Volume 31 · Number 1 · Fall 2013
Enter the genomics matrix
The ability to map all of an organism’s genes is revolutionizing the way scientists look at the world — and changing your future.
James Watson and Francis Crick’s 1953 discovery of the structure of DNA ushered in today’s genomics revolution.
(Photo illustration by Jay Leek/UC Davis)
In the science fiction movie The Matrix, the hero learns to see what he thought was the real world as computer code — streams of glowing ones and zeros. And with that knowledge, he has the power to alter the world around him.
Now, the young science of genomics is showing us the world as streams of DNA, copying and reproducing and making living things work. While invisible to your eye, DNA is all around you: your own DNA, your relatives’ and neighbors’; the DNA of the cat on your lap, the trees and plants outside, the insects and worms squirming in the grass; the DNA of billions of bacteria inside you and on your skin, keeping you healthy or making you sick; the DNA of invisible films of microbes on my desk, over the walls, across my keyboard, and floating through the air on specks of dust.
Enabled by technology, genomics is radically changing how scientists look at the world, much as the invention of the telescope and microscope did centuries ago.
Genomics is the study of genomes — all the genetic material of an organism. While classical genetics zooms in on individual genes, genomics pulls back the focus, allowing scientists to see all the genes of an organism at the same time, then to comb through them for trends, associations and interactions.
If genetics were baseball, the classical approach would be to know all about a single player. Genomics, on the other hand, means knowing something about all the players in every team in the league.
“We used to be limited by the amount of data, and that’s no longer the case. The limiting step in science now is adding knowledge that adds value to the data,” said Richard Michelmore, director of the UC Davis Genome Center.
At UC Davis, genomics is now being used to study crops like tomatoes, peppers and wheat; search for clues to cancer and autism; find ways to make new green fuels; and understand the microbes that live in, on and around us and make us healthy or sick.
“At UC Davis, we are very well placed to exploit the genome revolution because we study everything here. We have probably the largest, certainly the most diverse collection of biologists in the world,” Michelmore said.
A short history
Sixty years ago last February, Francis Crick announced to a crowded Cambridge pub that he and James Watson had discovered the “secret of life” — the double helix structure of DNA, the molecule that carries genetic information from generation to generation.
Watson and Crick’s double helix showed how the four molecules at the heart of DNA — adenine, guanine, cytosine and thymine, or A, G, C and T — can pair up: A with T, G with C. This meant, they realized, that any stretch of DNA could be copied and duplicated.
Over the next 30 years, molecular biologists learned how to identify and sequence stretches of DNA coding for genes for particular traits, and transferred snippets into other organisms to study them or to develop new breeds and products. This recombinant DNA technology is now widely used to make medicines and vaccines, as well as for new varieties of crops such as corn, cotton and soybeans.
But these efforts dealt with relatively small pieces of DNA. In 1990, the U.S. Department of Energy and the National Institutes of Health formally launched the Human Genome Project, an international effort led by the U.S. to determine the complete sequence of DNA of a human being — about 3 billion letters of DNA code.
Enter J. Craig Venter, an entrepreneurial biologist who believed genome sequencing would move faster with a different technical approach that became known as “shotgun sequencing.” He established a nonprofit organization, The Institute for Genomic Research (TIGR), and later a company, Celera Genomics, to pursue genome sequencing with the new methods, which depended heavily on automated sequencing machines.
Jonathan Eisen, now a professor at the UC Davis Genome Center, was a graduate student at Stanford University in 1995 when one of Venter’s partners, Hamilton “Ham” Smith, gave a talk at the campus.
“I was trying to clone individual genes from one organism, and Ham presented a list of organisms for which they were trying to sequence not one gene but the entire genome — including the one I was working on,” Eisen said. “I knew immediately this was a big deal.”
A couple of years later, Venter himself visited Stanford. Eisen finagled a dinner invitation, outlined on a napkin why he thought Venter was wrong on a couple of things, and was offered a job — although by the time he got to TIGR, Venter had moved on to Celera.
“I’ve never actually worked for Craig, but I’ve worked with him on a number of projects,” Eisen said. “He has pushed the field forward in extraordinary ways.”
Tensions between the government-funded Human Genome Project and Venter’s private-sector efforts would flare up through the 1990s. In 2000, the groups united to announce a “working draft” of the human genome sequence, with then-President Bill Clinton and British Prime Minister Tony Blair presiding over a joint news conference.
The Human Genome Project, completed in 2003, cost $3 billion. Today, sequencing a human genome costs about $3,000, and the price is falling. Within a decade, your personal genome sequence could just be part of your medical record. Perhaps we will carry them around on a thumb drive or store them in our cell phones.
“If I can measure my heart rate on my phone now, I’m pretty sure I’ll be able to have my DNA sequence on my phone,” said Bart Weimer, professor in the UC Davis School of Veterinary Medicine, director of the 100K Pathogen Genome Project to sequence disease-causing microorganisms and co-director of the BGI@UC Davis genome sequencing facility.
“You will know more than your physician,” said Harris Lewin, vice chancellor for research and a genome scientist. “Doctors aren’t trained in this yet, but it’s going to become an integral part of medicine.”
Conditions like heart disease, diabetes and cancer arise from a combination of genetic predisposition and environmental factors. If you know the risk factors in your DNA, you can take steps to change your environment — avoiding certain foods, for example — to improve your chances of a healthy life.
Actress Angelina Jolie recently had a double mastectomy based on a genetic risk of developing breast cancer. In the future, genomics might give us more accurate estimates of your risk of developing certain cancers, predict which tumors will become malignant, and tailor chemotherapy to your DNA profile. A specialist at UC Davis Health System is already advancing the use of genetic testing to determine the best possible treatment for patients with lung cancer. [See “The Master of the Art of the Possible,” page 24.]
Lewin predicted that genomics will also have a big impact in agriculture, energy and even manufacturing — guiding the breeding of new crops and livestock, the development of new biofuels and inspirations for industrial materials.
In agriculture, genomics could speed the creation of new varieties for desired traits, such as tolerance for the effects of climate change. Instead of introducing single genes as in genetically modified crops, genomics allows breeders to see exactly which traits they are selecting. It will also bring about a more profound understanding of the microorganisms that are vital to agriculture, whether helping plants fix nitrogen from the air or allowing cattle to digest tough plant material.
Researchers like Oliver Fiehn at UC Davis’ NIH-funded West Coast Metabolomics Center are searching for new ways to coax single-celled plants, or algae, into making biofuels. Genomics could also help us identify microbes that can clean up oil and gas wells. Those microbes might even be created from scratch, through “synthetic biology,” a new piece of DNA custom-made and engineered into a living cell.
“I envision genomics having a huge impact on synthetic biology and bio-inspired design of materials for biomedical, computing and industrial applications,” Lewin said.
UC Davis’ Genome Center was established in 2004 with Michelmore, a professor of plant sciences in the College of Agricultural and Environmental Sciences, as founding director. Michelmore deliberately decided against focusing only on DNA sequencing.
“The Genome Center is the technology antenna for the campus — if you have a bright idea, then we will provide access to state-of-the-art equipment and technology at cost, as needed,” he said. The center has core facilities in proteomics and metabolomics — large-scale studies of the proteins and metabolites that make living beings work — as well as DNA technology.
“We try to provide things you can’t get elsewhere,” Michelmore said.
In 2011, UC Davis signed an agreement with BGI, formerly the Beijing Genomics Institute, to establish a genome sequencing facility on the Sacramento campus. BGI is by far the world’s largest genome sequencing institute. The BGI@UC Davis facility currently has three sequencing machines and will eventually have up to 20. The joint facility gives UC Davis researchers access to BGI’s DNA sequencing facilities and expertise, and complements the resources of the Genome Center. In turn, BGI can tap the deep knowledge of UC Davis researchers about problems in biology, medicine, agriculture and the environment.
Biology: the new math
One of the great challenges of genomics is “Big Data”—how to handle and analyze very large, very complex sets of information.
The breadth of that expertise is reflected in the Graduate Group in Genetics, with more than 100 faculty members from 25 departments across the campus. The genetics graduate program, which marked its 50th anniversary last year, is preparing to change its name to Integrated Genetics and Genomics.
Janine LaSalle, a professor in the School of Medicine and chair of the graduate group, said the name change recognizes the growing importance of genomics and how it integrates different disciplines.
“Genomics plays to our strengths, the huge breadth of organisms that we study on campus,” LaSalle said.
Genomics is giving us unprecedented insight into ourselves and our environments — and with that knowledge, potentially, comes the power to manipulate our health, our environments, our animals and perhaps even ourselves.
For biologists, it’s comparable to the moment four centuries ago when Galileo saw the moons of Jupiter through his telescope and realized that what we thought we knew about the world was wrong.
In this new genomics revolution, UC Davis scientists are peeling back the old precepts to reveal a whole new universe of possibilities.
“We’re in for exciting times,” said veterinary professor Weimer.