Proteintech

A brief history of the antibody – Part I

January 20, 2011 at 2:43 pm | Posted in News | Leave a comment
Tags: antibodies, history, Polyclonal Antibodies

Throughout history, there were no defining “Eureka!” moments where an individual scientist made the “discovery” of antibodies. Instead, our knowledge and understanding of antibodies and their various uses have evolved, and continue to evolve, over time. One of our previous blog entries – Proteintech: Making better antibodies with whole proteins as nature intended – touched a little on the early days of antibody based technologies and inspired me to dig a little deeper into the ‘history of the antibody’. Of course, several hours later, I realized you could probably author a whole book on the subject and, as the title of this blog piece promises, I decided to keep it brief; Furthermore, I have broken it up into several parts for bite-sized (if you’ll pardon the pun), lunch time reading. Part I explores our first uses for antibodies and how they first came to be isolated from serum.

The first use of antibodies

Antibodies, whether knowingly or not, have been employed in biology and medicine for over a hundred years. As early as the 1890s, the serum of horses injected with diphtheria toxin was isolated and used to treat the effects of diphtheria infection (1) – long before anyone had even identified antibodies as the active immune components of blood serum.

Historically, diphtheria was a common disease and cause of death throughout the world – its deadliness conferred by the secreted toxin of the diphtheria bacterium. The neutralizing antitoxin produced by “antitoxin horses” was essentially the first effective treatment against a devastating disease in human history. It caused a media sensation at the time; reportedly causing a steady decline in diphtheria related deaths in the New York area from its availability there on 1^st Jan 1895 to 1900 (2). Horse serum continued to be used widely in the first half of the 20^th century to treat diphtheria – as well as several other diseases – before effective vaccines were made available, largely eradicating these once common-place infections.

 Theories

Emil von Behring, the scientist largely responsible for the diphtheria antitoxin, was able to help formulate some of the first theories on humoral (adaptive) immunity using serum therapy to support his hypotheses. Behring postulated that a certain mediator found in serum could react with foreign elements (3). Behring was not alone in thinking this: Paul Ehrlich – another prominent figure in antibody history – is thought to have coined the term “antikörper” or “antibody” to refer to this mediator (4). Ehrlich even developed the resoundingly accurate side chain theory, describing antibody-antigen interactions based on a “lock-and-key” model (5). The serum therapy breakthrough, however, not only led early immunologists to theorize and develop new treatments: it eventually led to the isolation of antibodies from serum. This time it was a new treatment for bacterial pneumonia that indirectly contributed to the antibody history books.

A “new remedy for pneumonia”: the isolation of antibodies from serum

In the early part of the 20^th century, serum therapies were widely used to treat many life-threatening and wide-spread diseases; however, they were not ideal. Many considered their side effects worse than the diseases they were meant to treat. Anaphylactic reactions were commonly observed after the administration of anti-sera, collectively dubbed “serum-sickness”, they included fever, rashes and joint pains (6). Efforts to isolate the curative element of serum from the components causing serum-sickness were made the world over; many scientists set out in search of Behring’s “antibody”. The first success was announced in the May of 1924 and came from the sustained efforts of a young Harvard scientist, Lloyd B. Felton (7). Felton, after many failed attempts, had been able to isolate a white crystalline powder from the anti-sera of horses immunized with S. pneumoniae. Through initial clinical trials using S. pneumoniae infected mice, Felton was able to demonstrate that the powder possessed similar restorative properties to the anti-serum that generated it, minus its usual side effects. Not long afterwards, 120 human patients with pneumonia were treated with Felton’s powder: all recovered from their infections without any observable serum-sickness (7). Felton had successfully isolated the pneumonia “antibody” and, in real terms, was the first to isolate antibodies from serum.

Advance at a glance

Much happened in the interim between Felton’s success and the use of antibodies as we know today. Countless important theories and breakthroughs have deepened our collective understanding of how antibodies work and how we can use them to our advantage. From Paul Ehrlich’s aforementioned side chain theory on the recognition of antigens – first put forward in 1897 – to Linus Pauling’s resolution of the crystal structures of antibodies in complex with antigens in the 1940s (8) –which confirmed the former theory’s lock-and-key model. From the discovery that antibodies were made out of protein in the 1920s (it was a breakthrough once!) to the identification of Fab and Fc regions (9) around the same time as the characterization of the Heavy and Light chain disulfide linked structure in the 70s (10).  This work has contributed irrefutably to our modern use of antibodies and continues to form the scientific basis of further antibody discoveries. To not even give the slightest mention of them here would serve for an incomplete article, but time is brief and, in the interest of brevity, we will skip past the basic antibody science to the use of antibodies for discovery, instead of the discovery of antibodies. (At the risk of sounding a bit cliché) stay tuned for next month’s installment of the Proteintech ‘brief history of the antibody’ blog article, where I try my best to cover the origins of our applicational use of antibodies – including: the discoveries that led to our understanding of the science behind polyclonals and the ‘invention’ of monoclonals.

If you have any suggestions or information for inclusion in the upcoming “brief history of the antibody” blogs, please leave a comment below or contact Deborah through Europe@ptglab.com. Our next installment of the “A brief history of the antibody” is due at the beginning of March – so keep checking the blog for the next installment!

(1)  MacNalty AS., Emil von Behring, BMJ, 1954;i:659-63

(2)  Markel H., Long Ago Against Diphtheria, the Heroes Were Horses, New York Times, 2007 – read the full article here

(3)  Nobel Prize.org, Emil von Behring – view the article here

(4)  Lindenmann J., Origin of the terms ‘antibody’ and ‘antigen’, Scand J Immunol, 1984, 19(4):281-5

(5)  Winau F. et al., “Paul Ehrlich–in search of the magic bullet”. Microbes Infect. 2004 6 (8): 786–9

(6)  Llewelyn MB et al., Discovery of antibodies, BMJ, 1992, 305, 1269-72

(7)  “Finds new remedy for pneumonia”, New York Times, May 9, 1924

(8)  Pauling L, Molecular architecture and biological reactions, Chem and Eng News, 1946, 24 (10), 1375-77

(9)  G. M. Delman and J. A. Gally, The nature of the Bence-Jones proteins, J. Exp. Med. 1962, 116(2):207-227

(10) Raju TN “The Nobel chronicles. 1972: Gerald M Edelman (b 1929) and Rodney R Porter (1917-85)”, Lancet, 1999, 354 (9183):1040