The first 10 volunteers of the Personal Genome Project, known as the PGP-10, included Church himself, technology oracle Esther Dyson, and Harvard psychologist Steven Pinker. All of the volunteers’ personal information—vital signs, allergies, medications, medical history, ethnicity, ancestry, traits, facial photographs, and yes, their genomic data sets—can be viewed, downloaded, and used without restriction at personalgenomes.org.
The Personal Genome Project was officially cleared to expand beyond the original 10 participants on DNA Day—April 25, 2009, the 56th anniversary of Watson and Crick’s letter to the journal Nature on the double-helix structure of DNA. Any U.S. resident who is 21 or older and is willing to share genetic, medical, and life experience information may apply. If you are accepted, your genome will be sequenced for free. Financing has come in part from Google and other corporate sponsors, as well as from Church and various private donors. “In 10 years the personal genome could be one of the most important data sets for each individual patient,” Hood says.
Before the Personal Genome Project had gotten off the ground, Church was already off and running on the next big thing. Beyond his corner office in Harvard Medical School’s New Research Building, with its floor-to-ceiling windows and imperial view down the Avenue Louis Pasteur, Church and his colleagues were busily developing MAGE, his shotgun approach to genetic modification.
The idea behind MAGE is to use the same kind of multiplexing technique that Church developed for sequencing (that is, breaking up a genome and tagging its constituent parts with enzymes) but then to add additional steps to insert, delete, and substitute passages of DNA. Instead of just copying existing sequences of DNA, MAGE could write new ones.
Church and his colleagues demonstrated the technique, in work published in Nature last July, by modifying the common bacterium E. coli to produce lycopene, an antioxidant found in tomatoes, watermelons, and red peppers. Scientists had previously used conventional genetic engineering techniques on E. coli to make it produce insulin and other substances, but they had typically targeted only one gene at a time. MAGE allowed Church to simultaneously target 24 genes, each playing a role in the production of lycopene.
Church started by producing thousands of variations of the target genes, concentrating on those passages of DNA that regulate how the genes interact with ribosomes, the parts of the cell that take information from the genes and use it to make proteins. With MAGE, he inserted these variations into the genomes of a large batch of E. coli cells. He began by using an electric current to open holes in the bacteria’s cell walls. Then he sent the new gene variants into the cell, where the bacteria’s own machinery for self-assembling DNA took over and incorporated the genes into the genome. In 24 hours Church was able to produce 4 billion different E. coli genomes. From there it was a relatively simple matter to select the variants that produced lycopene most prolifically.
This proof-of-concept experiment opens up staggering possibilities. Soon it may be possible to produce entire novel genomes or to make numerous changes in existing ones. In the lycopene experiment, Church did not know which modifications to make in the E. coli genes to get the result he wanted, but the technique could just as easily be used to introduce specific sets of changes into a genome, inserting and deleting hundreds or thousands of genes at once. This capability would allow scientists to give an organism’s DNA an extreme makeover, rather than just tinker with it.
A genetic sculptor could then alter physical traits or disease vulnerabilities that are not assigned to merely one or two stretches of DNA. For instance, a common lab mouse lives 2.5 years, on average, but a naked mole rat lives 25. That difference in life span might be governed by thousands of genomic variations, but soon we could have access to all of them. Once researchers identify the genes that contribute to the naked mole rat’s longevity, they could make analogous changes in the genome of human adult stem cells. Over the generations, it should be possible to progressively increase the human life span.
Church thinks MAGE may also open the door to the ultimate antiviral strategy. In order to replicate and do their damage, viruses hijack the genetic machinery of their host organisms. To thwart the invaders, you could make certain alterations in the genetic code of the host’s cells. If you could figure out which modifications work, and if you could also find some gene-therapy technique for delivering those changes to the host cells, you could in principle make a person (or livestock, or any other creature) inherently resistant not to just one virus but to all viruses, even those that have not been discovered.
MAGE could also be used to reverse-engineer the genome of a species, transforming it into the genome of another. On February 12, 2009 (the 200th anniversary of Charles Darwin’s birth), paleogeneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Germany announced that he and a team of researchers had sequenced about 63 percent of the Neanderthal genome. Afterward, Church told The New York Times that “a Neanderthal could be brought to life with present technology for about $30 million.”
Church would start by breaking up the human genome into 30,000 or so separate chunks, each about 100,000 base pairs long. Once Pääbo’s team had fully sequenced the Neanderthal genome, Church would use a computer to compare that genome, chunk by chunk, to the modern human genome to see where and how the two differed. Where the Neanderthal had gene variants for a larger skull, for instance, Church would use MAGE to modify the nucleotide sequences that constituted those genes in one or more of the chunks of human DNA. He would keep doing the same with the genes underlying every trait that made Neanderthals different from humans. Finally, he would put all the separate, reworked genetic chunks back into a human stem cell. Each would find its own way, via the cell’s natural ability to assemble DNA, to the proper location. The result would be a freshly minted Neanderthal genome in a living cell. From there, creating a living, breathing Neanderthal would merely require implanting the cell into the uterus of a chimpanzee, or perhaps into an adventurous human female.
The implications are so mind-blowing that I have to ask, “You don’t see anything sacrilegious about this?”
“I wouldn’t say sacrilegious,” Church responds. “Humans have been manipulating humans in many ways for many years.”
Despite juggling all of these projects, Church does not feel rushed. On the contrary, he feels that he has had a great deal of time to think through the implications of his work. “I’d like to see us have basic enabling technologies that improve our quality of life, so we can safely analyze and engineer biological systems, make biofuels, and have personalized medicine. And have deeper self-knowledge,” he says.
Resurrecting a Neanderthal strikes Church as a constructive project, not a lark. “You could argue that it would give us an inkling into an alien intelligence possibly greater than our own, one that could save our species someday or keep us out of intellectual ruts,” he says. “Or Neanderthals might be resistant to some key diseases like AIDS, smallpox, tuberculosis, or the next pandemic. You might even be able to converse with them at length.”
The Neanderthal, though, would first have to contact one of Church’s two secretaries.