I anticipate objections to the title that I have tagged onto this offering. The science of medicine is about attempting to cure disease, or at least alleviate the symptoms. Thus, treatment is what is central to the science of medicine. Certainly, diagnosis is an important step in that process. First, you try to figure out what’s wrong with the ailing person, and then you try to fix it, using whatever means are available. What’s central to medicine is effectively dealing with disease of all types. Diagnosis is important in that it – hopefully! – leads to treatment.

However, although medical treatment is the result of a colossal amount of intensive research, it has evolved from its earliest days through a series of fortunate discoveries – what we might call “lucky breaks.” The most widely-used drug in the world, aspirin, evolved from the discovery that a potion made from the bark of the willow tree would ease pain. And the users of this potion also found that it not only relieved pain but also brought down fevers, reduced swelling, and inhibited blood clotting. These discoveries were not due to the rigorous application of the scientific method, but to chance.

A similar lucky break took place in September of 1928, when Alexander Fleming left his petri dishes uncovered in his laboratory while he was on a two-week vacation. The petri dishes were growing a strain of staphylococcus, a very common bacterium that causes mostly skin and soft tissue infections.

When he came back from his vacation, he found that swatches of the staphylococcus had been totally eliminated from the broth in the petri dishes. It turned out that miniscule flakes of a mold, Penicillium notatum, had fallen in to the petri dishes. The penicillin killed the staphylococcus. And it was that lucky break that set in motion the discovery and development of the large family of antibiotics, which had not been previously known, and which completely transformed the treatment of infectious diseases.

There have been a great number of similar fortunate discoveries. The Pacific yew tree is the origin of the anticancer drug paclitaxel. Curare, harvested from a South American plant, was first used in poison arrows for hunting, and is now used as a muscle relaxant in anaesthesia. The bark of another South American plant, the cinchona, contains quinine, which is used to treat malaria. The number of possibly valuable drugs derived from natural substances is very large indeed. Discovering the usefulness of these substances and putting them to use certainly involved research, but research alone was not what led to their use.

Diagnosis, on the other hand, does not generally benefit from lucky breaks. It is the result of dedicated, dogged research. The word “diagnosis,” from the identical Latin and Greek words, “dia,” meaning “thoroughly,” and “gnosis,” meaning “to perceive,” first turned up in the English language in the 17th century. A 1791 textbook was entitled A Treatise on the Diagnosis and Prognosis of Disease. My OED defines diagnosis as the “determination of the nature of a disease condition; identification of a disease by careful identification of its symptoms and history.”

Our assumption is that treatment follows from diagnosis as the day follows night. The docs figure out what’s wrong with us, and then they go ahead and fix it. Or, at least, they try to fix it. Of course, we do acknowledge that sometimes they are unable to pinpoint exactly what is wrong with us. There can be flaws in the diagnostic process. But diagnosis is supposed to lead to treatment. That’s the basis of medical practice in the present day.

Diagnosis in the early days

It wasn’t always so, of course. Humans have always tried to figure out what was wrong when they didn’t feel right, and for all of recorded history there have been ways of attempting to identify the causes of illness and disease. Physicians in ancient Egypt could tell if a patient was having problems with his/her heart or digestive system or respiratory system or muscles of the arms, legs, or back. They could distinguish between liver, spleen, and menstrual issues. A papyrus dating from about 1500 BCE (before the common era) listed twenty-two vessels in the body that transport essential substances such as blood, air, semen, urine, tears, and mucus. That papyrus also mentioned a number of plant medicaments that could be used to attempt to treat disease, including opium, cannabis, myrrh, frankincense, fennel, cassia (Chinese cinnamon), senna, thyme, henna, juniper, aloe, linseed and castor oil. (Plant-based therapies have continued to be an important factor in medical practice right down to the present day.)

The Babylonians were observant and logical in their attempts to understand and diagnose illnesses. They closely observed and described the symptoms of epilepsy and other ailments that resulted in prominent bodily symptoms, and they focused closely on body temperature. Of course, they had no instruments that could measure temperature, but they could judge temperature based on feeling the patient’s body and comparing that with how the bodies of other persons felt. They were able to identify conditions such as what we now call pneumonia by observing the throat and phlegm of the affected person. They recognized epilepsy and stroke and understood, to some degree, the difference between these.

Hippocrates, a Greek physician from the fifth century BCE, made important contributions to medicine that have persisted to the present day. He emphasized that the physician needed to understand and carefully listen to whatever the patient was saying about his/her overall health conditions, beyond the immediate circumstances of the ailment that caused the patient to seek the physician’s care. Hippocrates sought to support the patient’s total health. He identified four “humors” as essential indicators of health. These were blood, phlegm, and yellow and black bile. What Hippocrates is often remembered for is his association with those four “humours,” and not his more general understanding and emphasis on the patient’s general health. However, the Hippocratic Oath survives to this day. Here’s a little piece of it:

”With regard to healing the sick, I will devise and order for them the best diet, according to my judgment and means, and I will take care that they suffer no hurt or damage. Nor shall any man’s entreaty prevail upon me to administer poison to anyone; neither will I counsel any man to do so. Moreover, I will give no sort of medicine to any pregnant woman, with a view to destroy the child. Further, I will comport myself and use my knowledge in a godly manner.”

The Greek philosopher Pythagoras is mostly remembered for the Pythagorean theorem, which we remember from 7th grade or so – that the square of the hypotenuse of a right triangle is equal to the sum of the squares of the other two sides. But Pythagoras also arrived at an interesting and highly consequential observation. He noticed that some otherwise healthy persons had serious and sometimes fatal reactions to eating fava beans, while others could eat fava beans with no ill consequences whatever. From this he concluded that there could be fundamental differences between individuals that could have profound effects on their health. His findings, reinforced by other similar findings over the next couple of centuries, eventually led to the basic understanding of potential underlying differences in what we would now term individual genotypes, which can have profound effects on health.

The Greek physician Galen, born in Pergamon, September 9, AD 129, moved to Rome, where he observed the bodies of gladiators who lay dying, with their bodies slashed open by the blades of their opponents. He noted the difference between blood flowing from different parts of the body, and came to the correct conclusion that arterial blood came from the heart, but, erroneously, that venous blood originated in the liver and that the liver pumped venous blood to the rest of the body. Prior to Galen’s observations, it had been assumed that what the arteries conveyed was air, and that the avenues for the transportation of blood were the veins. Galen was able to observe that bright red blood came from the lungs to the left side of the heart and that not-so-bright red blood came from the veins to the right side of the heart. His incorrect assumption that the darker venous blood originated in the liver was fairly reasonable, considering what he had to go on.

Even though Galen’s assumptions about the way blood circulated in the human body were not totally correct, they were a gigantic leap forward, in that he recognized that our blood was conveyed in our bodies through those little pipes that we call “blood vessels.” It would have been impossible to arrive at that understanding if Galen had not had the experiencing of observing the interiors of the bodies of living gladiators. Needless to say, physicians at that time did not practice vivisection. They did not cut open the bodies of living humans. And if by chance they had cut into the body of a corpse, they would not have directly observed the veins and arteries, since once the heart stops pumping blood, veins and arteries collapse into narrow strands that don’t in the least look as though they could accommodate the passage of blood. The general belief prior to Galen was that the body was suffused with blood, which was generated in the body and then consumed as a kind of nourishment. Galen’s observations were genuinely transformational.

About a thousand years after Galen, the Persian philosopher Avicenna wrote a book about human diseases called The Canon of Medicine (1025) which remained a standard medical textbook for more than 600 years. He examined the way in which the human body functioned, such as breathing, blood circulation, and digestion – i.e., physiology. He discussed matters such as the diagnosis of internal diseases, the relationship between sports and health, pediatrics, pharmacology, and other essential medical subjects. Avicenna’s work included close and careful observation of migraines and their differences from run-of-the-mill headaches.

In Europe almost into the 17th century, the science of medicine was essentially non-existent. Practitioners (whom I hesitate to call “physicians”) mostly gave their consideration to those four humours noted by Hippocrates, and also to the phases of the moon. Diagnosis was based on the position of the moon in relation to the constellations, which were associated with different regions of the body – head, arms, chest, stomach, legs. These practitioners would diagnose an illness looking at the zodiac signs in relationship with the patient, and whatever they concluded about the patient’s humoral status.

Physicians used many different techniques to analyze the imbalance of the four humours in the body. Uroscopy was most widely used for diagnosing illness. Physicians would collect a patient’s urine in a flask called a “matula”.  The matula was specific in shape and had four regions – circulus, superficies, substantia, and fundus – which supposedly corresponded to regions of the body. The circulus corresponded to the head, the superficies to the chest, the substantia to the abdomen, and the fundus corresponded to the reproductive and urinary organs. Urine was inspected based on color, consistency, odor, and presence of non-liquid matter that precipitated out.  Physicians analyzed the urine for the four criteria and used those results to point out where there was an imbalance of the four humours based on their location in the flask.  They also observed the viscosity and color of the blood as it was draining from the patient and/or contained in a vial. The color and viscosity supposedly denoted whether the patient had an acute, major, or chronic disease. This also, supposedly, assisted the physician with the next course of action.

Physicians would also observe a patient’s pulse, carefully noting the rate, power, and tempo of a pulsing artery. By interpreting the pulse, the physician would attempt to diagnose the type of fever the patient had. The pulse rate indicates the heart rate, of course, which is an important indicator of a person’s moment-to-moment physical status, but as far as distinguishing between one “type” of fever and another, the value of the pulse rate is highly questionable.

Advances in the 17th century & after

A major change occurred in 1628 when William Harvey’s Exercitatio anatomica de modu cordis et sangiunis in animalibus (usually known as De modu cordis) was published. In that tome, Harvey described precisely how the blood circulated. He also delivered lectures at the Royal College of Physicians in which he demonstrated the way the blood circulated in a live pig with its chest sliced open. Fellows of the Royal College could observe the blood gushing from the right ventricle of a live shrieking pig, then traveling into the pig’s lungs, and then returning into the left ventricle of the heart to be ejected into the aorta and its arterial branches.

Arriving at a clear understanding of the circulation of the blood of course had major implications for treatment, especially for the treatment of wounds.

A hugely important factor in the advancement of medical science was the invention of instruments of different types that permitted closer and more accurate observation and measurement of a range of phenomena. For example, at the end of the 16th century Galileo invented a simple water thermometer which was useful only in approximating temperatures above freezing. Below the freezing point, the water in Galileo’s thermometer froze, rendering the instrument useless. A little more than a century later, Daniel Fahrenheit developed a mercury thermometer. It was he who, somewhat arbitrarily, determined that the numerical value for the freezing point of water was 32 degrees on his scale.

Another crucial milestone in medical knowledge was the discovery of microbes and the realization that some microbes were causes of disease. The development of the microscope was central. Eyeglasses with glass lenses that in some measure bent the light rays entering a person’s eyes in such a way as to improve visual perception were first made in Italy in the 14th century, and a couple of hundred years later, Hans and Zacharias Janssen, Dutch eyeglass makers, put together the first microscope.

Towards the end of the 17th century, Anton van Leuwenhoek used a microscope to look at insects. It was van Leuwenhoek who first observed the presence of micro-organisms in unclean water. Prior to van Leuwenhoek’s observation, the German Jesuit priest Athanasius Kircher looked through a microscope at decaying material such as meat and milk and detected “an innumerable quantity of worms.” He came to the conclusion that disease and putrefaction was caused by the presence of invisible living bodies. When Rome was struck by the bubonic plague in 1656, Kircher investigated the blood of plague victims under the microscope. He noted the presence of “little worms” or “animalcules” in the blood and concluded that the disease was caused by microorganisms. He was the first to attribute infectious disease to a microscopic pathogen. He essentially invented the germ theory of disease.

Diagnosis has increasingly relied on being able to see what is happening inside the bodies of patients. Microscopes permit the investigators to look at the content and composition of blood and other bodily fluids.

The development of diagnostic imaging, beginning with the X-ray

However, the great leap forward in diagnosis was the discovery that a specific kind of radiation could penetrate some solids, such as flesh, but be blocked by other, denser solids, such as bone. When this radiation encountered a plate coated with photosensitive material, it would record the image of whatever denser solids the radiation had encountered and could not penetrate.

That clumsy sentence essentially describes the functioning of the X-ray. It was discovered by William Conrad Roentgen on November 8, 1895. When Roentgen examined the photographic plate that had been exposed to that radiation, he noticed that the plate contained an image of the bones of his hand. The radiation passed through cardboard and a book that Roentgen had placed in its path, and also through the flesh in his hand, but the bones had blocked the radiation. For this discovery, Roentgen was awarded the first Nobel prize in physics in 1905.

The radiation that Roentgen was experimenting with was cathode radiation, which consists of a stream of electrons, traveling from the cathode (the negative pole) to the anode (the positive pole). The term “X-ray” refers specifically to a stream of electrons with sufficient energy to bridge a large gap and penetrate solid material.

Roentgen was by no means the sole investigator into the potential of cathode radiation. Among the contributors to the discovery that cathode radiation could help physicians see the insides of bodies without cutting them open were his mentor, Dr August Kundt, who urged Roentgen to follow his gift of manipulating materials to detect and measure physical phenomena. The English physicist Sir William Crookes was the inventor of the vacuum tube (now known as the Crooke’s tube) in which the stream of high-energy electrons that led to Roentgen’s discovery was formed.

What we now call X-rays were only the beginning of diagnostic imaging, which has truly transformed the discipline of diagnosis. For a great many afflictions, the X-ray is the standard first step in the diagnostic process. Just in the past few months, I have been X-rayed twice. Recently I fell and banged my knee, which continued to ache for a couple of weeks after the fall. Went to the orthopedist, got it X-rayed, no fractures, got dismissed with the warning that I was very lucky. Also, before that I developed a vexing pain in the ball of my right foot. Nothing amiss showed on the X-ray, and treatment consisted of a simple supporting wrap. Treatment is often as simple as that, but it has to be preceded by a diagnostic procedure that shows that there is nothing more serious that needs attention. The X-ray is the simplest and least expensive of the diagnostic imaging procedures.

X-rays are not without risks. The radiation passes through the body, and the high energy electrons can cause damage, although the risk of harm is very small. The plates that are used to record the X-ray images are far more sensitive nowadays than the photographic plates that were originally used, so the X-ray dose is much smaller than when X-rays were introduced.

Since the discovery of the X-ray more than a century ago, several newer modes of diagnostic imaging have emerged. These include computerized tomography and computerized axial tomography, known at CT scans and CAT scans, also magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), fluoroscopy, positron emission tomography (PET scan), ultrasound, and nuclear medicine including bone and thyroid scans.

CT scans / CAT scans. These consist of a series of X-ray images taken from different angles around the body, which are then processed by computer to create cross-sectional images of the bones, blood vessels and soft tissues inside the body, providing far more information than single X-rays. The original term was “CAT scan,” for computerized axial tomography, but CT scans and CAT scans are one and the same. In order to obtain a CT scan, the patient is enclosed in a tube-like structure and the X-ray device moves around the body following the computerized instructions. “Tomography,” by the way, means that the images produced show the structures in three dimensions.

Fluoroscopy. While X-rays are basically still photographs, a fluoroscope is more like a movie. Multiple short burst of an X-ray are displayed on a computer screen to show internal organs and tissues moving in real time.

Magnetic resonance imaging (MRI). MRI scanners use magnetic and radio waves (rather than ionizing radiation like X-rays) producing detailed images of almost every internal structure in the human body, including the organs, bones, muscles and blood vessels. The MRI machine is a large, cylindrical machine that creates a strong magnetic field around the patient and sends pulses of radio waves from a scanner. The strong magnetic field created by the MRI scanner causes the atoms in the body to align in the same direction. Radio waves are then sent from the MRI machine and move these atoms out of the original position. As the radio waves are turned off, the atoms return to their original position and send back radio signals. These signals are received by a computer and converted into an image of the part of the body being examined. This image appears on a viewing monitor.

MRI may be used instead of computed tomography (CT) when organs or soft tissue are being studied. MRI is better at telling the difference between types of soft tissues and between normal and abnormal soft tissues.

Positron emission tomography (PET scan). PET scans differ from MRI scans in that they use radioactive material to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body, such as blood flow, bone formation, and cancers of different kinds.

Ultrasound. This imaging technique is the easiest and the least invasive. The ultrasound operator passes a device called a transducer over the area of the body, transmitting high-frequency sound waves into the body. The sound waves are at a frequency higher than we can hear, but these sound waves bounce off the structures inside the body and back to the transducer, which records them as electric signals. A computer converts these signals into real-time images, which are displayed on the computer screen. Ultrasound is valuable in that it quickly generates images of internal organs and soft tissue. It is commonly used in pregnancy to visualize the status of the embryo.

Many of these imaging tests are simple, quick, and painless. Some, such as the MRI, require the patient to lie inside a machine without moving for a considerable time while loud noises are going on. For some imaging tests, doctors insert a tiny camera attached to a long, thin tube into the patient’s body. The doctor moves it through a body passageway or opening to see inside a particular organ, such as the heart, lungs, or colon. These procedures often require an anaesthetic. However, those imaging procedures are the exception. The great majority are, at worst, no more than annoying.

Imaging has truly transformed the practice of medicine. Physicians can essentially see what’s going on inside the human body, which is a huge step in figuring out what’s wrong and what needs to be done to fix it. There are those who think that imaging sometimes goes just a bit too far, citing as an example the whole body image, which has been advocated by some investigators. A possible predicament with the whole body image is that it may show problems in the body that medical practice has no way of addressing. Why look for problem that we can’t fix?

But, other than that small reservation, X-rays and the successors in imaging have resulted in enormous progress in diagnosis, with consequent advances in treatment.

Cholesterol and heart disease

The English physician Caleb Parry, in 1799, published his discovery that angina pectoris (the feeling that the heart is under severe pressure) was due to obstructed coronary arteries – arteriosclerosis. This did not attract any significant attention. The symptoms of arteriosclerosis had been observed for millennia, but no one had any notion of what the reasons might be.

During the 19th century, physicians demonstrated increased interest in arteriosclerosis. There were at least three theories as to the causes of obstructed coronary arteries. One theory, the most dominant, was that arteries became obstructed simply as a result of aging. There was no specific pathology involved. Another theory, promulgated by the eminent pathologist Rudolph Virchow, was that arteriosclerosis was indeed a disease, but it sprang from some disturbed metabolism of the artery itself. A third view was that the obstruction of the arteries evolved from clots adhering to the walls of the arteries, which gradually changed into the typical arteriosclerotic plaques.

In addition to the differing notions about how these plaques came to be, there was also disagreement about the location in the arterial wall of plaques. Some believed it was in the inner lining of the artery that the plaques originated, others that it was the middle, muscular layer of the artery, and still others that it was in the outer coat of the artery that the arteriosclerotic process started.

It wasn’t until the early 20th century that investigators did actual experiments to attempt to determine the cause of arteriosclerosis. A Russian investigator fed rabbits a mixture of eggs and milk, and after a few weeks of keeping the rabbits on that diet, he sacrificed them and inspected their aortas. The aortas exhibited the same grayish-white plaques that had been observed in the aortas of human beings. The conclusion he arrived at from this experiment was that the source of the plaque was the protein content of the diet.

Another researcher, N. W. Stuckey, fed the rabbits three different supplements. One group received a muscle fluid supplement, a second group got an egg white supplement, and a third group was given egg yolks only. Only the rabbits on the egg yolk diet demonstrated the plaque in their aortas. Investigation of these plaques revealed that they were principally composed of lipid droplets. These same lipid droplets were also plentiful in the rabbits’ livers.

The supervising investigator, Nikolai Anichkov, was able to identify that lipid as cholesterol. Further experiments demonstrated that feeding rabbits a straight cholesterol supplement quickly resulted in the formation of cholesterol plaques in the rabbits’ arteries. The conclusion of these experiments was that it was cholesterol in the diet that led to the formation of arterial plaques and arteriosclerosis. Anichkov published the results of his discovery in 1913.

As we look back on this discovery, it was clearly monumental, but it was not widely recognized at the time or for several decades after. It was not until 1950 that an American investigator, John Goffman, published a paper in Science that established that cholesterol conveyed by low-density lipoprotein (LDL) particles, was responsible for the formation of arterial plaque and thus was a major contributing cause to heart disease. These lipoproteins were bundles that contained cholesterol, protein, phospholipids, and triglycerides. The high-density lipoproteins (HDL) were higher in protein, and the LDLs were richer in triglycerides. The LDL clumps were more apt to release cholesterol, which would latch onto arterial walls and form harmful arterial plaque.

Goffman and his co-workers were insistent that it was the quantity of LDL in the bloodstream that determined the cardiac health status, and not total cholesterol. Nonetheless, his work led to further investigation and recognition of the role of cholesterol in our diets, and perhaps to significant modification in the eating habits of a large part of the world’s population.

* * * * * * *

It should be obvious that these diagnostic advances led to major changes in medical treatment. When pathogens could be observed by means of a microscope, treating illnesses caused by these pathogens became more feasible. When what was going on inside patients’ bodies could be observed with the aid of the imaging techniques that became available, there was an avenue to directing treatment at what the imaging had identified as the issue, whether a broken bone or a problem with an internal organ. Diagnosis has led to greater accuracy and efficacy in medical treatment.

I need to acknowledge an excellent a highly readable book for a lot of the content of this piece – Medicine’s 10 Greatest Discoveries, by Meyer Friedman, MD, and Gerald W. Friedland, MD, 1998. Much of the book deals with discoveries in the area of diagnosis, but there are chapters on subjects like vaccination, anesthesia, antibiotics, and DNA.

I’ve observed that there’s a fair amount of new material to catch up on. Doc Gumshoe will attempt to rise to the challenge pretty soon. Stay well and enjoy the holidays! Best to all, Michael Jorrin (aka Doc Gumshoe)