Safety of synthetic biology

[Philip Goetz]

> From: Luis Goncalves <l...@vision.caltech.edu>
> Date: Sat, Jun 18, 2011 at 11:17 PM
> Subject: [diybio] Summary of SB5.0 Synthetic Biology Conference
> To: Luis Goncalves <l...@vision.caltech.edu>, socal-...@googlegroups.com

> Not only can the error be fixed, but two new base pairs can be added too, Z
> and P. Using these bases, the organisms developed could be safer, because
> they would not interact with our bodies (and other organisms).

Synthetic biology is safe.
Fears of synthetic biology going out of control are chicken-little panic.
It would be ironic if, in the grip of this irrational fear,
people created something truly dangerous.

Synthetic biology is safe because it is normal biology.
You can't accidentally make a pathogen that's more pathogenic than
existing pathogens with normal biology. They've been trying
to kill us ever since we evolved, and the number of genetic
experiments occurring out there in the wild (and in your body)
every second dwarfs the number of experiments
all the synthetic biologists on Earth could do in a lifetime.
If you're afraid of synthetic biology, you should be
absolutely TERRIFIED of shopping-cart handles
and bathroom doorknobs, and never go outside.

You can /deliberately/ make a pathogen that is more pathogenic,
by giving it an infection or fatality rate that is too high
to be adaptive; or by giving it a long latent period such
as HIV has. It will thus probably not be evolutionarily stable
in the former case; it will spread too fast and burn out its
own host base faster than they can infect others (as Ebola
variants sometimes do). The long latent period is harder to deal
with, particularly if the disease infects mainly gay men
or has a latent period that outlasts reproductive age
(both true of HIV in the US), in which case selection
for diseases resistance does not occur.

But the idea that someone could accidentally create a
terrible pathogen is akin to the idea that a tornado
could blow through a junkyard and accidentally construct
a Boeing 747. Nature can evolve a pathogen, by
constant selective pressure, because evolution is NOT
akin to a tornado blowing through a junkyard.
This selection and adaptation can not take place in a laboratory.

Perhaps a well-meaning idiot, say some postmodern
"artistic biopunk" who decided to take a library of all
known bacterial proteins and generate random permutations
of them in a high-throughput method as some sort of
"artistic statement", could theoretically create a worse
pathogen. (I doubt it.) But nature is generating these
random permutations all the time. Nature has already
optimized the process of designing super-pathogens
to kill people. That's why we had/have outbreaks of Ebola,
plague, smallpox, anthrax, HIV, etc. These will continue
to occur at a rate higher than pathogens created by
artists playing with bacteria; and so the defenses we already
have (hygiene, closed sewers, clean water, soap, immune
systems, antibiotics, and evolution) are more than adequate
for any threats posed by synthetic biology.

Someone will probably design a super-pathogen
intentionally. It will be someone who deliberately ignores,
or is exempt from, all of the regulations being proposed to
keep synthetic biology 'safe'. It will necessarily be
someone with access to stocks of dangerous
pathogens, probably working in a military lab.

A more disconcerting possibility is that someone could
take a low-grade pathogen, like an adenovirus, and
carelessly add one fatal thing to it. I suspect this is possible.
I also suspect it happens all the time. Human viruses
get into human cells and recombine with human DNA
an astronomical number of times every day; and there
are plenty of sequences in human DNA that could be
fatal if they had a promoter in front of them and were
spread throughout a body with a virus. I would be
surprised if there weren't already many cases of
mysterious fatal diseases that were actually caused
by a rhinovirus picking up some DNA from a human
host. These viruses would not last long in the wild,
because the additional DNA would be a major burden
to them. But they probably do arise from time to time.
And, importantly, whatever risk might be posed by a
synthetic biology lab working with a rhinovirus,
the risk posed by a single human INFECTED with
rhinovirus and walking around sneezing is far greater,
both in terms of the potential of a dangerous new
disease arising, and of its being spread.
So until we're prepared to quarantine everyone
suspected of having a cold, worrying about synthetic
biology labs is silly.

Abnormal biology, on the other hand, is not inherently safe.
It can afford to be patient and slow if other things can't eat it.
It can find new designs that haven't been found, and that
we haven't evolved defenses against. It may be immune
to our immune system. It may explode around the globe
like a gray goo, if it can eat bacteria and nothing can eat it.

It's important to distinguish these two classes of risk.
Synthetic biology using existing normal molecular biology
is safe (as far as pathogenicity is concerned);
or at least, much safer than a lot of other things we do,
like driving cars or not getting regular colonoscopies after 40.
We can use it to make super-pathogens only if
we work at it. Synthetic biology that deliberately
creates something outside normal biology, such as different
base pairs or mirror-image amino acids, is extremely
dangerous. The idea that abnormal biology is /safer/
is an ironic and dangerous misconception.

[Philip Goetz]

On Sun, Jun 19, 2011 at 11:37 AM, Philip Goetz <phil...@gmail.com> wrote:

> So until we're prepared to quarantine everyone
> suspected of having a cold, worrying about synthetic
> biology labs is silly.

Oh, and worrying about lab E. coli is extremely silly.
E. coli gets inside your body, but it doesn't actually
get inside your cells. So the range of possible harmful things
it can do is greatly reduced. And, again, there is already
lots of wild E. coli, in billion of people, conducting
astronomical numbers of unauthorized, unsupervised
genetic experiments every day and then being spewn
back into the environment. If E. coli in the lab is worth
worrying about, then after every trip to the bathroom,
both the bathroom and the person should be
decontaminated by a team of FEMA agents
in hazmat suits.

This might not apply if people are deliberately
adding genes from pathogenic bacteria.
Also, people routinely add antibiotic resistance
genes to lab bacteria, which would concern me more
if they didn't also routinely take antibiotics and then
piss into the toilet, not to mention needlessly
feed vast amounts antibiotics to livestock
who aren't even sick.
If you are worried about the creation of dangerous
new pathogens, you should be much more
concerned about pig and chicken farms
than about synthetic biology labs.
That is, after all, where most dangerous new
pathogens have historically come from!

[Cathal Garvey]

Well argued, although I don't completely agree. That's not to say I think SynBio is intrinsically dangerous or a cause for much concern; as you note, nature throws worse stuff at us every day. Bio-error is unlikely to result in a seriously dangerous pathogen.

However, I feel that saying "Synbio won't make bad pathogens because nature already does" is like saying "Laser technology won't ever lead to practical weapons because lightning and sunlight kill people already". Historically, virtually every technology has been adapted or repurposed to kill and maim other people. Someone will use Synbio to make an ultraweapon, and I don't think it's fair to assume that Nature is already the best pathogen-maker out there. Nature drops rocks on people, but nature never invented the gun; humans are far more talented at destruction than nature.

That's not a reason not to pursue Synbio. These biowarfare agents are already in existence, and more will be made. Nothing we do will stop the US/China/Iran from making more horrific bioweapons in the pursuit of military supremacy. Nothing we do will stop asymmetric warfare from leading to adoption of bio and chemical weapons; the forces driving that possibility are geopolitical, not scientific. The reason that someone will someday make a bioweapon of mass destruction is because larger countries keep invading his homeland and the hazards seem worthwhile, or because someone with a maddened ideology sees indiscriminate death as an acceptable outcome.

Synbio and DIYbio are public projects to create, not to destroy. So you are right to suggest that we press ahead with these projects and not let fear stop us.

One area I'd also disagree is on the E.coli safety angle. Yes, K12 derived E.coli is incompetent and unable to cause harm, but that doesn't absolve experimenters of responsibility for safety. All of the genes designed for K12 derived strains will also function in other, potentially more dangerous, strains of E.coli and even other pathogenic species besides*. A contemporary example of genetic exchange and crossover is the pathogenic E.coli doing the rounds. Although most projects are irrelevant to the pathogenicity of E.coli, some few might lead to unforseen harm if they were to wind up in an infectious strain, or even a strain that is simply competent of surviving and producing a product in the gut tract.

For a darkly amusing example, let me suggest that you consider what might happen if a gut-competent strain of E.coli inherited an LSD-producing plasmid, considering that murmurs from Synbio Slam suggest that someone has synthesised LSD in that manner. You could wind up with someone either dead or on a permanent LSD bender until their colon is cleared of an otherwise non-immunogenic strain of commensal bacteria. Whoops!

For that reason, I suggest that, early in the Synbio game, people seriously consider alternative platforms. Yeast doesn't generally live within people, nor are any close relatives of yeast considered pathogenic. B.subtilis isn't Gut-competent (although spores can survive gut passage), although even then I'm somewhat wary of its relatives, B.cereus and B.anthracis. I believe Mac is fond of the Halophilic bacteria, and for a while I was fond of V.phosphoreum (and still am, if I can find a strain that is deficient in a-TTX). E.coli's great and all, but I don't think it's quite a safe enough choice for us to base an entire next-stage industrial ecology on.

Anyway, nobody's gotten sick on a permanent LSD bender yet, so for now we're doing OK. One to watch, I suppose, and I'll carry on trying to make B.subtilis an easier platform to work with.

*Consider that many pathogens closely related to E.coli might arguably be better classified *as* E.coli except for a bias toward preserving E.coli's good name. Shigella springs to mind.

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[EJ]

There was an awesome talk at SB5.0 by the chemist Steven Benner about
making organisms where critical functions are dependent on a supply of
non-natural DNA bases. They would in theory be the perfect lab system
since the minute they got cut off from their supply of Z or P (as
opposed to G,A,T or C) they would die. If you made enough critical
systems unable to function without unnatural bases you would have a
pretty safe system. They also can be made less mutation-prone since
the hydrogen bonding can be made stronger, according to Benner.

[Cathal Garvey]

On the "unnatural requirements" thing, I'm with Philip: If you stick with natural precursors, then you're less likely to encounter anything seriously problematic. After all, someone with ill intentions is not going to use those safeguards anyway, and those without ill intentions are unlikely to accidentally cause harm provided they take some foundational safety considerations into account.

I don't like dependence on artificial nucleotides because those nucleotides are likely to be mutagenic to "normal" life, including us; how do you safely transition to public or industrial use of a culture that was designed to use something expensive and dangerous in its DNA? Nucleotide analogs are often used as chemotherapy agents precisely because our polymerases aren't designed to tell 5-flourouracil apart from a "normal" nucleotide.

I *do* like the idea of using natural-but-rare or incogruous combinations of nutrients for synthetic life; things like Opines which are rare in the wild, but which can be eaten by many widely found microbes, or like Lactose which is pretty rare outside of a mammary gland. If your strain and its close relatives does not live successfully on living tissue (for Lactose) or on plant tissues (for Opines produced by Agrobacteria), then the dependence on Lactose/Opines will make them pretty unsuccessful in the wild. However, the stuff they depend on can be used pretty safely because there are plenty of ways for it to degrade naturally, and may be innocuous or chemically insignificant to mankind and other species likely to be exposed.

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[JonathanCline]

On Jun 19, 8:37 am, Philip Goetz <philgo...@gmail.com> wrote:
>
> Synthetic biology is safe.

Manufacturing of products which, as a byproduct of the
experimental process, produce antibiotic-resistant organisms
(for example, ampicillin resistance) are not so gravy.


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[Simon Quellen Field]

It would seem to me that there is a bit of leeway here.

For example, there are antibiotics that can't be used in mammals because

of their toxicity. Creating a gene for resistance to an antibiotic that we can't

use anyway would make resistance only a problem for biologists who want

a way to select for their pet bug.

There are also antibiotics that we don't use for other reasons. Sulfanilamide

comes to mind. Are sulfa drugs still used anywhere?

Of course we could also use antibiotics which are not used much because

everything is already resistant to them, but they would hardly be useful to us

either, since they would not select for our pet bugs if the competition already

had resistance.

If we put out a call for antibiotics that researchers have given up on despite

their effectiveness at killing germs, those researchers and companies that

came up with the otherwise useless drugs might want to recoup some of their

investment by making them available as selection tools for synthetic biology.

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[Phil]

On Jun 19, 1:32 pm, Cathal Garvey <cathalgar...@gmail.com> wrote:
> Well argued, although I don't completely agree. That's not to say I think
> SynBio is intrinsically dangerous or a cause for much concern; as you note,
> nature throws worse stuff at us every day. Bio-error is unlikely to result
> in a seriously dangerous pathogen.
>
> However, I feel that saying "Synbio won't make bad pathogens because nature
> already does" is like saying "Laser technology won't ever lead to practical
> weapons because lightning and sunlight kill people already". Historically,
> virtually every technology has been adapted or repurposed to kill and maim
> other people. Someone will use Synbio to make an ultraweapon, and I don't
> think it's fair to assume that Nature is already the best pathogen-maker out
> there. Nature drops rocks on people, but nature never invented the gun;
> humans are far more talented at destruction than nature.

Sure - which is why I wrote,

>Someone will probably design a super-pathogen
>intentionally. It will be someone who deliberately ignores,
>or is exempt from, all of the regulations being proposed to
>keep synthetic biology 'safe'.

People trying to invent super-pathogens can, and
probably will, do so. But those people will not be
following the regulations that people are now
clamoring for to make themselves feel safe.
Nobody is going to accidentally make a new plague
virus out of E. coli. And nobody who would observe
any regulations is going to accidentally add a couple
of genes to Y. pestis that make it worse,
because nobody who follows rules is going to
play around with Y. pestis just for kicks.
We already have regulations restricting
access to Y. pestis and prescribing the
conditions under which it can be investigated.

Cathal also wrote:

> For a darkly amusing example, let me suggest that you consider what might
> happen if a gut-competent strain of E.coli inherited an LSD-producing
> plasmid, considering that murmurs from Synbio Slam suggest that someone has
> synthesised LSD in that manner. You could wind up with someone either dead
> or on a permanent LSD bender until their colon is cleared of an otherwise
> non-immunogenic strain of commensal bacteria. Whoops!

Hmm, you make a good point.
If there is a danger, it's with things like E. coli and the
adenovirus that are innocuous, and also
convenient for a wide variety of applications.
but are able to colonize or infect.
I still think that recombining proteins and domains
that are already accessible to these organisms
in the wild is nothing to be afraid of.
I'd be surprised if someone could get an E. coli
to produce LSD today, since LSD is not
naturally produced by any existing proteins -
AFAIK, you need a chem lab to produce it
(altho my knowledge is only based on Google and Wikipedia).
But maybe in a few years.

(BTW, yeast does live within people too, sometimes, Cathal. Just not
you or me.)

It's also possible that people who would be
law-abiding citizens might deliberately design
pathogens against non-human targets,
like the insects and birds eating their crops,
without being able to predict the consequences,
or possible adaptations to new hosts.
But, this would be just as easy to do
with existing molbio techniques as with
synthetic bio.

I guess I must retract my blanket statement -
to assess the safety of synthetic biology,
we need to see what people come up with.
Anything radically different from nature
could be dangerous. But I never see
anyone who is demanding regulation
making intelligent distinctions like that.
For the present, there is no need for anything
beyond the regulations we already have.
Any horror scenario you can imagine being
produced by synthetic biology can probably
be produced with restriction enzymes and ligations.

- Phil

[kingjacob]

From last weeks SB conference(PA200 in the book), Lysergic Acid in Bakers Yeast.

By Edwin Wintermute out of Pam Silvers lab.

http://img.ly/55An 

In case ya'll didn't get the memo, we are now living in the future :P

(BTW, yeast does live within people too, sometimes, Cathal.  Just not
you or me.)

It's also possible that people who would be
law-abiding citizens might deliberately design
pathogens against non-human targets,
like the insects and birds eating their crops,
without being able to predict the consequences,
or possible adaptations to new hosts.
But, this would be just as easy to do
with existing molbio techniques as with
synthetic bio.

I guess I must retract my blanket statement -
to assess the safety of synthetic biology,
we need to see what people come up with.
Anything radically different from nature
could be dangerous.  But I never see
anyone who is demanding regulation
making intelligent distinctions like that.
For the present, there is no need for anything
beyond the regulations we already have.
Any horror scenario you can imagine being
produced by synthetic biology can probably
be produced with restriction enzymes and ligations.

- Phil

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[Cathal Garvey]

I totally agree with your argument that negative regulation will not stop who it intends to stop.

Already, the ban on genes from "Select list" organisms seems a little silly to me; probably less than 5% of a pathogenic bacterial genome consists of genes related to pathogenicity. By blocking off the other 95%+, you're probably causing a little harm to research while offering no additional safety.

I am fond of telling people that in many ways it's easier to hide a molbio lab than a chem lab, and look how successful the chem labs are. Once you've got the know-how, you could probably run a molbio lab with little other than supermarket ingredients, but that does assume you're isolating or brewing up your enzymes..which is currently nontrivial. All the same, it's possible enough that trying to ban based on broad classes of experiment rather than intent will almost certainly fail (barring one or two highly publicised show trials ofc).

Re: Yeast,
I was referring to Saccharomyces, whereas the common pathogenic "yeasts" are generally Candida. They do cause disease in men as well but can be asymptomatic. Also, apparently they can cause lethal blood infections.

If it's true that eating yeasty foods promotes candida, I'd guess that's due to oral tolerance to common structural elements like chitin, although I would more readily blame sugar.

I don't think candida are HGT-compatible with Saccharomyces though, so hacking Baker's yeast shouldn't pose any risk. That said, I'm putting off Yeast until I've really got something going in Bacilli (fingers crossed!), so for now I certainly don't qualify as an expert in yeasty genetics.

On 21 Jun 2011 01:38, "Phil" <phil...@gmail.com> wrote:

[Cathal Garvey]

I keep hoping for a higher resolution shot of that to emerge, I find the concept fascinating. Really, only the last step is usually necessarily synthetic; the original synthesis was from an ergot fungus derivative. I imagine they nicked the main biosynthetic pathway from ergot; It's that final biosynthetic step that's new.

On 21 Jun 2011 07:14, "kingjacob" <king...@gmail.com> wrote:

[Simon Quellen Field]

Lysergic acid amides are produced by proteins in morning glory plants.

"http://www.erowid.org/plants/morning_glory/morning_glory_faq.shtml"

I imagine it would not be easy to produce those proteins in E. coli, however.

But why be afraid of something that has so little economic value?

Wouldn't it be far more likely that someone would find funding from organized

crime to develop organisms that produce cocaine, opiates, or canabinoids?

Or maybe it is someone with the best intentions. If everyone could grow their

own heroin in yogurt, the funding for the Taliban would dry up. If cocaine and

canabinoids were easily grown at home in engineered brewer's yeast, what

would happen to the crime and death rates in Columbia and Mexico?

If we are worried about engineered E. coli colonizing people's guts and producing

harmful substances there, why not worry about butanol

"http://www.physorg.com/news/2011-03-coli-record-setting-amounts-alternative-fuel.html"

"http://www.sciencedaily.com/releases/2008/01/080106202952.htm"

or diesel fuel

"http://www.technologyreview.com/energy/24422/"

or insulin

"http://www.littletree.com.au/dna.htm"

or any number of biopharmaceuticals?

Given that perfectly natural E. coli is capable of killing people, I'm not certain what the

fear is of creating one that produces LSD. It is like saying that we shouldn't make cars

that have doors because someone might slam their finger in one. What would have

happened to the computer revolution if laws had been passed against hobbyists

building computers, lest someone in Iran used them to run a nuclear plant?

Instead of making laws restricting what we can do with E. coli, why not invent some

cheap and effective ways to detect and/or kill E. coli in our food? We solve the problem

of the natural, deadly form of the bug, and we prevent potential problems with our

much more benign engineered forms. If we continue to develop safeguards, such as

required rare nutrients, increased susceptibility to natural defenses in mammals,

or easy detection (it glows, it smells like skunk, it tastes really bitter, so don't eat it),

then our engineered forms will be continue to be safer than what our cattle emit as

they become food.

How about a law that says cattle should be fed non-harmful forms of E. coli that out-compete

deadly forms in the guts of cattle? Perhaps engineered bugs that glow, smell like

skunks, and taste really bitter?

And maybe we should also irradiate our produce and meat products with X-rays or

electron beams. If we care about saving lives, we have the technology to do it. 

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On Tue, Jun 21, 2011 at 12:13 AM, Cathal Garvey <cathal...@gmail.com> wrote:

I keep hoping for a higher resolution shot of that to emerge, I find the concept fascinating. Really, only the last step is usually necessarily synthetic; the original synthesis was from an ergot fungus derivative. I imagine they nicked the main biosynthetic pathway from ergot; It's that final biosynthetic step that's new.

On 21 Jun 2011 07:14, "kingjacob" <king...@gmail.com> wrote:

[Cathal Garvey]

Ah, I think you missed my point. I wasn't saying "Aargh they're making LSD now, stop them!". That's a whole separate thing to Synthetic Biology itself. I was, however, suggesting a safety dimension of E.coli that is often overlooked; that they can live within people, and regularly do. If the LSD operons were made to operate in E.coli for whatever reason, I'm suggesting that it wouldn't be such a good idea, because they could easily wind up in a wild-competent strain and give someone a chronic dosing of LSD until the plasmids fell out of use. I know that might be assumed to be instant, but frankly we don't know that yet; biofilm-growing wild cells may not experience much plasmid instability, and if someone were making LSD (or whatever) on a semiindustrial scale, they'd probably engineer a more stable plasmid with post-segregational killing and a functional Single-Stranded Origin, etc.

So really, it wasn't about the LSD, or cocaine, or whatever. It was about the compatibility with internal commensal bacteria, and the added considerations that it imposes on a responsible biotechie.

[Simon Quellen Field]

One of my points was that there are native forms that are deadly.

If we make a gun that doesn't actually shoot bullets any more, do we

worry that pulling the trigger might cause a blister?

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[Cathal Garvey]

That suggestion sounds like "we've already got one, what's the harm in a few more?"

Making stuff that's dangerous just because there are already dangerous things doesn't mean you're in the clear.

On a more topical note, check out this clearly bamboozled article on SB5 which covers the Lysergic Acid yeast (not yet finished, apparently) and the supposedly "safer" orthogonal life (argh): http://www.guardian.co.uk/science/blog/2011/jun/21/scientists-make-lsd-from-microbes

Several amusing turns of bad grammar reveal that the author isn't really au fait with biotech, but did a remarkably good job in summary despite that.

[Phil]

Perhaps unwisely, I googled "LSD synthesis" and found this page, which, also probably unwisely, I visited: http://www.dogeatdogma.com/lsd.htm

It says that lysergic acid is just a necessary precursor for producing LSD.

BTW, I thought Wintermute was a purely fictitious name?

[Simon Quellen Field]

We seem to have different views on how many laws we need to have

to protect us from imagined dangers.

We allow people to make beer. That is clearly more dangerous than the risks

that someone will grow LSD bacteria in their gut and not know how to obtain

antibiotics and an enema. By your logic, we should outlaw anything capable

of making alcohol.

The fears stoke only help those who would outlaw all GMOs, prevent X-raying

food to kill harmful microbes, and outlaw man-made fertilizers. The number of

deaths caused by those fears outnumbers the deaths caused by amateurs

making bugs from BioBricks, and yet fear always trumps logic when it comes

to public policy.

There are all kinds of ways that we amateurs can help prevent death, illness,

and poverty by making things in our kitchens. Making it harder to do that by

stoking fears of unlikely things that have never happened does not help.

It is already too hard to obtain chemicals that were easily available when I was

a kid. This kind of fear-mongering only makes it harder for us to do what we do.

Do you want laws against BioBricks that code for antibiotics?

Laws that require a $100,000 bond before you can buy genes?

Laws that prevent cures because the bugs that made them were genetically

modified?

When we discuss imagined effects from things that have not yet been created,

let's at least label them as the science fiction they are.

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[Cathal Garvey]

Indeed, looked that up and you're right. Lysergic acid is a precursor for, and the final thing is Lysergic Acid DiEthylamide. My mistake thinking that was a unique new biosynthesis of an abiotic compound! :) Perhaps that's another year away.

http://en.wikipedia.org/wiki/Lysergic_acid_diethylamide

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[Simon Quellen Field]

Unwisely?

Do you fear that your government now has you on some list of dangerous people?

This list is really getting paranoid.

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[Cathal Garvey]

We're on totally different wavelengths. I haven't suggested outlawing anything, and I'm not even talking about the LSD thing from an "Oh No" perspective. I'm entirely talking about the personal responsibility of a bioengineer for the safety of their engineered device, just as you'd expect any engineer to minimise the hazard of the final work. Your dishwasher doesn't have any live wires exposed, does it?

I don't think we're in serious disagreement on much, but certainly not on the point of illegalising biotech in this instance.

[Cathal Garvey]

Um, this list *is* the list of dangerous people. There are definitely FBI folks on board, and probably CIA also.

Considering the state of civil rights in America, I'd be surprised if they *don't* invade the privacy of people who take their interest.

[JonathanCline]

On Jun 20, 11:14 pm, kingjacob <kingja...@gmail.com> wrote:
> From last weeks SB conference(PA200 in the book), Lysergic Acid in Bakers
> Yeast.

> By Edwin Wintermute out of Pam Silvers lab.http://img.ly/55An

>
> In case ya'll didn't get the memo, we are now living in the future :P

We are not yet living in the future. The entire pathway is years
from
working, if it ever does work, and only the 2nd step in a chain of
six
steps is currently successful, although the intermediate product it
is
being created in adequate quantities for subsequent steps to succeed.
The entire pathway may work at some point in the future, where the
future is approximately 6 to 10 years from now, or perhaps never.
i.e. the current student(s) will graduate before it is completed, and
the
project will continue with a new team.
As a comparison, Amyris took over 10 years to develop a simpler
pathway (as far as I understand the basics) although they invented
much of the technology on the way.


Link:

- Harvard scientists to make LSD factory from microbes
- Simple microbes such as those found in baker's yeast can be modified
to make LSD, suggests research by Harvard scientists
- http://www.guardian.co.uk/science/blog/2011/jun/21/scientists-make-lsd-from-microbes


I add all of the above to insert some perspective since the hype
typically far outruns the fact.

Regarding the news that DARPA wants to significantly fund syn
bio. Now this is related to homeland security funds. Shouldn't
the idea of the pentagon dabbling in syn bio raise some eyebrows?

"What I particularly admire in him is the firm stand he has taken,
not only against the oppressors of his countrymen, but also
against those opportunists who are always ready to compromise
with the Devil. He perceives very clearly that the world is in
greater
peril from those who tolerate or encourage evil than from those
who actually commit it." -- Einstein's tribute to Pablos Casals, in
Conversations with Casals

On Jun 21, 9:52 am, Simon Quellen Field <sfi...@scitoys.com> wrote:
> Unwisely?
> Do you fear that your government now has you on some list of dangerous
> people?

If you're not on the list, it's a sign you're not having enough fun.

[Anselm Levskaya]

Hello biopeeps,

re: making psychedelic E.coli in your gut:
I don't think we need worry too much about raver dysentery. All of
these secondary metabolite pathways are nontrivially expensive and
would incur a very large negative selective pressure on the host bug
in your gut, so they'd go defunct very quickly. Any lab strain and
probably most industrial strains of e.coli will be wiped out within
minutes of getting inside you. Selective pressures or the lack of
them operate extremely fast on bacterial genomes. The scary e.colis
EPEC/EHEC/UPEC/STEC/etc. like O157:H7 or the recent german O104:H4 are
not actually likely to interbreed with synthetic e.colis. Firstly,
because you're never going to actually eat your lab strains at the
same titres as shit-stained veggies or burgers, and secondly due to
the fact that their residence time in your gut will end up being so
momentously short due to being unfit.

Most pathogenic e.colis received their pathogenic "code" from ancient
phage integrations that are now called "pathogenicity islands". But
horizontal transfer isn't magic, it's pretty slow and requires lots of
cohabitation to be reasonably probable, esp. if it's not being
mediated by still-active prophages/phages. The whole reason we have
all of these pathogenic e.colis around is that the pathogenicity
islands help them rapidly spread in our industrialized agrobusiness
setting with tons of animals. Smelling like bananas, etc. would be
considerably less useful to an enterprising microbe.

It would take a state-sponsored actor with the sophistication of
amyris or the like to even have a chance at beating nature. You
really don't do it by accident.

re: illicit drugs from synthetic bugs:
It should be pointed out that the economics of making illicit drugs in
synthetic organisms is a little bit silly in the near term.
- LSA is already produced at grams/L or comparable %weight by wild
claviceps that you can just pick in the field. Doing it in yeast is a
cute PR trick, but short of engineering the non-ribosomal peptidyl
synthases to accept something as foreign as diethylamine you're not
making an economically disruptive product. It should be pointed out
that the poster at SB5 referred to work that had only just begun, the
entire pathway to LSA is still only partially understood and it has
not been functionally abstracted yet. The reason they picked it was
more that if you got even mg/L it might be valuable to pharma, a
pretty easy efficiency target.
- For cannabinoids you're competing with the enormous Cali pot
industry (or central-asian hashish industry) with plants that produce
sizable fractions of their dry weight as THC/Cannabidiol/etc. Ditto
for opiates -> poppy, cocaine -> coca. Just -maybe- it might make
sense to engineer hairy root cell cultures of the coca plant and
upregulate putrescine N-methyltransferase (pmt) and other tropane
alkaloid pathway enzymes to try to make hairy-root-cell bioreactors
stateside to avoid all that laborious submarine business... but I
think the cartels' existing logistical chains would be hard to compete
with on production efficiency.

In other words, I think there's much easier disruptive innovations to
be fruitfully exploited in the legal space, for those of you wanting
to shake things up. =)

-a

[General Oya]

I think that some canadians were already successful synthesizing morphine in yeast as of last year.
http://www.bluelight.ru/vb/showthread.php?t=493629

I'm not a fan of strungout zombies, however an off-topic discussion over the topic of the actual versus perceived dangers of drug prohibition itself might be of some value here. As I've stated earlier this year the National Cancer Research Institute began to self-censure this year when there scientific studies that proved the anti-cancer tumor actions of THC were released due to not fitting the status quo position put forth previously by the DEA and FDA, that stated very dogmatically that there is absolutely NO medical benefit from partaking of this benign herb, that was initially made illegal in response to ethnic and religious hysteria of the early 20th century as well as continual being an effective tool for racial profiling. The sheer waste of resources to root out and destroy the plants that produce this compound, in regard to the actual damage done to individuals that smoke and ingest it is ridiculous. Wouldn't it be cool if those funds were repurposed to destroy patches of poison ivy, oak, and sumac, plants that present a very real danger and loss of productivity that can kill. In sideline to biosafety how dangerous would a yeast or bacterium that produced the allergen urishiol become. Hell, poison ivy could be weaponized just by burning vines....

Ryan

On Jun 21, 2011 9:52 PM, "Anselm Levskaya" <levs...@gmail.com> wrote:

[Anselm Levskaya]

"They have to feed the yeast thebaine, a substance produced by the
opium poppy. The plant transforms most of the thebaine it produces
into codeine and morphine."

They've just cloned one step of the pathway. There's a looong way to
go before they have yeast competing with poppies.

[Giovanni Lostumbo]

"As I've stated earlier this year the National
Cancer Research Institute began to self-censure"

General Oya probably meant "self-censor," not "self-censure," though
the latter would be funny and appropriate after doing the former.

On Jun 21, 9:38 pm, General Oya <general...@gmail.com> wrote:
> I think that some canadians were already successful synthesizing morphine in

> yeast as of last year.http://www.bluelight.ru/vb/showthread.php?t=493629

> On Jun 21, 2011 9:52 PM, "Anselm Levskaya" <levsk...@gmail.com> wrote:

[Tom Randall]

a slight tangent

>
> Considering the state of civil rights in America, I'd be surprised if they
> *don't* invade the privacy of people who take their interest.
>

???

Cathal,
Try this at home in Eire:
http://www.roningenetics.org/Sequencing.html

see under the heading "An example sequence". This grew out of a
discussion over a year ago on this list over whether the sequence of
the GFP in the pGREEN sold by Carolina Biologicals was that of Genbank
Accession AB124780 or something else. Details of the sequence and the
raw chromatograph data are on that page. The sequence is actually
consistent with that suggested by a Carolina rep from US Patent
6027781.
Let me know when you can repeat that at home as I can without a
permit. I can clone, sequence and generally do biology freely here.
Ireland is a nice place to visit though, spent some time in Cork even,
but civil rights?
:)
I apologize ahead of time, I do not intend this to be mean and
generally enjoy your posts.
Tom

[Cathal Garvey]

If you mean to say that there's a patent impediment, actually in Europe patents don't apply to personal use or replication.

Besides, I was talking about freedom of speech and freedom from search/invasion of privacy without due cause and a warrant.

We're catching up dangerously quickly on the demolition of free speech, but it would be hard to argue that the US these days provides much if any protection from search, or even incarceration (or even torture), without due cause. I'm not USA-bashing, I love you guys. It's simply the facts of life these days, and unless something drastic happens (I'll admit, I thought Obama might turn things around..) it's likely to get worse.

But, that is all tangential to the topic, and was spurred only by someone suggesting that it was unwise to look up LSD. I aimed only to point out that violation of email was a more likely concern than internet traffic monitoring.

[Tom Randall]

> If you mean to say that there's a patent impediment, actually in Europe
> patents don't apply to personal use or replication.

it just sounded from previous posts that you needed some permission to
work with GMOs.

>
> Besides, I was talking about freedom of speech and freedom from
> search/invasion of privacy without due cause and a warrant.

Yes, I know, just having a little fun.

[Cathal Garvey]

Oh, and if you're referring to the License needed for cloning, you're right: I can't make a GMM without a license. However, two things prevent me from complaining overmuch on that score; firstly, that I wouldn't regard "Freedom to Engineer Life" as a fundamental human right like immunity from baseless search, seizure and arrest, and secondly that I can obtain a license once I prove myself to be competent at containment. It's no different from requiring a license for HAM radio operators; you can cause harm if you misuse the technology, so you are required to demonstrate that you won't do such harm.

Now, in both cases, HAM and Genetic Engineering, I feel that the requirements are somewhat too onerous. For example, you're not allowed use cryptography over HAM, which limits its otherwise amazing potential for global internet access and censorship circumvention. In like manner, the requirements for a "Controlled Release" in the EU are basically impossible for an independent scientist to meet. The EU makes biotech hard because the people of the EU are terrified of biotech, and pass the fear up the line. Hopefully DIYbio can prompt a grassroots re-evaluation of that fear.

Besides, if we're slinging mud over who's-nicer-to-DIYbio, at least I can legally sequence my own BRCA locuses over here! ;) Although you guys are close to beating us on the gene patenting issue soon, too. Good luck with that, it's an awesome step towards global genetic-freedoms sanity. I was in such a good mood when Myriad lost the first lawsuit!

[Cathal Garvey]

That I do; technically, it should be a process similar to a HAM. However, bureaucracy contaminates everything, so it remains to be seen if it's actually as reasonable as the text of the law suggests. I'm already dealing with rampant exploitation of the "Maximum Application Time" part of the text, and the 45-days-maximum for an application is starting to look like fantasy. At this rate, I might be a dad before I'm allowed to test the plasmid.

So you might be right; it's possible that individuals won't be allowed to do Biotech in Ireland. I'm the first to try, so I'll be the first to find out soon enough.

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[Giovanni Lostumbo]

I've noticed that Edwin Wintermute, publisher of several interesting papers on PubMed in 2011, including microbial synthesis pathways on Hydrogen, is now a former  lab member on the Silver Lab's OpenWetWare page. His Harvard email is also defunct. Anyone know if he has a website/contact or updates?