Washington People: Joseph Jez

Biologist unlocks proteins with a crystal key

Joseph Jez, PhD (right), associate professor of biology, and doctoral candidate Soon Goo Lee in the cold room checking a tray to see whether a protein has crystallized in any of its wells. Jez’s lab crystallizes proteins in order to figure out how these little biological machines work. (Credit: Joe Angeles)
When Soon Goo Lee, a graduate student in the Jez Lab at Washington University in St. Louis, clicked the mouse button that would reveal whether he had successfully cracked the structure of a new protein, his advisor Joseph Jez, PhD, whipped out his cell phone to record the moment.
Jez, associate professor of biology in Arts & Sciences, wanted a record because he knew how much it meant to Lee.

Jez knew every disappointment and setback Lee had weathered over the past six years: the proteins that wouldn’t crystalize; the proteins that crystallized into ill-formed “blobules”; and the proteins that grew into nice, big crystals but produced “sick” diffraction patterns that couldn’t be “solved” in any reasonable amount of time.

He also knew what it meant because he’d been there himself, standing there with his finger on the mouse button, taking a deep breath as he faced the moment of truth.
“What my lab does is crystallize proteins so that we can see what they look like in three dimensions,” Jez says. “The idea is that if we know the protein’s structure, it will be easier to design chemicals that will target the protein’s active site and shut it down.”
Recently, his lab crystallized a protein crucial to the protozoan that causes the most lethal form of malaria. Now that the protein’s structure is known, it might be possible to design a drug that would block it and prevent the disease without harming patients.
His lab also is looking at related proteins in parasitic nematodes, roundworms that cause huge losses both to crops and to livestock.

Nematicidal drugs are notoriously toxic because the parasites and their hosts share most of their biochemistry, so what kills one sickens the other. But the Jez lab might also have found targets for safer and more effective nematicidal drugs.

Not for the faint of heart
“Protein crystallography is a risky choice for a PhD project,” Lee says. “Unlike other types of experiments, it does not generate useful partial results. It’s an all-or-nothing game.“
So one of Jez’s main jobs is to be the lab’s unreasonable optimist, the one who tells the students it will be OK if a yeast gets into the lab and eats the protein in the crystallizing droplets; it will be OK if you accidentally break a $70,000 piece of analytical equipment; it will be OK if it takes another year to get a good diffraction pattern.
“It is easy to get depressed if you have a failed experiment,” Lee says. “But Dr. Jez never closes his office door. Whenever we want to talk to him, we just walk into his office. And he doesn’t criticize our mistakes. He always says ‘It’s a good learning experience!’

“As a mentor to several undergraduates, I’ve learned how hard it is to play that encouraging role.”

Practicing taking calculated risks
A climber though he fears heights, Jez climbed his way through graduate school and a postdoctoral fellowship, tackling everything from Livezey Rock to Joshua Tree. He still has the gear, he says, but these days he doesn’t have the time.
Jez cultivated optimism by climbing rocks, even though he is afraid of heights.

He started slow, climbing the side of the engineering building at Penn State University, his undergraduate alma mater, between classes.

“No one ever tried to stop climbing students,” he says. “We only went up a little bit, maybe 15 or 16 feet, and then we’d climb sideways.”
He kept at it, climbing higher and more often. He climbed his way through graduate school and a postdoctoral fellowship, often climbing three or four nights during a week and at least once on the weekend.
It’s embarrassing to explain how he gets a protein to crystallize, Jez says, because it’s more of an art than a science. Nobody really knows how to make it happen in any methodical or sensible way.
“You’re trying to coax this thing, which is big and flippy-floppy and kinda has a lot of movement,” Jez says, into becoming a crystal — a regular array of atoms.

“And you don’t really know how to do that — there’s no science to it. You start shotgunning random conditions and hope you find something that works,” he says.

Sometimes he is shotgunning several thousand different sets of growing conditions. Anxious graduate students check crystal growing trays once a day (for the first month or so, and then once a week for about 6 months) for crystals forming in droplets of protein hanging from cover slips over wells in the trays.
They need crystals — preferably nice, big ones — to stick in path of an X-ray beam at Argonne National Laboratory in Chicago.
If the crystal is a good one, and all the atoms are lined up properly, the X-rays will produce an unimpressive scattering of black spots.
The moment of truth
Embedded in that pattern, however, is the mathematical information needed to back-calculate to the position of the atoms.

A computer does the calculation, and then comes the moment of truth when a mouse click reveals whether the crystal is going to come up three cherries on the payline.

But once the mouse is clicked and a clean electron density map comes up, Jez says, “it’s like suddenly the wind has kicked up and you’re sailing free, because when you clicked that button you became the first person to ever see what that protein looks like in three dimensions.”
Lee says more simply that when he clicked the mouse: “I saw the light at the end of a five-year-long tunnel.”
A target for malaria
Lee’s payoff was an exceptionally clean electron density map for an enzyme from Plasmodium falciparum, the protozoan that causes the most lethal form of malaria.
It turns out that Plasmodium uses the enzyme to make its cell membrane.

“If you knock out this enzyme,” Jez says, “the organism can’t make more membrane, so it can’t replicate itself, and it dies.”

Malaria is notoriously hard to treat because protozoans — little animalcules with nuclei — are much closer to humans in evolutionary time than are bacteria. They share our basic metabolism, and all anti-malarial drugs that are hard on them are hard on us as well.
The enzyme that Lee crystallized — or its kissing cousin — is made by plants, by nematodes (roundworms), including both free-living and parasitic nematodes, and by Plasmodium — but not by people.
And that means, now that its structure is known, it may be possible to design a drug that would block the enzyme, kill Plasmodium, cure malaria and not be toxic to humans.
So the day Soon Goo Lee clicked the mouse button was a good day for the Jez lab.

Fast facts about Joseph Jez

Entered college intending to: Major in English and become a journalist
Bachelor’s degree: Biochemistry with an English minor from Penn State University
Doctoral degree: Biochemistry and molecular biophysics from the University of Pennsylvania
Postdoctoral work: Doing structural biology at the Salk Institute for Biological Studies in La Jolla, Calif.
Something he hasn’t mastered: Growing rock candy out of sugar water
What Jez means: “hedgehog” in Polish