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Press Release: The 1982 Nobel Prize in Physiology or
Medicine
NOBELFÖRSAMLINGEN KAROLINSKA INSTITUTET
THE NOBEL ASSEMBLY AT
THE KAROLINSKA INSTITUTE11 October 1982
The Nobel Assembly of Karolinska
Institutet has today decided to award the Nobel Prize in
Physiology or Medicine for 1982 jointly to
Sune K.
Bergström, Bengt I. Samuelsson and John R. Vane
for their
discoveries concerning "prostaglandins and related biologically
active substances".
Summary
Prostaglandins and
related substances constitute part of a new biological system. They
are formed from unsaturated fatty acids, primarily arachidonic acid.
Arachidonic acid is present in the cellular membrane, which also has
the enzymatic capacity to form prostaglandins. A release of these
compounds takes place when the function of the tissue is pertubed by
trauma, disease or stress, thereby maintaining or reconstituting the
normal function. The prostaglandins and their related substances,
which include the so-called stable prostaglandins as well as
thromboxane and prostacyclin, can therefore best be characterized as
local tissue hormones. They function in the defense of cells against
sudden changes.
The latest members of the prostaglandin
family, the leukotrienes, are formed only in a few tissues and
cells, chiefly in the lung and white blood cells. Release of
leukotrienes in allergic and inflammatory conditions is probably
responsible for the symptoms which characterize these diseases.
Prostaglandins are widely used in clinical medicine,
particularly in obstetrics and gynecology. Prostaglandins and their
analogues have also been successfully used in the treatment of
patients with circulatory disturbances and peptic ulcer. Compounds
inhibiting the formation of prostaglandins effectively relieve pains
provoked by menstruation, gall-stones or kidney-stones.
Sune Bergström is responsible for a crucial
breakthrough in prostaglandin research. He has purified several
prostaglandins and determined their chemical structure. He also
showed that prostaglandins are formed from unsaturated fatty acids.
Through this discovery the metabolism of unsaturated fatty acids
became of major interest in future research. Bengt Samuelsson
has given us a detailed picture of arachidonic acid and
prostaglandin metabolism and clarified the chemical processes
involved in the formation and breakdown of the various compounds in
the system. Samuelsson's discoveries of the endoperoxides,
thromboxanes and leukotrienes were crucial for our present
understanding of the biological significance of this system. John
Vane has discovered prostacyclin and has carried out detailed
analyses of its biological effects and function. In addition, Vane
has made the fundamental discovery that antiinflammatory compounds
such as aspirin act by blocking the formation of prostaglandins and
thromboxanes.
Biological processes in cells and tissues of
living organisms are regulated by a number of mechanisms in order to
maintain a steady state even when large changes occur in the
environment. For instance, the blood pressure and body temperature
normally vary within a very limited range. The organism also has a
large capacity to adjust to various needs, e.g. the blood flow is in
each situation well adjusted to the local need for energy. Prostaglandins
and related substances play an essential role in this connection by
forming a biological system with important regulatory functions.
The prostaglandin research started almost 50 years ago, when
U.
von Euler and M. Goldblatt independently found that seminal
fluid and seminal vesicles from most animals including man contain a
substance which causes contraction of the smooth muscle of the
uterus. Von Euler, Nobel Laureate in 1970, called the new factor
Prostaglandin.
The main breakthrough in the prostaglandin
research was made in the 1950ies when Sune Bergström
and his associates succeeded in the purification of two important
prostaglandins, PGE and PGF, and in identifying their chemical
structure. They found that the prostaglandins are formed by
conversion of unsaturated fatty acids, primarily arachidonic acid.
The presence of these fatty acids in most cells in the body provided
the basis for a new biological system of fundamental importance for
several processes in the healthy and diseased body. Bergström's
discoveries thereby focused the scientific interest on unsaturated
fatty acids.
Bengt Samuelsson, a co-worker of
Bergström already in the beginning of the 1960ies, has been the
leading scientist in the biochemistry of prostaglandins since 1965.
The credit for our present knowledge of the prostaglandin tree with
all its branches (see Figure) goes to him. Samuelsson and associates
have also clarified the biochemical processes by which the various
prostaglandins are formed and metabolized. It is now possible to
separate two distinct branches in this tree. In one of them the
cyclic endoperoxides constitute an important branching point from
which the stable prostaglandins as well as the more unstable
thromboxanes and prostacyclin are formed. The other branch consists
of the leukotrienes, where the very short-living leukotriene A
constitutes the basis for the leukotrienes B, C and D.
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John Vane has made fundamental
contributions to the elucidation of the system by the discovery of
prostacyclin and its biological significance. Furthermore, Vane has,
shown that aspirin and allied anti-inflammatory drugs block the
synthesis of the prostaglandins. Steroid hormones were found to have
similar properties. As illustrated in the figure steroids inhibit
the formation of both endoperoxides and leukotrienes from
arachidonic acid, while aspirin only blocks the formation of
endoperoxides. Thanks to this important discovery the mode of action
of aspirin, the most frequently used drug all over the world, was
clarified. It also provided the prostaglandin researchers with a
useful tool in their analyses of the role of these compounds in
various biological processes.
The prostaglandins are
involved in a large number of biochemical processes, often in
extremely low concentrations. The mode of action of the different
substances of the prostaglandin tree is, however, completely
different. The metabolites of the endoperoxides (the stable
prostaglandins, the thromboxanes and prostacyclin) haye been called
defense hormones. Their task is primarily to protect the integrity
of the organism and they are released when homeostasis is
jeopardized by trauma, disease or various stress factors. Thus, for
instance prostaglandins are continuously formed in the stomach,
where they prevent the tissue from being damaged by the hydrochloric
acid. If the formation of prostaglandins is blocked a peptic ulcer
can rapidly be formed.
When the kidney is exposed to stress
either by a decrease in the supply of oxygen or by hypotension,
certain hormones (renin, angiotensin) are released, which contribute
to a restitution of the blood pressure. These hormones in turn
release prostaglandin PGE which modulates the action of angiotensin.
If the release of PGE in the kidney is blocked, the renal function
rapidly deteriorates due to an uncontrolled action of the hormone.
A continuous blood flow is a prerequisite for a steady
energy supply to the cells. A damage to the wall of the blood vessel
will immediately affect the blood cells, thereby initiating the
process of blood coagulatlon. This is of vital importance for the
protection against loss of substantial amounts of blood. However,
the formation of a thrombosis can also severely damage the organ and
cause death. In order to protect the organism against the formation
of thrombosis, a complicated mechanism has evolved, in which the
prostaglandins are essential factors. Thus, a continuous production
of prostaglandins takes place in the platelets as well as in the
walls of the blood vessels. The thromboxanes in the platelets
initiate an aggregation of blood cells while the prostacyclin in the
vessel wall effectively inhibits such a process. Normally there is a
balance between the release of these two antagonistic
prostaglandins. A disturbance of this balance initiates the
coagulation process. In the last few years compounds have been
developed, which effectively and selectively block the formation of
thromboxanes in the platelets. These compounds are the most
effective anti-thrombotic drugs known today.
In contrast to
the prostaglandins as well as thromboxanes and prostacyclin the
leukotrienes do primarily not act as defense hormones. Furthermore,
the leukotrienes are formed in only a few tissues and cells,
i.e. in the lungs and white blood cells, where they evidently
play an important role for the development of allergic and
inflammatory manifestations. It has recently been shown that
leukotrienes are formed and released in lung tissue obtained from
asthmatic patients and exposed to allergy provoking agents. They
induce contraction of the bronchi and cause an accumulation of
liquid in the lung, thus eliciting changes which characteristic of
the asthmatic attack. No doubt the discovery of the leukotrienes
constitutes a breakthrough in the research on asthma. Compounds
which block the formation of leukotrienes are also supposed to
become effective anti-asthmatic drugs.
It is well known that
the white cells in the blood play an important role in the
inflammatory process, the mechanism however being unknown. It has
recently been shown that leukotrienes have the ability to accumulate
and aggregate white cells in the inflammatory tissue, and also to
increase the content of fluid in such tissue and to release agents
which destroy the tissue. Thus, the leukotrienes are important
factors in the initiation of the inflammatory process, and it can be
expected that compounds which selectively block the formation of
leukotrienes will be used against inflammatory symptoms.
Clinical use of prostaglandins
Prostaglandins
are now widely used in obstetrics and gynecology. Thus, naturally
occurring prostaglandins as well as their analogues are used in the
treatment of obstetric complications, to initiate delivery and to
interrupt a pregnancy. The ability of prostaglandins to soften the
cervix of the uterus has been successfully used in order to prepare
a surgical abortion or a delivery. This effect is rather unique
since it has previously not been possible to widen the cervix by
pharmacological means.
An early interruption of a pregnancy
has until now been performed by surgical intervention. A simple
pharmacological method to be used by the woman herself would mean a
significant progress. Intravaginal application of prostaglandin
analogues is now possible and early abortions have already been
performed by this technique. Undoubtedly this technique constitutes
a considerable step forward especially in developing countries where
there is a lack of doctors.
The cause of the often very
severe pain during the menstruation periods has so far been unknown.
However, it now seems as if this pain is due to an over production
of prostaglandins in the uterus. Various compounds blocking the
synthesis of prostaglandins have therefore been used and found to
effectively reduce this pain. Similarly, these compounds are also
superior in reducing pains induced by stones in the gallbladder and
kidney. Thus, a completely new type of treatment against severe pain
has been established.
Prostaglandins have also been tried
against other diseases. Thus, in patients with arteriosclerotic
stenosis of the arteries of the legs, the severe pain is often
relieved or abolished by prostaglandins. In patients with peptic
ulcers prostaglandin analogues significantly reduce the acid
secretion and often heal the ulcer. |
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