A little over one year ago, my team at the J. Craig Venter Institute announced the construction of the first cell completely controlled by a synthetic genome. After 8 years of work on DNA synthesis, assembly, and error correction, and on new ways to transplant and boot up chromosomes, we succeeded in creating a cell that used only a chemically synthesized chromosome to code for all aspects of the cellular phenotype.
DNA is the software of the cell, and our studies have shown that when we change the software we change the species. Because it is based on the digitized DNA sequence, the design of synthetic genomes provides a true interface between the computer and biological life. While genome design will dominate the future, the field has been limited to a few gene changes as a part of pathway design and to the engineering of novel biological circuits, such as oscillators, that can be used to construct semisynthetic biological machines.
One major limitation is the cost—in both money and time—associated with genome modification. For example, it required over a decade of work and reportedly more than $100 million for the team at DuPont to make a dozen or so modifications to the E. coli genome so that it would convert glucose into propanediol to make “renewably sourced” fibers. And while some clever techniques for codon modification in E. coli have emerged recently from the laboratory of George Church, these are a long way from genomes designed and constructed to perform unique metabolic activities.
The tools and techniques developed by my team to assemble a completely synthetic bacterial genome, while relatively efficient (we built the entire 1.1-million-base-pair synthetic genome in less than one month), are also still quite expensive ($0.30 per base pair) due to the current cost of oligonucleotide synthesis. Fortunately, this work has helped create a demand for rapid, accurate, cheap DNA synthesis, which has led to some very novel approaches that could help reduce these costs. Over the past 23 years, the cost of DNA sequencing has dropped 8 orders of magnitude. Similar improvements with DNA synthesis await technological breakthroughs that are tantalizingly close.
DNA is the software of the cell, and when we change the software we change the species.Genome design’s greatest limitation is not cost, however, but our fundamental lack of basic biological knowledge. Traditional overemphasis on so-called model organisms has limited scientific discovery largely to mice, which we have learned are not models for humans, and E. coli, which is not a good model for most other bacteria. The gene diversity is far more expansive than most ever imagined. Similar to the limited thinking that labeled noncoding DNA as “junk,” many believed that the new genes discovered during genome sequencing with no matches to known genes were likely to be of little biological significance. But extensive whole-genome shotgun sequencing of environments, ranging from the human gut to the oceans, has taught us that these unknown genes are highly conserved and highly abundant. Our attempts to generate minimal genomes by gene knockouts in the simplest cells show that up to 20 percent of genes essential for life are of unknown function.
These limitations mean that for the immediate future, genome modification and the creation of novel species will be primarily empirically based. We are working on DNA and genome synthesis automation capable of building thousands to millions of genomes per day. Such rapid synthesis will allow for what we call combinatorial genome synthesis—manipulating gene sequences and the order of genes to produce a large variety of genomes. With the use of well-designed screens, new cells with the desired biological properties can be rapidly selected.
Provided we can achieve such rapid synthesis and screening, this approach could become a dramatic new source of biological knowledge. As we overcome the current scientific and technical limitations, I am certain that genome design and construction will become the basis of an industrial and biological revolution that will provide new sources of food, chemicals, fuel, clean water, medicine, vaccines, and other materials. Such tools will offer the opportunity to create self-sustainable systems for long-term space flight, remote military needs, or most importantly, for the future of our planet, where the human population is growing by more than one billion every 12 years. Synthetic biology will clearly be part of the solution we need.
J. Craig Venter is the founder, chairman, and president of The J. Craig Venter Institute, a multidisciplinary genomic-focused research organization formed in October 2006, with locations in Rockville, Maryland, and San Diego, California.