Artificial insemination

The invention:

Practical techniques for the artificial insemination of farm animals that have revolutionized livestock breeding practices throughout the world.


The people behind the invention:
Lazzaro Spallanzani (1729-1799), an Italian physiologist

Ilya Ivanovich Ivanov (1870-1932), a Soviet biologist

R. W. Kunitsky, a Soviet veterinarian



Reproduction Without Sex

The tale is told of a fourteenth-century Arabian chieftain who sought to improve his mediocre breed of horses. Sneaking into the territory of a neighboring hostile tribe, he stimulated a prize stallion to ejaculate into a piece of cotton. Quickly returning home, he inserted this cotton into the vagina of his own mare, who subsequently gave birth to a high-quality horse. This may have been the first case of “artificial insemination,” the technique by which semen is introduced into the female reproductive tract without sexual contact.
The first scientific record of artificial insemination comes from Italy in the 1770’s.
Lazzaro Spallanzani was one of the foremost physiologists of his time, well known for having disproved the theory of spontaneous generation, which states that living organisms can spring “spontaneously” from lifeless matter. There was some disagreement at that time about the basic requirements for reproduction in animals. It was unclear if the sex act was necessary for an embryo to develop, or if it was sufficient that the sperm and eggs come into contact. Spallanzani began by studying animals in which union of the sperm and egg normally takes place outside the body of the female. He stimulated males and females to release their sperm and eggs, then mixed these sex cells in a glass dish. In this way, he produced young frogs, toads, salamanders, and silkworms.
Next, Spallanzani asked whether the sex act was also unnecessary for reproduction in those species in which fertilization normally takes place inside the body of the female. He collected semen that had been ejaculated by a male spaniel and, using a syringe, injected the semen into the vagina of a female spaniel in heat. Two
months later, she delivered a litter of three pups, which bore some resemblance to both the mother and the male that had provided the sperm.
It was in animal breeding that Spallanzani’s techniques were to have their most dramatic application. In the 1880’s, an English dog breeder, Sir Everett Millais, conducted several experiments on artificial insemination. He was interested mainly in obtaining offspring from dogs that would not normally mate with one another because of difference in size. He followed Spallanzani’s methods to produce
a cross between a short, low, basset hound and the much larger bloodhound.



Long-Distance Reproduction


Ilya Ivanovich Ivanov was a Soviet biologist who was commissioned by his government to investigate the use of artificial insemination on horses. Unlike previous workers who had used artificial insemination to get around certain anatomical barriers to fertilization, Ivanov began the use of artificial insemination to reproduce
thoroughbred horses more effectively. His assistant in this work was the veterinarian R. W. Kunitsky.
In 1901, Ivanov founded the Experimental Station for the Artificial Insemination of Horses. As its director, he embarked on a series of experiments to devise the most efficient techniques for breeding these animals. Not content with the demonstration that the technique was scientifically feasible, he wished to ensure further that it could be practiced by Soviet farmers.
If sperm from a male were to be used to impregnate females in another location, potency would have to be maintained for a long time. Ivanov first showed that the secretions from the sex glands were not required for successful insemination; only the sperm itself was necessary. He demonstrated further that if a testicle were removed from a bull and kept cold, the sperm would remain alive.
More useful than preservation of testicles would be preservation
of the ejaculated sperm. By adding certain salts to the sperm-containing fluids, and by keeping these at cold temperatures, Ivanov was able to preserve sperm for long periods.
Ivanov also developed instruments to inject the sperm, to hold the vagina open during insemination, and to hold the horse in place during the procedure. In 1910, Ivanov wrote a practical textbook with technical instructions for the artificial insemination of horses.
He also trained some three hundred veterinary technicians in the use of artificial insemination, and the knowledge he developed quickly spread throughout the Soviet Union. Artificial insemination became the major means of breeding horses.
Until his death in 1932, Ivanov was active in researching many aspects of the reproductive biology of animals. He developed methods to treat reproductive diseases of farm animals and refined methods of obtaining, evaluating, diluting, preserving, and disinfecting sperm. He also began to produce hybrids between wild and domestic animals in the hope of producing new breeds that would be able to withstand extreme weather conditions better and that would be more resistant to disease.
His crosses included hybrids of ordinary cows with aurochs, bison, and yaks, as well as some more exotic crosses of zebras with horses.
Ivanov also hoped to use artificial insemination to help preserve species that were in danger of becoming extinct. In 1926, he led an expedition to West Africa to experiment with the hybridization of different species of anthropoid apes.


Impact

The greatest beneficiaries of artificial insemination have been dairy farmers. Some bulls are able to sire genetically superior cows that produce exceptionally large volumes of milk. Under natural conditions, such a bull could father at most a few hundred offspring in its lifetime. Using artificial insemination, a prize bull can inseminate ten to fifteen thousand cows each year. Since frozen sperm may be purchased through the mail, this also means that dairy farmers no longer need to keep dangerous bulls on the farm. Artificial insemination has become the main method of reproduction of dairy cows, with about 150 million cows (as of 1992) produced this way throughout the world.
In the 1980’s, artificial insemination gained added importance as a method of breeding rare animals. Animals kept in zoo cages, animals that are unable to take part in normal mating, may still produce sperm that can be used to inseminate a female artificially.
Some species require specific conditions of housing or diet for normal breeding to occur, conditions not available in all zoos. Such animals can still reproduce using artificial insemination.

Artificial heart

The invention:

The first successful artificial heart, the Jarvik-7, has
helped to keep patients suffering from otherwise terminal heart
disease alive while they await human heart transplants.

The people behind the invention:

Robert Jarvik (1946- ), the main inventor of the Jarvik-7

William Castle DeVries (1943- ), a surgeon at the University
of Utah in Salt Lake City

Barney Clark (1921-1983), a Seattle dentist, the first recipient of
the Jarvik-7


Early Success

The Jarvik-7 artificial heart was designed and produced by researchers
at the University of Utah in Salt Lake City; it is named for
the leader of the research team, Robert Jarvik. An air-driven pump
made of plastic and titanium, it is the size of a human heart. It is made
up of two hollow chambers of polyurethane and aluminum, each
containing a flexible plastic membrane. The heart is implanted in a
human being but must remain connected to an external air pump by
means of two plastic hoses. The hoses carry compressed air to the
heart, which then pumps the oxygenated blood through the pulmonary
artery to the lungs and through the aorta to the rest of the body.
The device is expensive, and initially the large, clumsy air compressor
had to be wheeled from room to room along with the patient.
The device was new in 1982, and that same year Barney Clark, a
dentist from Seattle, was diagnosed as having only hours to live.
His doctor, cardiac specialistWilliam Castle DeVries, proposed surgically
implanting the Jarvik-7 heart, and Clark and his wife agreed.
The Food and Drug Administration (FDA), which regulates the use
of medical devices, had already given DeVries and his coworkers
permission to implant up to seven Jarvik-7 hearts for permanent use.
The operation was performed on Clark, and at first it seemed quite
successful. Newspapers, radio, and television reported this medical
breakthrough: the first time a severely damaged heart had been re-placed by a totally artificial heart. It seemed DeVries had proved that an artificial heart could be almost as good as a human heart.
Soon after Clark’s surgery, DeVries went on to implant the device placed by a totally artificial heart.in several other patients with serious heart disease. For a time, all of them survived the surgery. As a result, DeVries was offered a position
at Humana Hospital in Louisville, Kentucky. Humana offered
to pay for the first one hundred implant operations


The Controversy Begins

In the three years after DeVries’s operation on Barney Clark,
however, doubts and criticism arose. Of the people who by then had
received the plastic and metal device as a permanent replacement
for their own diseased hearts, three had died (including Clark) and
four had suffered serious strokes. The FDAasked Humana Hospital
and Symbion (the company that manufactured the Jarvik-7) for
complete, detailed histories of the artificial-heart recipients.
It was determined that each of the patients who had died or been
disabled had suffered from infection. Life-threatening infection, or
“foreign-body response,” is a danger with the use of any artificial
organ. The Jarvik-7, with its metal valves, plastic body, and Velcro
attachments, seemed to draw bacteria like a magnet—and these
bacteria proved resistant to even the most powerful antibiotics.
By 1988, researchers had come to realize that severe infection was
almost inevitable if a patient used the Jarvik-7 for a long period of
time. As a result, experts recommended that the device be used for
no longer than thirty days.
Questions of values and morality also became part of the controversy
surrounding the artificial heart. Some people thought that it
was wrong to offer patients a device that would extend their lives
but leave them burdened with hardship and pain. At times DeVries
claimed that it was worth the price for patients to be able live another
year; at other times, he admitted that if he thought a patient
would have to spend the rest of his or her life in a hospital, he would
think twice before performing the implant.
There were also questions about “informed consent”—the patient’s
understanding that a medical procedure has a high risk of
failure and may leave the patient in misery even if it succeeds.
Getting truly informed consent from a dying patient is tricky, because,
understandably, the patient is probably willing to try anything.
The Jarvik-7 raised several questions in this regard:Was the ordeal worth the risk? Was the patient’s suffering justifiable? Who should make the decision for or against the surgery: the patient, the researchers, or a government agency?
Also there was the issue of cost. Should money be poured into expensive,
high-technology devices such as the Jarvik heart, or should
it be reserved for programs to help prevent heart disease in the first
place? Expenses for each of DeVries’s patients had amounted to
about one million dollars.
Humana’s and DeVries’s earnings were criticized in particular.
Once the first one hundred free Jarvik-7 implantations had been
performed, Humana Hospital could expect to make large amounts
of money on the surgery. By that time, Humana would have so
much expertise in the field that, though the surgical techniques
could not be patented, it was expected to have a practical monopoly.
DeVries himself owned thousands of shares of stock in Symbion.
Many people wondered whether this was ethical.


Consequences

Given all the controversies, in December of 1985 a panel of experts
recommended that the FDAallow the experiment to continue,but only with careful monitoring. Meanwhile, cardiac transplantation was becoming easier and more common. By the end of 1985, almost twenty-six hundred patients in various countries had received human heart transplants, and 76 percent of these patients had survived
for at least four years. When the demand for donor hearts exceeded the supply, physicians turned to the Jarvik device and other artificial hearts to help see patients through the waiting period.
Experience with the Jarvik-7 made the world keenly aware of
how far medical science still is from making the implantable permanent
mechanical heart a reality. Nevertheless, the device was a
breakthrough in the relatively new field of artificial organs. Since
then, other artificial body parts have included heart valves, blood
vessels, and inner ears that help restore hearing to the deaf.




William C. DeVries


William Castle DeVries did not invent the artificial heart
himself; however, he did develop the procedure to implant it.
The first attempt took him seven and a half hours, and he
needed fourteen assistants. Asuccess, the surgery made DeVries
one of the most talked-about doctors in the world.
DeVries was born in Brooklyn,NewYork, in 1943. His father,
a Navy physician, was killed in action a few months later, and
his mother, a nurse, moved with her son to Utah. As a child
DeVries showed both considerable mechanical aptitude and
athletic prowess. He won an athletic scholarship to the University
of Utah, graduating with honors in 1966. He entered the
state medical school and there met Willem Kolff, a pioneer in
designing and testing artificial organs. Under Kolff’s guidance,
DeVries began performing experimental surgeries on animals
to test prototype mechanical hearts. He finished medical school
in 1970 and from 1971 until 1979 was an intern and then a resident
in surgery at the Duke University Medical Center in North
Carolina.
DeVries returned to the University of Utah as an assistant
professor of cardiovascular and thoracic surgery. In the meantime,
Robert K. Jarvik had devised the Jarvik-7 artificial heart.
DeVries experimented, implanting it in animals and cadavers
until, following approval from the Federal Drug Administration,
Barney Clark agreed to be the first test patient. He died 115
days after the surgery, having never left the hospital. Although
controversy arose over the ethics and cost of the procedure,
more artificial heart implantations followed, many by DeVries.
Long administrative delays getting patients approved for
surgery at Utah frustrated DeVries, so he moved to Humana
Hospital-Audubon in Louisville, Kentucky, in 1984 and then
took a professorship at the University of Louisville. In 1988 he
left experimentation for a traditional clinical practice. The FDA
withdrew its approval for the Jarvik-7 in 1990.
In 1999 DeVries retired from practice, but not from medicine.
The next year he joined the Army Reserve and began teaching
surgery at the Walter Reed Army Medical Center.

Artificial blood

The invention:

Aperfluorocarbon emulsion that serves as a blood
plasma substitute in the treatment of human patients.

The person behind the invention:

Ryoichi Naito (1906-1982), a Japanese physician.



Blood Substitutes

The use of blood and blood products in humans is a very complicated
issue. Substances present in blood serve no specific purpose
and can be dangerous or deadly, especially when blood or blood
products are taken from one person and given to another. This fact,
combined with the necessity for long-term blood storage, a shortage
of donors, and some patients’ refusal to use blood for religious reasons,
brought about an intense search for a universal bloodlike substance.
The life-sustaining properties of blood (for example, oxygen transport)
can be entirely replaced by a synthetic mixture of known chemicals.
Fluorocarbons are compounds that consist of molecules containing
only fluorine and carbon atoms. These compounds are interesting
to physiologists because they are chemically and pharmacologically
inert and because they dissolve oxygen and other gases.
Studies of fluorocarbons as blood substitutes began in 1966,
when it was shown that a mouse breathing a fluorocarbon liquid
treated with oxygen could survive. Subsequent research involved
the use of fluorocarbons to play the role of red blood cells in transporting
oxygen. Encouraging results led to the total replacement of
blood in a rat, and the success of this experiment led in turn to trials
in other mammals, culminating in 1979 with the use of fluorocarbons
in humans.


Clinical Studies

The chemical selected for the clinical studies was Fluosol-DA,
produced by the Japanese Green Cross Corporation. Fluosol-DA
consists of a 20 percent emulsion of two perfluorocarbons (perfluorodecalin
and perfluorotripopylamine), emulsifiers, and salts
that are included to give the chemical some of the properties of
blood plasma. Fluosol-DA had been tested in monkeys, and it had
shown a rapid reversible uptake and release of oxygen, a reasonably
rapid excretion, no carcinogenicity or irreversible changes in the animals’
systems, and the recovery of blood components to normal
ranges within three weeks of administration.
The clinical studies were divided into three phases. The first
phase consisted of the administration of Fluosol-DA to normal human
volunteers. Twelve healthy volunteers were administered the
chemical, and the emulsion’s effects on blood pressure and composition
and on heart, liver, and kidney functions were monitored. No
adverse effects were found in any case. The first phase ended in
March, 1979, and based on its positive results, the second and third
phases were begun in April, 1979.
Twenty-four Japanese medical institutions were involved in the
next two phases. The reasons for the use of Fluosol-DA instead of
blood in the patients involved were various, and they included refusal
of transfusion for religious reasons, lack of compatible blood,
“bloodless” surgery for protection from risk of hepatitis, and treatment
of carbon monoxide intoxication.
Among the effects noticed by the patients were the following: a
small increase in blood pressure, with no corresponding effects on
respiration and body temperature; an increase in blood oxygen content;
bodily elimination of half the chemical within six to nineteen
hours, depending on the initial dose administered; no change in
red-cell count or hemoglobin content of blood; no change in wholeblood
coagulation time; and no significant blood-chemistry changes.
These results made the clinical trials a success and opened the door
for other, more extensive ones.


IMPACT

Perfluorocarbon emulsions were initially proposed as oxygencarrying
resuscitation fluids, or blood substitutes, and the results of
the pioneering studies show their success as such. Their success in
this area, however, led to advanced studies and expanded use of these compounds in many areas of clinical medicine and biomedical
research.
Perfluorocarbon emulsions are useful in cancer therapy, because
they increase the oxygenation of tumor cells and therefore sensitize
them to the effects of radiation or chemotherapy. Perfluorocarbons
can also be used as “contrasting agents” to facilitate magnetic resonance
imaging studies of various tissues; for example, the uptake of
particles of the emulsion by the cells of malignant tissues makes it
possible to locate tumors. Perfluorocarbons also have a high nitrogen
solubility and therefore can be used to alleviate the potentially
fatal effects of decompression sickness by “mopping up” nitrogen
gas bubbles from the circulation system. They can also be used to
preserve isolated organs and amputated extremities until they can
be reimplanted or reattached. In addition, the emulsions are used in
cell cultures to regulate gas supply and to improve cell growth and
productivity.
The biomedical applications of perfluorocarbon emulsions are
multidisciplinary, involving areas as diverse as tissue imaging, organ
preservation, cancer therapy, and cell culture. The successful
clinical trials opened the door for new applications of these
compounds, which rank among the most versatile compounds exploited
by humankind.