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EXTRA CREDIT



Lessons
of a Lifetime

By Alan Friedman

IN PROMISING CLINICAL TRIALS, PITT GENETICIST JOHN BARRANGER REPLACES THE MUTATED GENES THAT CAUSE GAUCHER'S DISEASE WITH HEALTHY--AND REPLICABLE--COPIES.

A SWOLLEN GAUCHER, UNABLE TO DIGEST THE LIPID IT HAS ENGULFED

As teachers, human genes cover a vast body of material. They inspire incipient lungs to breathe, tap out a rhythm for a beating heart, and spark curiosity in the mind. Yet we rarely stop to marvel at how much our genes have been teaching the rest of our bodies--unless something goes wrong. Because of mutations, genes sometimes fail to convey critical instructions. Gaucher's disease is the result of one such oversight.

Gaucher's disease (pronounced go-shay) stems from a mutation that inhibits activity of the glucocerebrosidase (GC) enzyme. Without this enzyme, bone marrow doesn't generate macrophage cells capable of acting as the body's cleanup crew. Macrophages keep tabs on the buildup of a complex lipid by engulfing and digesting the cells in which the lipid is stored. When unchecked, the cells swell up, get sick, die, and end up walled off by fibrous tissue. Seas of these cell corpses, along with other debris and bacteria, result in the enlarged spleens and livers, eroded bones, anemia, and fatigue common to the disease.

Treating Gaucher's disease initially involved removing the swelled organs and struggling to compensate for their loss. But the advent of enzyme replacement therapy meant that Gaucher patients could receive infusions of the GC enzyme. By jump-starting macrophage capacity to degrade the stored lipid, the therapy gives the body a crash course in taking care of its own waste. But it's a lesson that needs to be repeated every two weeks--with a patient easily running up an annual tab of $50,000 to $75,000.

Although its effectiveness is limited, enzyme replacement therapy was a critical step for researchers. "It helped us in thinking about a longer lasting treatment," says John Barranger, professor of human genetics, molecular genetics, and biochemistry, who is testing the viability of a genetic "cure" in clinical trials.

Barranger took the first step along the path to a permanent cure by identifying and cloning the gene responsible for production of the GC enzyme. Then he had to find a way of insuring that his patients' bodies would accept it as one of their own and follow its orders. To that end, he resorted to the strategy made famous with vaccinations--defusing the virus by removing its genetic instructions for replication. Then, reminiscent of Isaac Asimov's Fantastic Voyage, he deposits the GC enzyme gene in the DNA space usually allotted for replication, dispatching this retroviral vehicle to stem cells, a specific class of white blood cells, via a test tube of the patient's own blood.

Once this sample is reinjected into the bloodstream, a moment of improvisation enters an otherwise strictly choreographed procedure. Success depends on the stem cells' ability to home in on bone marrow. Yet in spite of 20 years of feasibility studies that confirm that they can find their way to the bone marrow, Barranger shrugs when asked how. "They use homing signals that no one understands completely," he admits.

"If we can transduce the stem cells sufficiently well," he says, "it should be a cure." Once the stem cells have reached the bone marrow, they not only will generate blood cells carrying the gene responsible for GC enzyme production, but they'll renew themselves. Without their assistance, Barranger wouldn't be able to take out bone marrow-producing cells, correct them genetically, and return them to the patient.

Because his approach may one day be applied to a host of genetically inherited enzymatic diseases, researchers around the world are charting how well patients retain this lesson in self-sufficiency. Patients and doctors alike hope that Barranger's brief instruction, in a classroom over which genes usually preside, will help the body to feel as if its education is finally complete.






Old School
Days

By Vicki Glembocki


LONG BEFORE GOODNIGHT MOON, BEFORE

CURIOUS GEORGE, BEFORE DICK AND JANE,

THERE WERE CHILDREN'S BOOKS THAT TAUGHT

VERY DIFFERENT LESSONS. PITT'S COLLECTION OF

OVER 20,000 SCHOOLBOOKS, SOME CENTURIES OLD,

HAVE OFFERED ENGLISH PROFESSOR JEAN CARR

INSIGHT INTO THE HISTORY OF EDUCATION--AND

ALSO, OF LIFE.


"What a very beautiful rainbow. Taku wihmunke owanyag waste liinca." --From an 1870 reader used by missionaries working among the Dakota Indians.

On the yellowed, brittle page of a worn book spread open on a desk in Hillman's Special Collections room, there is a drawing of a man being burned at the stake in front of his wife and nine children. The poem beneath it reads:

Give ear my children to my words
whom God hath dearly bought.
Lay up his laws within your heart,
and print them in your thoughts.
I leave you here a little book for
you to look upon,
that you may see your father's
face when he is dead and gone.

The book is not a holy scripture or a medieval text of witches' spells. This image of punishment and death is found in a seventeenth-century primer--a child's schoolbook.

"What is the message here?" asks English professor Jean Carr as she looks down at the illustrated story of John Rogers, a Protestant martyr, whose tale was a standard one taught in the New England primers of the late 1600s. "Is it to be read, 'Hold fast to your beliefs and get burned at the stake' or 'Hold fast to your beliefs, get burned at the stake, and be as famous as a person who did that?' It's very interesting to try to figure out exactly what was being instructed."

By "instructed," Carr does not simply mean educationally, at least not in terms of reading, writing, and arithmetic. Carr's research on early American schoolbooks focuses also on what these fragile, disintegrating texts have to say about life and culture--how these books reflect a lifestyle just as the Dick and Jane books did in the 1950s.

But the messages in these early primers, some intended for five- and six-year-olds, are often far more extreme than "boy runs, girl reads." A list of vocabulary words in a pocket-sized 1690s New England primer reads: "benediction; education; fornication." "It's a Latinate word," says Carr. "It fits the pattern. There was no sense then that you needed to censor some of adult education, life, or language for children."

On the contrary, two, three, four hundred years ago, children were very much a part of what would today be considered adult life. Family members died at home. The bodies were laid out at home. Even children died in enormous numbers. Things were not viewed as simply as "A is for Apple, B is for Boy, C is for Cat." It wasn't unusual for seven or eight of the 26 letters defined in an alphabet book to discuss death:

G: As runs the glass, our life doth pass.
T: Time cuts down all, both great and small.
Y: While youth do cheer, death may be near.

"Children's books today don't deal with extremes," explains Carr. "They don't deal with hate or love. They don't deal with passion or grief or poverty or anxiety. They deal with things like friendship. They erase conflict. They smooth things out. We seem to think that small children should be sheltered from almost everything difficult--intellectually, morally, emotionally. So we have these very narrow educational books about idealized 1950s families, and we're giving them to children who are dealing with violence and death and families splitting up."

The attitude in early American schoolbooks is quite the opposite, says Carr. At that time, educators believed that students needed to learn certain things about moral behavior and public action in order to become good citizens. The McGuffey readers, first published in the 1830s, focused on how to speak properly. (Don't say "regaler, calcalation, gimme some bread.") Many mid-nineteenth-century books explain how to get out of debt. Late- nineteenth-century materials discuss racial prejudice.

The issues are quite familiar. And, in that sense, it doesn't come as much of a surprise that facsimiles of the old eighteenth- and nineteenth-century schoolbooks are still being used today. Nearly 80,000 copies a year are sold for home schooling. Carr, too, uses them in her American Literature classes, asking her students to compare the primers they read while growing up with those from previous centuries.

"My students were taught nice, cleaned-up civics lessons about America as a great melting pot, for example, welcoming all of its immigrants," Carr says. "The nineteenth-century primers, in contrast, are very frank about racial prejudice and stereotyping. My students are staggered to discover that the language of past prejudice wasn't as inflated as they believed it was." The books, then, become a forum for discussions of current issues, like race and gender. "In the context of these earlier books, the students can talk freely, without feeling defensive or threatened, without being so watchful of their words."




A potto's skull and tail (top and right) as compared to a pseudopotto's (bottom and left)



A Family
Affair

By Alan Friedman

A LONG-LOST COUSIN REMINDS PITT ANTHROPOLOGIST JEFFREY SCHWARTZ THAT THERE ARE A FEW SIDES TO EVERY FAMILY STORY.




Six billion humans are walking, if not crowding, the earth--but as a species we couldn't be lonelier. Gray squirrels keep red squirrels company, horses share the space of their genus with zebras, but in gorillas, gibbons, and chimpanzees, Homo sapiens doesn't find family even in the taxonomic sense of the word. Ever since each of the Neanderthal species died off, we've seen the world from a unique, but not necessarily enviable, vantage. There's no longer a community of linked lineages to which our species can feel it belongs. The human being has become an only child--an orphan by evolution.

While anthropologist Jeffrey Schwartz's discovery of a new genus and species of primate doesn't lessen our categorical isolation, it does allow us to enjoy a renewed wonder at the rich diversity of our order. And who knows what such lost chapters may one day reveal?

Had he been searching in isolated reaches of the ocean floor, the discovery of a new genus wouldn't have been so noteworthy. But identifying a new primate, this far along in the twentieth century, is extremely unusual. Schwartz had been at the Zurich Anthropological Museum studying its collection of the primitive African primates known as pottos. While examining boxes containing the skeletons of specimens, he chanced upon the remains of a kitten-sized animal that, in better days, had slept through the hot hours and took to the treetops by night in its native Cameroon. Many anthropologists have studied the species, both in display cases and in the wild, but Schwartz was the first to call this specimen into question. "Although I couldn't be sure of what it was," he says, "what it was was no potto."

Schwartz credits this flash of insight to a career-long interest in prosimians--the family that includes pottos, lemurs, bush babies, and other small scurrying distant relatives of humans. Two decades' worth of comparative observation have developed in him a sensitive eye for detail. If he hadn't scrutinized so many teeth and bones and examined specimens for the subtleties that make every being unique, he, too, may have mistaken what he saw for a potto. "But pottos have very short tails; this one had a longer tail. Pottos have big spines sticking out of the neck vertebrae; this thing didn't. This creature's teeth didn't have any of the salient features of potto teeth. Also, it was the smallest size of anything that's been called a potto," he points out, "but it was collected in an area that's home to the world's largest pottos." Schwartz has named the new genus Pseudopotto martini after the University of Zurich's Robert D. Martin, a pioneer in the study of primitive primates.

Schwartz expects this reevaluation to be met with some resistance from colleagues who've invested years in drawing conclusions that depend on the animal's potto-ness. But evolutionary theorists, if anyone, should be able to accept change. Two-dimensional, right-wrong thinking only does an injustice to science, he believes. This assertion stems from his days as a graduate student in New York, where he studied with people at the forefront of the field's most celebrated debates, such as whether evolution occurs at a constant rate or is punctuated by short-lived periods of accelerated change. He recalls, "I couldn't have been more fortunate than being exposed to such controversial characters." These mentors instilled in him a deep-seated respect for the way that great ideas often contentiously evolve.

It's unclear if the discovery of this new genus and species can clear away much of the brush that hides the switchback trails of human evolution from view. Schwartz hasn't tracked down the anthropological equivalent to immigration logs. Many questions remain concerning how, as a species, we came to be. What sort of fate was met by the less fortunate descendants of our ancestors? What made some members of the family unfit for this journey?

Pseudopotto martini's message is not so much a definite answer as it is a warning: Our understanding of the species we like to think we know best--ourselves--is anything but static. "A lot of people think they know evolution, but I think that by and large we don't. Whether the argument is about the discovery of this pseudopotto or finding a whole new array of fossils, we don't know enough to be as adamant as these debates would have us believe," says Schwartz.

After all, the pseudopotto and scattered fossils are only mere specks of all that evolution has engineered. Whether retracing our steps or meeting a relative we've never known, he adds, "these discoveries should serve to warn us that we are reconstructing something that we'll never fully know."


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