THE LAND-GRANT LEGISLATION that gave life to Massachusetts
Agricultural College in 1863 was based partly on the belief that
modern science could assist farmers and benefit humanity. That
belief still drives some advanced research at UMass today, but
the science has changed and so has the "pharmer."
Pharming the use of domestic animals to produce pharmaceutical products such as proteins, antibodies, and tissue for use in humans may well be a new agriculture for the future, and it's now under James Robl's microscope in Paige Laboratory. An associate professor in the veterinary and animal science department, Robl opened a small door to that future in January 1998, when he and his partners at Advanced Cell Research announced the birth of the world's first transgenic cloned calves.
UMass has a history of producing famous cows. Seventy-five years ago a Mass Aggie Holstein named Countess Chloe set national production records for milk and butterfat (29,803 lbs. and 1,022 lbs. respectively,) in a year-long test. George, Charlie, and Albert, residents of the South Deerfield farm, plus Texas brothers Joseph, Ulysses, and Theo, are in the spotlight today as products of a new technology that could drastically change the food and drug industries. Although, as males, our famous clones don't produce milk, Robl and ACT, under contract to Genzyme Transgenics Corporation, have generated young females whose milk they hope will contain human serum albumin: a critical protein currently available only through human blood donations.
The scientific leap between Chloe and Charlie is huge, but the philosophical leap, in terms of animal husbandry, is really quite small. Chloe was produced by the latest breeding techniques and the careful matching of sire and dam, then fed a calculated diet of grains, minerals and fiber to maximize her milk production. Chloe, like Charlie, was a result of modern science and research; although the cloned calves represent a significant scientific breakthrough, Robl says they're just the next step in animal agriculture.
"Cloning technology is little more than an advancement over A.I. [artificial insemination, the standard for breeding dairy cows]," says Robl. "What we're doing is really very, very simple," he adds. "If you look at what we know and what we can do, compared to what takes place in that one singe cell, we haven't even entered kindergarten yet."
The key to Robl's work, and what makes him a leader in the fast-paced clone-technology race, is genetic modification, meaning that the cloned animal's DNA is altered. These alterations, made by inserting new genes into fetal cells, allow scientists to customize animals to produce proteins like serum albumin, antibodies to treat diseases like AIDS, or, potentially, organs that can be accepted by the human body. And it is this work that reflects a basic change in the research of the veterinary and animal science department. No longer focused solely on the animal itself, researchers like Robl are using the animal to solve human health problems.
WE ARE A
DEPARTMENT of life sciences," explains
department head Robert Duby, "so we understand the need
to maintain and manage the animal. But we're also interested
in other uses of the animal."
Duby, a stout man who appears capable of haying a field single-handedly, came to UMass as a student in the Stockbridge School in 1957, when ice cream was still being made in Flint Lab and the primary fields of animal science research were breeding and nutrition. He stayed on to receive his B.S and M.S. degrees and a Ph.D. in reproductive physiology before joining the faculty in 1970.
"There was no real molecular or cellular work being done here at that time," says Duby; the department decided to move in that direction in the1980s. "We couldn't compete with the Big Ten ag schools in applied research, so we decided that we would look at animal science on the biological and cellular levels. I think it was the right decision."
Duby's graduating class in animal husbandry in 1962 numbered nine students; today 375 are working toward undergraduate degrees in the field, and Duby attributes much of that growth to the research now conducted in Paige Lab. The interest of prospective students quickens, he says, when they realize they can study under pioneers of cloning and reproductive technology. And as the field of biotechnology grows, graduating students find more career choices available today than ever before. "Graduates with applied training in animal management and experience in biological research will have a lot of opportunities in the future," says Duby.
One of those graduates, Jose Cibelli, has indeed found expansive career opportunities since receiving his Ph.D. under Robl's tutelage last year. Cibelli's thesis project was the production of transgenic cattle, and he did much of the lab work that created George, Charlie, and others. So forgive him if he feels a little possessive of the animals. "Those are my cows!" he says proudly.
Cibelli is now director of cell biology at ACT, the Worcester biotech company founded in 1994 by Robl and former UMass researcher Steven Stice `89G to develop commercial applications for their cloning research. Like Robl and other researchers in the field, Cibelli has been overwhelmed by media requests and speaking engagements as word of their successes has spread.
"Jim Robl and my work at UMass really opened doors for me," he says. "I've traveled abroad and had some great experiences and opportunities because of this research."
Cibelli echoes Duby's assertion that the department's new focus on cellular biology is forward-thinking. After completing his doctorate, Cibelli explored research positions at other universities. But none had the facilities or faculty in place to match UMass, he says.
"The situation is very unique at UMass," says Cibelli. "There are so many good professors doing outstanding research in the department." Cibelli adds that cloning receives undue attention because it's new, controversial, and has been picked up by mainstream media. "But all research in the department will have an impact, not just cloning."
FROM THE RETRO-DECOR
of James Robl's tidy office with its wooden
cabinet holding a microscope and obsolete precision lab scales,
its bookcases filled with science journals and thick books on
bovine reproductivity it's hard to imagine that he's a cutting-edge
researcher in one of science's hottest fields. The only sign
of modern technology is a desktop computer in one corner. Grazing
atop the wooden cabinet is a herd of small, nearly identical,
black-and-white plastic cows.
Robl has been experimenting with cloning technologies for fifteen years, and successfully cloned rabbits in the `80s using the same nuclear transfer process that created George, Charlie, and their siblings. In his quiet, thoughtful, Midwestern manner, Robl explains the science as if he were passing along his grandmother's recipe for apple pie.
Oocytes, or cow eggs, about the size of small specks of dust are shipped to Robl's lab from slaughterhouses in Nebraska and Kansas. Using an instrument called a micro-manipulator, which reduces hand movements on joysticks to a microscopic scale, the oocyte is held with a tiny pipette the width of a human hair while the chromosomes, or genetic material, are removed with another, even tinier, pipette. A fibroblast cell a cell that has partially differentiated toward specific tissues and organs which has been taken from a cow fetus and genetically altered, is placed near the oocyte. The cell is fused to the egg's cytoplast with a two hundred volt electrical charge, and chemically stimulated to induce normal divisions. After seven days in incubation, when the embryo has grown to about a hundred cells, it is transplanted into a host cow who carries the clone to term.
The nuclear transfer process is used in virtually all cloning research, but Robl's work differs in part because he begins with fetal cells rather than cells taken from adult animals. "We've never put much emphasis on trying to clone adults because our goal has been to use the technology for making genetic modifications," he says. "Fetal cells will grow much better and much longer in culture than cells from an adult." The longer lifespan is necessary to give Robl and his lab team time to insert new DNA into the cells, and to select out those with the desired genetic makeup. The efficiency rate for producing genetically modified cells is still quite low, notes Robl. From a dish of one million cells, he may start ten colonies of transgenic cells suitable for cloning.
For all the success in cloning research in recent years, scientists are still mystified by much of what occurs in the process. Robl and his team are trying to find out why certain cells and even certain animals are more clonable than others, and if those "highly clonable" cells can be identified. Even if all goes well and a healthy, transgenic, cloned animal is born, the new gene is not always expressed in the final product. Given the months of lab work required to create a transgenic embryo and the lengthy nine-month gestation period of cattle, cloning research is painstakingly slow and unpredictable.
"I think we were lucky to be in the right place at the right time," Cibelli says of his success while at UMass. "We just did it and it worked and we're not even completely sure why."
ANY FARMER
will tell you that breaking new ground
means plowing up a few rocks, and tilling the young field of
cloning is no different. Questions of ethics and the treatment
of domestic animals, not to mention the volatile subject of cloning
humans, are as troublesome and complicated as the science itself.
And doubts have been raised about the effectiveness of cloning
with reports of premature aging in Dolly, the sheep cloned by
Scottish scientists two years ago, and unusually high death rates
of some cloned animals.
Perhaps the past, present and future state of animal agriculture and research was best expressed by John Frost Winchester when, as a special lecturer at Mass Aggie on a cold December morning in 1879, he told his small group of students that "In the progress of civilization it has become necessary for domestic animals to be put to unnatural work and to live under unnatural conditions. . ."
Doctoral student Amy Burnside, who studies embryonic stem cells in Robl's lab, winces slightly at the mention of health problems in cloned animals today, but she also defends her work without hesitation. She points to numerous medical benefits for humans that have risen from reproductive research in animals and to the potential gains from cloning.
"Procedures like ICSI [intra-cytoplasmic sperm injection] are commonly used for people who are having reproductive problems," she says. "And that came from animal research."
Burnside's small, shared office in the basement of Paige Lab is filled with evidence of her affection for animals. An old glass fish tank is now home to six brown mice that she "saved" from the department's research population. Her desk is dotted with cat magnets, and Chessie, her chocolate Labrador Retriever pup, often accompanies her to work. Her pet menagerie at home includes three cats and a fat-tailed gecko named Marley. Burnside's animal amity brought her to her UMass master's program with future plans of veterinary school. But she found the cellular research both more appealing and more promising in terms of a career.
"These animals have been raised specifically for this purpose," she says in defense of animal research, "and we utilize them to gain understanding about both animals and humans."
Robl concurs. He also points out that cows exist in a symbiotic relationship with humans. "Cows depend on us for food, shelter and medical attention, and we depend on them for food and clothing and, more and more, for health care purposes. The cow couldn't get along without us and we couldn't get along without the cow." Robl holds that the cow has fared well under the husbandry of humans: "There wouldn't be a hundred million cows in the U.S. if they weren't of importance to humans."
Not surprisingly, Robl takes the view that inefficiencies in the budding technology of cloning can be resolved through research. In fact he's right now testing hypotheses that may tell us why some cloned animals have developmental problems in the womb.
"I look at these problems as our key concern," Robl says. "But I do believe we can solve them."
Robl is less worried by reports that Dolly's DNA may be older than her years, making her susceptible, some say, to premature aging or cancer. Telomeres, or caps on DNA strands that regulate the lifespan of the cell, are shorter in Dolly than in other sheep of her age. Robl and his team have not tested the telomere length of George, Charlie, and brothers.
"I don't have a lot of concern with it because I think, at least from mouse work, that the telomeres are long enough in most species that you're not going to have shortened lifespans in the first generation and maybe even the second generation. At some point down the road you might." Robl does say that if telomeres get short enough or disappear altogether, genetic defects could result.
Other possible problems associated with cloning, such as a reduced gene pool in domestic herds, are already being addressed through thoughtful husbandry, Robl says. Farmers, concerned with maintaining a viable product, have been aware of the need for genetic diversity since selective breeding took hold in animal management two hundred years ago.
Cloning won't become immediately widespread in agriculture, Robl predicts, but will instead be gradually introduced over the next forty or fifty years. Producers will likely create small groups of clones rather than one large cloned herd of identical DNA.
"I don't think we'll find that there's one perfect animal and we'll have huge numbers of clones of that animal. I think we'll have small clonal sets with tremendous variability in the industry."
Hadley farmer Ken Parsons '49 has seen a half-century of agricultural innovations change the way he and other small farmers go about their business. And while he doesn't fear new technologies, neither does he embrace them as a breakthrough for the farmer.
"It seems like cloning is just an acceleration of the selective breeding that we've been working with for years," Parsons says. "There are some pitfalls in selection and I suppose cloning will accelerate the pitfalls, too." He has confidence, though, that the modern science that creates new technologies can also refine them to avoid those pitfalls.
Parsons graduated from UMass in plant and soil sciences and immediately went to work on his father's vegetable farm in Northampton. Now, with the help of his son and nephew, Parsons raises hogs and sheep on 325 acres in Hadley and grows feed corn on the Northampton farm. He has seen many scientific advancements in farming, especially in areas of nutrition and medicine, and he has also seen highly touted technologies such as the bovine growth hormone BST make only minimal impact on agriculture. Parsons is not quite sure on which side of the fence cloning will fall.
"I think it's a great tool for producing proteins and tissues for humans," he says, "and, possibly at some point, it could have an impact on agriculture. But there are a lot of things to be ironed out, not the least of which is economics."
The "preferred market" for sheep and hogs raised on Parsons Farm is research institutions throughout the Northeast, which have very specific requirements for the type of animals they receive. Parsons says he would have no qualms about raising cloned animals if they were marketable. But as he readies himself for retirement, that's an issue his son will have to wrestle with, he says.
THANKS TO
SCIENCE FICTION, the term "human
cloning" often conjures images of a lone, mad doctor huddled
in a darkened lab replicating hordes of man-beasts that will
rule the world. Robl and other scientists agree that nuclear
transfer technology could be used to reproduce humans or human
embryos. In the real world of modern, market-driven biotechnology
research, cloning technology is little more than small, unidentifiable
masses of cells in petrie dishes. But the potential for those
cells to develop into a human being, Robl says, makes the subject
complex.
"Creating human embryos purely for research is something that we have to weigh very carefully," Robl says thoughtfully. "That embryo clearly has some value beyond any other two random cells and I think it carries even greater weight if we're creating that embryo, versus using something that will be destroyed anyway."
Robl would like to see a system that can quantify the value of human cloning research and weigh its value against what he calls "the repugnance factor." Certainly, most people would find those fictional, lab-hatched humanoids repugnant, but how do we feel about creating a human embryo, if cells from that embryo can produce organs for transplant or cure disease?
"I'm not necessarily a proponent of human cloning, I just think that when people make an argument for or against something the argument should be founded in facts and should be objective," Robl says. "So far the arguments against cloning are ones that are more emotional not to say those aren't real concerns."
Cibelli says that a distinction should be made between reproductive and therapeutic cloning. Most people find therapeutic cloning, which is ACT's field of research, acceptable, he says, especially if it means saving the life of a loved one. But he adds that reproductive cloning might also gain acceptance in time. Cibelli points out that when Joy Brown, the world's first test-tube baby, was born in 1978, public reaction was generally negative. Today more than 100,000 children are born each year as a result of that same technology.
Back to our man-beasts, running amok the world
over as their deranged creator succumbs to hysterical laughter.
James Robl, a smile creeping over his mustachioed face, is willing
to credit science fiction with pushing science into new realms.
"Science fiction probably did as much to start cloning research
as science did," he says, standing amidst the civilized,
bright-white environs of Paige Lab. "I like science fiction
myself, and, in fact, it does stimulate thinking and creativity
in science."
ENSCONCED TODAY
AT the campus barns in South Deerfield,
cloned steers George, Charlie, and their later-arriving but genetically
identical sibling, Albert, lead a quiet life among their fellow
Holsteins of the university's teaching herd. Their personal history
is, of course, unprecedented: a tale of genetic material harvested
in the Midwest, manipulated in Massachusetts, and implanted into
separate surrogate mothers in Texas. There, in January of 1998,
George and Charlie became the first of six genetically identical
cattle to be successfully brought to term as a result of the
research of UMass scientists James Robl and Steven Stice and
thus, the calves seen `round the world.
"For three days we did nothing but answer the phone," said Jane Pryor, lab director of the embryo transfer company Ultimate Genetics LLC, in May, 1998, as she gave us a tour of the small but immaculate laboratory, with its pristine equipment and ovary-collection logs, in the company's compact, metal-clad headquarters, with attached corrals, on the Camp Cooley Ranch in southeast Texas. The ranch leases land to Ultimate Genetics, which counts Robl and Stice among its clients. The UMass triplets were at that time still living on their native acres amidst a research herd including their brothers Theodore, Joseph, and Ulysses, who remained in Texas when the three eldest were trucked north to take up residence at UMass.
"Cow heaven," James Robl calls the 11,000-acre Camp Cooley Ranch. An amiable transplanted Kansan who tended beef cows as a boy, Robl enjoys visiting the ranch not only as part of his scientific rounds but for the landscape: rolling hills, oak trees, hedgerows a little bit of England with Stetsons and barbed wire. Robl also enjoys the chance to stay over at the main ranchhouse, the fully staffed occasional residence of the European owner of the ranch, an experience of luxury unusual in the life of a college professor.
Robl is not an unworldly academic. Asked if he thinks that ACT Advanced Cell Technology, Inc., the company he and Stice founded to market their techniques will make money, he said "I hope so!" On the other hand, if money were his primary interest he'd have been long gone. "I could make much more going full-time at my own company or another company," he says. "The bottom line is that I simply like being a professor." Robl continues to teach both undergrads and graduate students while running his research program. The research money that ACT brings onto campus, the opportunities it provides UMass students, and the royalties it returns to the university add up, Robl feels, to a situation with no losers. The only way the state could lose, he says, is by not moving to reduce the "bureaucratic hassles" that are a discouraging condition of doing entrepreneurial research within a public institution.
Meanwhile, back at the ranch last year, a still-adolescent-looking George, Charlie, et. al., grazed and munched, munched and grazed. The three UMass-bound boys were at this point newly steers "We double-checked with Dr. Robl about three times before doing it," said Pryor but seemed unaffected by their castrated state. If a casual visitor saw little to distinguish the cloned steers from their herd-mates or each other, it was a different story for the animal-savvy staff who'd handled them since birth: administering medicines, taking specimens, trotting them out for photographs by the scientists and science journalists who descended on the ranch from all over the world.
"Albert's pretty low-key; Charlie's more of a fighter," observed technician Barbara Jushka, leaning against a fence watching the celebrity steers and half a dozen others having a late-afternoon snack under a loafing shed. "George is somewhere in between." Surprised that her remark drew an expression of surprise, Jushka added, "Well, they're genetically the same, but their personalities are different. You can't clone a personality."
- Patricia Wright
