COVID-19 is just one reason we should know how the science of blood evolved
Amid the COVID-19 pandemic, we are struggling to understand how the virus affects our blood, the vascular system which carries it, and the pulmonary system which oxygenates it. COVID-19 was first known to us as a respiratory disease, with early patients and death associated with a desperate struggle to breathe. We know now that COVID-19 is far more than a respiratory disease, that it affects the vasculature, the brain, liver, kidneys, and more.
But our inability to breathe when hit hard by COVID-19 is still a signature symptom, and one we all fear. No one wants to drown in their mucus. The lack of oxygen getting from our lungs into our blood has been a signature metric – and something easy to measure for most of us.
Early in the pandemic, an ER physician, Dr. Richard Levitan, wrote an opinion piece in the NY Times about how a simple pulse oximeter can give an easy and early warning about possible coronavirus infection. In his experience, many COVID-19 patients showed unbelievably and even lethally low blood oxygen readings but did not show any of the expected signs of severe hypoxia such as unconsciousness or at least desperate gasping for breath. They were, as he said, just checking their cellphones as if nothing were wrong.
There is actually a deep and fascinating history behind the measurement of blood, and the evolution of the science and means of measuring our blood. Something worth touching on here.
In the beginning, there was Galen…
You could actually say it started with Marcus Aurelius, Emperor of Rome from 161-180 AD. General. Conqueror. Persecutor of Christians. Writer of The Meditations (which is still read today especially by those who appreciate Marcus’s stoic philosophy – perhaps appropriate again in today’s pandemic lock-down).
The most devastating event of Aurelius’s career was the Antonine Plague (Antoninus was his family name: Marcus Aurelius Antoninus Augustus). The plague, possibly smallpox, broke out around 165 AD and may have killed about 5 million people throughout the Roman Empire (approximately 10%), including the Emperor(s)... and is implicated in the empire's decline and fall.
Among the Roman troops and citizens being decimated by the plague was the outstanding physician/scientist of the ancient world, Galen. Decimated, by the way, is derived from the Roman word decimatio, a form of military punishment in which every tenth man was executed when a group was guilty of a capital offense such as cowardice or desertion.
Marcus summoned Galen upon the outbreak of the plague and tapped him as personal physician to both Marcus and his co-Emperor, Lucius Verus. This was during their campaign into what is now Germany. At the last minute, Galen was spared from campaigning among the Germanic barbarians, but stayed behind to care for Commodus, heir to the Imperial throne. Galen witnessed the plague among the Roman citizens as well as among the troops stationed in Aquileia. His descriptions of the symptoms were so important to medical history that the Antonine Plague was also known as the Plague of Galen (not an attribution I would value).
Galen was born in 129 AD to wealthy Greek parents in Pergamon (Bergama in modern day Turkey). His father, Aelius Nicon, spent lavishly on his son’s education. When Galen was 16 his father sent him off to study medicine. Nicon died in 148, leaving his wealth to a 19-year-old Galen. Galen used that new wealth to travel and study at some of the best medical centers of the time, eventually ending up at the best school of them all in Alexandria.
When Galen finally returned to Pergamon at the age of 28. According to his writings, Galen became physician to the gladiators who belonged to the High Priest of Asia. He accomplished this by a dramatic dare Galen posed to the incumbent physicians. He disemboweled an ape and dramatically challenged the others to repair the damage. None took him up. Galen did the surgery himself, and thus won his position. Only a couple gladiators died during Galen’s tenure, compared to sixty under the care of his predecessor.
Galen took advantage of the open wounds likely suffered by the gladiators to study the inner workings of the human anatomy, since dissection and vivisection of human bodies was prohibited. He also experimented on animals, mostly pigs and monkeys, to develop his understanding of human physiology.
Galen was about 40 years old when he accepted Marcus’s invitation to be the court physician. He had spent his adult life since a teenager, carefully observing his patients and experimenting on animals in order to better understand how the body worked. So he could be a better physician. Ensconced in Rome at the Emperor’s bidding and at the height of influence, Galen began writing so prodigiously, using an army of scribes, that his works are over half of the ancient writings that have survived to this day. Historians estimate that the known works of Galen are only a third of his total body of work.
Galen wrote about many subjects, but he defined Western thought about circulation for over a thousand years. In Galen’s time, medicine was dominated by ancient ideas of the four humors: blood, phlegm, yellow and black bile. Physicians then thought humors were in balance during good health, and out of balance during poor health. They prescribed many treatments to bring these humors back into balance. For example, an excess of blood (sanguine) required blood-letting such as with leeches - a practice that lasted thousands of years into the 1800s. They thought air from the lungs pushed blood through the left side of the heart and through the aorta. Galen used dissection to prove that arteries carried only blood, and no air. He was the first to show the two parts of the circulatory system, a darker venous system and a brighter arterial system.
Galen’s works greatly advanced ancient medicine and anatomy. His works were so revered and literally stood the test of time. Unfortunately, a cornerstone of Galen’s philosophy was lost to over a millennium of subsequent physicians and scientists: to use direct observation and experiments to learn. Unfortunately, the physicians who followed him learned by rote and were merely book-smart – smart on Galen’s books.
Al Nafis – Breaking from Galenic tradition…
Galen’s books had as many errors as they had insights and wisdom.
For example, Galen believed blood entering the right side of the heart permeated the septum (which separated the ventricles) via invisible pores to reach the left side of the heart. Galen believed the two systems of venous and arterial flow were two separate systems and only connected through those invisible pores. He believed arterial flow originated in the heart to dissipate heat, and he believed venous flow originated in the liver.
A thousand years after Galen, around the early 1200’s, an Arabic physician named Ibn al-Nafis directly challenged Galen’s claims of pores in the septum separating right from left ventricles. Al-Nafis used Galen’s methods of dissection and experimentation to discover the details of pulmonary circulation which eluded Galen. Al-Nafis also correctly showed that dark venous blood left the right ventricle, went through the pulmonary artery to the lungs, was infused with air and turned bright red, and finally passed through the pulmonary vein into the left ventricle. Al-Nafis also correctly deduced coronary and capillary circulation, and corrected Galen’s errors to show that the heart was the source of the pulse.
Vesalius – the West finally catches up…
It was not until Andreas Vesalius, a professor of anatomy at Padua University in Italy, that a Westerner challenged Galen in the 1500s. Galen’s works were still revered uncritically by the Catholic Church and thus the rest of the medical and scientific community in Europe. A few Spanish and Italian scientists, contemporary with Vesalius, began to propose the correct flow of venous and arterial blood through the pulmonary system.
Unfortunately, outside of the Arabic world, Galen’s teachings dominated medical thought until William Harvey in the 1600’s. Harvey rigorously applied experimental methods and was the first in the Western world to fully and correctly describe the circulatory system (at least within the limits of the technology available to him at the time – for example, he could not observe and did not predict the presence of capillaries connecting outgoing arterial blood flow to the venous return).
Harvey’s father was a mayor with good family connections. These beneficial networks gave Harvey access some of the best education at the time, including in Cambridge where he got his Bachelor degree. After some travelling throughout continental Europe, Harvey entered the University of Padua in Italy. After getting his Doctor of Medicine degree at Padua, he returned immediately to England to get another Doctor of Medicine degree from the University of Cambridge. To continue the extraordinary parallels to Galen’s personal story, Harvey eventually became personal physician to King James I.
After decades of observation and rigorous experiments, Harvey wrote his 1628 book De Motu Cordis (Anatomical Account of the Motion of the Heart and Blood) for which he is credited with being the first Western physician to correctly detailed the function of the heart and circulatory system. Finally, Harvey broke decidedly with Galen, whose errors on circulation were still vigorously defended by Harvey’s peers.
Galileo’s quantitative disciples…
A year before Harvey published his De Motu Cordis in 1628, Robert Boyle was born. Boyle was the fourteenth child of the First Earl of Cork at Lismore Castle. He also had the advantages of excellent education and traveled throughout continental Europe as a young man, even spending time in Florence during Galileo Galilei’s final years. When Boyle finally returned to England, he was determined to pursue scientific research, but to follow in Galileo’s quantitative footsteps. Boyle succeeded to such an extent that he is considered to be the father of modern chemistry. He gave us Boyle’s Law, for example, which established the inverse proportionality between pressure and volume of a gas. Among many other observations, Boyle proved air is necessary for combustion – and for life – by using an efficient vacuum pump of his own design. By pumping air out of a bell jar, he observed that a burning candle – and a mouse – were both extinguished in the absence of air.
But it was John Mayow, a contemporary of Boyle’s and a chemist and physician, who demonstrated air’s active and inactive fractions responsible for combustion and life. He also showed a fifth part of air was the active fraction which he called spiritus nitro-aereus. Mayow also correctly proposed that the lungs separated the active component from air and passed it to the blood.
Finally, in 1774 British clergyman Joseph Priestly isolated oxygen by thermal decomposition of mercuric oxide, and demonstrated that this isolated fraction was sufficient for combustion and life (again using candles and those unfortunate mice for subjects). Although Priestly is given precedence for his discovery of the life-giving molecule, it was French chemist Antoine Lavoisier who named it after conducting independent experiments on the same “vital air”. Lavoisier named it oxygen for his mistaken notion that this gas was the key constituent in acids. Despite this error, Charles Darwin’s grandfather Erasmus Darwin popularized the name in a poem titled Oxygen in his very popular book The Botanic Garden. Lavoisier's name stuck.
Hemoglobin – finally seeing the light…
Friedrich Ludwig Hunefeld, working in Leipzig in 1840, first discovered hemoglobin in dried worm’s blood and showed that hemoglobin bound to oxygen.
The reversibility of hemoglobin’s oxygen-binding property was described a decade later by Felix Hoppe-Seyler, described as the founder of modern biochemistry. Hoppe-Seyler’s observation showed how hemoglobin in red blood cells could take up oxygen in the lungs but then release it to the tissues where it was needed. Hoppe-Seyler was also the first to describe the absorption spectrum of hemoglobin in 1862 using a spectroscope, and to show that oxygenated hemoglobin absorbed light differently from deoxygenated blood.
Hoppe-Seyler used a spectroscope invented in 1860 by Robert Bunsen (who invented the Bunsen burner) and Gustav Kirchhoff (who developed Kirchhoff's circuit laws still used today). Bunsen originally invented his burner as a way to identify metals and salts by the colored flame they gave off. Kirchhoff suggested using a prism (first used by Isaac Newton in 1666 to separate white sunlight into constituent colors) to separate the colors into a spectrum so similarly colored flames could be further distinguished. The Bunsen-Kirchhoff spectroscope revolutionized analytical chemistry and biochemistry and led the way into non-invasive blood analysis.
About this time, a German physiologist Karl von Vierordt developed many tools and techniques for measuring blood circulation, such as a hemotachometer to measure the velocity of blood flow, and an early form of today’s sphygmomanometer to measure blood pressure. But one innovation he is not well known for, because it was so ahead of its time, was using the Bunsen-Kirchhoff spectroscope to measure blood oxygenation and consumption in tissues. He did this in 1876.
The first clinical development of a light-based instrument to measure blood oxygenation was not until 1935 by German physician Karl Matthes, almost 70 years after Vierordt’s first use of a spectroscope in a research setting. Matthes and his collaborator Franz Gross first reported the use of a red and infrared light in an oxygen saturation meter in 1939, and this is fundamentally (with many, many engineering improvements) the forerunner of today’s oximeters.
My own oximeter…
I was ecstatic when my oximeter was delivered within 4 days of my order instead of 2 weeks (Amazon’s deliveries were completely flummoxed by the early days of the pandemic, and I had been trained like Pavlov’s dogs to expect 1-day or even same-day deliveries).
I put two AAA batteries (included for Amazon’s bargain price of $34.99) into the oximeter, and pushed the on button to see the little red LED lights blink sleepily on. This little pulse oximeter is designed like one of those black triangular paper binder clips, you know, where you pinch the two nickel-plated wire arms and the black sheet metal clip opens like a mouth and bites down on the sheaf of papers you signed for your mortgage application… instead of paper this oximeter clip bites down on your finger. Gently. No blood.
Red LED lights flashed for a few seconds and then reported “%SpO2 95” and “♥/Min 68”. I guessed that it was telling me something like my blood oxygen level was 95%. But was that good, was that bad, did I have COVID-19?
I checked the kids and their pulse was higher than mine as expected, and their %SpO2 reading was in the 99-100% range. I checked the wife and her readings were similar to the kids. Huh. Why was mine 95%?
I then googled what was the expected blood oxygen range, and found that between 95 to 100 is normal. Huh. So then, I’m at the low end of the normal range – is that because I’m rapidly declining and about to fall into the abnormally low range caused by COVID-19, or have I always been on the low end of this measurement, or is it because I once had that youthful 100% reading but I’m now a middle aged duuude on the downhill slide to decrepitude…
Having a device and the data it reports is not enough to assuage the neuroses and questions that COVID-19 causes. Buyer beware. ;)