Cholesterol is essential for the functioning
of all human organs, but it is nevertheless the cause of coronary
heart disease—a condition that is responsible for more than
one-third of all deaths in the Western world. It is in fact the
number one killer in the United States and in other industrialized
Over the course of nearly a century of investigation, researchers
have developed four lines of evidence—experimental, genetic,
epidemiologic, and therapeutic—that irrefutably established the
causal connection between cholesterol-carrying low-density
lipoprotein (LDL) and atherosclerosis. Building on that knowledge,
scientists have been successful in developing an effective course of
therapy—the statin drugs.
Few other major diseases have been subject to such intensive and
ultimately fruitful research. Here, briefly, is how the history of
cholesterol research unfolded.
THE EXPERIMENTAL EVIDENCE
hint that cholesterol was related to atherosclerosis goes back to
1910, when the German chemist Adolph Windaus reported that
atherosclerotic plaques from aortas of human subjects contained 20-
to 26-fold higher concentrations of cholesterol than did normal
aortas. Three years later, the Russian pathologist Nikolai Anitschov
fed pure cholesterol to rabbits, which produced marked
hypercholesterolemia and severe atherosclerosis of the aorta. This
was the first experimental production of atherosclerosis, and
Anitschov's experiment has been repeated many thousands of times
ever since in virtually every animal species from pigeons to humans.
Windaus and Anitschov studied aortic plaques rather than the
coronary artery plaques that are responsible for heart attacks.
Aortic plaques in humans had been noted by 19th-century
pathologists, who believed that coronary artery plaques were rare;
they also believed that when a thrombotic occlusion of an
atherosclerotic plaque did occur in a coronary artery, it was always
a fatal event. This view persisted until 1918, when the syndrome of
nonfatal myocardial infarction was recognized by James Herrick, a
Chicago clinician, who made the first use of the electrocardiograph
to diagnose heart attacks in patients who presented with crushing
chest pain. Herrick provided the first clear demonstration that
thrombosis of a coronary artery was not always fatal and that
coronary heart disease was responsible for the acute chest pain that
had been previously ascribed to all kinds of causes, from
indigestion to apoplexy.
THE GENETIC EVIDENCE
connection between cholesterol and heart attacks was first made in
1938 by Norwegian clinician Carl Müller, who described several large
families in which high blood-cholesterol levels and premature heart
attacks together were an inherited trait. The genetic understanding
of this syndrome, which came to be known as familial
hypercholesterolemia (FH), was greatly advanced 25 years later by
the astute observations of Lebanese clinician Avedis K.
Khachadurian, who delineated two clinically distinct forms of FH in
inbred families—the homozygous form, in which affected
individuals manifest severe hypercholesterolemia at birth (with
plasma cholesterol levels of about 800 mg/dl) and heart attacks that
occur as early as 5 years of age, and the heterozygous form,
characterized by levels in the 300- to 400-mg/dl range and premature
heart attacks that occur typically between 35 and 60 years of age.
The incidence of heart attacks in children with homozygous FH
provided strong genetic evidence that hypercholesterolemia alone can
The mounting clinical interest in cholesterol led to an intense
effort in the 1950s to determine the process by which cholesterol
was synthesized in the body. Most of the crucial steps in this
complex pathway, involving 30 enzymatic reactions, were worked out
by four biochemists—Konrad E. Bloch, Feodor Lynen, John Cornforth,
and George Popják—in a triumph of technical virtuosity that combined
organic chemistry, enzymology, and one of the earliest uses of
radioisotopes. The major outlines of this pathway were completed by
THE EPIDEMIOLOGIC EVIDENCE
epidemiologic side of the cholesterol-coronary connection unfolded
in 1955 when John Gofman, a biophysicist at the University of
California at Berkeley, used the newly developed ultracentrifuge to
separate plasma lipoproteins by flotation. Gofman found not only
that heart attacks correlated with elevated levels of cholesterol
but also that the cholesterol was contained in one lipoprotein
particle, LDL. Gofman also observed that heart attacks were less
frequent when the blood contained elevated levels of another
cholesterol-carrying lipoprotein, high-density lipoprotein (HDL).
The epidemiologic connection between blood cholesterol and
coronary atherosclerosis was firmly established by a physiologist at
the University of Minnesota, Ancel Keys, whose classic Seven
Countries Study showed that the incidence of heart attacks in 15,000
middle-aged men followed for 10 years was linearly proportional to
the blood level of cholesterol. Keys also found that the cholesterol
level rose in proportion to the saturated-fat content of the diet.
Men living in eastern Finland, where the mean cholesterol level was
260 mg/dl, had eight times more coronary deaths in a 10-year period
than men living in a Japanese fishing village where the mean
cholesterol level was 165 mg/dl. Men living in Italy, where the mean
cholesterol level (200 mg/dl) was intermediate between that of Japan
and eastern Finland, had three times fewer coronary deaths than in
Finland and three times more than in Japan. Subsequent studies
showed that this wide range of cholesterol levels resulted from a
correspondingly wide variation of LDL levels in the blood.
In 1974, the authors of this article discovered that the level of
LDL in blood is controlled by the activity of a cell-surface protein
we called the LDL receptor, which binds LDL and delivers it to cells
where the lipoprotein is degraded; the cholesterol is then used
there for metabolic and structural purposes. We also found that FH
is caused by genetic defects in this receptor that ultimately block
removal of LDL from the blood. These studies provided the first
molecular link between LDL cholesterol and atherosclerosis.
THE THERAPEUTIC EVIDENCE
Akira Endo, a Japanese scientist at the Sankyo Co. Ltd., discovered
a fungal metabolite that could block cholesterol synthesis by
inhibiting the enzyme HMG-CoA reductase. This discovery led to the
first statin. In collaboration with Endo, we showed that the
inhibition of cholesterol synthesis led to an up-regulation of LDL
receptors, which explained how these drugs could selectively lower
LDL, the bad cholesterol, without lowering HDL, the good
cholesterol. We encouraged Merck & Co. Inc. to develop these
drugs for therapeutic use, and in 1986 the FDA approved the first
statin for human consumption. In 2003, more than 25 million people
worldwide will take statins.
In 1994 the landmark "4S" (Scandinavian Simvastatin Survival
Study) was completed. Sponsored by Merck and conducted by physicians
in four Scandinavian countries, it showed for the first time that
statins, by lowering LDL levels, could not only prevent myocardial
infarctions but could generally prolong life. In several large
multicenter trials, involving nearly 50,000 people followed for
three to five years, treatment with statins lowered LDL levels by
25-35 percent and reduced the frequency of heart attacks by 25-30
percent—even in high-risk people who had "normal" LDL levels at
entry. In these individuals, the high risk came from other
predisposing conditions such as chronic smoking, hypertension, or
diabetes. They benefited from statin therapy presumably because the
predisposing conditions render the coronary arteries prone to
inflammation at LDL levels considered "normal" in Western societies.
After nearly 100 years of exploration, we now have four lines of
persuasive evidence—experimental, genetic, epidemiologic, and
therapeutic—that implicate the cholesterol-carrying LDL particle as
the primary cause of atherosclerosis. Very few, if any, chronic
diseases of adults have ever been subjected to such intensive
research, and in very few, if any, chronic diseases of adults has
the cause been so convincingly demonstrated in so many ways.
Joseph L. Goldstein and Michael S. Brown shared the 1985 Nobel
Prize in Physiology or Medicine for their research on the mechanism
underlying cholesterol metabolism.
this story in Acrobat PDF format.
Photos: Reid Horn, Courtesy of Brown-Goldstein
Reprinted from the HHMI Bulletin,
September 2003, pages 10-19.
©2003 Howard Hughes Medical