LEAD STORY
How to Make a Monkey

BY PHILIP DAWDY
pdawdy@wweek.com


photos by Martin Thiel



Related sites about cloning, bioethics and primates.

Playing with cells takes really good equipment. Gerald Schatten's microscope is decked out with tiny hydraulics that allow him to make micron-size movements with monkey eggs.

 

The complete title of Gerald Schatten's paper was "Clonal Propagation of Primate Offspring by Embryo Splitting." In it, he did not mention that embryo splitting had ever been applied to other species.

 

Paper Chase: On Jan. 14 The Oregonian splashed the "cloning" of Tetra across its front page, calling it a "scientific first." The New York Times viewed Tetra differently. Its page A13 story said Schatten "did not achieve nearly the success that was reached with other animals."

 

At $1.7 million a year, Schatten's laboratory is securely funded through 2004; at $156,000 a year, he's one of OHSU's highest-paid researchers.

 

Schatten's laboratory is working on as many as 20 projects. Schatten and OHSU officials did not provide WW with a copy of his laboratory's grant proposal to the NIH.

 

Sources say Schatten is on the verge of packing up his laboratory and moving to the University of Pittsburgh. Schatten denies that he's leaving.

 

 

"It's going to prove difficult to routinely produce sets of twins, triplets or quadruplets by Gerry's technique," says OHSU embryologist Don Wolf.

 


Gerald Schatten prefers to keep his lips sealed and his experiments close to his vest.

 

 

 

In 1993, researchers at George Washington University in Washington, D.C., successfully split a human embryo. The ensuing political firestorm forced them to destroy the resulting embryos.

 

Embryo splitting was first performed in sea urchins by Theodore Dreisch in Germany in the 1880s. Realizing the implications of his work, Dreisch became a metaphysicist.

 

Asked about its lavish coverage of Tetra, The Oregonian's health, medicine and science editor, Renee Mitchell, declined to comment and said she'd have a managing editor return WW's call. No one ever did.

 

The top five research institutions, measured by NIH funding, are Johns Hopkins University, the University of Pennsylvania, the University of Washington, UC-San Francisco and Washington University (St. Louis, Mo.).

 

In the research world, the rhesus monkey is at the top of the food chain. Other common research models include brewer's yeast (containing 30 percent of human DNA), the fruit fly (60 percent), the roundworm (60 percent) and the mouse (90 percent).

  On Jan. 13, the eyes of the biological world focused on, of all places, Hillsboro. Gerald Schatten, a 50-year-old biologist at the Oregon Regional Primate Research Center, had created a rhesus monkey after splitting an embryo into four parts.

Tetra had actually been born back in September. But it was the publication that January day of Schatten's article in Science describing Tetra's creation that launched a global feeding frenzy.

Schatten hopped into his car that morning, drove off the primate center's campus through pines and Douglas firs, turned left into the suburbscape separating Hillsboro from Beaverton and headed for the destiny that awaits all rock-star scientists--a day in the media's glare.

When he arrived at Oregon Health Sciences University (which administers the primate center), high in the Southwest Portland hills, The New York Times and the Associated Press were on the phone. CNN was there with a satellite truck and camera; the network would devote hours of coverage to Tetra. That evening, Tetra would be on CBS, NBC and ABC, as well as The News Hour with Jim Lehrer. She was in the Philadelphia Inquirer and the New York Post. "Scientists have created the first monkey clone, a breakthrough that is likely to stir the debate over the ethical implications of genetic duplication," proclaimed Rupert Murdoch's tabloid.

Tetra was on BBC Radio and NPR. In the days to come, she made her way into the pages of Der Spiegel and Paris Match, as well as Le Monde, L'Observatore della Romana, the Daily Mirror and Brazil's GLOBO-TV.

Of all the ink devoted to the young simian, none would be more lavish than that of The Oregonian. The next morning, a looming front-page photo of Tetra under the headline "OHSU Researchers Clone Monkey" sprang from newsstands and front porches across the region.

Like most media, Oregon's paper of record hyped the event far beyond its context.

What was painted as cloning was something quite different. It was simply embryo splitting, something nature itself does to create identical twins. It's a process wholly different from clone-making and much less of a scientific achievement.

Still, the fawning over Tetra highlights the public's awe of scientists, its collective fascination and ignorance when it comes to biology and the intense footrace among biologists to map out new territory, any new territory, first.

Gregory Stock, director of UCLA's Program on Medicine, Society and Technology and a leading expert on the changes science enforces upon mankind, says this about the birth of Tetra: "It's not such a big deal."

Gary Anderson, chairman of UC-Davis' Animal Sciences Department, put it this way: "It's old news."

Barry Bavister, a University of Wisconsin professor of biomedical science and a leading conservation biologist, is even more acute: "The experiment was not successful."

To understand why these scientists, and others contacted by WW, have such a different view of Schatten's work than what the media portrayed, consider Dolly.

Born in Scotland in 1997, Dolly is a clone, the first mammal that was a perfect replicant of another. When her birth was announced, the world practically went into fits: If you could clone a sheep, you could clone a human. Politicians promised that they would defend the holy union of sperm and egg that has, so far, brought each human into existence.

Standing in the Rose Garden that day, President Clinton said, "Any discovery that touches upon human creation is not simply a matter of scientific inquiry. It is a matter of morality and spirituality as well. Each human life is unique, born of a miracle that reaches beyond laboratory science."

To make a cloned miracle in a laboratory, you need a donor cell--one from a 6-year-old sheep, say. Then take an unfertilized sheep egg. Strip it of its DNA. Place the cell in the egg. Give them a jolt of electricity. The donor cell and the egg are as one, a created cell. DNA-packed nucleus, cytoplasm, mitochondria: the works. Then you implant the cell into a female sheep's uterus. Let cell division run its course. Wait six months and a fully formed creature is born, one with the same DNA as its donor.

The opportunity and the threat of cloning is that, in theory, you can create an infinite number of clones. The advantage is that the more genetically identical animals you have to experiment upon, the more accurate the experiment. The downside is the fear that cloning would allow you to create entire colonies of humans who were somehow darkly other.

Schatten did not peer into the dark realm of cloning, despite articles suggesting that he did.

Last May, in a laboratory kept as hot as a womb, Schatten took a monkey egg and monkey sperm and mated them in a petri dish--the same way it's done with human eggs and sperm at in-vitro fertilization clinics the world over.

For three days the embryo grew cell by cell. Each morning Schatten put the petri dish under a 100x microscope and screwed it into focus. He counted the cells. Each cell is an exact genetic duplicate of the others; each cell is rhesus life and rhesus being. When the embryo reached the eight-cell stage, he dribbled an enzyme into the petri dish. The enzyme loosened the chemical bond holding the cells together and they floated apart, as though he'd scattered eight drops of olive oil on a puddle. Each cell was suctioned up a hollow pipette, a scientific straw. Then, two-by-two, Schatten squirted them into four DNA-less monkey egg shells.

He had tweaked one embryo into four embryos, each the genetic equal of the others. Each was implanted in a female rhesus.

Never before had any scientist created identical monkeys. Schatten wanted to show the world it could be done. His intent was quadruplets, but twins would be scientific proof aplenty.

Two of the pregnancies did not take; a third did, but the embryo died in placenta. The fourth pregnancy, however, was the charm. On Sept. 7, Tetra was born--moon-faced, chestnut-eyed and sticky.

But her birth was no revolution. Embryo splitting is old hat. Steen Willadsen, a Florida biologist, perfected it in sheep in 1978. Since then, it's been applied to cattle and mice, and George Washington University researchers briefly experimented with the technique using human embryos in 1993.

Schatten's accomplishment: He did it with a rhesus monkey.

One-sixth an average human's size, a rhesus monkey contains as much as 98 percent of a human being's DNA. Because biologically it shares so much with humans, rhesus monkeys are far more valuable to researchers investigating complex human diseases--AIDS and Alzheimer's, for example--than are biologically simpler mice.

To many scientists, the difference between splitting embryos and cloning is like the difference between shagging fly balls at Civic Stadium and making a shoestring catch at Yankee Stadium.

Embryo splitting, which still involves the first step of uniting sperm and egg, has its limits: You can only create a few animals at a crack. For moral traditionalists, the technique has the appeal that you continue to work with the genetic givens of the parents while retaining the seemingly magical unknown of which parent's genes will predominate in the offspring.

But cloning is the complete bypassing of natural reproductive methods. In theory, you could scrape a cell from Slobodan Milosevic and create his genetic identical, or thousands of them (whether the offspring would commit genocide 50 years later is another question).

There are technical problems with cloning: A newborn's cells are as old as its donor, which would skew experiments; and having DNA from one parent--instead of the usual male-female mixture--has led to problems with cell division.

Still, most scientists believe that these problems will be ironed out and that cloning is the significant advance. So the scientific community's reaction was predictable when Schatten's Science paper--which used the term "clonal" in its title--hit the streets Jan. 13.

"Using 'clone' in the title of the paper was stretching the word 'clone,'" says Ralph D. Schramm, a staff scientist at the Wisconsin Regional Primate Research Center.

"This would not have been published in Science if it didn't involve primates," says Anderson of UC-Davis. "It doesn't surprise me that it works in primates. We've seen similar types of procedures in livestock for 15 years. It's commercially available."

Other scientists say that Schatten's work is less than ground-breaking not merely because it involves embryo splitting but because he failed to create genetically identical twins, much less quadruplets.

"Schatten set out to produce identical offspring," says Bavister of the University of Wisconsin. "Only one was born; it's as simple as that."

"Tetra wasn't related to anything except a dead placenta," says Schramm.

The New York Times' Gina Kolata was perhaps the only journalist not seduced by the hype surrounding Tetra. While other newspapers gave Schatten's work front-page play, Kolata wrote a remarkably brief account of Tetra's birth that landed on page 13 of the Times' front section.

Contacted by WW, Kolata declined to criticize other reporters but made it clear she felt that Schatten's "breakthrough" had been treated like a revolution when it was little more than pamphleteering.

If Schatten's work didn't rate with scientists, why did Science--one of the world's preeminent scientific journals--publish his paper?

"We felt it represented a sufficient first step forward in an area with a lot of potential," says Barbara Jasny, a senior editor with the journal. She says embryo splitting in primates is a novel enough concept that it was important for the magazine to get the news to the scientific community and that the paper's peer reviewers--whom she declined to name--did not think the experiment unsuccessful.

"We don't publish papers to see them mentioned in The New York Times," she says. Jasny says it's more important that, when researchers put up slides of work at scientific conferences, other researchers see that the work was first published in Science, thereby further seeding the journal's prestige in the minds of one and all.

Schatten himself isn't responding to his critics. He agreed to two short interviews with WW; in both instances, he would only speak of his work in the vaguest of scientific terms, then depart before critical issues could be raised. After that, Schatten would only consent to e-mail interviews while on a two-week Hawaiian vacation.

But Lesley Hallick, OHSU's provost and vice-president of academic affairs, says Schatten's critics have a limited point.

Based on "pure molecular mechanics," she says, Schatten's experiment "doesn't look like a dramatic breakthrough. But if you look at it as a contribution to species modeling, it is amazing." By species modeling, Hallick means rhesus monkeys' ability to act as biological proxies for humankind.

Many scientists are scratching their heads, trying to square Tetra with her creator's claims. Schatten, they say, has not proven that genetically identical rhesus monkeys can be created, just that it's highly probable. A single live birth only proves that Schatten can create a single monkey.

"Quadruplets are a long time coming," says Schramm, who is splitting rhesus embryos at Wisconsin's primate center but is holding back from implanting them in females. "We're trying to get the technique right."

Public criticism in the big-ego world of research science is nothing new. But the barbs thrown at Schatten are especially pointed.

The reason may be that Schatten has a reputation as one of the less collegial members of his profession.

Typically, scientists share research data, seek advice from others who have similar expertise when they hit roadblocks and ask them to review their papers before they submit them for publication. It's all part of pure science's informal quality-control system.

Out at the primate center, Don Wolf--an OHSU embryologist of world renown--would be the natural person for Schatten to share his paper with.

Did Schatten show Wolf his Tetra paper?

"No," says Wolf, "I didn't review the paper." Wolf won't go into the complexities of his relationship with Schatten, but he admits that they are "competitors." He says he's not happy with the reality of fellow researchers competing with one another.

"I just kind of rebel against this," Wolf says.

Schramm, the Wisconsin primatologist, says "Schatten's lab doors are locked" to other researchers. He says he had no idea that Schatten was splitting monkey embryos until the Science paper was published, despite the fact that he's a well-regarded researcher in the small universe of primate embryologists.

"His attitude is very sad to see," says another scientist familiar with Schatten. "He's doing commendable work, but it's not revolutionary. So what is this paranoia about?"

OHSU's stake in all of this is more than mere prestige; it's dollars and cents. The $18.8 billion National Institutes of Health funds research at 2,400 institutions around the country. The dollars aren't doled out willy-nilly, either; they are based upon peer review, a jury of scientific peers. In major-league baseball, peer review would exist if the all-star team were chosen by players instead of fans.

The more peer-reviewed articles a researcher like Schatten publishes in journals like Science and Nature, the easier it is for him to nail down peer-reviewed grants.

Publication breeds dollars.

For OHSU, the more its 550 principal investigators, as laboratory leaders such as Schatten are known, get their work in high-quality journals, the easier it is for the institution to compete for research money and swipe researchers from other universities. Everyone in science looks to the grand pecking order of where people publish their work and where they stand on the NIH's list.

How high an institution is on that list says how well it rates with its scientific peers: New York Yankees or Minnesota Twins?

In the last 10 years, the Pill Hill complex has leapt from No. 70 to No. 34 on the NIH list; it currently takes in $106 million a year.

OHSU's Hallick isn't shy about saying that the institution wants to be No. 20, and having its researchers broadly covered in the popular media works into its plans.

"We want our researchers to publish in quality journals because it speaks to the quality of the research," says Hallick. And Schatten's paper? "It's another mark for OHSU."

It's not that outlandish, on one level, that Schatten's work was blown out of proportion: The social implications of biological research have forced the general public to pay attention in ways they wouldn't have only a generation ago.

It was in 1974 that recombinant DNA was discovered, after all. Ever since, biologists have displaced physicists as the rock stars of the scientific world. Sometime early this century those old dormitory posters of Albert Einstein will come down. In their place will go those of a molecular biologist--as soon as the discipline finds its philosopher-king--for, sometime in the next 25 years, biology will make good on its promise to crush the diseases that have afflicted mankind for aeons.

But there's something creepy in this dynamic as well: These days, even small advances like Schatten's are read as harbingers of a brave new world. People are so attuned to cloning as a fait accompli that they seize upon each whisper of cloning with the intensity that the music press seizes upon even a semi-passable British pop band as greater than the Beatles.

Biologists seem to have a pipeline to the Infinite, if even for an ephemeral moment.

Each day, spectacular claims for disease cures swamp the public's imagination. With the tacit collusion of scientists and scientific journals that know better, the media, like circus monkeys, oblige with breakthrough hype.

And so when Gerald Schatten and Science trumpeted the birth of a monkey that January day, the world media assumed that something deeply profound had to be afoot in Hillsboro and that it had the deepest implications for humankind.

Then the world moved on.

"Justices look at Scouts, abortion," was the headline on the next day's Oregonian.


The first three sites are good for general background information; after that, itıs science geek territory.

UCLAıs Gregory Stockıs excellent site with information on cloning and germline engineering:
http://research.mednet.ucla.edu/pmts/Stock.htm

The University of Pennsylvaniaıs useful bioethics web site: http://www.med.upenn.edu/~bioethic/index.shtml

A debate on whether cloning should be banned: http://hotwired.lycos.com/synapse/braintennis/97/37/index0a.html

A site full of cloning news, thatıs either thoroughly scary or encouraging depending on who you are:
http://www.globalchange.com/clone_index.htm

Links to the USıs regional primate research centers: http://www.crprc.ucdavis.edu/rprcp/CenterLinks.html

The Human Genome Project:
http://www.nhgri.nih.gov/

A nice primer on model organisms and species modeling, with good links. The site includes no information on using monkeys as model organisms, a measure of how infrequently they are used. http://genome.cbs.dtu.dk/gorm/modelorganisms.html



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Willamette Week | originally published February 16, 2000

 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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