SYNTHETIC BIOLOGY: This electron micrograph shows the first Mycoplasma mycoides cells living entirely based on genetic code synthesized by scientists as they divide.
Image: Tom Deerinck and Mark Ellisman, National Center for Microscopy and Imaging Research, University of California, San Diego
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This story was updated at 5:00 p.m.
The first microbe to live entirely by genetic code synthesized by humans has started proliferating at a lab in the J. Craig Venter Institute (JCVI). Venter and his colleagues used a synthetic genome—the genetic instruction set for life—to build and operate a new, synthetic strain of Mycoplasma mycoides bacteria, according to an online report published May 20 by Science.
"This is the first self-replicating cell on the planet to have a computer for a parent," said J. Craig Venter during a press briefing on May 20. "It's also the first species to have a Web site in its genetic code."
For the past 15 years, the genomes of thousands of organisms have been sequenced and deposited in databases. "We call this digitizing biology," JCVI molecular biologist Daniel Gibson told Scientific American. "We now show that it is possible to reverse this and synthesize cells starting from this digitized information….We refer to the cell we have created as being a synthetic cell because it is a cell controlled by a genome assembled from chemically synthesized pieces of DNA."
In other words, a chemical synthesizer stitched together various short iterations of man-made adenine, cytosine, guanine and thymine that were then assembled into a working genome that can successfully produce the proteins that enable life. Using stretches of DNA, known as cassettes, roughly 1,000 base-pairs in length, the researchers assembled a simplified version of M. mycoides genome from scratch in a succession of E. coli and yeast cells. The final synthetic genome—more than a million base-pairs long—was then inserted into an existing Mycoplasma capricolum cell. The synthetic cell then went on to behave as a M. mycoides, producing proteins from the instructions encoded by the synthetic genome and even dividing and growing.
"It is a big deal," geneticist and technology developer George Church of Harvard Medical School says of the achievement. "It's not incremental, but it's not final either," noting that other groups are already delivering useful products from partially reengineered genomes, such as biofuels from engineered E. coli.
Biological engineer Drew Endy of Stanford University clarified how to think of this creation. "It's not genesis, it's not as if mice are coming from a pile of dirty rags in a corner," he says. "The correct word is poesis, human construction. We can now go from information and get a reproducing organism. It lays down the gauntlet for us to learn how to engineer genomes."
Getting to this point was not without its challenges, including requiring at least $40 million in investment into relevant experiments over the past 15 years, primarily funded by Venter's private company Synthetic Genomics and the U.S. Department of Energy, among others. The researchers started with the intention of synthesizing the genome of Mycoplasma genitalium, which has the smallest known natural genetic instruction set. But that organism's slow growth and other properties led them to ditch it in favor of genetically more complex cousins such as M. mycoides and M. capricolum. To simplify things, they deleted 14 genes from M. mycoides natural genome, leaving behind hundreds.
Then the researchers could not find a way to transfer genomes from one bacterial species to another, eventually enlisting the yeast as an assembly waystation, permitting easier manipulation of genetic material and overcoming natural resistance in the microbes to tinkering with their DNA. The yeast also copies the synthetic genome numerous times with its own to allow spares for experiments, while adding its own genetic twists, such as eight single nucleotide polymorphisms now found in the synthetic genome. In fact, there are 19 total nucleotide sequence differences between the synthetic genome and its natural analog. And, thus far, genomes can only be swapped between closely related species. "Right now, we don't know how far phylogenetically speaking the donor and recipient can be," said JCVI microbiologist Carole Lartigue at the May 20 briefing.
But once this synthetic genome was inserted—the would-be host cell failed "and we did not know why," Gibson says. By cross-checking the entire genome gene by gene, they found the fatal flaw after three months of work: a single missing base in the dnaA gene, which is required for life. "Accuracy is essential," Venter said. "There are parts of the genome where it cannot tolerate even a single error."
Of course, the rest of the original cell remains "naturally" made, from the cytoplasm on down, but the billions of daughter cells are assembled entirely from proteins encoded by the synthetic genome. Once the perfected synthetic M. mycoides genome was inserted into M. capricolum, on March 26, it booted up the natural cell's machinery and busily set to work living, making proteins and, ultimately, dividing and thriving. By March 29, the researchers found a thriving blue colony of M. capricolum living as synthetically driven M. mycoides. "The cells with only the synthetic genome are self-replicating and capable of logarithmic growth," the researchers wrote, and grow "slightly faster" than their natural peers.
Venter and his colleagues also included four "watermarks" in the code to distinguish the synthetic microbe—dubbed Mycoplasma mycoides JCVI-syn1.0—from natural organisms, including 46 names of scientific contributors to the synthetic genome, an email address and a web site based on a code derived from the four letters of the bases and 64 combinations of the four letters, or triplets, possible in the genetic code. "When you put English text into [the code], it generates very frequent stop codons in the genetic code and won't produce big proteins," said JCVI microbiologist Hamilton Smith, a Nobel Laureate in medicine. "It's designed to be biologically neutral."
Gibson adds: "If one is able to translate the watermark sequences, they will be able to send us an email and prove that they decoded the sequences."
The man-made genetic code also includes three quotes: "To live, to err, to fall, to triumph, and to recreate life out of life" from James Joyce; "see things not as they are but as they might be" from Robert Oppenheimer via the Ethical Culture School in New York City; and "what I cannot build, I cannot understand" from physicist Richard Feynmann.
As for the first synthetic cells, they now lie dormant in a JCVI freezer. "If there's a cell museum, we may donate it," Venter said. "If we need it, we can thaw it out and it will start replicating again."
What could go wrong
The mere fact of human-directed life in the lab raises its own concerns, including the potential for synthetic life to escape the lab and exterminate its natural cousins, or infect them with synthetic DNA through horizontal gene transfer. Various methods to control this have been suggested, including building genetic sequences that cannot exist in nature, engineering in weaknesses to man-made cells, or even inserting suicide genes that kill the organism if it is removed from its lab environment. "We depend on algae for a fair amount of the oxygen we breathe, it would be bad if we messed that up," Venter noted.
Man-made creations are likely to be fragile compared to their robust natural counterparts that have been engineered by billions of years of evolution and competition, Church notes, but he also calls for strict oversight to be built into the process of working with or creating such synthetic organisms. "The first safeguard turns out to be to have other people review the work you're going to do so it's not one person coming up with an idea at the bench," Endy adds. "It's a buddy system if you will."
After all, the JCVI scientists "are now ready to build different organisms," Gibson says. "We would like to use available sequencing information and create cells that can produce energy, pharmaceuticals, industrial compounds and sequester carbon dioxide."
In fact, Venter hopes to use the techniques to begin synthesizing antiviral vaccines in days rather than weeks or months. "We have ongoing funding from [the National Institutes of Health] in a program with Novartis to use these new synthetic DNA tools to perhaps make the flu vaccine you might get next year," Venter said, as well as to develop vaccines for viruses that had previously eluded treatment because of their ability to rapidly mutate, such as rhinovirus (the common cold) and HIV (AIDS). And the researchers hope to tinker with the at least 2 million base pairs of an algae genome to help it more efficiently turn sunlight and CO2 into hydrocarbons.
Tackling even more complex genomes remains a daunting task, so many of the researchers involved will now focus on an attempt to create the simplest genome possible that can still permit life. "We can whittle away at the synthetic genome and repeat transplantation experiments until no more genes can be disrupted and the genome is as small as possible," Gibson says, estimating that this could be less than half of the more than a million base pairs required by this first synthetic genome. "This will help us to understand the function of every gene in a cell and what DNA is required to sustain life in its simplest form." As well as what DNA might be desired for a future synthetic biology.
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30 Comments
Add CommentThis is the quintessential Pandora's box moment - like the splitting of the atom or the cloning of Dolly the sheep. We will all have to deal with the fall-out from this alarming experiment... Synthetic biology is a high-risk profit-driven field, building organisms out of parts that are still poorly understood. We know that lab-created life-forms can escape, become biological weapons, and that their use threatens existing natural biodiversity. Most worrying of all, Craig Venter is handing this powerful technology to the world?s most irresponsible and environmentally damaging industry by partnering with the likes of BP and Exxon to hasten the commercialization of synthetic life-forms.
Reply | Report Abuse | Link to thisThere is now a facebook group set up for those who want to oppose this with comment from groups who are opposed to this:
http://www.facebook.com/?ref=home#!/pages/Stop-Synthetic-Life/122842021072292
Of course the paranoid amongst us are going to worry that this will create super-bugs by mistake- or create more competative-than-nature organisms.
Reply | Report Abuse | Link to thisI read on BBC about one organization already complaining.
Simple fact is, I suspect it's going to be many years before we can produce something to outcompete what nature has been producing for millenia.
A more realistic threat would be contamination of our "good-created bacteria" by wild-type bacteria in specific cultures and medicines, etc losing their punch.
Ooo, a Facebook group. Way to stick it to the man!
Reply | Report Abuse | Link to thisMan-made organisms are bound to escape the lab.
Reply | Report Abuse | Link to thisI am a studying biologist myself, so this is really exciting news. But the changes we are making to the environment (including GMOs) in such a short period of time will certainly affect the earth in a big way.
Over a long period of time, the planet is going to be unsustainable to us because what we are doing is compromising the earth's incredible natural systems.
We are going to be our own cause of extinction, I think. Come on, humans. Can't we show some self restraint? What are we doing?
Yes it's risky, yes we don't really know what all the gene sequences do. But you know what the beauty of this is? Now we can experiment selectively.
Reply | Report Abuse | Link to thisThis is the first step to truly understanding the nature of genetics. For now I'm going to take the optimistic road and say that this could be the start of one of the greatest achievements of mankind.
The world is not that different today as it was before this development. While a notable advance, the advent of synthetic life strikes me as nothing more nor nothing less than the culmination of genetic modification -- in other words, something we have already been doing. Genetically modifying organisms potentially promises many boons and also potentially threatens to inflict much damage, but let's not jump to the conclusion that all of these consequences have arrived just as a result of this one development. Synthetic life, like all genetic modification, cannot be appraised with blanket statements. The applications remain to be hatched, and each application must be evaluated in its own right. It is wise for us to have regulations in place, but not intransigent attitudes about the whole enterprise.
Reply | Report Abuse | Link to thisWhy hello there obvious troll.. How's the game today?
Reply | Report Abuse | Link to thisAs someone who has spent a lot of time working in the lab and genetically engineering bacteria, it never ceases to amaze me just how ignorant certain people can be about what science is able to do. While you may believe that only "God" can create life, don't forget that your "God" also created humans and allowed us to develop the technology needed to be able to create organisms in the lab.
Reply | Report Abuse | Link to thisIf the results of this experiment are real, which I suspect they are, it is a very scary thing. While my hope would be that these people are operating under biosafety level 4 conditions, I do not honestly know whether or not they are. I spent some time working with bacteriophage about 15 years ago, and I remember how easy it was to contaminate the entire lab with the phage. Depending on the species, it only takes a few organisms to create huge colonies outside of the lab. Someone who inadvertently drops just a tiny spray of bacteria from a micropipette on their clothing and then leaves the lab has the potential to contaminate, basically, the rest of the world. Since this is a brand new strain, essentially, no one has the power to know exactly how it grows, metabolizes, mutates, etc., and so I think that this really is quite dangerous. Although I am in awe of the actual science behind it, I have to say that this type of experimentation should be stopped/regulated/controlled very tightly.
Also, not to be a conspiracy theorist, but if a private company has the ability to do this in the lab, what does our government, or other governments have the ability to do without any of us being aware?
I am both amazed and terrified. But, I'll go easy on the terror. Like the article says, we've been able to alter the code for some time so we are not suddenly at a dangerous stage in genetic engineering. We've been here a while. Hopefully we will put in place a regulatory framework and safeguards before we learn from experience. All in all, congratulations, this will be a very important day in history. I'll guess we will see if it is a good day or bad day.
Reply | Report Abuse | Link to thisFor the benefit of vendicar9 and all the other trolls out there, In your face god! We did in 200k years what it took you 10b! Now, all you have to do is build a church and tell us how great we are every sunday. I hope we win, creator of the month...
@cesca08, I share your concern. One thing to keep in mind is that this is based on an existing bacterium rather than a random assembly of genes. But I think it is also worth while pointing out that we are currently experiencing a major environmental catastrophe cause by private sector mismanagement and a lack of government oversight due to systemic corruption. On the flip side, while we should be critical of corporate involvement, the public sector, a.k.a. the military will likely be looking for a way to weaponize this. Incompetent profiteers on one hand, incompetent megalomaniacs on the other. What is the doomsday clock currently set at...?
Reply | Report Abuse | Link to this@robert: I'm with you that this is based on an already well-studied organism, but we still need to be cautious because we never do know how a "new" assortment of genes will interact with each other, although on the one hand we've already been doing similar experimentation for years and years. So, the more I think about it, the more this is almost like recycled news. I'm sure the military has been looking at doing something similar for years, just hasn't published it in the mainstream yet just for the reason you stated: weaponization. It's unfortunate to have so much technology, and yet to misuse it SO much, but I supposed that is the nature of man...
Reply | Report Abuse | Link to this@vendicar9 Don't be rude. Also, some may not believe in god, so don't bring religion into the mix.
Reply | Report Abuse | Link to thisGet a grip! There are already extremely deadly bacterium and viruses that are stored in labs. Why do you think this would be any more likely to escape??
Reply | Report Abuse | Link to thisBesides, even if they did, why do you think it would be harmful?
You people read far too much science fiction. Not every groundbreaking step is the end of the world.
It is not new. Nature has changed through mutation "slow" life. But, this can be a good "discovery" to serve humankind or it can be the beginning of the end of human kind. The same as the nukes.
Reply | Report Abuse | Link to thisreally amazing!!!!!!!!!this is first step to create a new life!!!!
Reply | Report Abuse | Link to thisRobert, please be careful with the attacks on god and your statement of human arrogance regarding our creating life. The wacky right does not need any more encouragement and statements like that only inflame them more. Regarding this experiment, all we continue to do is take what has existed and rearrange it for our convenience; in an absolute sense we have crated nothing. Note the cellular machinery necessary to express the genome is completely derived from the natural world. While this technology will bear unintended consequences, it will not shatter the web of life on this planet. The horrors of Shelly and Jurassic Park aside; the most likely outcome of such work is disappointment that we still do not know enough to actually make it work efficiently to produce our desired goals. Remember, most human endeavors end in fizzles not bangs.
Reply | Report Abuse | Link to thisI recall Fred Hoyle , an Astro-Physicist of a short while back , wrote a science fiction book called "The Black Cloud".
Reply | Report Abuse | Link to thisIt was not a happy ending for us.
I think Fred probably had some understanding of the subject.
I know I am more nervous about this than I was
(actually not all) about the LHC creating a black hole.
Yes! indeed the artificial genome has its own disadv, but are we going to live to see something that far during which the mutant organisms escape out and infect the others turning them into a dangerous one. Laymen are only interested in quoting genetically modified organisms as the fathers of doomsday, but what about issues of pollution, green house effect, adulteration, mining etc., which have played the major role in the recent holocaustslike tsunami, iceland explosion etc., My point is that nobody knows what'll happen next. its just upto us to hope for the best. I believe that this is a real breakthrough in Genetic engineering, the future of which lies in curing genetic disorders, cancer, organ transplantation and astrobiology.
Reply | Report Abuse | Link to thisAbsolutely amazing. Keep up the research!
Reply | Report Abuse | Link to thisNatural events like horizontal and vertical transfer have allowed organisms to swap genetic data for billions of years and were it not for this mechanism, it's very possible we would not exist today. Organisms from every kingdom, particularly microbes, continue to share genes every day.
Reply | Report Abuse | Link to thisE=mc^2 has not destroyed our planet, we haven't been swallowed by LHC black holes, nor has our society been taken over by robots. On that note, GM crops have not only thus far failed to feed the hungry, but also failed to destroy the ecosystem.
I'm sure this research is under extremely tight control and even if this organism were somehow released, it would likely die out quickly. At worst, the natural laws of selection would impart balance. Even if that meant some sort of human plague or the extinction of our species (extremely unlikely), life would nonetheless go on. This organism is not above the natural laws of our universe.
Assuming these results can be repeated (if they are valid), we must remember that such experiments often fail or produce few results. The LHC has not created any black holes of doom and likewise has also failed to reveal the Higgs boson or the graviton. It is thwarted by continual electrical and technical breakdowns.
This synthetic organism is still nothing more than a composite mashup of other pieces and is little more miraculous than replacing a human hand with that of a monkey, and legs with that of a goat. Few scientific developments result in even minor utility, let alone worldwide disaster. I think the doomsday ideas are actually quite optimistic concerning the fitness of this organism and many of us would be impressed if this organism survived in the wild for a even short time.
Keep in mind that all of these genes already exist in nature and serve as templates for this "whittled-down" microbe. It is highly unlikely that an organism possessing pre-existing genes, yet with a much smaller genome, would end up with a greater fitness than those microbes possessing far more complex and fit genomes. It's akin to stripping a football player of all his padding and sending him into the field among much larger, protected players.
I think the best we can hope for is that this technology may be utilized for small successes, such as the use of GM to manufacture human insulin. At worst, $40 million will have been wasted and a little hodgepodge of genes will remain frozen and degraded in a San Diego storage freezer.
"We depend on algae for a fair amount of the oxygen we breathe, it would be bad if we messed that up,"
Reply | Report Abuse | Link to thisThis must be the understatement of the millennium!
Anybody programming a bug to eat the oill spills? Salud +
Reply | Report Abuse | Link to thisDid anybody else notice that the article said the genome was inserted into an E coli and yeast mix? Therefore, it is not alive on its own merit. Or did I read this wrong?
Reply | Report Abuse | Link to thisI have the same concern that messing with genes can result in some disasters, but also some benefits. We as a race as not wise enough to know what the results will be. So why are experiments like this going on?
Oh, I reread that part about where the genome was ASSEMBLED in e coli and yeast, and then inserted into a Mycoplasma cell. Not the same as independent life springing from mere DNA base pairs. Sorry guys, the claim that this is life based only on a constructed DNA just fell apart.
Reply | Report Abuse | Link to thisGetting hydrocarbons from algae is all very well. But first you have to feed the algae with more substances than just CO2. This is why sea-algae must be grown in huge, endless pens, whereas pyrolysing biomass produces biochar, and is therefore carbon-negative. Biomass pyrolysis technology has been scientifically vetted and is commercially viable now! See www.eprida.com for details.
Reply | Report Abuse | Link to thisIf only NASA would come on board and offer up a space station for biological research. That would effectively quarantine anything that got out of hand. Then again... it would also eliminate accountability from the public.
Reply | Report Abuse | Link to thisEveryone is worried about synthetic life somehow escaping the lab. Well it might not escape but it will be released on purpose!
Reply | Report Abuse | Link to thisImaging you own a company that makes flu vaccines. Now imagine the profit you would make if you have a scientist create a highly contagious version of the flu and release it? Its a dirty move but it could increase profits by tens of billions per year! So whats preventing a company from doing this... nothing! New laws need to be made preventing corporations from manufacturing vaccines or this is inevitable.
Modified viruses and bacteria won't escape they will be released on purpose by the very scientists who create them. Imagine you own a company that makes flu vaccines. You make a few billion per year. Well why not make an extremely contagious version of the flu and release it. That would increase your yearly profits by tens of billions. So unless new laws are made preventing corporations from selling vaccines then this is inevitable in the near future.
Reply | Report Abuse | Link to thisHi, I am helen
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Hi, I am helen
Reply | Report Abuse | Link to thishow are you,hope you are fine and in perfect condition of health. I went through your profile and I read it and took interest in it,please if you don't mind I will like you to write me on this ID(helenyak11@yahoo.com)hope to hear from you soon,and I will be waiting for your mail because I have something VERY important to tell you. Never in my wildest dreams did I ever believe this would ever happen. I never expected to fall so deeply in love so fast. It all started after reading profile first. Lots of love helen