Who Discovered the Single-Domain Antibody (Nanobody)?

It had been a long while since I wandered through the history of biology. I used to do that more during my bachelor’s and master’s studies. I wonder what led me to stop. It’s not like I had read enough. On the contrary, I had read too little. I hadn’t read Watson and Crick’s DNA article until my PhD when my advisor referenced it. I was shocked. I had a bachelor’s degree in molecular biology and genetics, yet I hadn’t read such a fundamental article.

I have been reading an article on antibodies to watch out for this year, and I began to wonder who discovered the first single-domain antibody. Antibodies were found in the 1890s, not as individual molecules. However, experiments showed that the serum of an immune animal would cure the infected animal (Behring won the Nobel prize in 1901 for this). But what about single-domain antibodies? When did they come into play?

When I want to find out when something was first discovered, I either go to the Wikipedia page or try my chances with a search on Google Scholar. The Wikipedia page didn’t contain any obvious information on its history, so I dug through Google Scholar. If Behring got the Nobel prize in 1901, then perhaps I could see if there was a hit for “single domain antibody” in 1900-1940. If I got a hit, I could narrow it down. If not, I could increase the time to 1940-1980 and so on. The oldest hit I got to “single domain antibody” had nothing to do with it, surprisingly. I am still puzzled why this was a match, but we will solve that mystery some other time.

The oldest hit from Google Search to the “single domain antibody” keyword

I had to go all the way up to 1990 to get a meaningful hit on my search, but it was worth it. I found a really fun-to-read article by Professor Heather M Dick from Ninewells Hospital and Medical School, Department of Medical Microbiology.

Dogma had it that antigen recognition and binding depend on the presence of segments or domains of both light and heavy chains; or at least their terminal domains.

Prof. Heather M DICK (DOI: 10.1136/bmj.300.6730.659)

I had no idea there was a stigma associated with the requirements for a therapeutic effect from an antibody. Scientists surprise me with these dogmas. We are supposed to be searching all the time, but perhaps there were experiments showing that both were needed, so it may not have been all baseless. If you have access to it, read it: A mystery comment about a patient being tied up makes me wonder what it actually means. Did they really tie the patient to a chair, or am I missing something? The article cited a commentary in nature (apparently, they were termed as dAb backed then): “Austin Penelope. Will dAbs Challenge mAbs? Nature 1989;341:484-5.” Unfortunately, I had no access to it.

It is such a pity that articles/commentaries like this are hidden behind a paywall. It really is. I couldn’t read that article, but at least I had learned that a group from “Medical Research Council” in UK was responsible for the discovery. So I had to do another Google search to find the name Prof. Sally Ward. Unfortunately, the sdAB-DB article doesn’t reference her study. From what I have gathered, the solubility and therapeutic potential of dAb were under debate because of the exposed hydrophobic regions. The citations in sdAB-DB go back to the 1993 study that discovered camelid antibodies that are naturally single chains.

So now you know who first showed that only a single domain was enough for binding, Prof. Sally Ward (Go check out her study). I will send special thanks to Prof. Heather Dick for that joyful read and I will finish off with another quote from the same article.

Clearly the Medical Research Council must be grateful that this is one fish that didn’t get away; it may well prove to be a valuable catch if its potential can be realised.

Prof. Heather M DICK (DOI: 10.1136/bmj.300.6730.659)