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Features May 2007: Volume 4, Number 2

The Cell
By Christopher Vaughan

In May, Craig Venter held a press conference to announce that he had created the first synthetic life form. “This is the first self-replicating species on earth whose parent is a computer,” Venter said. In making the announcement, Venter found himself in a familiar position. As he did during the sequencing of the human genome, Venter was making a media splash for research that some derided as trivial and others decried as dangerous, but most agreed was original, difficult and set the stage for big things in the future.

The Mycoplasma bacterium is a genus of bacteria that lacks a cell wall. There are over 70 types of Mycoplasmas. They are genetically simple, generally possessing a relatively small genome.

What Venter set out to do was not simply to make a synthetic cell, but to create a genomic haiku. The genome of every creature is littered with fossils of old, unused genes, genetic stutters of repeated sequences, and fragments of viruses that invaded generations previously, leaving DNA bones that mark their passage.  Venter wanted to find the smallest possible genome that can sustain life. He wanted to strip out all the junk and create an organism with the absolute minimum genetic material necessary.

In order to do that, he had to get cellular genomics into the digital age. Existing methods of genomic recombination were like editing a book by cutting a sentence out of another book, pasting it into the first book and seeing how it reads. He wanted a word processor. He needed a way to edit multiple, specific genes out of an organism in a precise way.  Being able to make a synthetic cell gives him that capability. Now he can change the genetic sequence in the computer, and then create a made-to-order organism with exactly that sequence. Having a synthetic cell, therefore, is his first step in creating an organism with the absolute minimum amount of genetic material.

The actual accomplishment of Venter and his team at the J. Craig Venter Institute was to take the known genetic sequence of the mycoplasma bacterium, use a DNA synthesizer to assemble all 500,000 nucleic acid “letters” of the sequence and transfer that into a bacterium that had been stripped of its own genes. Because they had pinpoint control of every letter in the bacterium’s sequence, the team was able to  insert “genetic watermarks,” certain sequences that are built into the DNA and show up in every copy of the organism, revealing that an organism had its origins in the Venter lab. They even invented a system for encoding all letters of the alphabet and punctuation marks. Using this code-in-a-code, Venter put into the DNA the names of the principal scientists on the project, three literary quotations and an internet address. “This is also the first organism to have the address of its own website encoded in its DNA,” Venter says.

In the journal Nature, Harvard genetics researcher George Church commented that “printing out a copy of an ancient text is not the same thing as understanding the language,” but Venter shrugs off such criticism. He points to the 15 years that the project took and the technical hurdles that were overcome in the process. If it is so easy to do this, why hasn’t anybody else done it, he seems to say. “There will always be critics,” Venter says, pointing out that previously the longest synthetic genetic sequence was 30,000 letters, and that wasn’t a complete genome. “There’s nothing else like this out there.” And of course, he points out, deciphering the ancient text of DNA is exactly what he now will be able to do. “This is the proof of concept—we showed that this is possible.”


All his life, Venter says, he has been attracted to challenges and risk. Even as a boy, he loved big projects, like building an electronic scoreboard for his junior high baseball field or constructing an eight-foot plywood hydroplane so that he could blast around a nearby harbor. He also loved the thrill of the race. Growing up near the nascent and unfenced San Francisco airport, he used to ride his bike to the runway and race DC-3s as they took off. In high school he was a champion swimmer, not usually the fastest in practice but able to turn it on and win during the actual competition. In his last year in high school, Venter and three teammates set an American record for the 400-yard medley. His coach felt he had Olympic potential.

But Venter was also a terrible student, a fact he now knows may be partly due to a gene he has, one typical of people with ADHD (attention-deficit hyperactivity disorder). Venter turned his back on a swimming scholarship at Arizona State and moved to Southern California to work, surf and party. Then the Vietnam War intervened. Although drafted into the army, Venter managed to enlist in the Navy instead. When Navy tests revealed Venter’s high IQ, the military offered him a choice of any career in the service. Venter looked down the list of careers and chose hospital corpsman, because that was the only one that didn’t require enlistment extensions. Nobody told Venter that the Navy didn’t require reenlistment from corpsmen because, as the people running around the front lines to tend to wounded soldiers, the majority of corpsmen didn’t make it through their first enlistment.

Through luck and savvy, Venter ended up in a critical care ward in a hospital in Da Nang. This is where Venter’s real education began, in what he calls his “University of Death.” Venter was deeply affected by the hundreds of severely wounded young men that came through his ward, many of whom didn’t make it out alive. Two cases in particular—one a Marine who survived despite being so severely wounded that the doctors had given him up for dead and the other a Marine who died despite having seemingly slight wounds—made him think deeply about the nature of life. Through this experience and encouragement from a doctor, he began to think that he might have a career in medicine.

After Vietnam, he enrolled in a junior college and then transferred to UC San Diego, partly because the recently formed campus had a good reputation for science and partly because it offered good venues for water sports. “Being able to enjoy science along with sailing, swimming and surfing is a good way to keep your brain active,” Venter says.

In graduate school at UCSD and later as a junior faculty member at SUNY Buffalo, Venter established his scientific reputation studying what for him seemed an appropriate target: the adrenaline receptor. It was this work that eventually led Venter to become an early adopter of a powerful new gene-sequencing technology and led him to the most controversial and most high-profile challenge of his
career—the sequencing of the human genome.

By this time, the gargantuan, international Human Genome Project had dedicated itself to the expensive, slow task of finding the order of every single genetic letter in the human genome. Venter came up with a faster, cheaper approach. He suggested pulling out the less than 2 percent of the genome that actually coded for proteins—the genes, in other words—and sequencing that first. This idea, called “shotgun sequencing,” promised to rapidly provide the sequences of every human gene, which was what everyone was most interested in. The leaders of the Human Genome Project rejected this approach, perhaps afraid that it would pull funding away from their own efforts and reduce support for sequencing the rest of the genome.

Frustrated that he couldn’t get funding for his approach, Venter established a private company, Celera, to pursue his strategy. The idea that a private company might cherry pick sequences of all human genes, and the decision by the National Institutes of Health (where Venter then worked) to file for patents on those genes, drove many of the researchers on the Human Genome project up the wall. In the minds of many, it was a story of benevolent, publicly funded science versus evil, private companies that wanted to lay claim to the human genetic patrimony—never mind the fact that human genes had been patented since the 1970s, and it was the U.S. government, not Celera, that was applying for the patents. Ultimately, after President Clinton pushed for a truce between the parties, they did agree to share data and then participated in a joint ceremony in the White House Rose Garden, in June 2000, to announce the successful sequencing of the human genome.

Venter is unapologetic about involving private industry in sequencing the human genome and is bemused that it is even an issue. “The idea that science and business are at odds with each other is an antiquated notion,” Venter says. Biology, unlike engineering, physics or chemistry, is the only field where people talk in terms of a conflict between science and industry, he notes.

After the sequencing of the human genome, Venter left Celera and embarked on a project that not only combined science and business, but also a personal passion—sailing. Inspired in part by Darwin’s voyage aboard the Beagle, Venter outfitted his 100-foot sailboat Sorcerer II for a round-the-world voyage and set out to collect and analyze samples of microscopic ocean life. Venter’s group discovered that the oceans hold an abundance of diversity. They estimate that each liter of seawater holds at least 25,000 different kinds of organisms. The team collected over 5 million genes, most of which had never been seen before.

Now back on dry land, Venter continues to work at both ends of public and private research on both sides of the country, leading the non-profit J. Craig Venter Institute in Maryland and the for-profit company Synthetic Genomics in La Jolla. Achieving a synthetic organism has given him a foundation for his next set of big challenges in both spheres.

Having the ability to precisely manipulate the genome now gives Venter a tool to tackle the search for the smallest genome possible. In addition, companies have expressed interest in using a synthetic organism for their own big projects. One pharmaceutical company is interested in using the technology to create vaccines much more rapidly. This could lead to better vaccines for diseases like the flu because they could be produced at the beginning of an outbreak. Currently, vaccine makers have to guess which flu strain will be most dangerous a year in the future because it takes that long to develop the vaccine. It might also lead to vaccines for diseases like the common cold, which are caused by viruses that mutate rapidly. Exxon-Mobil has invested $600 million in Synthetic Genomics to engineer organisms that can gather carbon from the air and create hydrocarbon fuels.

While many scientists are quite happy unlocking the mysteries of the universe, the thrill for Venter remains, as it has been his whole life, the challenge of doing something big that is also practical. “Publishing a paper will not change the world,” Venter says. “Unless an idea can be reduced to practice, for the most part it will have no impact on humanity.”

The ABCs of DNA

DNA is often called the “blueprint of life” because it contains the instructions for making proteins—the “building blocks of life.” The complete set of DNA instructions for making an organism is called the genome. The genome can be made up of billions of these molecules, all linked one to the other in long, twisted double chains. But these billions of molecules come in only four types, identified by their first letters of their names: A, T, G and C.  Specific combinations of these four DNA “letters,” make up the coded information that allows a cell to put together a specific protein. These protein-coding sequences are genes. There is also a lot of DNA—the majority in the genome, in fact—that lies outside the protein-coding, gene regions. The non-coding regions used to be called “junk DNA,” but now they are thought
to be very important for regulating when and how specific proteins are made.  Scientist can learn a lot about life by altering DNA—anything from changing a single letter in a gene to switching out a huge block of genes and non-coding DNA—and then observing the effect on the organism.

 

Christopher Vaughan has written numerous books and articles on medical and biomedical topics. He lives in the Bay Area.