Biotechnology : In Search of a More Perfect Pig
At a biotechnology center near this college town, two unusual creatures were born several weeks ago. The latest products of a company known as Embryogen, the creatures might provide the grist for an interesting theological debate. Namely, what do you call these fat, squirming babies? They look suspiciously porcine and, to be sure, the two newborns walk like pigs, squeal like pigs, roll around and get filthy like pigs.
As a matter of fact, they are pigs--but pigs like God never made. Using the latest biological engineering, scientists have instilled the cells of each creature with a gene from cattle, and the babies will grow into adults that are different from any other pigs that have ever lived.
Subtle Differences
To a layman, the differences will be subtle. When grown, the pigs will look and behave more or less the same as others of their breed. But Embryogen hopes that the cattle genes will produce metabolic changes in the pigs that the pork industry has been looking for: animals with more meat and less fat.
Previous experiments with genetic engineering of pigs have proven only partially successful. The leaner pigs also revealed vulnerabilities to a number of crippling diseases, including arthritis and nerve disorders. This time, Embryogen officials hope they have hit the jackpot.
Using new genetic regulators designed to forestall such health problems, the scientists may have come close to inventing the perfect pig. “We are very optimistic,” said Steven Holzman, vice president of Embryogen. The final judgment, Holzman said, will be made in three to six months after the young pigs mature into adults.
Embryogen and half a dozen similar companies around the country constitute the forefront of a new industry that is being created by advances in biotechnology. They are attempting, for the first time, to make new forms of animals that will be available commercially to serve man.
Patents Allowed
Though still in its earliest stage of development, the industry was given a dramatic boost in the spring when the U.S. Patent Office announced that it will consider new animal forms as patentable inventions. Holding an animal patent would give the inventor an exclusive right to sell that particular animal to farmers or others. Before that decision, plants and microorganisms were regarded as patentable items but higher life forms were excluded.
Industry officials say the decision will give companies the economic protection they need to profit from their creations, and will keep the United States competitive with other countries that are also working on new life forms. At present, according to one industry estimate, the total investment in new animal research amounts to only $5 million annually, a minuscule amount compared to the $3 billion being spent on plant and microorganism technology. Nonetheless, plans for the future are ambitious and, if realized, could produce startling results. Some examples:
- Farm animals, especially dairy cows, may be used to produce pharmaceuticals that now must be manufactured synthetically in the laboratory. According to scientists, the cows would be engineered to produce the drugs--insulin, for example--by altering their genetic makeup at the embryo stage of development. One of several organs would produce the pharmaceuticals and excrete it into the milk, where it would be extracted for commercial use.
- Scientists believe they will have the ability to engineer immunity against common diseases into livestock within the next decade. Some diseases can be devastating to farmers, especially chicken growers who sometimes lose thousands of birds in epidemics of Newcastle’s disease or avian influenza. Genetic immunity would also allow farmers to forgo the routine use of antibiotics in livestock feed, which is believed to promote drug-resistant strains of viruses and bacteria.
- Conversely, vulnerability to some human diseases could be built into laboratory animals, allowing researchers to test the effects of new drugs. Currently there are virtually no test animals available for some major diseases--such as AIDS, which strikes only man and chimpanzees. One company is attempting to develop a mouse that would contract AIDS or an AIDS-like disease.
- Livestock could be bred to tolerate extreme climatic conditions. These tolerances would allow farm animals to be raised in tropical regions of Africa or Asian tundra areas that are very hot, very cold, or very dry. Such areas, usually with primitive cultures, have little or no domestic livestock.
2-Year Prediction
Estimates of how quickly some of these plans will be achieved vary widely. The most optimistic supporters believe that the first biologically engineered animal--known in the trade as a transgenic animal--could be available within two years; others predict the process could take twice that long. Either way, most agree that when the new industry does arrive the economic potential will be impressive. A recent issue of Genetic Technology News, a trade newsletter, predicted that the agricultural value of genetically engineered animals would grow to $65 billion by 1995.
Iver Cooper, associate counsel of the Assn. of Biotechnology Companies in Washington, said he believes the major economic beneficiaries of such a boom would be small research companies such as Embryogen and farmers themselves. “The patent decision will help small companies build a position in the marketplace,” Cooper said, enabling them to compete with large agricultural firms. As for the farmers, Cooper predicted they would keep a larger share of farm revenues because their production costs will go down.
But the prospects of a brave new world in farm animals has also created apprehension and controversy. Several weeks after the Patent Office announced its decision, a coalition of farm organizations and environmental groups said they would ask Congress to reverse or at least delay the Patent Office action.
Ecological Fears
Michael Fox, scientific director of the Humane Society of the U.S. and one of the coalition’s organizers, said the decision would lead to cosmic changes in nature. “We are talking about the takeover of the natural world,” Fox said. As domesticated animals are made ever more efficient and able to tolerate harsh conditions, he said, they will drive wildlife from their last refuges. “If you have farm animals that can thrive everywhere, you will see wildlife thriving nowhere,” Fox contended.
Others argued that custom-tailored animals would lead to higher, not lower, costs for farmers because the prices of such animals will reflect the expense of their development. As a result, they predicted small operators would be increasingly driven out of business and agriculture would fall ever more into the arms of large corporations.
In a recent letter to the House subcommittee on courts and the administration of justice, the National Farmers Organization said the patent decision “could result in a virtual monopoly on major livestock breeds by a few corporations who would hold the patents. Individual producers would be left with the burden of paying expensive patent royalties for the right to produce.”
Last month the House subcommittee began a series of hearings on the issue, and the Senate passed a three-month moratorium on funding of patents for higher animals. But few foresee the passage of any legislation to reverse the Patent Office decision. At most, congressional sources say, the Congress will impose regulations on the new industry to prevent monopolization and ensure sharing of scientific information.
No matter what the political outcome, there is little doubt that biological engineering of higher animals has reached a threshold of sorts. Since 1981, when the first mouse was implanted with a human growth gene and grew much larger than its siblings, scientists have made steady progress against a host of technical problems in altering the genetic patterns of higher animals.
Difficult Task
A handful of laboratories around the country, for example, can now handle the extremely tricky business of gene insertion, including those at Texas A&M; University, UC Davis, and Granada Genetics of Houston. Successfully implanting a gene into the fertilized egg of a higher animal is far more difficult than performing the same task with one-celled organisms. The process requires a single egg to be held firmly while a micro-thin injector penetrates not only the egg but the nucleus itself. At that moment a tiny amount of the gene is squirted into the nucleus.
This technique alone took two years to perfect, according to Duane Kraemer, a veterinary researcher at Texas A&M.; In the beginning, scientists could not even see the nucleus well enough to make the penetration with the micro-injector. Now it is done routinely, using special stains that turn the nucleus a darker color.
Even so, the process is still fraught with uncertainty, Kraemer said. About 50% of the injected eggs fail because of the trauma involved. Of those that survive, only 10% to 40% actually take up the new gene. And unlike single-celled organisms, each generation of higher animals takes six months to a year before they mature and reveal the full effect of the experimentation.
Here in Athens, the elaborate process of creating a new animal type was begun last week at Embryogen’s laboratory outside the city. A sow, recently impregnated through artificial insemination, was hoisted onto an operating table and placed under general anesthesia. To a background accompaniment of Jimmy Buffet music, a veterinarian opened her belly with a four-inch incision and gently pulled her ovaries into view. They looked like a small cluster of grapes, some white and some red.
“The red ones have just ovulated,” the veterinarian said.
As his hands found the oviduct--the small tube that carries the fertilized eggs to the uterus--the veterinarian made a small cut in either end and squirted a neutral solution through the tube. The solution washed the eggs to the opening at the other end, where they were collected in a sterile container. Embryogen officials estimate that this technique recovers about 95% of the fertilized eggs.
Within hours, the eggs were driven to a second laboratory at the Edison Animal Biotechnology Center on the Ohio University campus. Edison was established in 1983 as a “bridge” institute to link university research with private enterprises such as Embryogen. Here the eggs were injected with the cattle growth gene--cattle genes are used because growth genes from pigs have not yet been isolated--and placed back in containers that match the temperature of the sow’s body.
The next day, back at Embryogen’s facility, another sow was chosen and she was also opened surgically. The fertilized eggs with the growth genes were placed in her oviduct and, if the pregnancy holds, she will become the mother.
Embryogen officials are excited about this generation of pigs because they hope they have solved one of the most difficult problems facing higher-animal experimentation: the appearance of undesirable side effects.
The sad truth is that most of the 100 or so larger transgenic animals born since 1981 have endured lives that were painful and short. The same genes that produced more efficient growth also produced vulnerability to a series of ailments affecting the skeletal and nervous systems. An example of these difficulties now lives in one of the barns adjoining the U.S. Department of Agriculture’s research center in Beltsville, Md. Pig No. 1514 is an efficient protein producer and sports a handsome dark-brown fur, but he has problems.
Born last November, No. 1514 quickly developed arthritis in his legs and now has difficulty walking. While other pigs snort and grunt their way around the pens in the barn, the transgenic pig flops in a corner, reluctant to move. He is possessed of a great lethargy in addition to his arthritis and--if he is like others of his type--he will soon develop internal infections that will lead to an early death.
Promoter Gene Suspected
Vernon Pursel, the USDA research biologist who supervised the making of No. 1514, says no one really knows why the growth genes have produced the side effects. But he suspects, along with other scientists, that the difficulty lies with an element of the gene known as the promoter.
The gene promoter plays a crucial function in cell biology. Every cell in the body contains the same collection of genes, but a liver cell must function very differently from, say, a brain cell. The differences are determined by the promoters, which turn some genes on and others off, creating the formula for proper liver cells or brain cells. Some genes are even turned on at certain stages of development and then turned off. Growth genes, for example, are most active during the early years of development in higher animals and much less so in later life.
In recent years genetic scientists have discovered that they can separate the promoter from one gene and attach it to another gene, a technique that is used to enhance the effect of a gene transplant. With the transgenic pigs, for example, a promoter was used that turns on the growth gene throughout life rather than fading it out after adolescence.
And that created the problem, Pursel believes. The promoter has made the growth gene too active and also may be expressing the gene in cells where it should not be expressed.
“There are thousands of genes in every cell,” Pursel said. “We are talking about an enormously complex system and one that we only dimly understand at this point.” He added that the research center has begun investigating other promoters that might not produce the debilitating side effects of Pig No. 1514.
Basis for Optimism
Back at Athens, Embryogen officials say they may have found a promoter that induces growth without the side effects. The new promoter was used in the latest generations of pigs and is the basis of their optimism, Holzman said.
“We are still in the hoping stage,” Holzman said. “We won’t know the full results until these pigs are grown.”
Whether Embryogen succeeds with its latest pigs, most agree that one research group or another will produce a commercially valuable animal type within the next half decade, and succeed in obtaining a patent for it. When they do, a new era of farming will have begun.
In the beginning, experts say, the changes will be subtle: chickens that are more resistant to disease, or the long-sought leaner pig. As the techniques become fully developed, animals are likely to become more specialized--possibly producing larger portions of the most desirable meat cuts--and more capable of outperforming their non-engineered counterparts.
Just how this will change agriculture is not fully understood, but it has raised the anxiety levels of some groups who see the technology leading to greater consolidation of agricultural wealth.
Jack Doyle, director of the agricultural resources project for the Environmental Policy Institute, recently told a congressional subcommittee that the patenting of sexually reproduced plants--allowed since 1970 under the Plant Variety Protection Act--has been partially responsible for a wave of acquisitions of seed companies by major corporations. At present, he said, at least 120 seed companies in this country are owned by such corporations; the Patent Office has granted 6,000 patents for plants and new applications are being made at the rate of 400 per year.
“Today, the seed industry is becoming a wholesale subsidiary of the chemical and pharmaceutical industries, and patenting and biotechnology have contributed to it,” Doyle said.
Return on Investment
The consolidations occur, Doyle said, because the patentable seeds--or patentable pigs--are attractive vehicles for delivering technology to farmers at a price. Without the patents, the cost cannot be exacted from the farmer.
Supporters of the patent decision say the situation would be made worse, not better, without the patenting process. If companies developing new animals do not have patents available, they contend, the companies will attempt to protect their research by treating it as proprietary information. They cite the recent history of the chicken industry as an example of what happens when patents are not offered.
Since the 1970s, the chicken industry has been dominated by five major breeders in this country, each of which markets particular chickens that were laboriously developed through selective breeding to be larger, more productive birds. Since these creatures are not protected by patents, the breeders have consolidated the raising of chickens into large, integrated concerns that can be centrally controlled. Researchers and other private concerns do not have access to the breeding information or the chickens themselves.
As to the predicted higher prices farmers will pay for the new animals, industry lobbyist Cooper argues that farmers will buy the new animals only if they are more economically attractive than the old types.
“When a transgenic animal comes out, it will have a price. That price will be weighed against the price of other available animals,” Cooper said. “For example, if an animal has 10% more disease resistance, the farmer will ask whether the disease resistance is worth the price. Then he buys, or he doesn’t.”
One unresolved issue involves the status of the progeny of patented creatures. If a farmer buys a patented cow and it produces a calf, is the calf also protected by the patent? At a recent congressional hearing, Rene Tegtmeyer, assistant commissioner for patents, said he believes farmers would have the right to breed patented animals for their own use without making further payments.
Genetic Sterility
But representatives of some research companies say the economic value of their patented animals would be seriously eroded under those conditions, and they would not accept such an arrangement willingly. Some have suggested that sterility would be engineered into patented animals if breeding were legally allowed. Others say they might create a two-tiered market that charges a lower price for sterile animals and a higher price for reproducing creatures.
Some experts say the economic repercussions of new animals will be so complex that forecasting the effect now is virtually impossible. Thomas Wagner, director of the Edison Institute in Athens, likes to consider the possibility that might arise from producing pharmaceuticals on the farm. In this concept, yet to be proven feasible, dairy cows would be engineered to produce various drugs through their milk.
He notes that farm products traditionally are low-markup items and pharmaceuticals are high-markup items. Coming from an agricultural region where farmers have lost their farms in large numbers, Wagner says, he looks forward to the day when dairy farmers would think of themselves not just as producers of milk but also of insulin and other drugs.
“That idea is very appealing to me,” he said.
