The “Known Unknown” Impact of Donald Rumsfeld
How the US Secretary of Defence became a mascot for microbial genomics.
Donald Rumsfeld, US Secretary of Defence under George Bush, died this week at the age of 88.
Rumsfeld is most famous for his role in the US wars in Iraq and Afghanistan. He is also responsible for one of the most infamous truisms of all time.
In 2002, responding to question by NBC’s John Miklaszewski, Rumsfeld said:
Reports that say that something hasn’t happened are always interesting to me, because as we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns—the ones we don’t know we don’t know. And if one looks throughout the history of our country and other free countries, it is the latter category that tends to be the difficult ones.
Rumsfeld’s answer was, understandably, lampooned. But bizarrely, his words resonated with microbiologists at the centre of a scientific revolution.
Meanwhile in Microbiology
2002 wasn’t all about WMDs and the Axis of Evil. In biology, the genomic revolution was starting to gain pace.
A handful of genomes had already been sequenced and, although not complete, a draft of the human genome was well underway.
Amid the gold rush, researchers in the Britain and Japan were racing to be the first to sequence the genome of a Streptomyces bacterium. Streptomyces produce useful natural products, including the clinical antibiotics, like chloramphenicol and tetracycline. Unravelling the secrets of their genome would be a crowning scientific achievement.
Led by Sir David Hopwood, the multi-national British team pipped the Japanese to the post. The genome of Streptomyces coelicolor was published in 2003.
With the genome sequenced, the team was able to identify nearly eight thousand genes. However, it wasn’t clear what all these genes were for. This revelation was met with excitement.
The abundance of previously uncharacterized metabolic enzymes, particularly those likely to be involved in the production of natural products, is a resource of enormous potential value.
The Japanese team, led by Satoshi Omura, published their genome later the same year. Their strain, Streptomyces avermitillis contained even more genes of unknown function.
The researchers believed that many of these genes were required for the production of natural products. The data suggested that the Streptomyces had untapped potential. An abundance of new drugs was waiting to be discovered by the researchers who could learn to manipulate the Streptomyces genome.
Genome Mining, Knowns and Unknowns
The Streptomyces genomes spawned a new discipline virtually overnight. According to Omura in his Nobel Prize lecture:
This created a new research mechanism, whereby production of compounds with specific structures can be predicted by gene analysis and later confirmed through actual production and isolation.
The genome-first approach became known as ‘genome mining.’
This is where we return to Rumsfeld.
His famous quote became a very effective way of categorising knowledge of natural products.
There are known knowns, where we know the product and the genes involved. There are known unknowns. Products that have yet to be isolated but can be predicted by the presence of particular genes in the genome. And, there are unknown unknowns. Those products that are so unique we have yet to isolate them and cannot predict their existence using existing genomic analyses.
As Mohammad Seyedsayamdost and Jon Clardy write in their paper Natural Products and Synthetic Biology:
While the phrasing of this tripartite classification was not intended to describe the current state of natural products research, it could have been, as it provides an apt description of the field today.
The phraseology has become so ubiquitous in the field that Rumsfeld is rarely referenced. Nevertheless, his infamous quote still pops up in conferences, seminars, and workshops.
Rumsfeld’s involvement in Bush era foreign policy will ensure that his legacy is controversial. Over the next few days, journalists will try to walk the tightrope of criticism and respect before the news cycle churns inevitably on.
Regardless of his political legacy, Rumsfeld will be unknowingly immortalised in a small corner of academia.
