Last week’s DNA Science post caused an uproar because I suggested that some people might think life begins at a period other than conception. This week’s post continues that theme with how a researcher created life. But not just any researcher – J. Craig Venter, now head of Synthetic Genomics Inc (SGI).
A Great Read
I usually don’t read books about DNA, because I write books about DNA. But when offered a copy of Dr. Venter’s new book, Life at the Speed of Light, (Viking; publishing October 17), I couldn’t resist. Not just another tale of genome sequencing, Dr. Venter’s latest effort tackles synthetic biology – chemically creating a simple genome, then transferring it into a receptive cell minus its own genome. Creating life, plus sampling bits of various environments and trolling for genomes – metagenomics – are what he’s been up to since the human genome project days.
I raced through the book, flashing back to grad school with every historical anecdote or recounted experiment that built to the ability to recapitulate the genetic headquarters of a living cell. Venter’s excitement is palpable, if a little reminiscent of Captain Kirk: “We were now ready to attempt to go where no one had gone before, to create a whole bacterial synthetic genome and try to produce the first synthetic cell.”
The tiny genome of Mycoplasma genitalium, the smallest of a free-living organism at a mere 582,970 bases, inspired the first synthetic genome. The story of creating the first synthetic genome-driven cell isn’t a gee-whiz, aren’t-we-brilliant narrative, because Venter intersperses the blind alleys and failures with the hard-won successes.
A case in point: using Deinococcus radiodurans as a model for stitching together a genome, for this bacterium does just that after radiation shreds its genome to smithereens. It uses a superb repair system and conveniently has extra copies of its genome. Helpfully, Venter and his team at the Institute for Genomic Research (TIGR) had sequenced the organism’s genome in 1999 “Brilliant!” I thought. But then Venter wrote, “After a tremendous effort, we were forced to give up. We had hit a dead end and needed a new strategy.” The team eventually harnessed the yeast Saccharomyces cerevisiae to test the synthetic genome.
First came a synthetic chromosome, dubbed Mycoplasma genitalium JCVI-1.0. The final experiments sent the synthetic genome into different Mycoplasma, changing one species into another. Another glitch happened right near the end: a one-base deletion, which threw off the three-base reading frame, creating gibberish genomes. But correcting that glitch worked. The researchers even stitched their names into the recreated genome using a lexicon of DNA triplets corresponding to letters of the alphabet, used as “watermarks” to distinguish synthetic life from the old kind.
The birth announcement for the first synthetic genome-driven cell came in the May 20, 2010 online edition of Science: Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. It’s name: Mycoplasma mycoides JCVI-syn1.0.
The first third of the book capture the discoveries and inventions leading up to creating synthetic life, while the middle third describes, sometimes in a bit too much detail for the average reader, the creation itself. The final third probes reactions and repercussions.
Venter readily acknowledges the skeptics – I was among them – who posit that creating life means allowing the genome to fashion the cell around it, not take over an existing one like a hermit crab taking up residence in an abandoned shell. But even renting a cell rather than building one’s own is scary, because it skirts the constraints of natural selection. “Synthetic biology frees the design of life from the shackles of evolution,” Venter writes. The language veers towards the anthropomorphic, which tends to happen when trying to capture the wonder of evolution. But cells didn’t “cooperate” to build multicellular organisms. Evolution is an ebb and flow of surviving phenotypes based on selective pressure, perhaps tweaked by mutation and altered by genetic drift. It isn’t a willful striving.
Like good science, Life at the Speed of Light raises more questions than it answers. Do we know enough to use synthetic life technology to create cells that can improve the world? Might one inventor’s idea of improvement become another’s weapon? What are unforeseen consequences of creating combinations of genes not seen in nature? Can the synthetic life community police itself, warding off what my grad school mentor Thom Kaufman called “triple-headed purple monsters” circa 1978, a time when the pioneers of recombinant DNA technology were establishing the containment procedures that persist today.
Venter touches on the “dual use” threat, but focuses more on happier applications: vaccines that could head off a flu pandemic, alternatives to antibiotics, and new energy sources from unexplored parts of the planet and possibly beyond. If anyone could harness a Martian energy source, it would be he.
Meeting Craig Venter
I’ve had a few interesting encounters with Dr. Venter. The man has a Darth Vader-like reputation in some circles, but my fleeting contacts with him have been quite positive.
Early in my career, when I was writing mostly for The Scientist and Genetic Engineering News, CV was always available to provide a quote, easy to reach on the phone in those pre-Internet and pre-genome days.
In 1999 he interviewed me, for a short writing gig – he’d wanted to create an atlas of normal, non-disease traits, only the genome hadn’t been sequenced just yet. Meeting him, walking down a hallway at Celera Genomics, I felt a bit like Dorothy approaching the great and powerful Wizard of Oz, but he wasn’t like that at all. Within minutes we were finishing each other’s sentences.
A year later, mid-winter 2000, I faced a conundrum. The fourth edition of my human genetics textbook was due to be published in July, I could make no further edits after April, and I knew that the two teams sequencing the human genome were careening towards the finish line. Who would be first? When? And most importantly, would it be done by the fall, when my book would be in the hands of students?
The government folks wouldn’t return my calls. CV emailed that he couldn’t tell me. I knew something was up. So, being in textbook mode, I sent him a test question:
If I were to write, in a genetics book published in July 2000, that the human genome had been sequenced, would that be (a) True or (b) False. He answered.
Some years later, Dr. Venter gave the closing talk at the American Society of Human Genetics annual meeting. Not too many were in attendance. CV described his risk variants for Alzheimer’s and cardiovascular diseases, and also announced that he learned that he has blue eyes, a preference for evening activities and novelty seeking, and a tendency towards substance abuse. “I can have two double lattes and wash it down with a Red Bull and not be affected by it,” he also learned from his genome sequence. Comparing his genome to that of DNA-discoverer Jim Watson, Venter quipped, “You probably wouldn’t suspect this based on our appearance, but we are both bald, white scientists.”
Through it all, the expressed sequence tag saga from when he was at the NIH, through the human genome sequencing, what excited me the most about Craig Venter’s long research career was the sequencing of the Mycoplasma genome, an organism so stripped-down that it just might reveal the minimal gene set required for life. My textbook always included that idea. And being so small, Mycoplasma provided a goal should one want to try to create a living cell. And that’s what Dr. Venter and his many colleagues did. And again, it intersected my career.
On May 20, 2010, I was attending the Presidential Symposium of the American Society of Gene and Cell Therapy’s annual meeting, in Washington DC. In a room packed with 2,000 geneticists, many crying, a 9-year-old boy walked onstage – Corey Haas had become able to see thanks to gene therapy. His story is the subject of my book The Forever Fix: Gene Therapy and the Boy Who Saved It (St. Martin’s Press, 2012).
I’d wondered why the gene therapy press conference had been so poorly attended, and no obvious media at the historic presentation. Because across town, Craig Venter was announcing that he had created life, inspiring my blog post Creating Life and Curing Blindness.
My most surprising recollection of a Venter talk was at the 4th International Meeting on Single Nucleotide Polymorphisms and Complex Genome Analysis, held in Stockholm on October 10-15, 2001. Attendance was down due to the recent attacks on September 11. The Scientist had sent me, back in the days when publications did that. CV not only showed up, but shocked the sparse crowd when, after he’d spoken for half an hour and predicted that human genome sequencing would one day take two hours, he grew suddenly silent.
Craig Venter lowered his head for an uncomfortably long time as photos of Ground Zero flashed behind him. Said he, finally looking up but still not back at the screen, in tears, “these are difficult slides for me to look at, and they should be for you, too. I was there last week. The forensics officials asked Celera to help with the sequencing, to use our high-throughput methods to help identify remains for the families. So I took these photos.” Another long silence. “I never, ever thought we would have to do DNA forensics at this level, and for this reason.”
I’m glad that today, he has a new reason – exploring what life can do.