Medical Milestones - The Past 500 Years

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 figure: 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 figure: 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 blood to the lungs; and the left ventricle pumps blood to the rest of the body.

Other major figures: 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 figure: 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 figures: 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 figure: 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 figure: 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 figures: 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.

Other major figures: Amadeo Avogadro (whose law permitted the calculation of 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 figures: 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 figures 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 figure: 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 figure: Richard Doll (who did a pioneering study of smoking [among British physicians!]).


5. Development of Anesthesia


First noteworthy step in modern anesthesia: 19th century.

Founding figure: 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 figures: 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 figure: 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 figures: 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


First noteworthy step in genetics: 19th century.

Founding figure: 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 figures: 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 figures: 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 figures: 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).

The first vaccine produced by DNA technology (for hepatitis B) was approved by 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 figure: 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 figure: 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 figures: 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) ; Howard Florey and Ernst Chain (who purified penicillin for 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 figure: 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 figures 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."

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

Last Editorial Review: 5/5/2003

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