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DNA Nanorobot Halts Growth of Cancer Cells

Soulskill posted more than 2 years ago | from the also-seem-to-enjoy-sousa dept.

Biotech 74

ananyo writes "DNA origami, a technique for making structures from DNA, has been used to build devices that can seek out and potentially destroy cancer cells. The nanorobots use a similar system to cells in the immune system to engage with receptors on the outside of cells. The barrel-shaped devices, each about 35 nanometers in diameter, contain 12 sites on the inside for attaching payload molecules and two positions on the outside for attaching aptamers, short nucleotide strands with special sequences for recognizing molecules on the target cell (abstract). The aptamers act as clasps: once both have found their target, they spring open the device to release the payload. The researchers tested six combinations of aptamer locks, each of which were designed to target different types of cancer cells in culture. Those designed to hit a leukemia cell could pick that cell out of a mixture of cell types, then release their payload — in this case, an antibody — to stop the cells from growing. The researchers designed the structure of the nanorobots using open-source software, called Cadnano."

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But, but, but... (5, Funny)

nadszyszkownik (2543098) | more than 2 years ago | (#39073911)

Bill Gates said open source *is* cancer.

Re:But, but, but... (0)

Anonymous Coward | more than 2 years ago | (#39073951)

ahahaha, ohhhh the irony...

Re:But, but, but... (5, Funny)

Anonymous Coward | more than 2 years ago | (#39074611)

Steve Jobs said open source *causes* cancer.

Too soon?

Re:But, but, but... (2)

K. S. Kyosuke (729550) | more than 2 years ago | (#39076781)

Steve Jobs said open source *causes* cancer.

That's the point, isn't it? This is a microscopic amount of Open Source being injected into the patient, clearly a homeopathic treatment.

Re:But, but, but... (0)

Anonymous Coward | more than 2 years ago | (#39077583)

Which means it probably is not covered by insurance....

Re:But, but, but... (1)

i kan reed (749298) | more than 2 years ago | (#39075459)

Fact check, not that it matters: It was Ballmer who likened Linux in particular to a cancer.

Re:But, but, but... (1)

Saintwolf (1224524) | more than 2 years ago | (#39075885)

Because the growth of Linux is very fast? I don't see any way that this could be construed as an insult toward Linux. Nothing better then a competitor giving free advertising :)

Re:But, but, but... (1)

gorzek (647352) | more than 2 years ago | (#39077403)

Nah, it was in reference to the way the GPL "spreads" through code. What Microsoft likes are licenses such as BSD, where you can take an open codebase, change it, package it, and sell it--all without ever having to share your modified source with anyone. Microsoft didn't like the GPL because it meant to use GPL'd code they would have to share any changes they made to it, and when's the last time you saw Microsoft giving useful code away?

MS doesn't seem to much mind giving away binaries, but source code is seemingly sacred there.

Note marketeers (3, Funny)

Anonymous Coward | more than 2 years ago | (#39073917)

Origami has shown up twice on slashdot recently and could be a good buzzword candidate.

Re:Note marketeers (1)

abarrow (117740) | more than 2 years ago | (#39074385)

Yeah, but you need to use it with another buzzword. How about "meta origami"?

Re:Note marketeers (1)

Spykk (823586) | more than 2 years ago | (#39075587)

"When we finish implementing our new strategy the competition will origami like a house of cards. Checkmate."

Asteroids video game? (1)

dimeglio (456244) | more than 2 years ago | (#39073935)

Sounds like it plays asteroids with cancer cells. I hope there are no UFOs to mess things up and it doesn't attack anything else.

Killer apps? (3, Insightful)

History's Coming To (1059484) | more than 2 years ago | (#39073939)

You have to wonder about the other applications of this technology - targeting specific genetic groups with a vaccine or even a weapon for example.

Re:Killer apps? (5, Funny)

Anonymous Coward | more than 2 years ago | (#39074013)

You have to wonder about the other applications of this technology - targeting specific genetic groups with a vaccine or even a weapon for example.

this is why we can't have nice things.

Re:Killer apps? (1)

Anonymous Coward | more than 2 years ago | (#39074043)

Ethnic cleansing tools.

Re:Killer apps? (0)

Anonymous Coward | more than 2 years ago | (#39074327)

Is that really even possible? i thought humans were pretty closely related. Not a whole lot of distinct differences unless you're talking about very old groups. Try to take out one group, end up hitting most of the others.

Might make for a nice sci-fi short story...evil villain commits the deed only to find out his great great great great great grandparents were African Jews who had a child that later married an Irish/Inuit who had a child with an east European. And their virus takes out everyone including the villain! ...or something.

Oh, the irony!

Re:Killer apps? (3, Informative)

ByOhTek (1181381) | more than 2 years ago | (#39074405)

It is possible - yes. But it would be, by no means, a "scalpel". There will be many in the ethnic group who lack the appropriately formed receptor, and many in the other groups that have it.

Probably more for the GP, but even so, many tools can be used for malevolent purposes, does that mean we shouldn't have them around for the good purposes? Do you think that just because someone came up with it for a benevolent purpose, if they hadn't nobody would have come up with it for a malevolent purpose later.

Re:Killer apps? (1)

History's Coming To (1059484) | more than 2 years ago | (#39076249)

"many tools can be used for malevolent purposes, does that mean we shouldn't have them around for the good purposes?"

Not at all, but it's important to be aware of the malevolent purposes. It's important to consider all the implications of new technologies.

Old gag:
Q: What do you get if you cross an octopus with a monkey?
A: An immediate cessation of funding and a stern rebuke from the ethics committee.

Re:Killer apps? (1)

TheCarp (96830) | more than 2 years ago | (#39079537)

Is it actually?

As technology improves, things only get easier and enter more hands. Every technology has evil uses. You can't realistically ever stop them from being used in any given way. Even if you keep your knowledge secret, anything you can invent, someone else can too. As each new layer of invention piles on the next, the idea that we can ever prevent evil is the most ridiculous pipe dream.

Re:Killer apps? (1)

History's Coming To (1059484) | more than 2 years ago | (#39081595)

[wild theorising]
There's a lag between the bad applications of a technology and the widespread knowledge of that technology nullifying it's usage. For example, if vaccines had been covered up then they'd have made a great weapon, just vaccinate your soldiers and send them in with carriers of whatever bug you've chosen. However, as soon as vaccines are widely available this stops working.
[/wild theorising]

Given the current debates about publishing weaponisable biotechnology this would suggest that ALL technologies should be open sourced, worldwide, as soon as possible.

Re:Killer apps? (1)

TheCarp (96830) | more than 2 years ago | (#39139305)

Have you read Lawrence Lessig's "Insanely Destructive Devices": http://www.wired.com/wired/archive/12.04/view.html?pg=5 [wired.com]

I think the article, and student who proposed it, hit the nail right on the head:

If we can't defend against an attack, perhaps the rational response is to reduce the incentives to attack. Rather than designing space suits, maybe we should focus on ways to eliminate the reasons to annihilate us. Rather than stirring up a hornet's nest and then hiding behind a bush, maybe the solution is to avoid the causes of rage. Crazies, of course, can't be reasoned with. But we can reduce the incentives to become a crazy. We could reduce the reasonableness - from a certain perspective - for finding ways to destroy us.

I think there is a lot of truth to that. Its not hard to imagine the mindset that would lead a person down the path to doing terrible things. It doesn't even really require anything that I would call particularly insane. Its not hard to put together some anti-US rhetoric, for example. All you need to do is do things like point to the dichotomy between claiming respect for human rights and calling out others for torture, then having a torture program of our own. Starting wars...which can never truely be fully controlled and will always result in atrocities....every one of which is a recruitung tool for those who would claim such tactics.

Reducing the reasonableness, from other perspectives than our own, of finding ways to destroy us is not exactly hard, however, it does require actually giving a shit, which doesn't seem to be compatible with the belief that you are the best and the strongest and don't have to care.

Re:Killer apps? (2)

WalkingBear (555474) | more than 2 years ago | (#39074717)

The book "The White Plague" by Frank Herbert already has something similar to this. Scientist sees his family killed by an IRA bomb in Ireland, goes nuts and creates a plague that targets only Irish women. Spreads and kills most females worldwide. Kind of a scary book.

Re:Killer apps? (1)

VikingOfNorth (2570199) | more than 2 years ago | (#39074807)

You have to wonder about the other applications of this technology - targeting specific genetic groups with a vaccine or even a weapon for example.

Deus Ex, anyone?

Re:Killer apps? (1)

belg4mit (152620) | more than 2 years ago | (#39080739)

"Written in blood" by Chris Lawson, in Asimov's (1999), "Centaurus: Best Australian Science Fiction", and volume 5 of the excellent "Year's Beat SF" edited by David G Hartwell.

Nobots? (2)

mcgrew (92797) | more than 2 years ago | (#39073963)

Wow. I am continually impressed with the advance in various technologies, especially medical tech. In 1966 McCoy's displays in sick bay were far-out future fantasy, today they look primitive.

When we have nano-robots that can build more nano-robots, I think the time will come when a 3D printer will seem not only quaint, but as primitive as McCoy's sick bay.

Are these devices really "robots," though?

Re:Nobots? (1)

sakdoctor (1087155) | more than 2 years ago | (#39074159)

The rate feels slower today than when I was a kid.
And why did the previous generations always get the cool people. What happened to all the von Neumanns, Turings, and Freeman Dysons?

Re:Nobots? (2)

LordOfTheNoobs (949080) | more than 2 years ago | (#39074357)

They're at work right now. You'll hear about their accomplishments when some historian writes a popular novel detailing the incredible inventor of X, savior of mankind. The titles a work in progress of course.

Re:Nobots? (2, Insightful)

sjames (1099) | more than 2 years ago | (#39074373)

They didn't have the right bullet points for HR and didn't fit well enough in the corporate mold, so they're digging ditches and hauling your garbage away.

Re:Nobots? (2)

DrgnDancer (137700) | more than 2 years ago | (#39075185)

Turing, specifically, was killed by his own government for a crime that most people wouldn't even consider a matter for concern now, just a half dozen decades later. We see him as a "cool people": then he was was an unusually bright man who did some interesting research; but was tragically social maladjusted. This is true to a greater or lesser extent of all the "cool people" from the past. Einstein was a minor celebrity, but then so are Carl Sagan and Stephen Hawkings. Most of the "cool people" of our time won't be recognized as such until {20,30,50} years from now. It's the nature of the beast, you never know who the really important contributors are until you can look back in retrospect.

The same is true in any field. Elvis, The Beatles, The Back Street Boys, Justin Bieber: four groups/singers that all held essentially the same role in four different eras. They were all teeny-heart-throb muscians, who were more popular than anyone but God for a length of time. In retrospect the Beatles were probably the most enduringly popular, Elvis was probably the most "important" (in the sense that he truly changed the music world), the Back Street Boys were nothing but a pointless fad, and who knows about Bieber. He's still a kid. He could be a flash in the pan like the BSB, develop into a musician with real staying power like the Beatles... He could even change the music world one day. 50 years from now people could talk about him like they do Bach, or never know who he was.

Re:Nobots? (1)

Saintwolf (1224524) | more than 2 years ago | (#39075937)

He could be a flash in the pan like the BSB, develop into a musician with real staying power like the Beatles... He could even change the music world one day. 50 years from now people could talk about him like they do Bach, or never know who he was.

Oh God I fucking hope not!

Re:Nobots? (2)

DrgnDancer (137700) | more than 2 years ago | (#39076449)

I don't know. He seems like a nice kid. I don't like his music, but that doesn't mean I can never like any of his future music. I'm no huge fan of Lady Gaga, but after being essentially forced to watch her Thanksgiving special I have to admit the woman can, in fact, sing. Seeing her do Jazz standards in fairly normal clothing made me realize that there's a lot more to her than loud noises and obnoxious stunts. If she could be convinced to do more stuff like that, I could be convinced to buy some of her music. Similarly I could envision a future in which Justin Bieber released music I'd be willing to listen too. He just hasn't done so yet.

Regression Testing (3, Insightful)

cthlptlk (210435) | more than 2 years ago | (#39074025)

I am not a biologist or a roboticist, but as a programmer I suspect regression testing on altered proteins is going to be a bitch.

Re:Regression Testing (2)

stillnotelf (1476907) | more than 2 years ago | (#39074489)

It is. Big Pharma is pretty unwilling to use non-antibody scaffolds for protein-based drugs. There are a fair number of antibody drugs on the market these days: http://en.wikipedia.org/wiki/Monoclonal_antibody_therapy [wikipedia.org] . There's not much in the pipeline for non-antibodies, because nobody knows how the immune system will react to introduced proteins. Antibodies are given a pass because they're part of the immune system; even then industry is careful not to modify the antibodies more than is strictly necessary.

Taking bets (1)

Stoopiduk (1593855) | more than 2 years ago | (#39074049)

Science has shown that the cure for cancer WILL cause a zombie apocalypse, place your bets as to when it will start, where ground zero will be and how long it will take for the annihilation of the human race.

Re:Taking bets (0)

Anonymous Coward | more than 2 years ago | (#39075665)

Science has shown that the cure for cancer WILL cause a zombie apocalypse,

When the angry men of right wing talk radio latch onto such fears and find it profitable, this will be one of their first narratives. Their audience tunes in each week expecting tales of disaster which never seem to happen, but still rush out to purchase the gold and emergency supplies presented in the commercials.

Test in humans (1)

Extremus (1043274) | more than 2 years ago | (#39074135)

Why this cannot be tested in humans right now?

Re:Test in humans (5, Informative)

Anonymous Coward | more than 2 years ago | (#39074195)

If you read the linked article, it says that human defense mechanisms quickly destroy and remove the DNA nanobots (liver filters them out and nucleases, enzymes chew up stray bits of DNA, breaks them up).

Re:Test in humans (5, Funny)

Anonymous Coward | more than 2 years ago | (#39074695)

That's easy. Just remove all the cancer cells from the patient, put them in a petri dish, and unleash the nanobots on them there. When finished, put the dead cancer cells back into the patient.

Easy peasy, no?

Re:Test in humans (2)

argosian (905196) | more than 2 years ago | (#39074773)

Sounds like a good thing to me...apply the nanobot hunter-killers directly to the tumor, they do their job, then the host's own housekeeping systems clean up the nanobots.

Either that or develop nanobot hunter-killer hunter-killers (let's call them "snakebots") and when those start to overrun the place, apply nanobot hunter-killer hunter-killer hunter-killers ("gorillabots" perhaps?) and when wintertime rolls around they simply freeze to death

A few queries (2, Interesting)

Taibhsear (1286214) | more than 2 years ago | (#39074215)

A few things I didn't see in the article that may be of concern. The immune system itself tends to see loose (extracellular) DNA as foreign and attacks it. Have they tested this to see how the natural immune system responds to this delivery system? Does the DNA structure they used possibly have segments that could be used in transcription, should the nanobot become damaged and broken off loose DNA somehow makes it way into a cell? I only have a bachelor's in biochemistry so I'm sure these guys have considered such things but I'm curious to know.

Re:A few queries (1)

grandprairie (2576725) | more than 2 years ago | (#39075009)

One possibility would be to use this for liver tumore via chemoembolization techniques. Presently a wire tipped with chemo is snaked to the tumor via groin artery. The chemo is inserted into tumor in highly concentrated form, then the blood vessels to tumor are sealed off. Substitute nanorobots in this isolated environment might be a start.

Immune Suppression? (0)

Anonymous Coward | more than 2 years ago | (#39075863)

Possibly that during the treatment of the nanobots, the immune is suppressed at a level to make the specific nanobot dosage to work.

It's like Embryonic Stem Cell Research. They use immune suppressed mice to ensure the Embryonic Stem Cells are not fought off by an immune system, and the stem cells beocome cancerous. In this case, it is to allow the nanobots to do their work.

Anyone else strangely reminded of I,Robot?

Re:A few queries (1)

ananyo (2519492) | more than 2 years ago | (#39088791)

Hi - I think actually that the linked Nature news article answers your question. In short, yes it is a problem with the technology as it stands but... "What’s more, the nanorobots are quickly cleared by the liver or destroyed by nucleases, enzymes chew up stray bits of DNA. It might be possible to coat them with a substance such as polyethylene glycol, widely used to boost the length of time a drug can remain in the body, says Douglas, or “maybe to borrow inspiration from other biomolecules or cells” — such as red blood cells — “that can circulate in the blood for a long time”. He and his colleagues are just beginning to think about testing the nanobots in mice, he says." So its possible PEG might prevent the bots from being broken down quickly. As for the DNA somehow getting into the cell, the danger seems quite small - not only would it have to get into the cell, but it would then have to get into the nucleus. Unless it then had a start codon, I guess it would have to incorporate into the genome, and then somehow avoid then immediately being removed by DNA correction enzymes...?

Borg (0)

Anonymous Coward | more than 2 years ago | (#39074419)

No comparisons to Borg nanoprobes with a nice helping of "I for one welcome..."? I'm disappointed Slashdot.

Re:Borg (1)

Anonymous Coward | more than 2 years ago | (#39074509)

I for one welcome our meme-pandering overlords. There, happy?

Re:Borg (1)

madhi19 (1972884) | more than 2 years ago | (#39087055)

Alright you want a Borg scenario. Nanobots are inserted in an host to kill cancer they multiply trillions of times to finally achieve a collective sentience state then they take over the host to find new hosts!

And next year... (0)

Anonymous Coward | more than 2 years ago | (#39074565)

This will quietly fail. Ain't gonna work. Sorry.

Re:And next year... (1)

mmell (832646) | more than 2 years ago | (#39075507)

Y'know, that's exactly what they told the Wright brothers, and Orville still managed to make Wilbur fly . . .

Another fantastic story... (0)

Anonymous Coward | more than 2 years ago | (#39074615)

about advances is medical technology. It seems like I have read hundreds of these every year for the past 10 years. SO WHEN ARE WE GOING TO SEE SOME ACTUAL PRODUCTS UP IN HERE!!!!

Re:Another fantastic story... (0)

Anonymous Coward | more than 2 years ago | (#39075487)

NEVER, they don't want the poor to have access to life saving or life prolonging drugs or treatments. there has not been any cure for any disease (released to the general population) in the last 50 years, or so, yet with primitive technologies, amongst others, polio and smallpox were completely eradicated! The last 50 + years have seen a denial of cures, in favour or expensive and ETERNAL treatments to relieve symptoms only, to prolong the the illusion of enjoyment of quality of life. Any cures and actual treatments are quickly hushed up, and put aside for military and ultra-rich use only. The average human will never have access to these cures and life prolonging treatments. The plan is to wipe out 6.5 billion people, leaving more than a sufficiency of resources and infrastructure for the rich, and the rebuilding of the perfect society - New World Order. the only question the military survivors should be asking is - which of you will be the 1% technoGODs, and which will be the 99% Abydosians?

Molecular Submarines (0)

Anonymous Coward | more than 2 years ago | (#39075051)

In my opinion, this is a dramatically over-complicated solution to a problem that could better be solved by playing around with cooperative binding to cell surface receptors. Drugs need to be extremely simple and easy to purify, and as far as I understand, these complexes are composed of hundreds of oligonucleotides of dubious purity. No doubt the work is very cool, but I'd call this a classic example of a solution (a scheme for complex molecular self-assembly) being forced to fit a seemingly sexy problem (targeted chemotherapy).

Re:Molecular Submarines (0)

Anonymous Coward | more than 2 years ago | (#39075237)

So why haven't you cured cancer with your simpler solution? Are you holding out on the world because you haven't been paid enough? Is the whole of the cancer research establishment ignoring your work because there is a conspiracy of suppression by their big pharma paymasters? Or are you armchair bioengineering in a field you know little or nothing about?

Re:Molecular Submarines (0)

Anonymous Coward | more than 2 years ago | (#39076563)

I'm not working in the field of cancer therapeutics, but I do read the literature. And I don't quite understand your point, or why you're insinuating I have some agenda. Since the 90's there's been a lot of good incremental work at using cooperative binding interactions to target therapeutics to cells (which is what this paper is proposing) using much simpler constructs. A single DNA duplex for instance, or various other means of conjugating aptamers. My problem here is that these sorts of complex stunts, which receive a lot of hype for being "nanorobots", are ultimately not what makes it into pharma pipelines, and for good reason. It paints the wrong picture to the public in the same manner that K. Erik Drexler's "grey goo" painted an incorrect version of nanotechnology.

My sub of this (yesterday) was re: Singularity (1)

wisebabo (638845) | more than 2 years ago | (#39075213)

I guess the editors didn't like my flights of fancy.

wisebabo writes
"The Singularity I've thought will be achieved when we get two things 1) true atomic level control over matter as demonstrated by human designed robots that can replicate themselves from the lego blocks of nature, atoms, and 2) when we have supra-human intelligence that can take over the difficult process of thinking. (Of course having #2 will make it a lot easier to achieve #1 but that's another topic).

Well it looks like we're getting closer to the first goal. Harvard researchers have built robots made from DNA. While I'm not sure the robots themselves can self-replicate, it seems probable that using PCR it would be easy to make trillions of these things at a time.

I know robots made from DNA may not be as flexible or robust as ones made from a completely "bottom up" approach (by Eric Drexler's assemblers) but it's a (good) start.. By using these self-assembling systems as a base, we can hopefully use them to make more general purpose machines. And as long as they're made from fragile DNA (carbon links) there's less chance of them becoming an unstoppable Grey Goo!

Now if only we could solve that pesky A.I. problem. If Siri and Watson had a baby, would it be HAL? ;)

Link to Original Source

Wow, now THAT was quick o_O (2)

Johann Lau (1040920) | more than 2 years ago | (#39075895)

earlier today [slashdot.org]:

This kind of bullshit technology is always featured here on fanboi central, but never turns into anything real.

Why don't we focus on what's really important and stop fucking around with these stupid stories?


Re:Wow, now THAT was quick o_O (0)

Anonymous Coward | more than 2 years ago | (#39077859)

that's just it - ALL these promising technologies, that just mysteriously vanish off the radar, and NEVER turn into anything... I know there's one of you out there that can do some research into this and see just how many promising technologies, and scientists for that matter, have vanished / been hushed up in the last 5 decades - suddenly we don't seem to hear from these inventers either after the initial hub bub...

Re:Wow, now THAT was quick o_O (1)

Johann Lau (1040920) | more than 2 years ago | (#39078033)

and what, pray tell, would be the sinister benefit of withholding a cure for cancer? I know our evil overlords are dumb, but that dumb?

Re:Wow, now THAT was quick o_O (0)

Anonymous Coward | more than 2 years ago | (#39088693)

and what, pray tell, would be the sinister benefit of withholding a cure for cancer? I know our evil overlords are dumb, but that dumb?

A cure for cancer is only profitable if there is no alternative solution. It's far better, economically speaking, to develop a drug which stops cancer from growing without actually killing it; this way you will pay for the drugs for the rest of your life or die, regardless of price (they've got you by the balls).

Analog Magazine in the 80's (1)

onepoint (301486) | more than 2 years ago | (#39076037)

How I love my old issues of Analog Magazine, they somehow have predicted the future more than once.
this was covered back in the day and I have been wondering when it was going to come about.

If the pattern keeps up, in 12 years we will see the trial runs of this, and cancer reduction across the entire
world population. it would seem that it viable, just a lot of testing needs to be done.

Analog gave (me) hope to the future, a future where knowledge and being a good DIY can advance the world.


Great news, but when (1)

hesaigo999ca (786966) | more than 2 years ago | (#39077337)

We always hear these same cool stories that they have come out with the next n of x field and will be able to do zyx with it.
I think it is very cool that they found a way of doing this, but it would also be very cool to actually see/hear when the fully
operational model available to the public will be done.

Already exists (0)

Anonymous Coward | more than 2 years ago | (#39077895)

Umm... There already exists a compound that does something similar... Good luck finding publicly available research, though - big pharma is just as ruthless as the RIAA/MPAA when it comes to doing anything possible to make people pay them more money. Research amygdalin. DON'T confuse it with laetrile. Laetrile is a failed attempt at synthetic amygdalin. Laetrile is dangerous, while amygdalin has never been shown to be so. Also, don't let the term "vitamin B17" confuse you - people may be referring to either amygdalin or laetrile, so it's best to avoid the term.

These Aren't the Driods Your Looking For (2)

Favonius Cornelius (1691688) | more than 2 years ago | (#39078463)

Wow I had no idea that the people engaging in this technology could be so sensationalist about how they talk about it. It is profound and very promising, but I hate how they are calling all these constructs 'robots' and 'nanobots' and talk about 'programming' them. That's a load of BS and it cheapens the power of the organic. These constructs are made of organic materials, not steel and silicon robots. Using this language gives the world an entirely wrong idea about what it is about and cheapens the decades of hard work of biologists and biochemists by piggy-backing sci-fi/electronic ideas and fame. Call it a biobot if you must. But then I guess as soon as you start talking about the fact that this is a reactive biological thing created by man, all the bible-bangers of the world get their panties in a bunch.
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