Gene Therapy Makes Near-Blind Patients See by Strengthening Neural Connections

http://www.dddmag.com/articles/2015/07/gene-therapy-makes-near-blind-patients-see-strengthening-neural-connections

by forloop • 11 years ago

100 27 11 years ago

cryoshon5• 11 years ago

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.

navi543• 11 years ago

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?

cryoshon5• 11 years ago

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.

netcan• 11 years ago

Give us so more, you tease!

ChuckMcM• 11 years ago

Cool, I expect it is the beginning of the end of genetic disease. What that means overall I'm not sure I can say but for people whose life can be improved dramatically by fixing a genetic mixup it will be literally life altering.

My sister is especially interested in gene therapy research associated with Downs Syndrome.

dekhn6• 11 years ago

I can see gene therapy making significant progress in the next decade on diseases for which gene therapy can be effective, but there are some serious problems. you still have to get the therapy to the cells that need it; the delivery problem is hard. Further, it's not certain that you can easily identify which "patch" (to the extent the idea of patching the genome is actually a valid one) is going to work in an individual.

I woudl say that we will see the end of some genetic diseases, similar ot the way that vaccines reduced the incidence of some diseases. Other diseases, especially complex, multifactorial ones, we simply don't have the theory to understand their mechanism, and in general, you need to have some amount of mechanistic understanding to come up with therapies.

dekhn6• 11 years ago

Technically, we were just getting started with solving the easy to fix problems with gene therapy over twenty years ago.

The field was moribund- for a number of reasons- for quite some time. New results are great, but nothing truly transformative, and basically as hard as delivering classic pharma or biotech treatments.

Frozenlock• 11 years ago

Any contact to get gene therapy for muscular dystrophy? :-p

navi543• 11 years ago

I made an 1 day e-mail, so if you can send me your e-mail I will write to you all my questions I have. The mail is navi54@yopmail.com .

DiversityRules• 11 years ago

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?

toufka2• 11 years ago

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

cryoshon5• 11 years ago

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.

fr0styMatt2• 11 years ago

As someone with glaucoma and bilateral amblyopia (I had congenital cataracts in both eyes) the answer to this interests me greatly!

I'd also add:

Will this kind of gene therapy allow protection or regeneration of the optic nerve?

WalterBright• 11 years ago

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).

ilurk• 11 years ago

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?

toufka2• 11 years ago

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.

Gene Therapy Makes Near-Blind Patients See by Strengthening Neural Connections

Related Stories