On a Mission to Sequence the Genomes of 100,000 People

New York Times, June 7, 2010

Traditionally, biology is about taking apart things like cells to better understand them. For the geneticist George M. Church, the main objective is to put the pieces back together.

Strolling through his laboratory, one of the larger ones at Harvard Medical School, Dr. Church, 56, points out benches where students and colleagues work on everything from basic genetics, proteomics and biocomputing to synthetic biology and the impact of the millions of microbes that inhabit our guts.

“I’m a polyglot who believes in integration,” he said. “That’s my specialty.”

Dr. Church — a tall man with a long graying beard and rumpled clothes — oversees 45 students in his lab and has co-founded or advises some 22 businesses, many of them startups that focus on things like synthetic biology, genetic sequencing and companies that provide genetic testing to consumers.

His most visible work is the Personal Genome Project, which has 16,000 volunteers, 12 of whom have had their genomes sequenced and made publicly available. These include science and technology celebrities like the Internet pioneer Esther Dyson and the Harvard psychologist and best-selling author Steven Pinker.

Eventually Dr. Church wants to sequence the entire genomes of 100,000 people — nearly every one of the six billion As, Cs, Gs and Ts that occur in a human.

“The goal of getting your genome done is not to tell you what you will die from,” he said, “but it’s how to learn how to take action to prevent disease.”

So far, the science of predicting a person’s health future using genetic markers has not produced much useful information for common diseases, although Dr. Church believes that this will change.

“We need full genome sequences to understand what is really going on genetically,” he said. “Until recently, this wasn’t feasible.”

The project is becoming possible as the speed and efficiency of sequencing increase dramatically, and the once-prohibitive costs drop from millions of dollars for a genome two years ago to under $10,000 today.

Ultra-low sequencing costs will also allow researchers to study interactions between genes and environmental components — microbes, allergens, viruses, toxins, autoimmunity.

Typically, Dr. Church has been at the center of the development of the technologies that are making this possible. He advises or has licensed technology to most of the companies active in this field. This makes his potential conflicts of interests almost byzantine, since many are rivals, particularly in the hotly competitive field of genetic sequencing.

But he is undisturbed and open about his various commercial and scientific involvements — and seems to be like Teflon in avoiding the sort of criticism that other scientists often face for such entanglements.

Indeed, he starts his frequent lectures with a disclosure slide packed with the logos of companies he is involved with — among them LS9 (biofuels), Knome (personal genomes), Alacris Pharmaceuticals (cancer) and Joule Unlimited (photosynthesis).

“I want to move the science into application,” Dr. Church explains, “and I’ll support anything that gets it there. I won’t support one over the other. If they tell me something secret, I can’t tell anyone until it comes into the public domain.”

Dr. Edward R. B. McCabe, a geneticist and physician at the University of California, Los Angeles, said: “George has been an important figure in molecular genetics and its evolution, including genomics and bioinformatics. If we are to understand the complexity of biological systems, then integration on the scale George recommends will be essential.”

A leader in the Human Genome Project during the 1980s and ’90s, Dr. Church first came to prominence while still a graduate student, for developing some of the earliest genetic sequencers. These machines and processes combined a love of computers, engineering and science that began in high school.

“I always loved computers — it’s something inside you,” he said in an interview. But as a boy growing up in Clearwater, Fla., Dr. Church did not have access to computers. “So I made one myself,” he said. Later, when his mother married a physician, he became interested in biology.

As an undergraduate at Duke University, he majored in zoology and chemistry and worked in a lab that used sophisticated X-rays to identify the shapes of crystallized proteins.

“I got to use math, physics, chemistry and computers,” he said. “This was also one of the few areas of biology at the time that used robots.”

As scientists go, Dr. Church is an active public figure who gets more than his share of news media attention, which he clearly enjoys and takes in stride. In fact, little seems to disrupt his equilibrium.

“I’m pathologically calm,” he said — which may be one reason he has ruffled so few feathers in the hypercompetitive world of high-stakes science.

His lab includes cold rooms filled with tissue samples, machine shops with clamps and drills, and benches overflowing with electronics equipment. He points out where teams are studying antibiotic drug resistance, microbial fuels, metabolic engineering and epigenetics (the turning on and off of genes, usually by environmental influences).

He presides over his bio-empire with a tiny Sony laptop that he carries like someone else might cradle a baby, or a poodle. Shuffling from bench to meeting to lecture, he mostly listens to students and colleagues, asking a few pointed questions while multitasking on his computer.

Sometimes, Dr. Church seems to veer into science fiction. At a dinner a few months ago, he sat with colleagues discussing a project that involves “mirror biology” — the creation of DNA, cells and organisms that are exact opposites of the natural versions.

He explained that this was like building a replica of an old-fashioned clock by looking only at its reflection. “The copy will predictably tell time, but the numerals will be flipped and the hands will rotate counterclockwise,” he said.

“While mirror life may look identical to current life,” he said, “it is radically different in terms of resistance to viruses, pathogens and enzyme digestion, among other things, because molecular interactions of life are very sensitive to the mirror arrangement of the atoms.”

Dr. Church expects to have a proof of concept — a functioning mirror cell that serves some useful purpose — in two years. “The mirror project is challenging because it requires building an entire cell from parts,” he said.

He added that this was more complicated than creating, say, the entire genome of a microbial organism and inserting it into a living cell — a feat recently announced by the geneticist J. Craig Venter.

When a student stopped by his small office to chat about a just-published study in Science about the genetic sequencing of a Neanderthal, he said playfully, “Maybe one day we’ll make Neanderthals.”

Maybe so. He prizes imagination in his students and associates.

“I like to keep the median age in my lab low because they will indulge me in my dreams,” Dr. Church said. “They don’t yet think things are impossible.”