David Roos runs the lab from an office lodged at its center. He’s a young man with a curly mat of black hair and a chipped front tooth. He speaks coolly, comfortingly, his answers rolling out in paragraphs and pages with references ahead and back from the subject at hand, with hardly a pause for collecting thoughts. On the sunny day I visited, he was explaining to me how he came to study the parasite that he carries by the thousands in his own brain: Toxoplasma gondii. Overhead are charcoal drawings of human figures, a reminder of Roos’s days as an art student in college. That came after a stint after high school as a computer programmer—“I thought I wouldn’t go to college, since I was having so much fun and making so much money as a programmer, but that got old fairly quickly”—and before Roos took up biology. When he began studying biology, he contemplated working on parasites. “There’s no more interesting question biologically than how does one organism survive off of another, especially inside another cell? But as a graduate student I looked around and talked to a couple of labs, and the systems just seemed so archaic.”
By this, Roos meant that parasitologists had a harder time with husbandry than other biologists. A lot of scientists who study how animals develop from fertilized eggs, for example, study the fruit fly. If they find an interesting mutation in a fly, they know how to breed a line of them that all carry the same mutation; they have the tools to isolate the mutated gene, to shut that gene down or replace it with a different version. With these tools, biologists can map out the web of interactions that turn a single cell into a noble insect. But parasitologists struggle just to keep parasites alive in a lab, and breeding interesting strains is often impossible. Fruit fly biologists have a giant toolbox at their disposal. Parasitologists have been stuck with a broken hammer and a toothless saw.
The frustration didn’t appeal to Roos, so he went off to work in graduate school on viruses, and later on mammalian cells. His work paid off well, landing him a job at Penn, but by then he wanted something new to study. He learned that in the years he had stayed away from parasites, other researchers had had some early success in using them like fruit flies. One parasite looked particularly promising: Toxoplasma. It might not have the cachet of its close relative Plasmodium—the parasite that causes malaria, a sophisticated creature that can turn a barren red blood cell into a home in a matter of hours—but it seemed to take well to life in the lab. Perhaps it could act as a model for malaria, since many of their proteins worked in similar ways. “I thought, maybe very naively, that one of the reasons people had not worked on Toxoplasma in the past was that it was rather boring,” Roos said. “Like anybody else, biologists like to work on sexy topics. But maybe if this organism is so boring—meaning more or less like things we’re more familiar with—it wouldn’t require completely reinventing the wheel to develop genetic tools.”
Roos started building the tools, and he found success unnervingly simple. “Some people think we have golden hands in my lab, but in truth we work on an easy organism,” he says. His lab learned how to riddle the parasite with mutations, how to switch one gene with a new one, how to see the parasite more clearly than before. Within a few years they were able to start using their tools to ask questions, such as exactly how Toxoplasma invades cells, or why some drugs kill Toxoplasma and Plasmodium, while the parasites manage to resist others.
In 1993, Roos began studying a drug that kills both parasites, called clindamycin. It’s not used to cure malaria, though, because it takes too long to kill Plasmodium; instead, it’s chiefly used against Toxoplasma in AIDS victims who need a drug they can take for years without side effects. “The funny thing about clindamycin,” Roos says, “is that it shouldn’t work.”
Clindamycin is actually used mostly as an antibiotic to kill bacteria, which it does by clogging up the bacteria’s protein-building structures, known as ribosomes. “Eukaryote cells have quite different ribosomes, and clindamycin doesn’t interfere with them, which is good, because otherwise it would kill you. That’s what makes it a good drug. Now Toxoplasma, these guys aren’t bacteria. They have a nucleus, they have mitchondria.” (Mitochondria are compartments where eukaryote cells generate their energy.) “They’re clearly more closely related to you and me than to bacteria.”
And yet, clindamycin kills Toxoplasma, and Plasmodium as well. How it killed them no one knew. Scientists knew that they didn’t affect the regular ribosomes in the parasites. But eukaryotes also carry a few extra ribosomes in their mitochondria that are different from the rest. Mitochondria carry their own DNA, which they use to build their own ribosomes, among other things. Yet, researchers found that clindamycin left the ribosomes of mitochondria unharmed as well.
Roos rememberd that Toxoplasma actually had a third set of DNA. In the 1970s, scientists had discovered a circle of genes that didn’t belong to its nucleus or its mitochondria. This orphan DNA contained the recipe for a third ribosome. Perhaps, Roos thought, clindamycin attacked the third ribosome and killed the parasites in the process. He and his students destroyed the circle of DNA and discovered that indeed Toxoplasma couldn’t survive without it.
But what exactly was this ring of genes? Roos and his students discovered that it sat inside a structure floating close by the parasite’s nucleus. In the past, scientists had given the structure many names—the Spherical Body, the Golgi Adjunct, the Multi-membraned Body—all of which may make you think they knew what it was for. They didn’t.
Roos now knew it was for housing the genes that make Toxoplasma vulnerable to clindamycin. But he didn’t know yet what the ribosome that the genes made was for. To get some insight, he compared the genes to other genes in Toxoplasma and other microbes. The closest match he found was not among the genes inside Toxoplasma’s nucleus or mitochondria. It was the chloroplasts in plants, those solar-powered factories that make the plants on the laboratory shelves grow. “They look for all the world like a green plant,” says Roos.
Roos had hoped to figure out how Toxoplasma and Plasmodium die like bacteria, even though they live like us. Now he had simply traded one puzzle for another: How can malaria be a cousin to ivy?
To nineteenth-century biologists such as Lankester, parasites got to be the way they are now by degeneration. Their evolutions were tales of loss, of the abandonment of all the adaptations that made an energetic, free-living existence possible, of settling for a spoon-fed dinner. In this century, that notion of degeneration has hung on; for decades, evolutionary biologists simply thought that the story of parasite evolution was not worth thinking about compared with sagas like the origin of flight or the enfolding of the brain. Yet, the ability of Trichinella to make its host build itself a nursery in its muscles, of Sacculina to make a male crab into its mother, of blood flukes to become blood-invisible—all of these are adapations produced by evolution. Many parasitologists don’t have evolution as their main business; they study parasites as they live today. And yet, evolution elbows its way into their work.