The nasty, ugly fact of off-target effects
Once upon a time, it was imagined that siRNAs specifically knock down the intended target gene.
Unfortunately, this turned out to be wrong.
The disappointing results from siRNA screening following the initial high hopes brings to mind T.H. Huxley‘s famous quote about a beautiful theory being killed by an ugly, nasty little fact.
As pointed out by S.J. Gould in Eight Little Pigs, the origin of the quote is given in the autobiography of Sir Francis Galton.
Galton’s autobiography is inspirational. As one reviewer put it, “there is a feeling of calmness and awe that comes from knowing that a person of his genius, wisdom and versatility actually existed.” He was 70, and had already made significant contributions to genetics, statistics, meteorology, and geography, when he published his first major work on fingerprints, which would become the basis for modern forensic fingerprint analysis.
His work on fingerprints also provides the context for the famous Huxley quote:
Much has been written, but the last word has not been said, on the rationale of these curious papillary ridges ; why in one man and in one finger they form whorls and in another loops. I may mention a characteristic anecdote of Herbert Spencer in con- nection with this. He asked me to show him my Laboratory and to take his prints, which I did. Then I spoke of the failure to discover the origin of these patterns, and how the fingers of unborn children had been dissected to ascertain their earliest stages, and so forth. Spencer remarked that this was beginning in the wrong way ; that I ought to consider the purpose the ridges had to fulfil, and to work backwards. Here, he said, it was obvious that the delicate mouths of the sudorific glands required the protection given to them by the ridges on either side of them, and therefrom he elaborated a consistent and ingenious hypothesis at great length. I replied that his arguments were beautiful and deserved to be true, but it happened that the mouths of the ducts did not run in the valleys between the crests, but along the crests of the ridges themselves. He burst into a good-humoured and uproarious laugh, and told me the famous story which I have heard from each of the other two who were present on the occurrence. Huxley was one of them. Spencer, during a pause in conversation at dinner at the Athenaeum, said, "You would little think it, but I once wrote a tragedy." Huxley answered promptly, " I know the catastrophe." Spencer declared it was impossible, for he had never spoken about it before then. Huxley insisted. Spencer asked what it was. Huxley replied, "A beautiful theory, killed by a nasty, ugly little fact." Memories of My Life, pp 257-258