Metchnikoff and the starfish: how simple creatures revealed the secrets of the immune system

“One’s ideas must be as broad as nature if they are to interpret nature”

- Sherlock Holmes

Have you thought about your immune system recently? Did it let you down over the holidays and leave you sniffling? Are you thinking of ways that you could boost your immunity? Are you drinking probiotic yoghurt drinks to support your friendly bacteria?

We take the idea of the immune system for granted today, so it may surprise you to learn that less than 200 years ago, most people didn’t realise the body had any natural defences against disease. Most scientists thought that disease was spontaneous. It took Louis Pasteur, Robert Koch and the “blue skies” thinking of John Tyndall (see box below references) to show that food didn’t spontaneously go bad, but that microbes in the air were responsible for putrefaction. Similarly, it was microbes in the air (and water and food) that caused disease in living animals, including people. Even with these revelations, the human body was considered a passive figure in the disease process; the study of infections focussed on the microbes and not the host. Scientists and medical practitioners had noticed that cells from the body (white blood cells) gathered around wounds and areas of infection, but these were considered passive bystanders at best. A popular theory at the time was that these cells took up bacteria and spread the infection around the body.

Élie Metchnikoff began his career around this time (in the 1860s) as a zoologist interested in the development of the digestive system. Metchnikoff was born in the Russian Empire, near Kharkiv in modern-day Ukraine, where he received his bachelor’s degree. He graduated after only two years (the course usually took four) and began a varied professional career that would take him all over Europe [1]. Always working with small, transparent organisms, Metchnikoff was able to utilise microscopy to observe development and cellular movement. He maintained a broad enough knowledge base, however, to connect his observations with those coming from other biological fields.

An early adopter of the theory of Darwinian selection [1], Metchnikoff worked with the assumption that there is continuity of traits from simple to complex organisms and that unspecialised cells in simple organisms gradually develop into organs and systems with highly specific functions. This conviction no doubt directed and influenced his research, allowing him to come to the (correct) realisation that the semi-specialised cells used by simple corals to digest food could also serve to digest and remove invading pathogens during infection [2]. In one seminal experiment at Messina in Sicily, he observed that these cells will gather around foreign objects as if trying to digest them. In this case, he used thorns stuck in starfish larvae but reasoned, again from Darwinian theory, that these cells were directly equivalent to the cells that had observed gathering at sites of injury in higher animals – including humans. With these experiments, he was able to prove that white blood cells found at sites of injury were neither inactive bystanders nor were they spreading infection. In a series of experiments using pH-sensitive dyes, Metchnikoff showed that these cells took bacteria into specialised compartments, which were then acidified to neutralise and destroy the infection [3].

In this series of experiments, starting with digestive processes in starfish and corals, Metchnikoff discovered white blood cells as we know them today. Along with Paul Ehrlich, who was studying the immune protection afforded by antibodies, Metchnikoff was awarded the 1908 Nobel Prize in physiology or medicine, establishing immunology as an independent field and paving the way for the development of many medical advances throughout the 20th Century and into the 21st.

Image from The Library of Congress [Public domain], via Wikimedia Commons
http://commons.wikimedia.org/wiki/File%3AElie_Metchnikoff_-_Between_ca._1910_and_ca._1915_-_LOC.jpg

Personally, Metchinkoff was much more opaque than his specimens. A man who drank soured milk every day in the belief that it would increase lifespan, he also attempted suicide twice [1]. Following the death of his first wife from tuberculosis, Metchnikoff took a large dose of morphine. Fortunately for the scientific community, the emetic effect thwarted this first attempt. Ironically, his second attempt failed because his immune system worked too well. To spare his family the shame of suicide, Metchnikoff had deliberately infected himself with relapsing fever – a particularly nasty bacterial infection that still causes mortality of 30-70% [4]. Despite a period of serious illness, he recovered and, characteristically, isolated bacteria from himself for use in future experiments.

Metchnikoff was remarkable for the breadth of his understanding and his ability to make theoretical and mechanistic connections between different biological systems. His elegant use of small, transparent organisms to demonstrate the accumulation of immune cells at the site of injury was enough to convince him of the significance of white blood cells in the control of infection; a stance which he defended against fierce criticism from his contemporaries in the scientific community. In addition to his scientific achievements, Metchnikoff was keen to involve the general public in his findings, gave many public lectures and encouraged other scientists to do the same. As he said in his Nobel lecture,

“[T]he study of immunity is a chapter in medical theory and theory is often hard to expound... Fortunately... [w]hatever concerns health is of real public interest. I take advantage of this to make my address less arduous for you. I shall moreover use the opportunity to show you the practical value of pure research.” [5]

In these days of austerity, when scientists are battling for funding and are under ever-increasing pressure to justify their research in terms of immediate benefit, we may do well to remember “the practical value of pure research”. It was a zoologist studying digestion in sponges and jellyfish who first realised the real significance of white blood cells at sites of infection, paving the way for a whole new field of biological research. Without knowing which fields of study will lead to the next big revelation, we must not leave basic research behind in the race for funding.

 References

1] Vaughan (1965) Med Hist. 9(3): 201–215. The romantic rationalist a study of Elie Metchnikoff (Open access article!) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1033501/

2] Karnovsky (1981) N Engl J Med 304(19):1178-80. Metchnikoff in Messina: a century of studies on phagocytosis. http://www.ncbi.nlm.nih.gov/pubmed/?term=7012622

3] Gordon (2008) Eur J Immunol 38: 3257–3264. Elie Metchnikoff: Father of natural immunity. http://www.ncbi.nlm.nih.gov/pubmed/?term=19039772

4] Louse-borne relapsing fever. CDC website, accessed 2014-03-27 http://www.cdc.gov/relapsing-fever/resources/louse.html

5] Metchnikoff (1908) Nobel lecture http://www.nobelprize.org/nobel_prizes/medicine/laureates/1908/mechnikov-lecture.html

Box

John Tyndall was a 19th Century physicist whose work on the light-scattering properties of dust gave us the phrase “blue skies research”. Blue skies research refers to scientific studies that have no obvious immediate benefit, but which have historically led to unexpected and impactful results. John Tyndall’s curiosity as to the different colours of the sky during sunset led him to conduct several experiments in which he shined light through water containing colloidal particles (milk, if you want to use the technical term). The scattering of light he observed is now referred to as Tyndall scattering. Not quite done with dust, Tyndall continued his research using boxes coated in glycerin to create “optically pure air” or air containing no dust or other particles. He found that meat broth didn’t go bad for months in optically pure air, providing more evidence for Pasteur’s theories that putrefaction and disease are caused by external microorganisms.