18 May 2020
The Red and the White of the war against SARS-CoV-2
Written by Nobel Laureate Professor Peter Doherty
It seems, programmed into our DNA, that we confront clear and present danger by fight or flight. When it comes to discussing medical threats, we use the language of conflict: defeat an infection, battle cancer, fight for life, the war against COVID-19. For flight, on the other hand, social distancing seems to work for COVID-19, though where’s the drama in that!
Reflecting on the red and white of conflict takes us to the Red versus White armies of post-revolutionary Russia, the red rose of Lancaster and the white rose of York in England’s 1445-85 War of the Roses, or way back to the red-on-white cross of St George and the 10th century Crusades. Both white shrouds and spilling blood red rivers in some power struggle or other are central to the human story. And, what happens with the red and the white of blood is at the heart of the confrontation between SARS-CoV-2 and the human organism, the biological battleground we call COVID-19.
“Yet who would have thought the old man to have so much blood in him”. in Lady Macbeth’s case, the insight that King Duncan had more blood than expected came from sticking daggers into the poor guy as he slept and experiencing a consequent spray over the hands. “Out, damned spot”. Lady M finds that excitement hard to forget as she later agonises and ‘washes’ long-gone blood away.
Old men may, indeed, have 20 per cent less blood volume than the young, and they are particularly susceptible to SARS-CoV-2 infection. Unusually for a viral pneumonia, our circulatory system is intimately involved in the most severe manifestations of COVID-19. Blood clots and oxygen transport/availability can be central to clinical compromise, along with cardiomyopathy, or damage to the heart muscle: more about that in later essays.
Writing Macbeth around 1607, Shakespeare neither knew that the heart is a pump, nor understood why blood is red. Science has always been international. English surgeon William Harvey travelled to the anatomy group in Padua at, perhaps, the world’s first research Medical School, where he did the dissections that explained (1628, in De Motu Cordis) the role of the heart and the blood circulation. Wanting to see the preserved 1595 anatomy lecture theatre, I was due to lecture in Padua in early April. That was cancelled; Lombardy, where Padua is located, has had (between 21 February and 13 May) more than 13,000 deaths from COVID-19.
In 1658 Amsterdam, Jan Swammerdam used a primitive, single-lens microscope to see red blood cells, or erythrocytes, for the first time. Working in Bologna (117 kilometres south of Padua) three years later, microscopist Marcello Malpighi described the pulmonary and capillary networks and analysed the process of blood clotting (de Polypo Cordis, 1669) that is of such great interest for COVID-19. With superb lenses that magnified 50-300x, Delft draper Antonie van Leeuwenhoek made, in 1695, the first illustrations of erythrocytes and established that they are the reason our blood is red. The red is the iron-containing haemoglobin protein that carries oxygen to our body tissues, an understanding that came much later (from 1840). What those 17th century microscopists also missed were the much scarcer white blood cells (WBCs).
The discovery of the WBCs waited 150 years until the development of powerful compound microscopes, not too different from those we use today. In 1843, French Professor of Medicine, Gabriel Andral, and English doctor, William Addison, published books describing what they called the “colourless corpuscles”. Addison showed that these corpuscles pass through the walls of capillaries and accumulate in sites of pathological damage. These are the inflammatory cells that, in the process of trying to eliminate SARS-CoV-2, contribute to the severity of pneumonia and oxygen deficit in ways we do not yet fully understand. Addison also did studies exposing the corpuscles to, for instance, port wine, which makes him an early in vitro experimentalist.
The WBCs remained colourless until, in 1879-80 Berlin, Paul Ehrlich stained them using aniline (from coal tar) dyes. With the cell membranes permeabilised following exposure to alcohol or formalin ‘fixatives’, acidic (red) or basic (blue) dyes showed dramatically that the corpuscles comprise a spectrum of nucleated cell types we collectively call the WBCs or leukocytes. Stained monocytes, macrophages, neutrophils, basophils, and eosinophils are visually impressive and have fascinated generations of haematologists, who tended to be less interested in the bland-looking small lymphocytes.
As we go forward to discuss the cellular basis of the host response to infection and how that works in COVID-19, those hitherto boring lymphocytes will be central to our analysis of the very specific adaptive immune response. The other WBCs, especially the monocytes, macrophages and neutrophils, will figure more as we consider innate immunity (see earlier Immunis article). So that’s the beginning of my story re the red and the white of COVID-19. It’s not about the human constructs of racial or political stereotypes, but about the realities of biology, immunity and recovery versus pathology, disease and death. To be continued…