Transgenic Livestock May Become Biotech’s Cash Cow
The world shook when Dolly the sheep was cloned. But nary a ripple greeted the news of Rosie the calf.
That was so even though the sweet-faced Holstein made its own impressive history earlier in February, becoming the first cow to produce milk with significant levels of a human protein--promising enrichment for infants and elderly alike.
Both beasts are products of laboratory tinkering in a field of agricultural biotechnology known as transgenics--in which the DNA of other species, often from human beings, is introduced into the genes of animals.
Transgenic livestock breeding promises to be the bread and butter of a burgeoning 21st century biotechnology industry--Rosie, after all, is a potential cash cow if ever there was one. Cloning, with its allure of quickly replicating animals with desirable traits, is more likely to be the icing on the biotech cake.
A handful of companies have been engaged in transgenics for the last decade with varying success, among them Scotland’s PPL Therapeutics, which runs the labs that produced Dolly and Rosie.
Some of these companies--often with funding from medical supply and pharmaceutical giants--inject human genes into the embryos of mice, pigs, goats and cows in the hope of sharply lowering the cost of producing nourishing proteins and healing drugs. Others, such as Nextran and Alexion Pharmaceuticals, nurture pigs with altered hearts and kidneys that could one day be transplanted into human beings--a market projected to be worth billions of dollars.
Meanwhile, university and government research labs plug away with farmers in mind, seeking to create livestock containing human genes that help resist disease or produce more milk or leaner meat.
But the twisting path to this brave new biotech world will be littered with obstacles, and scientists recognize that they are bound to stumble along the way. The research is painstaking and tedious, and societal backlash can threaten at any turn.
Even the staunchest proponents of ag biotech acknowledge that it will be at least five or 10 years before practical, profitable applications are commonly available. And all this expensive poking and prodding of animals raises moral and ethical questions about whether society has the right to pursue the science, and the stomach to deal with the consequences.
Israeli researchers have reported work on featherless chickens; the birds don’t use up precious energy producing their plumage, but they look grotesque and don’t function normally. In Australia, sheep were injected with a genetically engineered hormone that produces breaks in wool fibers as they grow, enabling simple removal of the wool. Among the unforeseen side effects for these self-shearing sheep: severe sunburn and heat stress.
Problems have been apparent since U.S. Department of Agriculture researchers reported the world’s first transgenic livestock in 1985. Growth hormone was inserted into genetically engineered pigs, which indeed grew faster and contained less fat than their plain Jane counterparts. But the pigs could not cope with the accelerated growth and suffered from crippling arthritis, infertility and more than their usual share of gastric ulcers. The research was halted amid a public outcry.
“There’s [only] a certain distance you can go in the name of science,” said Caird E. Rexroad Jr., a member of that team and research leader at the federal Agricultural Research Service’s Gene Evaluation and Mapping Laboratory in Beltsville, Md. “You have to make a judgment.”
Benefits, Risks of Barnyard Biotech
At PPL Therapeutics, the judgment has been that the potential benefits of barnyard biotech--for both society and the company’s bottom line--far outweigh any risks. The company’s lead product is a protein for the treatment of cystic fibrosis and emphysema.
PPL’s U.S. branch is ensconced on several hundred acres amid the rolling hills of Blacksburg, Va., near Virginia Tech. Working with pigs, cows and rabbits, researchers at the 4-year-old operation view their mission as generating transgenic livestock that can become individual factories, churning out therapeutic proteins in greater quantity and for less money than would be feasible by any other method. Once produced in milk, the proteins can be isolated for inclusion in pharmaceuticals--or, eventually, sold as is, as a beverage with enhanced properties.
Scientists in February held a coming-out party for Rosie, the firstborn of more than a dozen transgenic calves, after her initial milking revealed strong levels of alpha-lactalbumin. The human protein provides an excellent balance of amino acids, making it highly nutritious and especially suitable for premature infants who cannot nurse.
Although all potential applications haven’t been worked out, “infant formula is certainly a possibility,” said Will Eyestone, PPL’s head of bovine technology in Blacksburg. Clinical trials are expected to begin within two years.
The aim of Alexion Pharmaceuticals in New Haven, Conn., is quite different: to develop a herd of organ donors for the thousands of individuals--many of them at death’s door--awaiting transplants. The 5-year-old company is working with about 50 pigs containing two human genes.
These high-tech hogs are housed in horse stalls at Tufts University’s School of Veterinary Medicine, an hour’s drive west of Boston. The pigs’ appearance betrays no hint of their special properties. But, thanks to one of the human genes, the animals’ hearts, kidneys and lungs bear a human-like sugarcoating that the company theorizes would make them compatible with the human body. The other gene, researchers believe, would mop up any inflammation resulting from a transplant.
Alexion is testing this double-barreled approach by transplanting pig organs into baboons. Organs from the transgenic pigs survive for days, versus the hour or so a normal pig organ would last, said Stephen Squinto, Alexion’s co-founder and vice president of research. That survival time does not yet justify a clinical test on human beings, the prospects for which, Squinto said, “will be absolutely dependent on data from the primate model, and we’ll have a good feel for that within the next 12 months.”
The company has received $10 million in funding from U.S. Surgical Corp., a Norwalk, Conn., surgical supply company. Shares of Alexion, which went public a year ago at $8.25 each, traded recently on the Nasdaq exchange at about $11 before falling to $8.75. The cloning news from Scotland did not sway interest one way or the other.
“The people who are investors understand our technology,” Squinto said.
Cloning is not part of Alexion’s research, but if it could be made commercially feasible--a big if--it could provide a more effective, efficient way of making colonies of animals. For now, the technique used in Scotland is far too inefficient. It took scientist Ian Wilmut 25 often-frustrating years and 277 tries to produce Dolly.
Demand for Organs Is Enormous
The market for “xenotransplantation”--the use of animal organs for transplantation into human beings--could be enormous. According to the United Network for Organ Sharing, 3,000 patients in the United States die each year waiting for a transplant; 100,000 die annually without having qualified for a spot on the waiting list. Salomon Bros., a Wall Street investment firm, projected last year that demand for organs could be worth $6 billion by 2010, with patients worldwide seeking 450,000 organs a year.
That number seems high--but only by $1 billion or so--to executives at Nextran, a division of Baxter International, a medical products and services company. Based in Princeton, N.J., Nextran is a leader in the field, having launched a Phase I clinical trial to test the safety and effectiveness of using transgenic pig livers outside the human body to treat patients with acute liver failure.
In this procedure, doctors pump blood from a vein in a patient’s leg through the pig liver, which is stored in a sterile container at the patient’s side. The blood is then pumped back into the body through the jugular vein. The idea is to maintain liver functions until a human organ becomes available.
The company expects to report results within the next year. Nextran is the only company so far to have won approval from the U.S. Food and Drug Administration to use a transgenic pig organ in human testing.
“Of all the ag products I can think of . . . this will have the greatest impact clinically,” said John S. Logan, vice president of research and development. “If someone’s dying of heart or kidney failure, it could save a life.”
Marvin L. Miller, Nextran’s president and chief executive, foresees that, if approved eventually for transplantation, such organs would fetch $10,000 to $18,000 each. That, he said, raises questions: Can society afford to have that many transplants done? Is it willing to shoulder the financial burden?
Cost aside, society probably will have no qualms about using genetically engineered pig organs, said Bernard E. Rollin, author of “The Frankenstein Syndrome: Ethical and Social Issues in the Genetic Engineering of Animals” and a professor of philosophy and biophysics at Colorado State University.
“In a society that eats pigs, there won’t be a big uproar,” he said. After all, surgeons have successfully used pig heart valves in patients for years. (And June will mark the 20th anniversary of the first transplant of a baboon heart into a human being.)
Consumer Reaction Hard to Predict
But Rollin sees many potential dangers in high-tech breeding techniques. “You can’t predict what the insertion of a gene will or will not do,” he said. “A lot will depend on unintended consequences.”
Animal rights activists have long protested such research. Six years ago, well before the world knew of Wilmut’s breakthrough cloning work at the Roslin Institute, activists torched two laboratories there. (The institute is run by PPL Therapeutics.)
Consumers’ resistance to some bioengineered food products--and the difficulties researchers have encountered in identifying favorable genes for use in transgenics--make the payoff seem distant for private industry. As a result, companies have slashed funding for researchers involved in genetic engineering of livestock strictly for the sake of farming, rather than for producing drugs. Most researchers attempting to aid farmers must rely on funds from the USDA and other government entities.
“It really is a hard slog,” said James D. Murray, a professor of animal sciences and veterinary medicine at UC Davis. “It’s very expensive and very long term and very hard to get it funded. That’s why most work is done by pharmaceutical companies, which see a big pot of gold.”
Murray succeeded recently in changing the fundamental properties of mouse milk by injecting a gene that produced a human enzyme. The enzyme, found in tears and saliva, can dissolve certain bacteria. Introducing the enzyme in cow’s milk, he figures, might cut down on gastrointestinal infections in children who drink the milk. The presence of the enzyme could also aid the dairy cows, decreasing the amount or severity of udder inflammations and therefore reducing the need for antibiotics.
But to prove his speculation, Murray needs a transgenic cow. In 20 pregnancies so far, the calves have all proved negative for the enzyme. The process “is very inefficient,” Murray said, adding ironically: “Our success rate is in keeping with the worldwide average.”
The Possibilities Are Intriguing
Consider Dolly, the longshot cloning success from Scotland. Until researchers can dramatically boost the efficiency of Wilmut’s technique, most scientists agree, it will be merely a momentous novelty.
Nevertheless, the research world is attracted by the possibilities. After the announcement, scientists at the University of Wisconsin immediately set about reproducing Wilmut’s feat in cattle, using fetal skin cells rather than the adult mammary cells used in Scotland. (Up till now, genetic engineering efforts focused on dividing animal embryos to produce twins or triplets, or on injecting genes into a fertilized egg in the hope that the offspring would have specific traits.)
Although the interest now is purely scientific, Wisconsin researcher Neal First, a noted expert in the field, said the hope eventually is to develop a reliable cloning method that could help farmers copy animals that produce desirable cuts of meat, copious amounts of gene-enhanced milk--or even pharmaceuticals.
Striving to keep pace with consumers’ wishes, farmers for decades have been fooling with livestock genetics using artificial insemination, in vitro fertilization and plain old crossbreeding. Just as cloning would, those technologies tend to reduce genetic diversity.
Take the dairy industry, said George Seidel, a cattle rancher and a professor of physiology at Colorado State University. At the end of World War II, there were 25 million dairy cows in the United States. Today, about one-third that many cows produce 10% more milk than did the postwar herds. The total feed consumed and manure produced are about half the earlier levels.
Helping to account for the improved milk yield is a decline in genetic diversity: 90% of the dairy cows are Holsteins, versus 40% four decades ago. Holsteins produce more milk with less fat than other breeds.
“That reduces genetic variation,” Seidel said. “But it’s what consumers wanted. If we had cloned cows from the 1950s, they would be much inferior to today’s cows.
“Cloning,” he added, “is not in any sense an ultimate technology for improving animals. It’s another tool.”
* A DEAD END? All the recent scientific accomplishments defy warnings that the end of science is near. B2
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Question
What do you see ahead for private-sector agricultural biotechnology in light of the cloning of Dolly, the Scottish sheep?
Jim McCamant, editor of the AgBiotech Stock Letter, Berkeley, Calif.:
“I don’t think it has had any significant impact at all [on the stock prices of biotech companies]. It’s not a big deal, investment-wise.”
****
Robert D. Bremel, managing director of Gala Design, a “designer milk” biotech company, Sauk City, Wis.:
“For many purposes, cloning is not needed. The reason the Dolly process was done is that PPL Therapeutics is looking to remove a gene and replace it. They need the cloning to make that work. So cloning is a necessary means to an end. With current technologies, you can add genes but if you need to take one out and put a new one in, it’s much more complicated. [The Dolly procedure] makes it conceivable to do that. Whether they can get their efficiencies up to make it commercially viable is another question.”
****
Vernon Pursel, research physiologist, Agricultural Research Service’s Gene Evaluation and Mapping Laboratory, Beltsville, Md.:
“Pharmaceuticala and xenotransplantation [the transplantation into human beings of organs from genetically engineered animals] are the hot areas, with great financial potential. It’s financially driven. Several of us in the [U.S.] Department of Agriculture are still working toward production purposes--growth [of animals], disease resistance--that might have considerable use in the future. But we don’t know how far off that is.”
****
Bernard E. Rollin, professor of philosophy and physiology and biophysics at Colorado State University, Fort Collins, Colo.:
“With cloning, one can multiply a putatively desirable animal, but one can make mistakes. [A researcher] could screw up things that would show up in a year or two.”
****
Caird E. Rexroad Jr., research leader, Gene Evaluation and Mapping Laboratory, Beltsville, Md.:
“Should we make a super-pig and tie up all our genetics in that? I think the answer is clearly no. My vision is that designer genes are for specific purposes. This is a tool--it’s not a panacea, nor is it a Pandora’s box.”
****
George Seidel, professor of physiology, Colorado State University:
“There will be casualties with any kind of new experimentation. More people were saved by penicillin than by any other drug. But more healthy people were killed by it. There is a cost to every technological benefit.”
****
Vernon Pursel:
“Population growth is a huge problem. There’s a net increase in population of 2.8 persons per second. It is frightening. That means that either we have to somehow reduce population growth or be lots more efficient in how we produce our food. The increases we had [in farm production] in the 1950s and ‘60s resulted from fertilizers and insecticides. We pumped a lot of bad stuff onto the soil. We have to find alternative ways to do that. Biotech is one of the ways. But look at the Flavr-Savr [a genetically engineered tomato that failed to hold up to the rigors of transportation and handling]. Getting any of these things from the lab into the grocery store--that’s a huge undertaking.”
****
Keith Haglund, executive editor, The Journal of NIH Research, April 1997:
“Goodbye, Dolly....It’s time for you to leave center stage. Time for the scientists and ethicists and policy-makers to play their parts.”
Compiled by MARTHA GROVES / Los Angeles Times
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Agrotech Vocabulary
* Agricultural biotechnology: Involves the genetic engineering of livestock and seeds of plants to instill desirable traits such as higher yield, better taste, more durability or resistance to disease and/or pests.
* Transgenics: Involves the transfer of a genetically engineered segment of DNA, often from a human being, into the genetic material of another species. The aim is to enable the animals to produce proteins and drugs for treating diseases or making nourishing foods at low cost.
* Xenotransplantation: The use of organs from genetically engineered animals for transplantation into human beings.
Compiled by MARTHA GROVES / Los Angeles Times
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About This Series
The cloning of a sheep named Dolly sent shockwaves throughout the world this year. But that is only one of a host of advances in biotechnology. The revolution is touching virtually all corners existence, from conception to nutrition to disease control. The genetic engineering advances also raise basic questions about how society will deal with these newfound abilities, who should control their use and how far research should be allowed to proceed.
Sunday: The biotechnology revolution--the future has arrived.
Monday: What is the “self” and can it be cloned?
Tuesday: The U.S. government’s reluctance to regulate reproductive technology raises some thorny issues.
Wednesday: The quest to map the human genome leads down some unusual roads.
Today: Barnyard biotech--of cows with medicinal milk and pigs with human-like organs.
ON THE WEB: Graphics, photos and stories from “In Our Own Image” are available on the Los Angeles Times World Wide Web site at: https://www.latimes.com/cloning/
