17 December 2008

Artificial hormone




The invention: 

Synthesized oxytocin, a small polypeptide hormone
from the pituitary gland that has shown how complex 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 ;


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