
Telomere lengthening via gene therapy in a human individual - mkagenius
http://www.neuroscientistnews.com/research-news/first-gene-therapy-successful-against-human-aging
======
kumarski
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](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](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://www.nature.com/mt/journal/v18/n3/full/mt2009286a.html),
[http://virologyj.biomedcentral.com/…/10.1186/1743-422X-10-74](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.

~~~
krpa
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...](http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004191)
...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?

~~~
Apofis
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?

------
kumarski
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.

~~~
joeyspn
_> 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](https://en.wikipedia.org/wiki/Mar%C3%ADa_Blasco_Marhuenda)

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

------
wavesum
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...](http://bioviva-science.com/2016/04/21/first-gene-therapy-successful-
against-human-aging/)

------
zavi
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.

~~~
patall
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.

~~~
CuriouslyC
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.

~~~
patall
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.

~~~
darawk
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.

~~~
semi-extrinsic
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".

------
bitL
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).

~~~
nickthemagicman
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".

~~~
megalodon
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 :)

~~~
Balgair
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.

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

~~~
meeper16
"... 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.

~~~
charlesism
"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.

------
seanwilson
> 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?

~~~
maxander
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.

~~~
Al-Khwarizmi
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?

~~~
toufka
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.

------
tosseraccount
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.

~~~
crusso
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.

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

Too short is bad, too long is bad.

------
ozborn
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...

~~~
patall
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.

------
reasonattlm
From BioViva: [http://bioviva-science.com/2016/04/21/first-gene-therapy-
suc...](http://bioviva-science.com/2016/04/21/first-gene-therapy-successful-
against-human-aging/)

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...](http://www.eurekalert.org/pub_releases/2016-04/brf-
dkl041916.php)

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/](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.

~~~
forloop
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).

~~~
reasonattlm
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.

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

~~~
reasonattlm
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.

------
meeper16
I wonder what Google's CalicoLabs
[http://calicolabs.com](http://calicolabs.com) thinks about this...

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

