Modern Medicine and Physiology

Dr. C. George Boeree

Technology and the brain

In the 1800's, anatomy had reached a point of sophistication that allowed medical artists to make such intricate drawings that modern surgeons could still benefit from them.  But there was always a limitation involved:  It was one thing to carve up a dead brain -- quite another to actually see a living brain at work.  In the late 1800's and throughout the 1900's, we see some remarkable efforts at exploring the brain without removing it from its owner:  First, Wilhelm Konrad Roentgen invents the x-ray in 1895.  A remarkable tool for physicians and researchers, it proves less useful when it comes to the soft tissues of the brain.  In 1972, Godfrey Hounsfield added the computer to the x-ray and developed computerized (axial) tomography -- the CT (or CAT) scan -- which sums multiple extras into a far more detailed three-dimensional image.

In a very different approach,  Hans Berger developed the first electroencephalogram (EEG) in 1929.  In 1932, Jan Friedrich Tonnies created the first modern version, with its moving paper and vibrating pens.  The EEG records the minute electrical coordinated pulses of large number of neurons on the surface of the cortex.  It was only a matter of time before researchers added the computer to the equation.

In 1981, the team of Phelps, Hoffman, and TerPogossian developed the first PET scan.  The PET scan (positron emission tomography) works like this:  The doctor injects radioactive glucose (that’s sugar water) into the patient’s bloodstream.  The device then detects the relative activity level -- that is, the use of glucose -- of different areas of the brain.  The computer generates an image that allows the researcher to tell which parts of the brain are most active when we perform various mental operations, whether it’s looking at something, counting in our heads, imagining something, or listening to music!

In 1937, Isidor I. Rabi, a professor at Columbia University, noticed that atoms reveal themselves by emitting radio waves after first having been subjected to a powerful magnetic field.  He called this nuclear magnetic resonance or NMR.  This was soon used by scientists to identify chemical substances in the lab.  It would be many years later that a Dr. Raymond Damadian would recognize the potential of NMR's for medicine.

Damadian is an interesting and controversial person.  He was born in New York City in 1936.  When he was only eight years old, he was accepted by the Juilliard School of Music.  He was awarded a scholarship to the University of Wisconsin at Madison, and then went on to medical school at the Albert Einstein College of Medicine of the Yeshiva University in the Bronx.  He received his MD in 1960 at the tender ago of 24.  From there, he began medical research at Brooklyn's Downstate Medical Center.

Investigating tumors in rats, he noted that the NMR signals from cancerous tumors were significantly different from the signal from healthy rats.  He hypothesized that the reason was the larger number of water molecules (and therefore hydrogen atoms) in these tumors.  His findings were published in Science in 1971.

Realizing that this was the basis for a non-surgical way to detect cancer, he got the idea for a large-scale NMR device that could record the radio waves coming from all the atoms in a human being.  You only had to create a magnetic field big enough!

In 1977, he and his students built a temperamental prototype of the modern MRI -- magnetic resonance imaging -- which they called the Indomitable.  He tried it, unsuccessfully, on himself first, then on a graduate student named Larry Minkoff.  The result was a mere 106 data points (recorded first in colored pencils!) describing the tissues of Minkoff's chest.  The Indomitable is now in the Smithsonian.

Damadian's story continues with his recording of a patent and years of litigation trying to fight off companies like Hitachi and General Electric who disputed his patent.  He has also stirred up controversy by supporting the work of so-called "creation scientists."

There have been a number of other scientists studying NMR who were in fact heading in the same direction as Damadian.  One person in particular with a legitimate claim to co-discovery is Paul Lautenbur. He developed the idea of using small NMR gradients to map the body while at SUNY Stony Brook.  In 1973, he used his technique on a test tube of water, and then used it on a clam.  His work was published in Nature, and it is his technique that is favored today.  Lautenbur and British MRI researcher Peter Mansfield were awarded the Nobel Prize in 2003.

The MRI works like this:  You create a strong magnetic field which runs through the person from head to toe.  This causes the spinning hydrogen atoms in the person’s body to line up with the magnetic field.  Then you send a radio pulse at a special frequency that causes the hydrogen protons to spin in a different direction.  When you turn off the radio pulse, the protons will return to their alignment with the magnetic field, and release the extra energy they took in from the radio pulse.  That energy is picked up by the same coil that produced the energy, now acting like a three dimensional antenna.  Since different tissues have different relative amounts of hydrogen in them, they give a different density of energy signals, which the computer organizes into a detailed three-dimensional image.  This image is nearly as detailed as an anatomical photograph!

On the more active side, direct electrical stimulation of the brain of a living person became a fine art in the 1900's.  In 1909, Harvey Cushing mapped the somatosensory cortex.  In 1954, James Olds produced a media sensation by discovering the so-called "pleasure center" of the hypothalamus.  By the end of the century, the specialized areas of the brain were pretty well mapped.

Brain surgery also became more effective.  In the process of looking for surgical relief for extreme epilepsy, it was discovered that cutting the corpus callosum, which joins the two hemispheres of the cerebral cortex, greatly improved the patients' condition.  Roger Sperry was then able to discover the various differences between the left and right hemisphere in some of the most interesting studies in history.  He was awarded the Nobel Prize for his work in 1981.

The other aspect of technology is its use in attempting to heal people with mental illness.  Although extremely controversial to this day, the evidence strongly suggests that electroshock therapy, first used by Ugo Cerletti and Lucino Bini in 1938, can be effective in the care of very depressed patients.  Electroshock (also known as electro-convulsive therapy or ECT) involves sending a strong electrical current through an anesthetized patient's brain.  When they awake, they cannot seem to recall several hours of time before the procedure, but also feel much less depressed.  We aren't sure why it works.

Less effective and much more radical is the lobotomy, first used on human beings by Antonio Egaz Moniz of the University of Lisbon Medical School, who won the Nobel Prize for his work in 1949.  The lobotomy was turned into a mass-production technique by Walter Freeman, who performed the first lobotomy in the U.S. in 1936.  To read more about lobotomy, click here.

The psychopharmacological explosion  

In the 1800's, the basic principles of the nervous system were slowly being unraveled by people such as Galvani in Italy and Helmholtz in Germany.  Toward the end of the 1800s, biologists were approaching an understanding of the details.  In particular, Camillo Golgi (who believed that the nervous system was a single entity) invented a staining technique that allowed Santiago Ramon y Cajal to prove that the nervous system was actually composed of individual neurons.  Together, they won the Nobel Prize in 1906.

The British biologist Sir Charles Sherrington had already named what Ramon y Cajal saw: the synapse.  He, too, would win a Nobel Prize for his work on neurons with Edgar Douglas Adrian.

In 1921, the German biologist Otto Leowi completed the picture by discovering acetylcholine and the idea of the neurotransmitter.  For this work, he received the Nobel Prize, shared with Henry Hallett Dale.  Interestingly, acetylcholine is a relative of muscarine -- the active ingredient of some of those mushrooms that some of our ancient ancestors liked so much.  In 1946, another biologist, von Euler, discovered norepinephrine.  And, in 1950, Eugene Roberts and J. Awapara discovered GABA.

In the early part of the 1900's, we see the beginnings of psychopharmacology as a medical science, with the use of bromide and chloralhydrate as sedatives.  Phenobarbital enters the picture in 1912 as the first barbiturate.  In the second half of the 1900s, with the basic mechanisms of the synapse understood, progress in the development of psychoactive drugs truly got underway.  For example...

In 1949, John Cade, an Australian psychiatrist, found that lithium, a light metal, could lessen the manic aspect of manic-depression.

In 1952, a French Navy Doctor, Henri Laborit, came up with a calming medication which included chlorpromazine, which was promoted as the antipsychotic Thorazine a few years later.

Imipramine, the first tricyclic antidepressant, was developed at Geigy Labs by R. Kuhn in the early 1950's, while he was trying to find a better antihistamine!

In the late 1950's, Nathan Klein studied the use of reserpine in 1700s India, and found it reduced the symptoms of many of his psychiatric patients.  Unfortunately, the side effects were debilitating.

In 1954, the drug meprobamate, better known as Miltown, became available on the market.  Its chemical foundation was discovered a decade earlier by Frank Berger, while he was trying to discover a new antibiotic. He found a tranquilizer instead!

Iproniazid (an MAOI antidepressant) was developed in 1956 by the Hoffman-LaRoche pharmaceutical company for tuberculosis patients.  It appeared to cheer them up a bit!  Although it was banned because of side effects, it was the first in a long series of antidepressants.

Leo Sternbach also worked for Hoffman-LaRoche, and discovered the drug Valium (diazepam) in 1959, and Librium (chlordiazepoxide) the following year -- two of the most useful and used psychoactive drugs ever.

The progress of psychopharmacology was greatly aided by increased knowledge of the activities at the level of the synapse.  John Eccles, Alan Lloyd Hodgkin and Andrew Fielding Huxley shared the Nobel Prize in 1963 for their work on the neuron's membrane.  And in 1973, Solomon Snyder and Candace Pert of Johns Hopkins discovered "internal morphine" or endorphin, and the "lock-and-key" theory -- the basic mechanism of psychoactive drugs -- was confirmed.

In 1974, D. T. Wong at Eli Lilly labs discovered fluoxetine -- Prozac -- and its antidepressant effects.  It was approved by the FDA in 1987.  This substance and others like it -- known as the serotonin selective re-uptake inhibitors or SSRIs -- would dramatically change the care of people with depression, obsessive-compulsive disorder, social anxiety, and other problems.

In the 1990's, new neuroleptics (antipsychotic drugs) such as clozapine were developed which addressed the problems of schizophrenia more completely than the older drugs such as chlorpromazine, and with fewer side effects.

What is the future going to be like, in regard to psychopharmacology?  Some say the major breakthroughs are over, and it is just a matter of producing better variations.  But that has been said many times before.  Biochemistry is still progressing, and every year brings something new.  The rest of us can only hope that many more and better medications with psychiatric applications will be found.

Genetics and the human genome

The science of genetics begins in the garden of an Austrian Monk named Gregor Mendel.  In 1866, he published the results of his work suggesting the existence of “factors” -- which would later be called genes -- that are responsible for the physical characteristics of organisms.

A Columbia University professor, Dr. Thomas Morgan, provided the next step in 1910 by discovering that these genes are in fact carried within the structures called chromosomes.  And in 1926, Hermann J. Muller discovered that he could create mutations in fruit flies by irradiating them with X-rays.

Finally, in 1953, Dr. Rosalind Franklin and, independently, Dr. James D. Watson and Dr. Francis Crick outlined the structure of the DNA molecule.  And Dr. Sydney Brenner completed the picture by discovering RNA and the basic processes of protein construction.

The next phase of genetics involves the mapping of the DNA:  What is the sequence of bases (A, T, G, and C) that make up DNA, and how do those sequences relate to proteins and ultimately to the traits of living organisms?  Two researchers, Frederick Sanger and Walter Gilbert, independently discovered a technique to efficiently “read” the bases, and in 1977, a bacteriophage virus was the first creature to have its genome revealed.

In the 1980’s, the Department of Energy revealed a plan to bring together researchers world-wide to learn the entire genome - of human beings!  The NIH (National Institute of Health) joined in, and made Dr. James Watson the director of the Office of Human Genome Research.

In 1995, Dr. Hamilton Smith and Dr. J. Craig Venter read the genome of a bacterium.  In 1998, researchers published the genome of the first animal, a roundworm.  In 2000, they had the genome of the fruit fly.  And in the same year, researchers had the genome sequence of the first plant.

In June of 2000, at a White House ceremony hosted by President Clinton, two research groups -- the Human Genome Project consortium and the private company Celera Genomics -- announced that they had nearly completed working drafts of the human genome.  In February of 2001, the HGP consortium published its draft in Nature and Celera published its draft in Science.  The drafts described some 90% of the human genome, although scientists knew the function of less than 50% of the genes discovered..

There were a few surprises:  Although the human genome is comprised of more than three billion bases, this is only a third as large as scientists had predicted.  And it is only twice as large as that of the roundworm.  It was also discovered that 99.9% of the sequences are exactly the same for all human beings.  We are not as special as we like to think!

The human genome project is not just an intellectual exercise:  Knowing our genetic makeup will allow us to treat genetic illnesses, custom-design medicines, correct mutations, more effectively treat and even cure cancer, and more.  It is an accomplishment that surpasses even the landing on the moon.

Copyright 2002, C. George Boeree