, each time cells split the strands shorten a bit eventually leading to age related illnesses. AFAIK there are no benefits to telomere length shortening with time.

As I understand it, after we've reproduced and raised children - which we generally do before age-related illnesses kick in - we only have limited evolutionary value and no longer face stringent selection pressures. So it's probably that there were few opportunities for evolution to correct age related illnesses, or few survival-of-the-fittest opportunities (since we've already reproduced by the time they occur). However, this theory ignores the ability for grandparents to look after children. I suppose it's only minor enough for us to have evolved to live to ~80 but doesn't require youthful health any more.


Two thoughts ..

#1 No details of the "gene therapy". Did they paste telomerase genes into a virus, infect white blood cells and re-inject them?

#2 Telomeric lengthening can be a double edge sword. You don't want all your cells to live forever ... particularly in things like cancer cells.


There are some details in the AMA that Parrish hosted, but not the specific technique or vector used. One can probably make educated guesses based on who was involved and their past work. It was a whole-body approach, not targeted to any specific tissue. Telomere length was measured in white blood cells because that is the present standard assay in the scientific community, not because immune cells were targeted specifically:

https://www.reddit.com/r/Futurology/comments/3ocsbi/ama_my_n...

"The genes targeted are human telomerase reverse transcriptase (hTERT) and follistatin (FST). In animal models neither FST nor hTERT have increased the risk of cancer. We expect to see the same result on myself, and to that effect we are measuring all known cancer biomarkers. The gene therapies on my body are to measure the effects on humans. There is plenty of animal research to support these gene therapies but no one was conducting human tests. We are using both visual biomarkers, MRI and a panel of blood and tissue testing including work on telomere length and epigenetic testing. We are collecting as much data as we can, but unfortunately we currently don't have the coverage rate for this therapy, how much of the tissue of the body is affected. Depending on the tissue and vector used we ultimately expect to see similar rates of transfection as seen in mice, which is somewhere between 5 to 60%."


On #2, they're lengthening telomeres, not disabling the telomere mechanism. I'd think that one of the first mutations a cell needs to undergo on the road to being considered "cancerous" is to completely disable the telomere mechanism so that it will become immortal.


Long telomeres are necessarily better in fact it increases the risk of cancers.

Too short is bad, too long is bad.


A good article, but if you take a look at the 7 problems that SENS "Strategies for Engineered Negligible Senescence" identifies as needing to be solved to address ageing the telomere length issue is just one subset of single issue (cellular senescence). Furthermore they appear to have fixed this only for a single cell type - white blood cells which are easy to obtain and do gene therapy on.

Nonetheless it is still encouraging progress...


I disagree. This is not a good article, it does not state anything (what kind of genetherapy, what kind of gene, how was it administered) but wants to tell a personal story. You can not even say how they achieved longer telomeres in white blood cells. Have they transduced hematopoetic stem cells? Or just transplanted (some kind of) white blood cells, that will be gone from the body in a few months? That would not be progress.


From BioViva: http://bioviva-science.com/2016/04/21/first-gene-therapy-suc...

They are a startup in their funding-press-funding-doing-things-press-funding cycle, so expect a certain amount of positioning. This is all serious work, however. Deep Knowledge Life Sciences recently took a position, so BioViva is within the circle that includes the reputable In Silico Medicine, Biogerontology Research Foundation, and other for- and non-profit groups in life science and aging research and advocacy:

http://www.eurekalert.org/pub_releases/2016-04/brf-dkl041916...

Take a look at the BioViva board of advisors, and note the presence of George Church, who is essentially the center of the network of connections for all gene therapy activities these days, and a luminary in the field.

The nature of the BioViva press here is that they did a thing, and the thing worked as expected based on the only available way to take a short-term measurement. That seems quite a reasonable thing to announce when you are a young company working on traction. It doesn't really imply rejuvenation without more useful data, such as DNA methylation assays of biological age, for example, and the details on that front are complicated, see below.

Telomerase gene therapies to treat aging are heading for human trials one way or another. Look at this position paper for example, from one of the groups to have demonstrated improved health, stem cell function, and longevity in mice using telomerase gene therapies in past years:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815611/

BioViva's principals are taking the stance that present regulation and talk of moratoriums are ridiculous given the fact that so much good might be done, and that new gene therapy technologies such as CRISPR are now making it cheap and easy to run these sorts of edits in humans. I agree with this.

So telomerase gene therapy in mice extends life modestly: there are years of pretty robust results to demonstrate that. Average telomere length appears to be a reflection of aging, most likely not a significant contributer to aging. It is a poor measure, as the trend downward with age is statistical over populations. Average telomere length is some function of stem cell activity (delivering new cells with long telomeres) and cell division rates (shortening telomeres with each division). Stem cell activity declines with aging. Average telomere length is presently measured in white blood cells, which are going to have a whole lot of influences on cell division and replacement rates that don't exist in other tissues, due to immune system reactions to circumstances. Telomerase is clearly doing a lot of other things beyond telomere lengthening. Look at the work suggesting it is acting as a mitochondrial antioxidant, for example, or other cryptic activities.

The present consensus is that telomerase therapies in mice extend life through increased stem cell and/or immune activity. Mice have very different telomere dynamics, however, and there are concerns regarding cancer risk in humans. Trying it in dogs or primates would be the next safe thing to do - move to a mammalian species with telomere/telomerase dynamics that are closer to ours.

There is an argument that runs along these lines: telomerase gene therapy is just (primarily) another way of triggering old stem cells to get back to work, and therefore vis a vis cancer and risk should fall in the same ballpark as stem cell therapies carried out over the past fifteen years, and therefore full steam ahead because all of that work produced far less cancer that was feared. Prudence would suggest trying it out in something other than mice first, but I suspect the sudden ease of gene therapy means that this will be bypassed by the adventurous.

I'm totally in favor of adventure when it comes to gene therapies for follistatin/myostatin - I think the risk situation there is pretty much as low as it can get prior to hundreds or thousands of enhanced human patients. I'm more cautious on the cancer and telomerase front; I think more data there would be desirable before I stepped up to try it out. Other people can have other viewpoints, and that is the point - it should be the patient's informed decision, not that of a bunch of self-interested bureaucrats.


There's a vid of George Church talking at length on edge.org[0]. As with all edge.org vids, it's profound.

[0] https://www.edge.org/conversation/george_church-the-augmente...


They fixed their RSS feed—for their blog—a few days ago, so I ended up on the site (having previously subscribed). It was interesting to see they're looking at using the therapy for other conditions.

Do you know if there's any scope for doing something to reduce cancer risk, with this tech? Such as enhancing P53, or something like that (if that doesn't damage the individual).


One of the GRG regulars raised the suggestion that perhaps we don't see increased cancer risk in mice following telomerase therapy - and that's after the research group in question dropped the addition of tinkering with P53, and moved to straight telomerase overexpression, interestingly - because the immune system improvement means that there is more and better cancer immunosurveillance going on. I'm not aware of any earnest data to support or contradict that hypothesis, however.


What's GRG? Do you have a link to the comment?


The Gerontology Research Group, originally organized by the late Stephen Coles. The mailing list is a watering hole of sorts for the gerontology community and some of the surrounding advocates and entrepreneurs, though much less so now than used to be the case.

It is a closed list, so no link, I'm afraid.


Thanks!


I wonder what Google's CalicoLabs http://calicolabs.com thinks about this...


It's Theranos all over again, with lower stakes.




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