05/05/2018 Medical Milestones - The Past 500 Years

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The New England Journal of Medicine (NEJM) commented on the end of the
millennium by choosing the most important medical developments of the past
thousand years. Their choices were restricted to developments that "changed the
face of clinical medicine, not preventive medicine or public health or health care
delivery or medical ethics  ." They arbitrarily chose 11 and presented them "not in
order of importance, but in rough chronologic order according to the first noteworthy
step taken in a given area."

There were few advances in clinical medicine until the Renaissance. "There are many
reasons little progress was made" until then "but one of them was surely that the only
fit pursuit for scholars in those centuries was considered to be knowledge of God, not
of man. Only with the flowering of humanism that characterized the Renaissance did
that change…." So, the major developments of the past millennium are really those of
the past 500 years. Here are the major developments as presented by NEJM in
outline form.

1. Elucidation of Human Anatomy and Physiology

First noteworthy step in contemporary anatomy: 16th century.

Founding gure: Andreas Vesalius in 1543 published his great anatomical

treatise. The illustrations (by an unknown artist) set a new standard for the
understanding of human anatomy.

First noteworthy step in physiology: 17th century.

Founding gure: William Harvey established that the blood circulates within a
closed system with the heart serving as a pump; the pulse is due to the filling of
arteries with blood after the heart contracts; the right ventricle  of the heart
pumps
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of the body.

Other major gures: Stephen Hales (first measured blood pressure [in a horse]);
Werner Forssmann, Andre Cournand, and Dickinson Richards (the clinical use of
heart catheterization); and Robert Gross, Elliott Cutler, Charles Hufnagel, and
Alfred Blalock (open-heart surgery).

2. Discovery of Cells and Their Substructures

First noteworthy step in cell biology: 17th century.

Founding gure: Antony van Leeuwenhoek, with an object held close to the lens
 he had made (and with his nearsightedness  ) was first able to see minute
"animalcules" (probably bacteria and protozoa) and discover that tissues had
complex inner structures.

Other major gures: Robert Hooke (described plant cells); Matthias Schleiden
and Theodor Schwann (described animal cells); and Rudolf Virchow, Ludwig
Aschoff, and Carl Rokitansky (their work in cell biology led to insights into
disease processes).

First noteworthy step in subcellular biology: 20th century.

Founding gure: Ernst Ruska made the first electron microscope in the early
1930s. With this primitive apparatus and, later, more sophisticated machines,
the rich subcellular structure of the cell became visible.

Another founding gure: George Palade in the 1950s developed ways of

isolating subcellular elements such as mitochondria. "The elegant choreography
of the various elements in particular cell types could finally be appreciated."

3. Elucidation of the Chemistry of Life

First noteworthy step in biochemistry: 17th century.

Founding gures: Thomas Willis set forth the idea in 1659 that "every Disease
acts its tragedies by the strength of some Ferment." This notion was amplified
by scientists such as Antoine Lavoisier, Jons Jakob Berzelius, and Louis
Pasteur.
Medical Milestones - The Past …
Other major gures: Amadeo Avogadro (whose law permitted the calculation of
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atomic weights, the determination of molecular structure and an understanding

of the enzyme reactions); Leonor Michaelis and Maud Menten (who found how
to express enzyme reactions in mathematical terms); Otto Warburg (who
deduced pathways of metabolism  ); and Hans Krebs (who discovered the
pathway called the citric acid cycle).

Other major discoveries: Hormones and neurotransmitters; the ways cells

communicate with each other (which has led to an understanding of diseases
such as diabetes mellitus  ); the relation of sodium to edema and to
dehydration; and the importance of potassium in the fluid loss from diarrhea.

4. Application of Statistics to Medicine

First noteworthy step in modern statistics: Turn of the 17th century.

Founding gures: Pierre de Fermat and Blaise Pascal developed probability

theory to analyze games of chance. Their ideas of relative frequency were first
applied to mortality from the plague in 17th-century London.

Famous clinical trial: James Lind treated 12 ship passengers who had scurvy 
with either an elixir containing citrus juice or a remedy recommended by the
ship's surgeon. The success of the citrus-containing treatment led the British
Admiralty to mandate the provision of lime juice to all sailors (who became
limeys), thereby eliminating scurvy from the Royal Navy.

Other major gures in statistics: John Graunt (introduced the concept of

inference from a sample to an underlying population and described life
expectancy); Karl Friedrich Gauss (developed modern statistical reasoning); the
18th-century English theologian Thomas Bayes (showed how probability can be
used in inductive reasoning); Sir Ronald Fisher (the principle of randomization
as a method for avoiding bias in studies); and Jerzy Neyman (the theories of
estimation and testing).

First noteworthy step in modern epidemiology: 19th century.

Founding gure: John Snow demonstrated the transmission of cholera from

contaminated water by analyzing disease rates among people served by the
Broad Street Pump in London. He stopped the spread of the disease in 1854 by
removing the pump handle from the polluted well.

Another major gure: Richard Doll (who did a pioneering study of smoking
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[among British physicians!]).

5. Development of Anesthesia

First noteworthy step in modern anesthesia: 19th century.

Founding gure: In 1799 Humphry Davy recognized the analgesic  (pain  -

relieving) properties of nitrous oxide when he inhaled it while he had a
toothache. He coined the term "laughing gas."

Other major gures: The dentist Horace Wells (who in 1844 first used nitrous
oxide to anesthetize patients); his former partner, William Morton (who
demonstrated ether anesthesia  in 1846 at the Massachusetts General
Hospital); James Young Simpson (who in 1847 administered chloroform to a
woman in childbirth): and Harold Griffith (who introduced the routine use of
muscle relaxants during surgery in 1942).

6. Discovery of the Relation of Microbes to Disease

First noteworthy step in discovering the relation of microbes to disease: 19th

century.

Founding gure: Louis Pasteur established bacteriology as a science. He proved

that "all living things, microbes included, come from other living things"; he used
heat treatment (pasteurization) to destroy microbes, showed that vaccination of
sheep with weakened anthrax bacteria protects them against the disease, and
discovered that the agent of rabies, a virus, could be weakened; his
immunization  of a young boy bitten by a rabid dog prevented what had been
a fatal outcome.

Other major gures: Robert Koch (first person to isolate bacteria in pure culture;
discovered the agents of cholera and the cause of tuberculosis, and used his
own criteria [Koch's postulates] to distinguish a bacterial culprit causing a
disease from an innocent microbe); and Joseph Lister (who used carbolic acid
spray to kill bacteria, insisted that antiseptics be used on hands, instruments,
and dressings and made it safe to do major surgery).

7. Elucidation of Inheritance and Genetics

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First noteworthy step in genetics: 19th century.

Founding gure: Gregor Mendel did experiments and reported his results on the
segregation of traits in peas in 1865. (Mendel's work was ignored until 1902,
when William Bateson and others rediscovered it.)

Other major gures: Archibald Garrod (who showed that inborn errors of
metabolism  are inherited); Thomas Hunt Morgan (who drew maps of genes
along chromosomes); George Beadle, Edward Tatum, and Boris Ephrussi (who
showed that genes specify enzymes); Thomas Avery, Colin MacLeod, and
Maclyn McCarty (who found that DNA is the genetic material); Erwin Chargaff
(who described the bases of DNA and the rules of base pairing); Rosalind
Franklin (whose x-ray diffraction pictures of DNA permitted the discovery of the
double helix); James Watson, Francis Crick, and Maurice Wilkins (the double
helix); Jacques Monod and Francois Jacob (DNA to protein via messenger
RNA); Frederick Sanger and Walter Gilbert (who created methods for decoding
the sequence of bases in DNA); and David Baltimore and Harold Temin (who
discovered reverse transcriptase, which converts RNA into DNA).

Famous train ride: On a train from Denver to Chicago in 1949, William Castle told
Linus Pauling about sickle cell anemia. Pauling and coworkers then
demonstrated the molecular consequence of a mutation (sickle hemoglobin)
that causes a genetic disorder (sickle cell anemia) and termed it "a molecular
disease." (The sickle mutation was later shown by Vernon Ingram to be due to a
single amino acid substitution in the molecule).

8. Knowledge of the Immune System

First noteworthy step in immunology: 19th century.

Founding gures: Emil Behring and Kitasato Shibasaburo in 1890 developed a

diphtheria antitoxin and, in the process, discovered antibodies. Almost
simultaneously, Elie Metchnikoff identified cells called phagocytes that can
engulf foreign particles and put forth the cellular theory of immunity.

Other major gures: John Enders (measles vaccine) ; Thomas Weller, Frederick
Robbins and Enders (the polio vaccine); Albert Sabin (the live weakened polio
virus); Jonas Salk (the killed-virus vaccine); and Michael Heidelberger (laid the
foundation for the pneumococcal vaccines).

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the Food and Drug Administration in 1986. The new millennium "promises a
potentially revolutionary form of vaccination based on sequences of DNA that
encode microbial antigens."

9. Development of Body Imaging

First noteworthy step in body imaging: Turn of the 20th century.

Founding gure: Wilhelm Konrad Roentgen discovered x-rays in 1895, a

discovery for which he received the first Nobel prize for physics in 1901.

First stage: Imaging science has evolved in three stages. In the first stage, the
aim was to develop imaging techniques to define the anatomic features and
functions of the internal organs. Additional "rays" for this purpose were
discovered, including ultrasound and radioactive tracers, and contrast agents
were developed to reveal previously indiscernible structures.

Second stage: The interior of the heart and blood vessels were delineated by
angiography  . Other new tools included computed tomography (CT or CAT
scan  ) and magnetic resonance imaging (MRI), which permitted resolution of
very small structures throughout the body.

Third stage: Imaging methods are now being used to guide therapy directly --
from long-term guidance of cancer therapy to immediate, on-line guidance of
minimally invasive surgery.

10. Discovery of Antimicrobial Agents

First noteworthy step in the discovery of antimicrobial agents: Turn of the 20th
century.

Founding gure: Paul Ehrlich discovered salvarsan (also known as "606," the
606th compound he had tried) as a treatment for syphilis  and showed that
certain dyes also had antimicrobial  activity.

Other major gures: Gerhard Domagk (who found that the red dye Prontosil
cured strep infections, which led to the development of the sulfa drugs);
Alexander Fleming (who stumbled onto the inhibition of Staph bacteria by a
mold, Penicillium)
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clinical use); Rene Dubos (who found an antibiotic  in an organism in the

soil); and Selman Waksman (who searched systematically among soil
organisms for antibiotics and there discovered the second clinically important
antibiotic, streptomycin).

11. Development of Molecular Pharmacotherapy

First noteworthy step in molecular pharmacotherapy: Turn of the 20th century.

Founding gure: In the course of his experiments on the therapeutic potential of

organic dyes, Paul Ehrlich coined the word "chemotherapy" and extended the
concept of the "magic bullet" from infectious diseases to cancer  .

Other major gures Thomas Beatson (who used ovariectomy [removal of the
 ovaries] for breast cancer); Charles Huggins (showed value of orchiectomy
[removal of the testes] for prostate cancer). Alfred Gilman and Frederick Philips

(found that nitrogen mustard -- the mustard gas of World War I - helped treat
lymphomas); Sidney Farber (introduced methotrexate for treating childhood 
leukemia); Barnett Rosenberg (discovered the anticancer drug cis- platinum);
and James Black (whose work led to the development of beta- blockers).

The ongoing revolution in molecular biology permits the recognition of a great

number of new potential drug targets, while pharmacogenetics is beginning to
explain the genetic variability among people in their responses to drugs.

Conclusions

The effective treatment and prevention of disease has "extended life expectancy and
reduced disability beyond the most optimistic hopes of physicians even a few
decades ago -- and far beyond the dreams of their predecessors a thousand years
ago. We are no more able than they were to predict what this new millennium will
bring."

SourceThe Editors. Looking back on the millennium in medicine. New Engl J Med
342: 42-49, 2000.

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