From Genes to Global Solutions

It’s often said that the relationship between science and the natural world follows a five-step process: observe, describe, explain, predict, and control. Over the past 50 years, the effort to control has increasingly been focused on the molecular level, with labs racing one another to achieve ever more sophisticated feats of genetic engineering. But long before “genetic engineering” was a buzzy phrase—and even before anyone knew what a gene was—humans were using the process to feed themselves more efficiently. 

The first time a nomadic tribe bred an especially large ram with a particularly tasty ewe, for example, or the first time a society cultivated wild wheat so that it would grow when and where they wanted—both were practicing early forms of genetic engineering.

While the College of Natural Resources’ 150-year history is a blink of time from an evolutionary perspective, CNR’s land-grant mission has placed it at the forefront of agricultural genetic engineering since the beginning. In the early 1900s, that might have meant laboriously developing new cultivars for California’s booming orchards, but now Berkeley is taking the lead with a new genome-editing technology that promises to reshape the future of agriculture, medicine, and the meat and dairy industries.

Commonly known as CRISPR—an acronym for Clustered Regularly Interspaced Short Palindromic Repeats—the genome-editing technique takes elements of adaptive bacterial immunity to viruses and makes highly targeted alterations to the genome of a plant or animal. To make DNA edits, scientists wield the Cas9 protein like a “molecular scalpel,” slicing out mutated DNA and adding in a healthy genetic patch. Although CRISPR technology is still in relative infancy, the possibilities are staggering—from the creation of drought-resistant crops to new treatments for cancer and sickle cell anemia.

Just as UC Berkeley helped pioneer the land-grant college system and the Cooperative Extension programs a century and a half ago, a new powerhouse, the Innovative Genomics Institute (IGI), is poised to lead the charge on CRISPR and other emerging technologies. It’s a joint effort between UC Berkeley and UC San Francisco, bringing together a team of professors and researchers to advance genome engineering with the ambitious goals of curing disease, ensuring food security, and preserving the environment. 

Combining four broad research areas—biomedicine, agriculture, microbiology, and society—the IGI is an interdisciplinary hub with wide-ranging potential. Jennifer Doudna, the UC Berkeley professor of chemistry and molecular and cell biology who co-developed CRISPR genome editing just a few years ago, serves as executive director. And CNR faculty play critical roles on the scientific team, working toward advances in the fields of agriculture, microbiology, and the societal and economic challenges of bringing CRISPR technology into widespread global use. 

One of the core members of the new institute is Brian Staskawicz, a professor in the Department of Plant and Microbial Biology (PMB) and the scientific director of the IGI’s agricultural research. Staskawicz, who earned his PhD in plant pathology at Berkeley in 1980, has been on the faculty here for 34 years. His contributions to the field of plant disease and immune response stretch back decades. In 1984, his was the first lab to publish on the fact that plant pathogens deliver proteins—now widely known as effector proteins—that actively suppress the immunity of the plant host. Ten years later, his lab broke new ground again by cloning one of the first disease-resistance genes. 

Two years ago, Staskawicz immediately recognized the potential of CRISPR to rapidly introduce genetic disease resistance into crops, possibly overcoming many significant problems in modern agriculture. “This technology is really a game changer for agriculture,” says Staskawicz, whose group is working with genome editing to make plants more sustainable in an environmentally friendly manner. “We think we can use CRISPR to make plants more drought resistant,” Staskawicz says. “We can also edit in resistance to disease, and maybe even make plants more efficient in the way they use nitrogen.” Given that the Food and Agriculture Organization of the United Nations has predicted that population growth will require food production to increase by 70 percent by 2050, the promise of greater efficiency isn’t just a nicety but a life-sustaining necessity.

Part of CRISPR’s great potential is the speed with which new plant types can be produced. In classical plant breeding, introducing a trait from a wild species takes years of backcrossing to achieve the desired result. But with CRISPR, says Staskawicz, “we’ll take the same genes we normally use to do genetic crosses, but now we’re going to be able to introduce them singly or in groups precisely into the already high-yielding variety that we want and not bring in all the baggage that we don’t.” This is likely to prove especially valuable in the face of rapidly changing environmental conditions such as global warming. “A lot of the genetic-disease-resistance traits break down at high temperatures,” Staskawicz says, “so we’re going to start seeing new epidemics coming. We’re going to see changes in populations of pathogens.” While traditional responses might be to add more pesticides or deforest more land for agriculture to produce greater crop yields, CRISPR may be able to quickly create disease-resistant seeds for farmers.

And while the science is fascinating and papers are being published at a rapid clip, CNR faculty aren’t losing sight of the fact that the ultimate goal is to get these products into the fields where they’re most needed. “We’ve purposely chosen to work on wheat, rice, and other crops that affect developing countries and that have been ignored by companies because they don’t make money,” says Staskawicz. One of his current projects involves cassava, among the most important food crops in the tropics. Although it’s drought tolerant and relatively productive in marginal soils, cassava also produces cyanide, which in turn causes konzo, a so-called disease of poverty that affects 100,000 people per year. Currently, farmers remove toxins using laborious (and often imperfect) postharvest techniques; gene editing could revolutionize the way millions of people safely feed themselves.

To advance the plant-genomics research agenda at Berkeley, the IGI has been scaling up its team—hiring four postdoctoral researchers in that area last year. The Department of Plant and Microbial Biology is working to hire at least three new faculty members who will be involved in the IGI as well.

“I was attracted to Berkeley because it’s now the center of genome-editing technology,” says Ksenia Krasileva, BS ’05, PhD ’11, Microbiology, one of the new hires, who starts as an assistant professor in PMB this summer. At the moment, Krasileva—based in the UK and partnering with an NGO in Kenya—is working with wheat, which requires heavy doses of fungicides to combat afflictions of yellow rust. As wheat was domesticated from wild relatives, she explains, “selection was made for size rather than the health of the plants, and the natural diversity that allowed them to withstand pathogens got lost.” The ability to introduce very targeted disease-resistance genes hasn’t been perfected yet, “and that’s the research that’s happening at Berkeley,” she says. “We’ll figure out how best to do very precise changes to make disease-resistant crops.”

It’s easy to talk about CRISPR as an exciting new tool that scientists have just invented, but Jill Banfield, the scientific director of the microbial arm of research at the IGI, points out that the technology long preexisted human knowledge of it. A geomicrobiologist with appointments in the departments of Environmental Science, Policy, and Management (ESPM) and Earth and Planetary Science as well as at Lawrence Berkeley National Laboratory, she is quick to give credit where credit is due. “Let’s back up and say the CRISPR-Cas system was invented by microbes and used by microbes as a defense system against viruses and plasmids. We anticipate that there are many different genome-editing tools present in the genomes of microbes that have not yet been discovered.” 

So it would be more accurate to say that the scientists at the IGI are piggybacking on a system that has been used by bacteria since the earliest days of life on Earth and adapting it for a different use in plants, livestock, and humans. It had been speculated that the microbial genetic feature that came to be known as CRISPR actually works as an immune system, and research from Banfield’s lab helped scientists understand. “If you remove this system from microbes,” she says, “they’ll die of viral infections.”

In the course of her research, Banfield discovered that CRISPR systems in nature have evolved incredibly rapidly. That led her to collaborate with Doudna in the heady early days of explaining CRISPR’s potential to the worldwide scientific community. Banfield’s current involvement in the IGI is not so much in the eventual applications of CRISPR technology, but in building up a tool kit for other scientists to use. “Our group is looking for new CRISPR-Cas systems that could have value for the purposes of genome editing,” she says. 

To do this, Banfield and her students are making use of vast amounts of sequence information that they’ve obtained from the natural environment. While most of us look at the world and assume that life consists of the plants and animals we’re familiar with, Banfield points out that the majority of organisms are actually the bacteria and archaea we rarely consider. 

“The genomes of most organisms in the world have not yet been sequenced,” she says. And even when the sequencing has been done, “in some organisms, 50 percent of the genes have no known function. There’s enormous potential there.” Banfield and her collaborators—including Doudna—have already discovered simple systems similar to CRISPR-Cas9 in previously unexplored bacteria. These new systems are highly compact, and if they can be reengineered as CRISPR-Cas9 has been, their small size could make them easier to insert into cells to edit DNA.

Banfield’s search for new organisms has led the world to reconsider and expand its understanding of the biological “tree of life,” demonstrating that the great majority of species are invisible to the naked eye. This work has taken her to some unlikely places, from a sweltering underground acid mine to a high-intensity dairy farm in the Central Valley, where the team pumped up groundwater while slogging through cow pies and sewage lagoons. In addition to being the basis of new genome-editing tools, microbes have great potential in their own right, as sources of novel antibiotics, as instruments of wastewater treatment, or as part of the process of creating sustainable sources of bioenergy. “Microbial communities can be harnessed to meet societal needs,” Banfield says. “They mediate our air quality, our water quality, and so much more.” 

It may turn out that the greatest impediment to the use of CRISPR is not scientific but political. Although the USDA considers CRISPR crops differently than it does genetically modified organisms, some of the same cultural battle lines are beginning to emerge. “Food is so much more than calories; it’s culture. And that’s why it can be so polarizing,” says Matthew Potts, an ESPM associate professor. Potts and David Zilberman, a professor in the Department of Agricultural and Resource Economics, are working together as part of a project funded by the IGI that focuses on maximizing the social, economic, and environmental benefits of using gene-editing technologies in agriculture. “We already have many different technologies to modify crops,” Potts continues. “So part of what we’re doing is trying to understand how to get this new technology rolled out by learning from why GMOs weren’t widely accepted.”

Zilberman is a little more blunt, focusing on the risks of not using CRISPR. “The U.S. can survive without CRISPR technology, without GMOs,” he says. “But how about developing countries? To me, the hope of gene editing is for people in places like Africa, to help them deal with malaria, with sleeping sickness, and to improve agricultural productivity.”

Zilberman’s work often focuses on supply-chain issues, and he believes that the advent of CRISPR technology holds the potential to solve many problems humanity has created for itself. “Plants are incredible chemical factories,” he says. “We can go from relying on chemicals we mine to ones that we grow. We can go from deforestation to carbon sequestration. With plants doing most of the work, we can transition to a renewable economy.”

Across all the IGI’s program areas, getting the technology to the end user is a primary goal, which is where policy comes in. “Policy and science go hand in hand,” Zilberman says. “CRISPR without institutions and without policy is not as valuable.” To that end, the IGI is ensuring that the technology does not become bound up in bureaucracy. 

“The initial work is all being supported by philanthropic funds,” says plant biologist and IGI managing director Susan Jenkins, PhD ’96 Plant Biology. “Projects won’t be siloed off due to funding coming in from different corporate partners. The things we develop can get out to the people who can use them, not become the property of one entity that would control it.” From a practical perspective, the IGI has established a Plant Transformation Facility to perform rapid, large-scale trials. “Our ability to do industrial-scale transformation and gene editing in important agricultural crops gives us an edge,” says Staskawicz. 

With top-notch faculty steadily joining up to work together in creative, interdisciplinary ways, the IGI is poised to be a world leader in CRISPR and whatever genome-editing technologies follow it. “The IGI is becoming the frontier of what can be called the bioeconomy,” says Zilberman. “CRISPR is the most important tool enabling us to use the capacity of biology to solve global problems in a sustainable manner.” With 150 years of proven success, it’s no surprise that CNR’s faculty will lead the way. After all, innovation for the public good is in Berkeley’s DNA.