Many people are familiar with the story of Alexander Fleming’s accidental discovery of penicillin produced by mold growing in a bacterial culture. These same people would probably be surprised at how often carefully planned scientific experiments yield unexpected (and even unwanted!) results, usually leading to repetition of the experiment to discover where things went wrong. However, one mark of a really good investigator (like Fleming) is the ability to recognize when the “error” may actually be a truth that provides a key new insight. The phenomenon of looking for one thing and serendipitously finding another plays a surprisingly frequent role in the process of scientific discovery.
A case in point can be found in studies of motor neuron degeneration being carried out in the laboratory of Dr. Dongxian Zhang, associate professor at Sanford-Burnham. The death of motor neurons in the spinal cord is responsible for lethal diseases such as spinal muscular atrophy and amyotropic lateral sclerosis (Lou Gehrig’s disease), neither of which is treatable or curable. Dr. Zhang’s group hypothesized that motor neuron death might be caused by the absence or malfunction of a specific type of membrane receptor called MNR. To test their theory more directly, they paid a commercial company to create a mouse in which MNR was genetically deleted. Sure enough, motor neurons in these mice degenerated a few days after birth. To further prove their point, the group attempted to rescue the lethal defect by genetically adding back the MNR gene. To their consternation, these transgenic rescue mice still died shortly after birth.
“At that point we were completely stumped and discouraged,” confesses Dr. Zhang.
This setback forced the research team to carefully re-examine the strategy used to create the MNR knockout mouse. They found that the company had used a common shortcut to target and ablate the MNR gene. This shortcut resulted in the removal not only of MNR, but also a stretch of “junk” DNA that was not initially recognized as coding for a protein.
Dr. Zhang and his team eventually realized that this stretch of DNA might actually hold the recipe for a novel protein after all, and named the hypothetical protein SIP (short for Syvn-interacting protein). Their next step was to create a new mutant mouse in which only SIP was missing, leaving MNR untouched. The SIP-deficient mice once again experienced motor neuron death, which in this case could be rescued by re-introducing SIP into the mouse.
At this stage, SIP is still a protein without a known function. Dr. Zhang’s group is now carrying out experiments to determine the importance of SIP in motor neuron physiology and to understand why its loss causes motor neuron degeneration. They are finding that human SIP contains mutations that may be associated with the disease distal motor neuropathy. Solving these puzzles, using the serendipitously discovered SIP-deficient mouse as a model, might provide clues that lead to treatments for motor neuron degeneration in humans.
Hang in there, Steven Hawking!