Craig Venter & The Cell With A Synthetic Genome: Taking Your Car in for a New Battery and Coming Back to Find That the Mechanic Has Substituted Homemade Replacement Parts for Everything Under the Hood

The Thursday night, May 14^th, 2010, early release of a paper in the journal Science by Craig Venter’s team (See Gibson, Glass, Lartigue et al 2010) set off a tsunami of headlines suggesting that scientists had finally created artificial life.

What Venter’s team did, after many false starts and a great many successful preliminary studies (Benders, Noskov, Denisova et al 2010, Gibson, Benders, Andrews-Pfannoch et al 2008, Gibson, Benders, Axelrod et al 2008), was to map and then effectively duplicate most of  the DNA sequence of a very simple microorganism Mycoplasma mycoides using an electromechanical  assembler of small units of DNA (oligonucleotides) , called an oligonucleotide synthesizer. 

What’s important to recognize in this step is that the team did not snip up the microorganism’s own natural DNA and let some particularly desired portion multiply itself using the Polymerase Chain Reaction, the way most genetic engineers proceed when they want to obtain  some desired DNA for later  insertion into some other target organism’s genome.

 Rather, the team decoded the entire  sequence, and essentially placed that sequence into the equivalent of a cookbook that could be scanned by a robotic cook who worked from simple molecular ingredients, following one step after another.

The robot cook took baked some short segments,  then it assembled them into longer segments (Gibson, Young, Chang et al 2009),  and then ultimately linked the longer segments into a giant loop, the way the natural DNA within the microorganism is organized.

Technically they took the synthetically recreated giant loop of  Mycoplasma mycoides DNA and put it into the pre-existing cellular vesicle of a Mycoides capricolum, after they had taken out the pre-existing DNA of the Mycoides capricolum that had been “living” there.

The Mycoides capricolum provided a more robust housing that apparently reproduced itself better. In a sense the natural Mycoides capricolum, provided the auto body, and the synthetic DNA loop provided the engine, transmission, and everything else mechanical and electrical.

For safety’s sake they edited out some snippets of DNA that might cause this bacterium to become virulent.

Furthermore, they put in some tell-tale markers that enabled the researchers to look into the cell culture into which these microorganisms were growing, and be able to see under a microscope which micoorganisms were really the synthetic ones, and which were contaminants or some  Mycoides capricolum that had somehow kicked out the synthetic DNA, and somehow managed to regain their own native DNA.

It is very clear from those tell-tale markers that these synthetic DNA supplied microorganism are, in fact, the ones reproducing themselves.

Had this Ever Been Done Before?

No, no one had basically replaced everything that was natural DNA within a cell with a complete functional complement of  synthetically produced DNA, and had that cell successfully reproduce itself using only  the new totally synthetic DNA.

Why Hadn’t This Been Done Before?

Two reasons come to mind.

The most obvious answer to the general public would be that it must have been incredibly hard to do this, and indeed, according to a highly readable exposition from Elizabeth Pennisi (cited below),  it took a team of 20 scientists more than a decade and tens of millions of dollars to accomplish this.

The other reason is more practical.

For decades now,  genetic engineers have been using existing viruses, bacteria, yeasts, and eukaryote cells to do their hard work, by inserting only the specific piece of DNA that would change their behavior in some favorable way.

We’ve used snippet insertion genetic engineering to get us drugs that will control excess bleeding (Li & Heide 2005, Moltzan, Anderson, Callum et al 2008), kill virulent microbes (Gillor, Nigro & Riley 2005), limits out-of-control growth hormones (Piasley, Trainer & Drake 2004), make insulin (Vajo & Duckworth 2000), and give us  natural insecticides (Wang, Zhang, Song et al 2006, Yan, Song, Shu et al 2009).

Why Then,  Do It the Hard Way?

This most recent paper is a proof-of-concept study. It basically reassures at least some investors and many scientists that it is possible to swap out everything, when genetically engineering a new microbe.

The advantages could be the avoidance of some untoward immunological/allergic response, should it be used in humans, or the better elimination of  any opportunity for the microbe changing back to some wild version. 

There are existing ways genetic engineers can do many of these things, but the take-home lesson from experience is that  even the best genetic engineers cannot predict with absolute certainty what the 99.999% of the original DNA might do or mutate into doing, after that highly desirable one-thousandth -of-one-percent snippet of desirable is in a human body or released into some vast antibiotic cell culture factory.

By holding the non-target  DNA to the absolute minimum, and knowing what the job for that minimal portion is, then the genetic engineer using the Venter approach can eliminate even the possibility for untoward further genetic mutations.

Will This Make Venter Famous, or Win Him the Nobel Prize?

Craig Venter is already world famous, and very likely Nobel-worthy,  for his work studying the webs of interacting DNA -----the metagenomics-----in complex microbial communities in the sea ( see for example Sharon, Tzahor, Shmoish et al 2007, Shaw, Halpern, Beeson et al 2008) and for essentially ending  his race with the massive and massively funded research community of the NIH  for a complete map of the human genome in a dead heat, despite working with a vastly smaller crew  with fewer and smaller private investor funds with which to work (Venter, , Adams, Myers et al. 2001)

Furthermore, he has mapped the complete genomes of nasty microbes, like  Aspergillus fumigates (Fedorova, Khaldi, Joardar et al 2008) and those of some experimental organisms that are commonly used to study basic problems in biology, like the hydra (Chapman, Kirkness, Simakov et al 2010).

He’s a huge fan of analyzing the actual genome of individuals with a view of making medical decisions that fit the patient as closely as possible, an approach which he calls personalized medicine (Ng, Murray, Levy & Center 2009, Ng, Zhao, Levy, Strausberg & Venter 2008, Venter 2010.

And believing, perhaps,  that there would be no more interesting genome than his, has had done this for  his own total genome (Levy, Sutton, Ng et al 2007), and placed it as an exemplar of how such a database might be  web-searchable (Axelrod, Lin, Ng et al 2009).

Among the genes in his genomes publicized are those leading to alcoholism (I don’t know if he drinks) tobacco use and nicotine addiction (I don’t know if he smokes or chews) and a few that match to some degree, at least in the minds of his critics and some of his business associates,  his more public persona (novelty seeking and conduct disorder).

And there are the usual banes of modern man: a propensity for coronary artery disease, high triglycerides, high blood pressure, obesity, metabolic syndrome,  and even Alzheimers…….although, in a kind of Benjamin Franklin-endored way,  it appears that he is also genetically predisposed to going to bed early each night, and arising very, very early the next day (Advancedd Sleep Phase Syndrome).

But so far, no one has identified where the genetic locus of his drive,  insight, entrepreneurial,  and self-promotional spirit, and yes, likely his flat-out genius resides.  

But judging from his incredible record, it’s in there somewhere.

Tony Stankus, FSLA [email protected] Professsor, Life Sciences Librarian & Coordinator of Science Librarians

University of Arkansas Libraries MULN 233E

365 North McIlroy Avenue

Fayetteville, AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

Axelrod, Nelson, Yuan Lin, Pauline C. Ng, Timothy B. Stockwell, Jonathan Crabtree, Jiaqi Huang, Ewen Kirkness, et al. 2009. The HuRef browser: A web resource for individual human genomics. Nucleic Acids Research 37, (01): D1018-24.

Benders, Gwynedd A., Vladimir N. Noskov, Evgeniya A. Denisova, Carole Lartigue, Daniel G. Gibson, Nacyra Assad-Garcia, Ray-Yuan Chuang, et al. 2010. Cloning whole bacterial genomes in yeast. Nucleic Acids Research 38, (8) (05/01): 2558-69.

Chapman, Jarrod A., Ewen F. Kirkness, Oleg Simakov, Steven E. Hampson, Therese Mitros, Thomas Weinmaier, Thomas Rattei, et al. 2010. The dynamic genome of hydra. Nature 464, (7288) (03/25): 592-6.

Fedorova, Natalie D., Nora Khaldi, Vinita S. Joardar, Rama Maiti, Paolo Amedeo, Michael J. Anderson, Jonathan Crabtree, et al. 2008. Genomic islands in the pathogenic filamentous fungus aspergillus fumigatus. Plos Genetics 4, (4) (04): e1000046-.

Gibson, Daniel G., Gwynedd A. Benders, Cynthia Andrews-Pfannkoch, Evgeniya A. Denisova, Holly Baden-Tillson, Jayshree Zaveri, Timothy B. Stockwell, et al. 2008. Complete chemical synthesis, assembly, and cloning of a mycoplasma genitalium genome. Science (New York, N.Y.) 319, (5867) (02/29): 1215-20.

Gibson, Daniel G., Gwynedd A. Benders, Kevin C. Axelrod, Jayshree Zaveri, Mikkel A. Algire, Monzia Moodie, Michael G. Montague, J. C. Venter, Hamilton O. Smith, and Hutchison,Clyde A.,,3rd. 2008. One-step assembly in yeast of 25 overlapping DNA fragments to form a complete synthetic mycoplasma genitalium genome. Proceedings of the National Academy of Sciences of the United States of America 105, (51) (12/23): 20404-9.

Gibson, Daniel G., John I. Glass, Carole Lartigue, Vladimir N. Noskov, Ray-Yuan Chang et al. 2010. Creation of a bacterial cell controlled by a chemically synthesized genome. Science, 328 (May 20, 2010) epub ahead of print doi: 10.1126/science.1190719

Gibson, Daniel G., Lei Young, Ray-Yuan Chuang, J. C. Venter, Hutchison,Clyde A.,,3rd, and Hamilton O. Smith. 2009. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nature Methods 6, (5) (05): 343-5.

Gillor, Osnat, Lisa M. Nigro, and Margaret A. Riley. 2005. Genetically engineered bacteriocins and their potential as the next generation of antimicrobials. Current Pharmaceutical Design 11, (8): 1067-75.

Glass, John I., Hutchison,Clyde A.,,3rd, Hamilton O. Smith, and J. C. Venter. 2009. A systems biology tour de force for a near-minimal bacterium. Molecular Systems Biology 5, : 330-.

Lartigue, Carole, Sanjay Vashee, Mikkel A. Algire, Ray-Yuan Chuang, Gwynedd A. Benders, Li Ma, Vladimir N. Noskov, et al. 2009. Creating bacterial strains from genomes that have been cloned and engineered in yeast. Science (New York, N.Y.) 325, (5948) (09/25): 1693-6.

Levy, Samuel, Granger Sutton, Pauline C. Ng, Lars Feuk, Aaron L. Halpern, Brian P. Walenz, Nelson Axelrod, et al. 2007. The diploid genome sequence of an individual human. Plos Biology 5, (10) (09/04): e254-.

Li, S-M, and L. Heide. 2005. New aminocoumarin antibiotics from genetically engineered streptomyces strains. Current Medicinal Chemistry 12, (4): 419-27.

Maróti, Gergely, Yingkai Tong, Shibu Yooseph, Holly Baden-Tillson, Hamilton O. Smith, Kornél Kovács L., Marvin Frazier, J. C. Venter, and Qing Xu. 2009. Discovery of [NiFe] hydrogenase genes in metagenomic DNA: Cloning and heterologous expression in Thiocapsa roseopersicina. Applied and Environmental Microbiology 75, (18) (09): 5821-30.

Moltzan, C. J., D. A. Anderson, J. Callum, S. Fremes, H. Hume, C. D. Mazer, M. C. Poon, G. Rivard, S. Rizoli, and S. Robinson. 2008. The evidence for the use of recombinant factor VIIa in massive bleeding: Development of a transfusion policy framework. Transfusion Medicine (Oxford, England) 18, (2) (04): 112-20.

Ng, P. C., Q. Zhao, S. Levy, R. L. Strausberg, and J. C. Venter. 2008. Individual genomes instead of race for personalized medicine. Clinical Pharmacology and Therapeutics 84, (3) (09): 306-9.

Ng, Pauline C., Sarah S. Murray, Samuel Levy, and J. C. Venter. 2009. An agenda for personalized medicine. Nature 461, (7265) (10/08): 724-6.

Paisley, Angela N., Peter J. Trainer, and William M. Drake. 2004. The place of pegvisomant in the acromegaly treatment algorithm. Growth Hormone & IGF Research: Official Journal of the Growth Hormone Research Society and the International IGF Research Society 14 Suppl A, (06): S101-6.

Pennisi, E. 2010. Synthetic genome brings new life to bacterium. Science 328: 958-959.   

Shaw, Allison K., Aaron L. Halpern, Karen Beeson, Bao Tran, J. C. Venter, and Jennifer B. H. Martiny. 2008. It's all relative: Ranking the diversity of aquatic bacterial communities. Environmental Microbiology 10, (9) (09): 2200-10.

Vajo, Z., and W. C. Duckworth. 2000. Genetically engineered insulin analogs: Diabetes in the new millenium. Pharmacological Reviews 52, (1) (03): 1-9.

Venter, J. C. 2010. Multiple personal genomes await. Nature 464, (7289) (04/01): 676-7.

Venter, J. Craig, Mark D. Adams, Eugene W. Myers et al. 2001. The sequence of the human genome. Science 291 (5507): 1304-1351.

Wang, Guangjun, Jie Zhang, Fuping Song, Jun Wu, Shuliang Feng, and Dafang Huang. 2006. Engineered Bacillus thuringiensis GO33A with broad insecticidal activity against lepidopteran and coleopteran pests. Applied Microbiology and Biotechnology 72, (5) (10): 924-30.

Williamson, Shannon J., Douglas B. Rusch, Shibu Yooseph, Aaron L. Halpern, Karla B. Heidelberg, John I. Glass, Cynthia Andrews-Pfannkoch, et al. 2008. The sorcerer II global ocean sampling expedition: Metagenomic characterization of viruses within aquatic microbial samples. Plos One 3, (1): e1456-.

Yan, Ginxin, Fuping Song, Changlong Shu, Jingjing Liu, Chunqin Liu, Dafang Huang, Shuliang Feng, and Jie Zhang. 2009. An engineered Bacillus thuringiensis strain with insecticidal activity against Scarabaeidae (Anomala corpulenta) and Chrysomelidae (Leptinotarsa decemlineata and Colaphellus bowringi). Biotechnology Letters 31, (5) (05): 697-703.

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