
Gene Therapy Makes Near-Blind Patients See by Strengthening Neural Connections - forloop
http://www.dddmag.com/articles/2015/07/gene-therapy-makes-near-blind-patients-see-strengthening-neural-connections
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cryoshon
I work in gene therapy; expect a lot of headlines like this in the coming
years. We're just getting started with solving the easy-to-fix problems and
disorders right now, but they're falling quickly.

Soon it'll be possible to seriously talk about improving working functionality
via gene therapy-- I'd expect simple musculoskeletal augmentation first.

~~~
navi54
Could you describe a bit more about your job? I am currently in training. Any
advice would he helpful. I am thinking of doing an PhD.

Edit: Let me rephrase that: can I PM you somehow for more details and
questions?

~~~
cryoshon
I didn't go the academic science route, but I can maybe tell you a bit about
some people who did/are currently. I'll start at the very end, then work
backwards:

The professors: These guys lived the dream from start to finish. They now have
multiple postdocs working to answer the scientific questions that interest
them. The professors are responsible for fundraising and presenting the
research, and are almost never inside of the laboratory. In general, the
professors dictate the direction of the laboratory and have many people
working for them. They make less than 120k/year even at the very best places
to have professorships. They have probably worked about 20 years to get into
this position, and most will hold onto it until they retire. Professors are
not the workhorses of academic science. They hardly have anyone to answer to,
and can disappear for weeks at a time to go to conferences in exotic locales.
They take sabbaticals as needed. They will boss you around via email while on
sabbatical about projects they've barely heard of. They have limitless
quantities of time to spend with their family, as everything can be covered by
the postdocs. The professors are elite, even the bad and underfunded ones.
They have "won" the academic game, and are invested in continuing the academic
establishment. The academic establishment furnishes the professor with cheap
and educated scientific labor in exchange for accepting the legitimacy of the
system.

The PhDs (postdocs): These are the workhorses. After five (eight?) years of
grueling work to earn their PhD, they must now work for professors once again
in order to build their resume before getting a professorship of their own.
Many postdocs have been in the postdoc game for 5-10 years, and range in age
from late 20s (rare) to early 40s-- once you hit your mid 40s, they tend to
give you another job title out of pity. In academia, postdocs make from
32k-60k per year. For the most part, they have had the fire of life beaten out
of them, and it shows. Postdocs are notorious for working early mornings, late
nights, weekends, holidays, etc. They're some of the people you see sleeping
in the laboratory. They tend to enjoy drinking alcohol with other postdocs,
and can be difficult to relate to on a personal level because of their jaded
visage. Postdocs frequently pursue their own projects in addition to the
projects handed down to them by their professor. Postdocs must churn out
research papers as fast as they can manage. Postdocs tend to be pretty "laid
back" about things like hygiene and manners. Postdocs are also seen skimming
the abstracts of journal articles, then saying they have read the paper in
order to start a conversation. Postdocs will have their name as first or
second author on their papers; their boss, the professor, will also have his
name on the paper somewhere, even if he didn't contribute. Postdocs spend most
of their time toiling in the laboratory or office, but can sometimes escape
for vacations or important conferences. Postdocs are criticized very
frequently and very severely in public during their presentations. Postdocs
can sometimes spend years chasing hypothetical scientific concepts with only
tenuous evidence. They are the heroes of the modern scientific story, but
certainly the biggest losers as well-- many (most?) do not date/marry or
maintain close friendships. They are married to the science. Frequently they
are sad, defective, or damaged human beings. The foreigners are generally
slightly (and only slightly) more balanced than the Americans.

Graduate students: These are the other workhorses. You will start at this
level. This phase will take about five years, so get used to it. You are in
your early to mid 20s to early 30s at this level. The first rule of being a
grad student is that your time (which is to say, the physical minutes of your
living and breathing life) is worth absolutely zero. Hot new kit can do an
ELISA in half the time? Too bad, you're stuck with Old Bessie until 11 PM,
then you'll have a similarly avoidable problem which will hold you up until 3
AM. By the way, there's no overtime, and no pats on the back for doing
anything, whether or not it's expected of you. You earn a stipend for the 80
hour weeks you pull, usually from 11k-30k. You have no say in the direction of
things, and will work tirelessly on the projects given to you by postdocs and
the professor. The professor is supposed to be your mentor, but you will
rarely meet with him. You will take a couple of classes, but largely your time
will be spent churning out work for someone else to put their name on. Perhaps
you will have a project of your own that is given to you by someone else.
Sometimes you will be allowed to give a presentation, and rarely you can go to
a conference to do so. You will be criticized a lot. Nobody cares what you
have to say. You are probably far from home and your support network. You may
still find time to have a relationship somehow at this phase, but usually not.
If you get a shit professor, you're going to be in for a bad time. This is the
phase in which your hygiene and manners start to slip, but you still have a
very long way to fall before you are at the DGAF levels postdocs and
professors make look easy. Many people drop out of academic science at this
level, and nobody can blame them.

That's my take on academia, having left it recently.

I don't want to say too much publicly about my job since I work with many
confidential proprietary programs and technologies, but if you want to send me
a PM (does this website even have that? if not, just use the email on my
profile)and we can chat.

~~~
return0
Good luck man, i wonder what the industry is doing differently than academia
to speed up the process. Also what is the course of the most passionate
people, academia or otherwise?

~~~
cryoshon
So far I'd say that academia has more passionate people whereas industry has
more effective people.

I'd also say that the industry people seem to think that the passion of
academics is related to their narrowmindedness/tunnel
vision/stubbornness/navel gazing.

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DiversityRules
Does the strengthening of neural connections only work with people with that
specific gene? Could this be extended to other cortical visual disorders, such
as amblyopia?

~~~
toufka
The protein, RPE65 [1][2] allows cells to produce a required pigment necessary
for both rod and cone-mediated vision. Getting that sequence into the (correct
cells in the) patient was the hard part. This particular protein helps prevent
blindness in these patients precisely because their natural version of this
protein is an ineffective variant of the canonical RPE65 (the sequence of the
RPE65 they have is different or truncated from the sequence in [1]). The
delivery via Adeno-associated virus works because the eye is special -
immunologically privileged. So gene therapies work well for tissues that are
immunologically privileged, or can be extracted from the body, affected, and
then re-implanted (the eyes and T-cells respectively). This allows the therapy
itself to avoid triggering your immune system and fighting the therapy. This
is why most of the first gene therapies you will see here soon are targeted
towards these two systems.

Different disorders will require addressing the truncations/deviations of
different proteins. But if the delivery mechanism works properly, and the
knowledge about which proteins are ineffective for particular diseases, this
[gene therapy] is _the_ mechanism for curing a whole host of diseases not
caused by a foreign agent. At this point, the delivery is the significant
technological hurdle. Combined with the effectiveness of Cas9-genomic
targeting, and the past 20 years of reading genetic code, there is a lot here
to watch.

[1] the 534 amino acids of RPE65 that are required - to the bit - in order to
see:

    
    
      MSIQVEHPAGGYKKLFETVEELSSPLTAHVTGRIPLWLTGSLLRCGPGLFEVGSEPFYHLFDGQALLHKFDFKEGHVTYHRRFIRTDAYVRAMTEKRIVITEFGTCAFPDPCKNIFSRFFSYFRGVEVTDNALVNVYPVGEDYYACTETNFITKINPETLETIKQVDLCNYVSVNGATAHPHIENDGTVYNIGNCFGKNFSIAYNIVKIPPLQADKEDPISKSEIVVQFPCSDRFKPSYVHSFGLTPNYIVFVETPVKINLFKFLSSWSLWGANYMDCFESNETMGVWLHIADKKRKKYLNNKYRTSPFNLFHHINTYEDNGFLIVDLCCWKGFEFVYNYLYLANLRENWEEVKKNARKAPQPEVRRYVLPLNIDKADTGKNLVTLPNTTATAILCSDETIWLEPEVLFSGPRQAFEFPQINYQKYCGKPYTYAYGLGLNHFVPDRLCKLNVKTKETWVWQEPDSYPSEPIFVSHPDALEEDDGVVLSVVVSPGAGQKPAYLLILNAKDLSEVARAEVEINIPVTFHGLFKKS
    

[2]
[http://www.uniprot.org/uniprot/Q16518](http://www.uniprot.org/uniprot/Q16518)

~~~
cryoshon
Definitely strongly agree with delivery being the most significant hurdle.
Many problems arise from difficulty delivering gene therapies via viral
vectors, most notably treatment efficacy and treatment durability, which
should never really be a problem because you're replacing the genes. There's
also the much-feared off-target effects, which can and do rapidly and
gruesomely kill people in the gene therapy clinical trials-- an eminently
solvable problem given more research into the correct epitope targeting, I
think.

Most of the current viral delivery vectors are shitty in a multitude of ways,
but the kinks are being rapidly worked out for AAVs and lentiviruses.
Crispr/Cas9 genome engineering is also a huge leap forward, as you mentioned.
It's important to note that some groups were having luck with gene therapy
even before Crispr, though-- imagine what they can do now, barely two years
later. The door to de novo synthetic biology has been kicked open.

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ilurk
Excuse my naive questions, but this left me very curious.

1) Have we reached a phase where the difficult part is finding the genes
responsible for X? With the delivery being now boilerplate code (CRISPR?).

2) What exactly are the limitations of gene therapy?

3) How does aging fit into the picture? For example, if grey hairs are the
result of cell aging/damaging, will we be able to reverse/restore it?

~~~
toufka
1) for the most dangerous of diseases, we tend to know their mechanism
(gene(s) responsible), precisely because if they're dangerous then they are
interesting genes and have been studied in the lab already. That's not to say
we know everything - but that information about genes is currently not
limiting (for the field).

2) But what you can do in a close environment of the lab with clean rooms,
infinite cells, lots of time, infinite do-overs, 30% success rates, and
single-cell type environments you can't do in a live body. We've taken apart
enough 'cars' to know how the engine mostly works - which are the ignorable
parts and which are critical. We've even practiced remaking certain parts,
even being creative about making _better_ parts (synthetic bio) to upgrade the
engine - however - doing all of the above on a running car that's going 60mph
is a whole different story. Currently, the largest challenge is delivering
your genetic payload to exactly, and _only_ exactly where you want it. Nowhere
more, nowhere less, nowhere wrong, and just right. That delivery is key (and
part of why Cas9/crispr is a big deal, it solves part of the problem ( _where_
in a genome)). But even if we can target where in a genome, we still need to
target where in an organism, and where _not_ in an organism. Delivery is the
current limitation. You are made of 3 billion base pairs of information
duplicated between a few trillion cells; A 0.00001% mis-delivery rate of this
absolutely stunning, perfectly designed new gene/part/function is likely
unacceptable.

3) Aging is a lot of things depending on who you ask. Generally mammalian
cells are designed to stop growing - otherwise you'd be a thousand-pound
sphere of goop at this point rather than a well-defined human with shape. This
is a good thing. But it means there are built-in limits on how many times a
cell intended to divide. Imagine a book with blank pages up front and in back,
where the copy machine can't copy the covers, so it always skips the first and
last page. Human cells have about 60 blank pages before they start eating into
the text (genetic code) at which point they hit their last life and just try
to never die (senesce). There are things we can do to add more pages with
genetic therapy, but you got to be careful you don't cause rampant growth
(cancer). SO aging is tricky, and a huge frontier that we know very very
little about (hard to do experiments where your mean time to finish the assay
is 60 years). But there's nothing inherently intractable about the concept
that gene-therapies shouldn't be able to affect.

Small molecules ('drugs' as you think of them), are great at killing invaders
- things that are distinctly non-human (bacteria/viruses/fungi/etc.). They are
not good at affecting 'disorders', cancers or other issues where your own body
is over/under/mis-reacting. For that you need to change/alter/upgrade the
body's own toolkit. This ability is what synthetic biology promises - access
to that toolkit.

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WalterBright
This is a very exciting development. I had been reading recently that gene
therapy had been nearly completely written off as unworkable (in regards to
cystic fibrosis).

