George Streisinger’s big eureka moment was also a big Eugene moment.
By Eric Tucker
This year marks the 30th anniversary of a groundbreaking paper published by UO biologist George Streisinger in the journal Nature in 1981.
The paper described his landmark achievement in science history: the first-ever large-scale production of genetically uniform clones of a vertebrate organism. It further established his organism of choice—the zebra fish—as a superior model for genetic research while also laying the groundwork for the University of Oregon to become the zebra fish research capital of the world.
Zebra fish lino cut by Lotte Streisinger; zebra fish lab photo by Jack Liu.
From humble beginnings in a small Quonset hut on the north side of Franklin Boulevard, the UO zebra fish facility moved to the basement of the biology building in the late 1990s; it has since come to house 80,000 zebra fish in floor-to-ceiling tanks in a 5,000-square-foot space and will soon be doubling its space by expanding into an adjacent building.
There are now six high-profile labs in the UO Institute of Neuroscience and Institute of Molecular Biology that rely on the zebra fish as their model organism for research. And the UO is also home to the Zebrafish Information Network (ZFIN), an online resource that allows the worldwide research community to share zebra fish data and scientific insights.
Indeed, the legacy of Streisinger (who died in 1984) reaches far beyond Eugene. His techniques have spread to more than 500 developmental and genetics labs in 32 countries. Many of the mutant strains that Streisinger himself created are still used in labs throughout the world to study human and animal health.
But why zebra fish?
Born in 1927 in Budapest, Hungary, Streisinger and his family fled to the United States in 1939. His first scientific paper, which he co-authored when a senior at the Bronx High School of Science, was on fruit fly courtship. He earned a BS from Cornell University in 1950 and a PhD from the University of Illinois in 1953; in 1956 he completed postdoctoral studies at the California Institute of Technology. Following stints at Cold Spring Harbor and the Carnegie Institution of Washington, he joined the UO Institute of Molecular Biology in 1960.
After toiling for years on the genetics of bacteriophages—simple viruses that infect bacteria—Streisinger, a home-aquarium hobbyist, turned to the diminutive zebra fish to investigate how genetic mutations affect nervous-system development in vertebrates.
His initial experiments, conducted throughout the 1970s, garnered little notice at first. In fact, as is the case with many creative breakthroughs, Streisinger’s work initially inspired skepticism among his contemporaries. Why waste precious time studying zebra fish, they wondered, when other, more widely recognized model organisms—such as mice, fruit flies and nematode worms—were readily available, along with their established toolboxes of genetic tricks?
But Streisinger persisted. As he tinkered, he soon realized the numerous advantages of a creature known mostly, till then, for its ubiquity as a pet-store commodity.
It Takes Some Backbone
Zebra fish have backbones—unlike other common research organisms like phages, fruit flies and nematode worms—and thus are remarkably similar to human beings in both genetic makeup and embryonic development.
Streisinger often referred to the zebra fish as “a phage with a backbone.” The presence of a backbone signifies the presence of a brain, a spinal cord, optic nerves and a vast network of peripheral nerves, making the zebra fish an ideal organism for studying human disorders.
“Zebra fish are one of the best systems for doing vertebrate genetics,” said biology professor Monte Westerfield, whose lab looks at zebra fish sensory systems and their connection to human diseases. Read about the Westerfield lab.
The other five UO labs that rely on the special attributes of the zebra fish are also striving to find treatments for human biological disorders that have analogues in specific zebra fish mutant strains. For instance, the work of John Postlethwait, whose lab studies the evolution of zebra fish gene networks, could lead to therapies for a wide variety of human genetic ailments, including Fanconi’s anemia, a disease that affects DNA repair. Other UO research ranges from potential cancer interventions to treatment for human skeletal defects. Read about the Postlethwait lab.
The Power of Observation
Unlike mouse embryos, zebra fish embryos develop ex utero (outside the mother’s uterus) and grow inside transparent eggs, allowing researchers to observe embryonic development without the use of invasive procedures and without harming the mother.
“With mice, we can’t see inside the mother,” said Judith Eisen, a 2010 Guggenheim Fellow. “But we can follow zebra fish throughout their development.”
Eisen’s lab focuses on the growth and development of neurons in the zebra fish spinal cord. Her team is looking at how individual neurons learn their roles, form networks and allow organisms to carry out complex physiological functions, such as movement and behavior. Read about the Eisen lab.
“From the first cell, you can see the embryos,” said biology associate professor Philip Washbourne. “There is no operating on pregnant moms, no opening up of skulls.”
Washbourne, whose lab studies synapse formation within developing zebra fish brains, speaks with enthusiasm about the potential of optogenetics, a new technology that allows researchers to influence the behavior of cells with beams of light. When researchers shine a beam of light on, say, a developing zebra fish brain, light-sensitive proteins inserted into the brain absorb light and open channels, causing specific neurons to fire. Read about the Washbourne lab.
Because zebra fish embryos are transparent, Washbourne can observe these effects without invasive surgery or scans.
“It’s almost as if Streisinger anticipated our needs,” he said. “He knew back then that we needed an organism that was see-through, so that we could see the nervous system as it developed.”
Master Manipulators
The conditions of zebra fish embryonic development facilitate genetic experimentation, as genes supplied by a single parent can be readily manipulated to produce mutant strains.
Because vertebrate embryos contain DNA material from two parents, genetic experiments with vertebrates have historically required elaborate and time-consuming breeding techniques to yield mutations and other recessive traits. For instance, to manifest a rare recessive mutation, vertebrate embryos require two copies of the mutated form of the gene—one from each parent. But Streisinger’s cloning technique gave researchers the advantage of working with embryos that contain only the mother’s genes, thus greatly simplifying the process of studying organisms with specific mutations.
Scientists can also manipulate the development of zebra fish embryos by transplanting or removing cells or groups of cells. By observing the biological effects of such experiments, researchers can learn valuable information about the role that specific genes play in the overall health of the organism.
This has been a boon to Westerfield’s lab, which looks at zebra fish sensory systems and their connection to diseases such as Usher syndrome, the leading cause of deaf-blindness in humans.
“We are trying to figure out what genes are in common between photoreceptors in the eye and sensory hair cells in the ear,” he said. Identification of such genes in zebra fish could lead to the discovery of the corresponding genes in humans.
In Usher syndrome, children are born deaf, and visual loss is slow and progressive, said Westerfield. Babies are tested for hearing at birth, but cannot be tested for vision, thus doctors may miss a diagnosis of Usher syndrome. If doctors were to know that these children would later become blind, this could influence their treatment decisions.
“The only current way to test is through genetic testing,” said Westerfield. “And the only way genetic testing works is if we know what genes are responsible.”
Critical Mass
Because zebra fish display a rapid life cycle (embryos proceed from fertilization to birth in about three days) and reproduce in abundance in the laboratory setting (each female can produce up to 5,000 eggs per year), researchers can expedite identification and genetic analysis of mutants.
Identifying the source of genetic mutations in zebra fish is the first step toward discovering the cause of—and perhaps the cure for—corresponding genetic ailments in humans.
Their rapid life cycle facilitates the work of UO biology associate professor Karen Guillemin. Guillemin investigates the impact of gut flora on human diseases such as colorectal cancer. Read about the Guillemin lab.
“For zebra fish, it takes only five days to go from fertilization of the egg to the development of the gut,” said Guillemin, whose lab can produce thousands of zebra fish at a time. “The same process takes three months in mice.”
Guillemin’s experiments have revealed that resident microbes in the developing zebra fish gut send cell-proliferating signals via the same pathway used by cancer-causing genetic mutations.
Recent microbial research, such as that conducted by Guillemin and her team, has led to a strategic shift in humanity’s ongoing battle against cancer, as scientists are beginning to recognize the significant impact that resident microorganisms have on cancer growth.
The implications? “Even if you can’t fix a mutation, you might manipulate the associated microbes to change the interaction and reduce unwanted cell proliferation,” said Guillemin.
An organism that has a backbone, that begins life as a transparent embryo and develops outside the mother’s body, that allows for quick and precise genetic manipulation and that reproduces and matures rapidly—Streisinger recognized and exploited all of these important traits in the humble zebra fish.
The final ingredient? Patience, as he waited for the rest of the world to catch up.
Sidebar: Zebra Fish Groupie and Other Streisinger Legacies
Another dimension of the Streisinger story is the strength of the research community he established at the UO. In many other universities, professors tend to keep their doors closed and the grad students don’t talk. Not so at the UO, said emeritus professor Charles Kimmel, who joined the UO biology faculty in 1969 and interacted closely with Streisinger even before the seminal Nature article was published. Read about the Kimmel lab.
For instance, inspired by the atmosphere of open-door collegiality fostered by Streisinger, the biology department now sponsors a gathering on Monday mornings called zebra fish groupie, during which members of all six labs convene to discuss work and to help forge a sense of community among students and faculty members.
“George was a forerunner, and not just in science,” said Kimmel. “He was very much involved in social issues, the environment, war protest.”
In an interview published in From the Sidelines, a memoir by his wife, Lotte, Streisinger spoke of his fear of global nuclear war, as well has his grave concerns regarding the widespread use of hazardous chemicals, the dangers of runaway population growth and the ever-widening gulf between the rich and the poor. Download an excerpt from From the Sidelines.
A lover of the Oregon outdoors, Streisinger died in 1984 in a scuba-diving accident off the central Oregon coast.
“George must have known he would live a short life,” said Charline Walker, a faculty researcher in Kimmel’s lab who worked with Streisinger from 1972 to 1984. “He did everything very intensely.”
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