The Search Magazine Article November 19, 2014

Genomics icon lands at JAX

“I never met a genome I didn’t like,” George Weinstock, Ph.D., tells me, chuckling, as we talk one afternoon in Boston. A superstar in the field of genomics, Weinstock joined The Jackson Laboratory for Genomic Medicine in 2013, bringing a trove of knowledge and experience to the organization and to his new role as professor and associate director of microbial genomics.

His career spans several fundamental revolutions in biomedical science, from the first experiments to stitch together or “recombine” DNA from multiple sources (known as recombinant DNA technology), to the development of methods for decoding or “sequencing” DNA, to the emergence of genomics as a formal scientific discipline. Weinstock has played varied roles in those scientific transformations: student, teacher, enthusiast, leader and, of course, pioneer.

Charles Lee, Ph.D., professor and scientific director of JAX Genomic Medicine, calls him “a legend in the field of genomics who passionately devotes himself every day to understanding the biological impact of each DNA sequence variant obtained, on human biology and pathology."

At this moment in our interview, though, I ask Weinstock something decidedly less weighty: Does he have a favorite genome?

Just a glimpse of his genomic scorecard reveals a menagerie of organisms whose genomes he has helped lay bare: Treponema pallidum, the bacterium that causes syphilis, as well as countless other microbes; the rodent kings of the laboratory — rat and mouse; the geneticist’s darling, the fruit fly Drosophila melanogaster, and its insect cousin, the honeybee; and the sea urchin, a model organism beloved for its photogenic chromosomes.

The list goes on, but let us not overlook the genome that catapulted genomics into the limelight — our own. Weinstock was a leader of the Human Genome Project, an international effort to sequence the complete genetic code contained in our cells. Launched in 1990 and lasting just over a decade, it spurred a new generation of discoveries fueled by genome-based knowledge.

Those include so-called “personal” genome projects that reveal the genetic blueprint of a single person, such as Dr. James Watson, the legendary co-discoverer of the double helical structure of DNA. Weinstock led the team that sequenced Watson’s genome in 2007.

And entirely new fields have been born, such as metagenomics, the study of whole communities of organisms through the sequencing of their combined genetic material. This approach has opened the floodgates on studies of microbial ecosystems, particularly our own — the human microbiome. A diverse world of

microbes, including viruses, bacteria and fungi, resides in and on our bodies. Some of these passengers summon health, while others inflict disease. Weinstock has been at the forefront of this work, too, revealing the genomic underpinnings that distinguish microbial friend from foe, and, more recently, applying that knowledge to real-life medical problems.

With such a wide-ranging view of the genomic universe, spanning the DNA of organisms both great and small, it is perhaps understandable that Weinstock struggles to name a favorite genome. “They all have their own personalities,” he says. “They are all great.”

From the beginning

A giant, a legend, a pioneer — all are words used by others to describe Weinstock and his contributions to genomics.

Indeed, the arc of his career knits together a string of remarkable accomplishments. It also mirrors some of the seminal moments in the last few decades of biological research — tracing the birth and rise of genomics.

“George Weinstock has been one of the leaders in genomics since the beginning of the Human Genome Project,” says David Botstein, Ph.D., the Anthony B. Evnin Professor of Genomics at Princeton University, who was Weinstock’s graduate adviser at the Massachusetts Institute of Technology (MIT). “I know nobody who has a broader or deeper command of all the elements of genomics, from nucleic acid biochemistry to computational analysis.”

Although the field of genomics is relatively young by science’s standards, Weinstock has devoted his entire career to its pursuit, basically doing “genomic-y” things before there even was a word to describe the application of large-scale, systems-level approaches to biological problems.

“It’s basically, if you think about it, what I’ve been doing ever since [my career began]. It’s just that the technology has become more and more advanced,” he says.

Perhaps it is not surprising, then, that his path in science — and in life — begins with the story of another remarkable era in science.

Big science: a family affair

Weinstock’s parents met at the Los Alamos National Laboratory in New Mexico while working on the Manhattan Project, which produced the first atomic bombs during World War II. His father was a physical chemist and his mother a toxicologist. Although their work at Los Alamos lasted only a few years, the experience was transformative — for them and for their future son.

“There were lots of stories about all of the amazing people who were there and the things that were done. So, I was exposed to that, ” Weinstock says. Even still, science

was not a calling he initially embraced. “I was growing up. I was rebellious. I didn’t necessarily want to be a scientist. ”

Despite the rebellion of his youth, Weinstock unearthed a deeply rooted interest in science while an undergraduate at the University of Michigan. A talented chemistry teacher helped ignite his passion for science, and he decided to major in chemistry, then physics and ultimately, biophysics.

Although he didn’t follow in his father’s footsteps scientifically, Weinstock credits his father with kindling his own passion for big, transformative science. “My father always had some sense that it’s good to pick something really important to work on, not just something incremental.”

In 1970, Weinstock left for Cambridge, Mass., to pursue a graduate degree at MIT.

It was a formative time, not just in his career, but also in molecular biology and genetics. Several seminal discoveries were made as the fields bloomed, many by Weinstock’s MIT colleagues, and even himself.

He also met his future wife and scientific colleague, Erica Sodergren, Ph.D., then a fellow MIT graduate student. The couple married in 1974, and later headed west to Stanford University for their postdoctoral training. Eventually, they landed in Texas, where Weinstock became an associate professor at the University of Texas at Houston.

Although the couple often worked together as colleagues, it was usually at a distance. “She waited 20 years before working in my lab,” Weinstock says.

Sodergren hesitated because she worried deeply about disrupting the dynamics of their family and of Weinstock’s lab. “I had seen other husbands and wives working together, and there could be heightened friction,” she says. “They had their home life together and they had their scientific life together and it was like there was no separation.”

Ultimately, her concerns proved unwarranted — the couple has worked together in the same lab, harmoniously, for some 30 years.

The genome guy

Weinstock cut his teeth on sequencing genomes long before the approach was mainstream. He and a University of Texas colleague were awarded a National Institutes of Health (NIH) grant to sequence Treponema pallidum, the bacterium that causes syphilis. The grant was Weinstock’s first to sequence a genome

And while he didn’t have to set up a large genome center to sequence that microbe, he worked for one several years later. In 1999, he joined the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine, also in Houston, where he co-directed the HGSC and served as professor of molecular and human genetics.

Sodergren joined him in his new role, helping to set up the genome center and boost its efforts around the Human Genome Project.

Baylor’s HGSC was one of the five major centers to contribute to the Human Genome Project, working on the sequences for human chromosomes 3, 12 and X, and made many other important scientific contributions under Weinstock’s leadership.

It was an exhilarating time for him, his wife and many others throughout the scientific community. “There would be one point where we would have 10 or 15 of these different projects, where you are working with whole communities of hundreds of scientists to sequence ‘their’ genome, and then you do some analysis and turn out a transformative paper for the whole field,” says Weinstock.

As Baylor’s genome center and others cranked through various genome projects, a number of leading scientists, including Weinstock, began to push for something new — to tackle an unexplored frontier. One of the most intriguing areas was the human microbiome, sometimes called the second human genome.

In some ways, it was a daunting prospect. The number and diversity of microbes that call the human body home are staggering. As Weinstock recently told a crowd at the grand opening symposium for the new campus of JAX Genomic Medicine in Farmington, Conn., “There are more bacteria in your mouth than there are people on Earth.”

But such microbial exploration was indeed feasible, enabled by dramatic advances in the technologies for decoding DNA. These so-called “next-generation” methods, lower in cost and higher in throughput than earlier versions, made it possible to sequence not just one species of bacteria, but whole communities of them — with hundreds, even thousands of different species — all at once.

With the backing of the NIH, the Human Microbiome Project was launched in 2007. The initial five-year effort culminated with a flurry of scientific papers that offered a first glimpse of the types and diversity of microbes associated with the healthy human body. The basis for this work was a vast collection of samples from nearly 250 healthy volunteers, drawn from as many as 18 different body sites across five major anatomical areas, including the airways, skin, mouth, gut and vagina.

Now, in the project’s second phase, researchers across the country, including Weinstock, are extending these findings by probing the microbiome in various states of health and disease, such as pregnancy, type 2 diabetes and inflammatory bowel disease.

A life-long colleague

Working so closely with Weinstock over many years, Sodergren has a unique perspective on his life’s work. One of his lesser-known gifts, she notes, is teaching.

“He’s taught undergraduates, pre-med students, graduate students in research and medical students. And he’s been very successful in all of these approaches,” she says. “That is a really impressive talent that many people don’t have.”

She also highlights his ability to bridge disciplines.

“I see him as a Renaissance thinker,” says Sodergren. “Many scientists make the choice to really channel their focus and they don’t go outside their area of expertise very much. So now they have to form these consortiums where they can bring in a lot of different expertise to address complex problems.

“But George has always done consortia-type work; he is always collaborating with people with broad backgrounds. That is a really powerful scientist to have as your colleague.”

Third act

After spending nearly a decade at Baylor and its HGSC, Weinstock and Sodergren moved in 2008 to another prestigious genome center at Washington University in St. Louis. He became associate director of The Genome Institute and pursued his pioneering work on the microbiome as well as countless other projects. As self-professed “genome center people,” the Weinstocks had little inclination to leave.

Then he stumbled across the Laboratory’s plans for expansion in Connecticut and its bold new vision for genomic medicine. He knew JAX President and CEO Edison Liu as well as many others at JAX. “I felt I had to take a look at this, even though we weren’t looking to move because, boy, it would just be a perfect place to finish up.”

Now, as one of JAX’s newest fixtures, Weinstock brims with enthusiasm for what lies ahead. He plans to extend his foundational research on the microbiome, advancing both its basic and clinical applications. He is also working hand-in-hand with physicians to translate next-generation sequencing into clinical use. That includes forging collaborations across the Connecticut medical community, including the University of Connecticut Health Center, Hartford Hospital and the Connecticut Children’s Medical Center.

As just one example of his latest research, Weinstock and his colleagues are using DNA sequencing to analyze stool samples from newborns in the neonatal intensive care unit. These infants are supremely vulnerable to infection, and sequencing can provide a window on which patients are likely to develop a viral or bacterial illness — sometimes days before it emerges clinically.

Given his impressive reputation, it is not at all surprising that Weinstock is pushing the envelope of genomics and technology in this way. No one knows precisely where things will go from here, but it is certain to be a remarkable journey.

“You get through some ceilings and you are suddenly in a new realm of being able to see things,” Weinstock says. “That’s what pulls us forward, and that trip is not over yet.”

Nicole Davis, Ph.D., is a freelance writer and communications consultant specializing in biomedicine and biotechnology. She has worked as a science communications professional for nearly a decade and earned her Ph.D. studying genetics at Harvard University.