least risky human hello world?

[Nathan McCorkle]

Are certain organs less likely to metastasize? Could you rub a virus
onto your hair that temporarily disables your innate dye/dark
compounds to lighten your hair? Or vice-versa, that temporarily
produces dyes in blonde/light hair?

What about something that temporarily changes urine color?
Bioluminescent urine could be pretty neat, it might make evaluating
toilet cleanliness/effectiveness easier (imagine that on kickstarter,
etc...).


--
-Nathan

[Mega [Andreas Stuermer]]

AFAIK you could eat small silencer RNAs and silence hair pigmentation or skin pigmentation. 

Monsanto did this with insects, they fed them siRNA to silence a virus. 

[Mega [Andreas Stuermer]]

Btw, why want to change hair colour. Wouldn't it be better to have a remedy stopping alopecia?

[Mega [Andreas Stuermer]]

Consume a lot of berberine and your urine turns very yellow and is (orange?) fluorescent

[Nathan McCorkle]

Just thinking that skin is an organ, so it's easy to access it and
chop it off should it go cancerous (though this would do nothing if it
had metastasized). Just seems like it could be an easy stepping stone
to a more useful modification!

[Mega [Andreas Stuermer]]

I don't think the problem is metastasis (unless you add oncogenes) but rather necrosis. Add GFP - strange protein. Now comes some solar radiation --> cell damage + GFP ----> GFP is bad ----> destroy cells with GFP. 

Now imagine the GFP cells have divided strongly and your immune system would reject like a very big patr of your arm skin. 

[Nathan McCorkle]

Yeah I guess my point is that it is easily surgically removed...
probably an out-patient (no overnight stay) procedure. As long as
infection doesn't migrate (whether it is metastasis or just cells
migrating, or virus particles leaking from dermal tissue into
free-flowing bloodstream)

[Patrik D'haeseleer]

How about human microbiome? If you consider the gut microbiome as an organ in itself, inserting engineered bacteria would probably be the safest "human" hello world. At least you wouldn't be risking turning one of your own cells cancerous. 

Patrik

[Cathal Garvey]

Actually, the wrong microbiome could certainly predispose you to long
term consequences; obesity, dementia, cancers.. the microbiome is still
being explored and it's associated with virtually everything if you look
for subtle enough effects.

A lot of that hasn't been teased out of the realm of correlation and
into causation, so for example obese persons may have a certain
microbiome because it thrives on low fibre, high sugar/saturate diets.
Even studies that observe 'biomes prior to obesity and observe outcomes
may be simply seeing the effects of diet on the microbiome prior to the
effects of diet upon metabolism.

Also, the odds of successfully inoculating yourself with a new species
are, it would seem, pretty low. Some rare species can colonise a gut
without much difficulty, but in most cases it seems that if you already
have a microbiome, throwing more bugs at it won't lead to much change. I
imagine diet is the primary cause here; bifidobacteria may be associated
with good health, but you probably can't force them to grow simply by
bif-spamming your colon if your diet doesn't support their continued
competitive survival in the gut.

So, I'd say there are a lot of unknowns and a low chance of success with
microbiome engineering at present, and we understand so little of the
"levers" by which the microbiome acts on metabolism that it's doubtful
you could come up with a comprehensive way to engineer it, anyway.

That's my view, at least!
-Cathal

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[Koeng]

How about "flooding" your colon virus particles that carry your specific insert? It could easily be manufactured, and if you select for integration with a self selection mechanism like the toxin-antitoxins Cathal was going to use in his indiegogo project, which could be fairly easy to select out the bacteria that don't have your required insert. 

That does have some problems of its own, thou. Maybe a better idea would be a conjugation plasmid inside packaged inside of a virus. Engineer it for minimal metabolic tole, and have it encode several viral repressor molecules (such as lambda's cro and cll). Then after you insert the plasmid, select by using a lytic phage for your insert. 

-Koeng

[Mega [Andreas Stuermer]]

Hm, like adding the vitaminC pathway onto a coliphage plus Colicin-delf selection. Sounds very interesting because you wouldn't change your skin microbiome composition at all.

Add elements from the F-Plasmid so it wsomtimes excises from the genome and is transfered to other bacteria.

You'd just have to hope the gut microbiome doesn't already have Colicin

[Mega [Andreas Stuermer]]

Another thing... http://petapixel.com/2014/08/25/retinal-neuroscientists-rebuttal-humans-cant-see-infrared-matter-eat/ This reminded me... 

Take Adeno-Associated virus, put in some infrared-sensing protein. Put it into your eyes and you should be able to see infrared? I saw some gene therapy approaches by AAV. They cannot replicate because they need cells that carry AV proteins. 

It would be also possible to engineer some kind of small Cestoda into something like a Goa'uld, I guess. It may seem be pretty disgusting to me, It would eat a part of your food so you don't get obese. And it could provide you with vitamin K, vitamin C, growth factors.. 

AFAIK if you cut a nerve it won't rejoin because of inhibition. I you add a growth factor (I remember a press article claiming the discovery of this nerve growth factor several years ago), it can rejoin. 

However, not sure whether such a "symbiote" would sense nerve injury in your hand if it lives in the gut...  

[Mega [Andreas Stuermer]]

Speaking of that symbionte, it would very likely be possible to exchange mRNAs and uRNAs. 

I mean digesting palnt material, you can even find plant RNAs in your bloodstream. Parasites exchange RNAs with the host in plants. http://www.the-scientist.com/?articles.view/articleNo/40770/title/Interspecies-RNA-Shuffle/

[Tom Eberhard]

Adding some infrared sensing protein to a virus and putting that into your eye: if you're tying to put the DNA that encodes that protein into the DNA of your eye cells, wouldn't you also need all the associated control mechanisms? Promoters, repressors, etc. You'd have to make sure it doesn't get over expressed or (maybe) you'd just see IR and nothing else. I'm a noob at biotech and not an expert by any stretch of the imagination, but maybe you should try this on fruit flies first. If you need fruit flies, I got some WT's in the kitchen.

Tom.

[Mega [Andreas Stuermer]]

Exacty. I'd just take the same promoter from the normal green light receptors. 
The green light receptor originated by duplication of the red receptor (or was it the other way round?). They are very close together, so they can recombine and thus the inability to make a distinction between  red and green light is caused.

[Mega [Andreas Stuermer]]

Basically these receptors sense darkness rather than light. Light changes the conformation of the proteins so it shuts down ion flow out of the visual nerve cells. 

So no downstream signaling proteins to consider? 

Wikipedia says the colour-sensing proteins actually are G-coupled proteins...So there will be downstream proteins... 

http://de.wikipedia.org/wiki/Iodopsin

[Nathan McCorkle]

I never found NIR camera images too interesting, but longer-wavelength
IR has always been cool ('heat vision'!). I was reading about this a
few years ago a bit more, but it would be awesome to add somewhere...
maybe the nose would be a good spot to embed a new eye? I say this
because the eyeball will probably absorb a lot of the IR signal,
snakes for instance use more of a pinhole camera than lenses
supposedly:
https://en.wikipedia.org/wiki/Infrared_sensing_in_snakes#Molecular_mechanism

(it doesn't actually sense photons, rather it is affected directly by
molecular heat vibrations)

This would not qualify in my book as a Hello World experiment though!

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[Mega [Andreas Stuermer]]

Want to be resistant to influenza for life? Influenza usually propagates in the lungs. Express silencer RNA against few influenza-proteins. Delivery method: http://www.pnas.org/content/93/21/11454.full.pdf 

Use a vector that doesn't integrate (potentially giving you cancer). 

Would that count as a "hello world"? Btw, it is illegal in most of the world. 

[Nathan McCorkle]

On Sep 14, 2014 4:18 AM, "Mega [Andreas Stuermer]" <masters...@gmail.com> wrote:
>
> Want to be resistant to influenza for life? Influenza usually propagates in the lungs. Express silencer RNA against few influenza-proteins. Delivery method: http://www.pnas.org/content/93/21/11454.full.pdf 
>
> Use a vector that doesn't integrate (potentially giving you cancer). 
>
>
> Would that count as a "hello world"?

Hello world is usually simple enough that it works, but simple and benign enough not to cause much difficulty.

Working with disease or immune response is a little far from the simplicity I'd be comfortable with trying.

> Btw, it is illegal in most of the world.

What do you mean? In the U.S. unless a chemical is on the scheduled list, I'm pretty sure it's free to be used internally. I wonder if the NRA (gun rights advocates) would support gene guns as a constitutionally-protected implement.

[Andreas Stuermer]

Well silencing RNA very very likely won't trigger an immune response. Usually it takes protein structures for antibodies to recognize. To put it that way it would be safer than putting GFP in your skin. 

GFP is a foreign protein and your immune system may some day recognize the GFP and kill all cells that carry it. Bad if they already make up like 5% of your skin. Necrosis. 

I think the influenca silencing would be the safest diy hello world transhumanist project xD  

Second opinions? 

Btw, you say in America I am allowed to genetically alter my skin cells or lung cells? 

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[Mike Horwath]

I would say a "human hello world" should have these characteristics:

1) Transient transfection with a plasmid, rather than integrating DNA (safer, easier)
2) Target dividing cells (easier to transfect)
3) Target easily-observable cells (probably on body surface)
4)  Transgene should be safe and essentially non-interactive with the host (so not growth factor, cytokine, etc)
5)   Effect should be observable even if only a small % of cells get transfected.

I think best approach may be targeting skin with luciferase or fluorescent protein plasmid.  There are already techniques developed in animals for injecting plasmids into the skin, then electroporating.  Injection is necessary to get the plasmid to the live, dividing cells underneath the top layer of dead/dying keratinized cells.  It may be difficult to get enough expression to actually see with the naked eye...easiest would be using a sensitive detector for luciferase activity.

Mega, I like the creativity of your idea, and the lack of transgene protein expression (so no immune response) is certainly a plus.  However,the probability of actually getting a reduction in influenza seems low.  The paper you quoted got a maximum of about 1% alveolae expressing their transgene, so if it were siRNA the other 99% of the lung would still be susceptible. Also, this is transient plasmid expression, so after a few weeks all protection will be gone.  Proving there was actually a protection from flu would require a clinical trial with appropriate controls, recruitment, legal paperwork, etc. etc...way beyond DIY capability.  Finally...kind of nit-picking here...but most flu strains target the upper airways, not the lung.

Not sure about legality.  This is great stuff to think about and discuss, but the DIY setting seems better for  non-human experiments right now.

Mike

[Andreas Stuermer]

Mike, yes the paper was about transient. But you can easily add an element that allows the DNA to be maintained as an episome. 

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[Nathan McCorkle]

On Sun, Sep 14, 2014 at 2:16 PM, Andreas Stuermer
<masters...@gmail.com> wrote:
> Well silencing RNA very very likely won't trigger an immune response.

Hmm, yeah, that's a good point.

> Usually it takes protein structures for antibodies to recognize. To put it
> that way it would be safer than putting GFP in your skin.
> GFP is a foreign protein and your immune system may some day recognize the
> GFP and kill all cells that carry it. Bad if they already make up like 5% of
> your skin. Necrosis.
>
> I think the influenca silencing would be the safest diy hello world
> transhumanist project xD

While it might be safe in its mechanism, think about how to get the
result. You'd have to go try to get sick with flu, if you don't end up
sick, maybe it worked, or maybe you were around the wrong people or
your body was already immune.... but if it doesn't work then you get
the flu and are sick.

That doesn't sound like a fun/benign test/experiment. :)

>
> Second opinions?
>
> Btw, you say in America I am allowed to genetically alter my skin cells or
> lung cells?

Yeah I am mostly sure, as long as you're following all the laws
regarding chemical storage and disposal, buying all your reagents
through unobfuscated channels (i.e. you have a business license, and
the owner/landlord of the building the lab is in knows you are doing
lab work). You only have to do moral/ethical reviews when part of an
institution or asking /other/ people to get experimented on (AFAIK).

[Cathal Garvey]

Silencing RNA needs to be delivered somehow. Naked RNA will trigger an
innate response, and naked DNA (if it survives at all) may trigger a
toll-like receptor response unless you make sure the DNA methylation
patterns are all kosher.

Then your RNA might screw up translation of any number of other genes,
in gross or subtle ways.

Also, making people feel immune to a virus when they are in fact not
immune may cause more harm than good. Naked RNA/DNA have an extremely
low transfection rate, and if the method is insufficient to actually
protect against infection, yet the recipient thinks it works, they're
more likely to get infected.

I'll just say this again: I don't think there is such a thing as a "safe
transhumanist gene therapy hello world experiment", at all. Not yet, not
for decades.

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[Nathan McCorkle]

On Mon, Sep 15, 2014 at 11:47 AM, Cathal Garvey
<cathal...@cathalgarvey.me> wrote:
> I'll just say this again: I don't think there is such a thing as a "safe
> transhumanist gene therapy hello world experiment", at all. Not yet, not
> for decades.

Are you saying any gene therapy is to be considered transhumanist?

Timelines weren't really part of my question. But your two sentences
there seem to conflict. I'm interested in why you think the future
will break your first statement.

[Cathal Garvey]

> Are you saying any gene therapy is to be considered transhumanist?

In the same way that I consider carrying an instant communication /
information retrieval device to be "transhumanist", then yes. But I
personally feel that humans are already "transhuman" and have been for
thousands of years. Whether the tools are external or internal doesn't
change the impact they have on human potential, behaviour and society.

While internalisation of some technologies is advantageous or intrinsic
to their utility, the internalisation alone isn't enough for me to
consider them separately from the plough or a mobile phone.

> Timelines weren't really part of my question. But your two sentences
> there seem to conflict. I'm interested in why you think the future
> will break your first statement.

If or when we get to the age of trivial gene therapy (that is, sandboxed
gene expression in "disposable" tissues with pre-defined "safe"
expression cassettes; apt-get for genetics!), which will probably
require such a drastic reworking of the entire genome or even physiology
of humans to attain, then it will be safe to "apt-get install antiflu".
But getting there is far away. Until then, "safe" gene therapy will
require a professionally trained technician and physician to deliver,
and is not something that should be encouraged or performed at home.
Certainly not as a suggested "beginner's project".

[Mega [Andreas Stuermer]]

Yeah uncapped RNA can trigger an immune response. But when you put the DNA as a stable episome in cells? It codes for RNA and thus gets capped/methylated/...

[Mike Horwath]

On Monday, September 15, 2014 12:18:09 PM UTC-4, Mega [Andreas Stuermer] wrote:

Mike, yes the paper was about transient. But you can easily add an element that allows the DNA to be maintained as an episome. 

I agree, that would be a good approach if someone wanted to pursue this project in a professional setting.  I'm skeptical about the "easily" part, since the episomal vectors are usually larger and more difficult to transfect than a simple expression plasmid.  Not sure what the smallest/easiest episomal vector is though.

I'll add on one more requirement to my "hello world" list:
6)   Transfection should be carried out on a limited patch of tissue, such that even if every affected cell dies, there is little permanent damage/disability.

Responding to Cathal that there is no safe human hello world: 
I agree that real transhumanist, gene therapy stuff is much too difficult and dangerous for a DIY setting at this time.  However, a transient plasmid transfection on a limited patch of skin seems a lot less risky.  Not zero risk, but sometimes people take a risk doing something they are passionate about...I'd put it at lower risk than climbing everest or some of the home surgery the grinders are doing.

Of course I'm not doing any of those things myself :)

[Mega [Andreas Stuermer]]

People smoke, giving them an x percent chance of cancer. Or damage their brain with ethanol.

One should not take gene therapy as easy project or in a diy setting. But, I think the risks of a certain vector can be estimated.

[Cathal (Phone)]

Would you recommend any of the comparably dangerous stuff you just mentioned? If no, why suggest self-therapy is ok just because it's no worse? (Hint: it can be far, far worse than a risk of cancer; see "cytokine storm")

On 16 September 2014 16:45:26 GMT+01:00, "Mega [Andreas Stuermer]" <masters...@gmail.com> wrote:

People smoke, giving them an x percent chance of cancer. Or damage their brain with ethanol. 

One should not take gene therapy as easy project or in a diy setting. But, I think the risks of a certain vector can be estimated. 

--
Sent from my Android device with K-9 Mail. Please excuse my brevity.

[Cathal Garvey]

> Responding to Cathal that there is no safe human hello world:
> I agree that real transhumanist, gene therapy stuff is much too difficult
> and dangerous for a DIY setting at this time. However, a transient
plasmid
> transfection on a limited patch of skin seems a lot less risky.

Again: cytokine storm. Also, immune cross-reactivity could give you a
permanent autoimmune condition after transient transfection with
something wacky.

Gene therapy is also immunotherapy, because right now to do safe gene
therapy you need to know enough about the immune system to avoid blowing
it up. Having studied gene therapy for cancer for ~2.5 years (after 2
years of modules featuring virology and medical genetics), I don't feel
confident doing so. So, IMO, neither should someone who *hasn't* spent
that time studying cancer and gene therapy.

[Andreas Stuermer]

Alright, very good points!

[Jarrad]

Hey Cathal,

Do you have any resources / book recommendations we can read to learn more about the immune system in this context?

[Cathal Garvey]

I'm not really aware of any books in particular; I'm more of a primary
research junkie. Books on immunology will give the background on how the
system is currently known to work (make sure your book is recent), and
if you can find one specifically about gene therapy (make sure it's
*very* recent!) that'd deal with the methods and the challenges.

Understanding the immune system first will make it easier to grok the
gene therapy challenges; if you just hear the gene therapy end first,
and only think it's about antibodies and HLAs, then you'll not have the
background to think around the problem (e.g.: what about TLR9 when
dealing with naked DNA?).

I'd also recommend, for those fortunates with full access, to read
review papers on the subject and even primary research papers, to stay
totally current. I, for the record, have not stayed very current. I
instead spent several blessed years working in a basement lab on
in-vitro stuff, likely blasting away any chance of resumed employment in
academia or conventional biotech, and am now adrift without paper
access. Still, if someone had fixed the problems I recall from my gene
therapy days in the interim, I'm sure I'd have heard about it by now.

[Mike Horwath]

How about an ex vivo experiment?  Not as dramatic but certainly safer.  Pull out some of your own leukocytes or cheek epithelia and transfect them in a dish.

Yeah, cytokine storm and autoimmunity should be considered...  My first-pass assessment is that chances are low for a small # of transfected cells and a well-studied protein.  Luciferase has been used in many animal models, and although transfected cells may be eliminated by CD8+ response, I'm not aware of any reports of cross-reactivity or autoimmunity.  I would definitely want to read up more and do more risk-assessment before trying it myself.  I've been an immunology grad student for the last 3 years, but the immunology of gene therapy is pretty new to me.

[Mega [Andreas Stuermer]]

Mike, I think the problem is: You transfect luciferase with mice. It's a foreign protein, but there are no signs of cellular damage -> IS does not react. No autoimmune attacks. Then they catch a flu, and the cytokines are present? cytokines + foreign protein --> destroy transformed cells.

Remember: The mice are often sacrificed, you would have to live on 50 years and it should not make any trouble.

If you are born with the gene (or if you are a plant :D ) you should be fine

[Mike Horwath]

Hi Mega,

I think we are talking about different things.  We can agree that the immune system will probably eliminate luciferase-expressing cells.  For a small patch, transient transfection, this may uncomfortable, but on its own not very dangerous.

The more dangerous concern is development of an autoimmune disease targeting self-antigens, not the transgene.  This could occur if there is homology to a self protein, or if the immune system randomly breaks tolerance to an unrelated self-antigen in the skin (a minor risk for inflammation in general).  My argument is (1) there is a risk, (2) at first assessment the risk looks small, (3) more risk-assessment needed before trying it.

Mike

[Cathal Garvey]

> I've been an immunology grad student for the last 3 years, but
> the immunology of gene therapy is pretty new to me.

Frankly, it's new to everyone. The trials where people ended up with
cancer, permanent damage or even death? Conducted by experts in the
field. So, it's unlikely that anyone here is in a position to do better,
and the stakes are too high.

> Luciferase has been used in many animal
> models, and although transfected cells may be eliminated by CD8+
> response, I'm not aware of any reports of cross-reactivity or
> autoimmunity.

We used to work with lux and some fluorophores in mice where I used to
work, to do whole-body imaging. I can say that yes; at least as far as I
heard, the mice never exploded from the gene delivery used, and the
worst obvious consequence was a gradual decline in fluorescence that may
have been due to a CD8 response.

OTOH, lab mice are an entirely artificial population, largely selected
for by their amenability toward research that might lead to explosions
in a wild mouse. And, wild mice have such a different metabolism to
humans to begin with, that you're already far removed from something you
can safely compare to humans. The infamous "cytokine storm" trials that
lead to the most spectacular failures in gene therapy were, I'd like to
emphasise, expected based on repeated prior research in various animals
to be totally safe. And yet, the human immune system behaved differently
to the cells, mice and other animals trialled upon beforehand, and
things got ugly extremely fast.

On 16/09/14 22:34, Mike Horwath wrote:
> How about an *ex vivo* experiment? Not as dramatic but certainly safer.

[Cathal Garvey]

> If you are born with the gene (or if you are a plant :D ) you should
> be fine

This is basically the lament of everyone ever involved in gene therapy.
"Why couldn't you have just been born fluorescent goddamnit?"

Carefully prefacing this with "don't do this at home ever, I'm just
speculating aloud":

Your problem, therapy wise, is that the immune system *has* mechanisms
to avoid responding to stuff, but that they are locked down for obvious
reasons as the immune system matures. Don't want any of those pathogens
figuring out how to trick the immune system into considering them
*self*, do you?

However, the lockdown isn't complete. At the point of antigen
presentation, a key step in the development of an acquired immune
response (which, therefore, has nothing to do with the innate immune
response), antigens are tested for cross-reactivity. This is a
complicated dance; *hopefully* the sort of thing that bacteria can't
evolve a hack against, because first they'd need all those other CDXX
proteins. But an intelligent "attacker" could probably figure out a way
to get their desired antigen presented first, in such a way that any
T-cells that might respond to the antigen are instead rendered anergic
(deactivated).

So, hypothetically you could clear out the potential for an immune
response, slowly, by injecting dendritic cells engineered to induce
anergy in T-cells that respond to the antigen at all. When I say "you
could" I mean "highly resourced experts in a carefully controlled and
regulated environment".