Artificial hormone

The invention: 



Synthesized oxytocin, a small polypeptide hormone

fromthe pituitary gland that has shownhowcomplex polypeptides

and proteins may be synthesized and used in medicine.



The people behind the invention:



Vincent du Vigneaud (1901-1978), an American biochemist and

winner of the 1955 Nobel Prize in Chemistry

Oliver Kamm (1888-1965), an American biochemist

Sir Edward Albert Sharpey-Schafer (1850-1935), an English

physiologist

Sir Henry Hallett Dale (1875-1968), an English physiologist and

winner of the 1936 Nobel Prize in Physiology or Medicine

John Jacob Abel (1857-1938), an American pharmacologist and

biochemist









Body-Function Special Effects



In England in 1895, physician George Oliver and physiologist

Edward Albert Sharpey-Schafer reported that a hormonal extract

from the pituitary gland of a cow produced a rise in blood pressure

(a pressor effect) when it was injected into animals. In 1901, Rudolph

Magnus and Sharpey-Schafer discovered that extracts from

the pituitary also could restrict the flow of urine (an antidiuretic effect).

This observation was related to the fact that when a certain

section of the pituitary was removed surgically from an animal, the

animal excreted an abnormally large amount of urine.

In addition to the pressor and antidiuretic activities in the pituitary,

two other effects were found in 1909. Sir Henry Hallett Dale,

an English physiologist, was able to show that the extracts could

cause the uterine muscle to contract (an oxytocic effect), and Isaac

Ott and John C. Scott found that when lactating (milk-producing)

animals were injected with the extracts, milk was released from the

mammary gland.

Following the discovery of these various effects, attempts were

made to concentrate and isolate the substance or substances that

were responsible. John Jacob Abel was able to concentrate the pressor

activity at The Johns Hopkins University using heavy metal salts

and extraction with organic solvents. The results of the early work,

however, were varied. Some investigators came to the conclusion

that only one substance was responsible for all the activities, while

others concluded that two or more substances were likely to be involved.

In 1928, Oliver Kamm and his coworkers at the drug firm of

Parke, Davis and Company in Detroit reported a method for the

separation of the four activities into two chemical fractions with

high potency. One portion contained most of the pressor and antidiuretic

activities, while the other contained the uterine-contracting

and milk-releasing activities. Over the years, several names have

been used for the two substances responsible for the effects. The generic

name “vasopressin” generally has become the accepted term

for the substance causing the pressor and antidiuretic effects, while

the name “oxytocin” has been used for the other two effects. The

two fractions that Kamm and his group had prepared were pure

enough for the pharmaceutical firm to make them available for

medical research related to obstetrics, surgical shock, and diabetes

insipidus.





 A Complicated Synthesis



The problem of these hormones and their nature interested Vincent

du Vigneaud at the George Washington University School of

Medicine.Working with Kamm, he was able to show that the sulfur

content of both the oxytocin and the vasopressin fractions was a result

of the amino acid cystine. This helped to strengthen the concept

that these hormones were polypeptide, or proteinlike, substances.

Du Vigneaud and his coworkers next tried to find a way of purifying

oxytocin and vasopressin. This required not only the separation

of the hormones themselves but also the separation from other impurities

present in the preparations.

During World War II (1939-1945) and shortly thereafter, other

techniques were developed that would give du Vigneaud the tools

he needed to complete the job of purifying and characterizing

the two hormonal factors. One of the most important was the

countercurrent distribution method of chemist Lyman C. Craig at

the Rockefeller Institute. Craig had developed an apparatus that

could do multiple extractions, making possible separations of substances

with similar properties. Du Vigneaud had used this technique

in purifying his synthetic penicillin, and when he returned to

the study of oxytocin and vasopressin in 1946, he used it on his purest

preparations. The procedure worked well, and milligram quantities

of pure oxytocin were available in 1949 for chemical characterization.

Using the available techniques, Vigneaud and his coworkers

were able to determine the structure of oxytocin. It was du Vigneaud’s

goal to make synthetic oxytocin by duplicating the structure

his group had worked out. Eventually, du Vigneaud’s synthetic

oxytocin was obtained and the method published in the Journal of

the American Chemical Society in 1953.

Du Vigneaud’s oxytocin was next tested against naturally occurring

oxytocin, and the two forms were found to act identically in every

respect. In the final test, the synthetic form was found to induce

labor when given intravenously to women about to give birth. Also,

when microgram quantities of oxytocin were given intravenously

to women who had recently given birth, milk was released from the

mammary gland in less than a minute.





Consequences



The work of du Vigneaud and his associates demonstrated for

the first time that it was possible to synthesize peptides that have

properties identical to the natural ones and that these can be useful

in certain medical conditions. Oxytocin has been used in the last

stages of labor during childbirth. Vasopressin has been used in the

treatment of diabetes insipidus, when an individual has an insufficiency

in the natural hormone, much as insulin is used by persons

having diabetes mellitus.

After receiving the Nobel Prize in Chemistry in 1955, du Vigneaud

continued his work on synthesizing chemical variations of the two

hormones. By making peptides that differed from oxytocin and

vasopressin by one or more amino acids, it was possible to study how

the structure of the peptide was related to its physiological activity.

After the structure of insulin and some of the smaller proteins

were determined, they, too, were synthesized, although with greater

difficulty. Other methods of carrying out the synthesis of peptides

and proteins have been developed and are used today. The production

of biologically active proteins, such as insulin and growth hormone,

has been made possible by efficient methods of biotechnology.

The genes for these proteins can be put inside microorganisms,

which then make them in addition to their own proteins. The microorganisms

are then harvested and the useful protein hormones isolated

and purified.





 See also: Abortion pill; Artificial blood; Birth control pill;

 Geneticallyengineered insulin; Pap test.