Boning Up on Evolution
For David Kingsley, there's a story in every skeleton
By Steve Mirsky
David Kingsley's office at Stanford University might look to some observers like a Halloween supply store-it's filled with skeletons. "I have a turtle, an armadillo, a mole rat, an axolotl [a kind of salamander]," Kingsley says. "I have a piranha head from someone's trip to South America, and one of my students came back with a monkey skull she got for two dollars in a Philippine market. I like skeletons-that's one of the central themes in the lab."
A forensic scientist might study bones to try to figure out how someone died. Evolutionary biologist Kingsley appreciates bones of different creatures because they help him study one of the biggest questions about life. "We're interested in how evolution creates new organisms," he says.
Kingsley, a Howard Hughes Medical Institute investigator, presides over a bustling laboratory of about a dozen researchers at any time, including postdoctoral fellows, graduate students, technicians, and the occasional undergraduate student. Their projects examine the genes behind the big anatomical solutions that evolution comes up with in organisms' struggle for survival. These kinds of investigations aren't easy-Kingsley likes projects that, he says, "are on the edge of doability."
He continually takes the "hit by a bus" test. "This is a tough test to ask yourself every day when you get up to go to work on your chosen scientific problem," he explains. "If you were hit by a bus on your way to work, would it make any difference for the field you work in?" If the field would keep on humming while the paramedics were racing to the scene, Kingsley would rather be doing something else.
The tall, thin 46-year-old researcher was born and raised in Des Moines, Iowa, but for the last quarter century he has opted for one coast or the other. He received his undergraduate degree from Yale University and a doctorate from the Massachusetts Institute of Technology. He then did genetics research with mice at the National Cancer Institute in Maryland before joining the faculty at Stanford University in California. He brought some of the Midwest with him, though-his wife, Cindi, whom he's known since eighth grade. They have two sons, 15-year-old Davis and 12-year-old John.
Most genetic researchers work with tiny invertebrates, such as fruit flies or Caenorhabditis elegans, a kind of worm. These animals reproduce quickly, take up little space, are relatively easy to work with, and have provided huge amounts of biological information over the last century. But Kingsley always wanted to do similar kinds of research with vertebrates, thereby stepping squarely in the path of the bus. Vertebrates take up more room, have slower generation times, and are more expensive to keep. But Kingsley thought there were questions that could only be addressed properly with vertebrates. "Many of my best friends are vertebrates," he winks. "Studying vertebrates feels like you're studying yourself and where humans came from."
Kingsley notes that anyone working with vertebrates should make wise choices about what exactly to study. "You should use vertebrates," he says, "to study things that aren't better studied in one of the other available model organisms," such as fruit flies or yeast. For example, examining how an individual living cell accomplishes some of its biochemical tasks might be much more easily done in a yeast cell and still illustrate basic biology common to all cells. Not so with bones, though. "This is going to sound really simple," he says, "but the skeleton is a system that's best studied in vertebrates."
Skeletons have a twin relevance that also appeals to Kingsley. "They're obviously important in human health," he explains. "At least half the people in the United States will suffer from bone fractures, osteoporosis, or arthritis during their lifetimes. And at the same time, skeletons provide one of the best displays of basic patterning and evolution in vertebrates. Organisms have to modify the size and shape and the number of all those bone parts in order to build bodies that solve the different kinds of problems that evolution addresses."
Using mice, Kingsley and his group have found various genetic mutations that disrupt the proper development of skeletons and even influence the likelihood of eventually getting arthritis. These kinds of studies also reveal which genes are intimately involved in the normal progression of a fertilized egg to a healthy offspring. Kingsley's primary interest is in how skeletal development is genetically determined for any particular organism. Understanding these genes and the effects of mutations can inform researchers directly interested in preventing human birth defects, repairing bone fractures, and controlling susceptibility to arthritis.
In the last 25 years, molecular biologists have discovered that the genetic similarities among organisms are much closer than anyone guessed. That finding leads to a profound question: if we're almost identical genetically to other vertebrates, how has evolution come up with the obvious and important differences? In order to address that problem, in 1998 Kingsley decided he needed a whole new kettle of fish.
The little stickleback, a fish typically two or three inches long, has been a popular research subject for decades. Dutch researcher Nikolaas Tinbergen shared the 1973 Nobel Prize in Physiology or Medicine in part for behavioral studies he had done in the 1930s and 1940s using the fish. For Kingsley, sticklebacks represented a unique opportunity to take advantage of natural experiments that evolution has been carrying on for millennia.
Ocean sticklebacks are like salmon, migrating into freshwater streams and lakes to breed in the spring. With widespread melting of glaciers at the end of the last ice age, populations of migratory marine sticklebacks were able to colonize many newly formed lakes and streams in coastal regions throughout the Northern Hemisphere. Some of these bodies of water became isolated, and the newly established stickleback populations underwent dramatic evolutionary changes in response to local ecological conditions in the new postglacial environments. For example, marine fish are heavily armored with many bony spines and plates and have jaws and teeth appropriate for feeding on plankton. In contrast, many of the freshwater populations have less armor, lighter and more flexible bodies, and teeth and jaws that allow them to feed on shallow-water food sources like clams and snails. In fact, the skeletal and physiological changes seen in different stickleback populations are as large as those seen between different species. But because different stickleback populations have diversified only very recently, it is still possible for them to interbreed, and simple genetic crosses can be used to determine the molecular basis of the differences. Kingsley and co-workers therefore decided to examine the different sticklebacks and see what chromosome regions controlled the evolutionary changes.
This strategy was practical because they clearly couldn't run an experiment from scratch that would take 10,000 to 15,000 years to complete. For Kingsley, the strategy was also necessary philosophically. "The only way to address the genetic basis of real evolution is to study real populations," he says. "I'm often asked whether I think evolution works this way or that way. And my reaction is that I can imagine lots of ways that evolution might work. But let's go find some real, evolved animals and let them tell us how they got that way!"
Kingsley and postdoctoral fellow Catherine Peichel, now a faculty member at the Fred Hutchinson Cancer Research Center in Seattle, couldn't just order these study subjects from a supply house. Collecting sticklebacks would be a bit of a departure for scientists used to working in the lab. They tromped around the globe in boots and waders, carrying buckets of fish fetched from lakes in California, Washington State's Olympic Peninsula, Canada's British Columbia and Northwest Territories, Iceland, and the Outer Hebrides in Scotland. They also collaborated with Dolph Schulter at the University of British Columbia to analyze classic populations from the area around Vancouver.
Back in the lab the fish were put to work-making more fish. By analyzing the offspring of matings between members of the smooth and armored groups from various locations, Kingsley and his colleagues found out that old fish can learn new tricks in the wild. Well, a few new tricks, anyway: changes in a gene called Eda modified the armor plates along the sides of the fish, and changes in a gene called Pitx1 controlled the loss of pelvic spikes. Both Eda and Pitx1 happen to be major developmental regulators that play a key role in generating hair, teeth, pituitary glands, and hindlimbs in mice and humans-complete inactivation of these genes is detrimental in mammals. In sticklebacks, however, changes in these genes have presumably beneficial effects for fish that find themselves in a new environment. And different populations of sticklebacks that go through the same anatomical adaptations apparently achieve those adaptations through similar genetic tinkering. It's likely that the lithe variants are better able to make a living in their murky, weedy environs, while the armored fish do better at fending off predators in the open water.
A major change in anatomy that serves the fish's best interests while having no detrimental side effects is a nifty evolutionary move, and random variation and selection apparently kept figuring that out. "It's an exciting result because it suggests that there are general principles that are going to underlie the way traits evolve in wild populations," Kingsley notes. "It gives me great encouragement that by continuing to study these interesting natural experiments we'll be able to figure out fundamental things about how organisms actually evolved."
Kingsley's work in evolution and development has made him take a public stand against some real estate development that could lead to habitat destruction. Proposed construction near Fresno, California, could wipe out a local set of armored and unarmored sticklebacks in the San Joaquin River beneath the Friant Dam. "It's a situation symptomatic of a larger problem," Kingsley says. Indeed, loss of habitat is one of the biggest threats to the survival of untold numbers of species around the world. His support of efforts to stop development at the Friant Dam is a case of enlightened self-interest. "You have this experiment that nature has been performing for the last 10,000 years that could get wiped out by decisions made in the next six months," he says.
Concern for the big picture takes Kingsley away from his microscope and puts him behind a telescope-astronomy is the biologist's hobby. "A lot of our biology research is designed to try to understand where we come from," he explains, "and astronomy is the same question on a different scale. In the lab we study the origins of forms of life that you see on earth. When I'm staring into the sky with a telescope, I'm thinking about where the rest of it came from. Where did the earth come from, where did the solar system come from, where did our galaxy come from, where did other galaxies come from? Where did the universe come from? It's a great hobby for combining both visually stunning scenes that you can just enjoy aesthetically with a consideration of how the universe itself has evolved, on a very large and very ancient scale."
Kingsley's quest for origins may have its own origin in the death of his father. "My dad died when I was very young," Kingsley says. "He was only 34. And I grew up acutely aware that we might not have that much time here. So what are you going to spend your time doing? I can't imagine a better way to spend your time than having the privilege of getting to ask really fundamental and basic questions."
The distinction is important: getting answers is a pleasure, but asking questions is the privilege. "That's science," Kingsley says. "I have enough humility to realize the difference between the scale of the questions and the answers we're supplying. But I really feel, and I say this to students all the time, that it is a remarkable privilege to live when we do, in this wonderful little sliver of time where tools and methods are now available to ask and answer questions that people have wondered about forever. We right now can apply those methods and in our own lifetimes get answers that have been impenetrable up until now. And I think people will look back on this era 100 years from now and say that it must have been an incredible time to be doing biological research."
David Kingsley's research
Early stickleback research
Mouse and C. elegans as model organisms
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