A key to making discoveries: ask “Why?”
Asking Why? is crucial to see below the surface and find what others have missed.
“There is our little Ehrlich; he is a first-rate stainer of tissues, but he will never pass his examinations,” remarked his medical school professor to future wunderkind Paul Ehrlich’s mentor, famed microbiologist Robert Koch. Another professor scoffed, “Ehrlich? Ach, an abominable student. He learned nothing. He memorized nothing. But such beautiful stains and dyes and colors he could mix…indeed, he should have been a painter!”
Paul Ehrlich as a medical student was fascinated with staining of biological tissues and devoted his doctoral thesis to the topic. He colored his desk and lab with a rainbow of colors — bright greens, yellows, purples and reds. His colorful stains led to the discovery of five new kinds of human blood cells, which earned him his medical degree.
One day, he injected one of his stains, methylene blue, into a living rat. “Herr Gott!” he shouted. “Look at this. I inject methylene blue into this nice little rat, and it colors all the nerve endings such a beautiful blue. Now, how does that happen, hein? Why does it color only the nerve endings?”
Further thought and experimentation led him to the answer to his why question — affinity. His blue dye had a chemical stickiness, an affinity, for nerve endings. That led him to propose that beautiful dyes could also be medicines — he might find colors that had affinities for pathogens, cancers, and deadly creatures that invade the body. With this simple and innovative idea, he founded the modern pharmaceutical industry, which has now grown to a >$1 trillion market.
A crucial step in the research process is to ask the why question, especially, or even primarily, when it seems inconsequential or impossible to answer. Many people will have asked the why question about obviously important phenomena, but few people ask the question about minor details. Yet, hidden in the answer to this question can be the key to unlocking discoveries. Swiss scientist Jean Senebier asked why vegetable oil went rancid and thereby laid the foundation for discovering lipid peroxidation, a key process involved in ferroptosis and numerous diseases.
Children are masters of this question: in 1943, three-year old Jennifer Land asked her father why she had to wait a long time to see the pictures he was taking with his camera on their vacation. Rather than sweeping her question aside, he pondered it deeply; that sparked the idea for an instant camera, which his company Polaroid would ultimately develop and market to great success.
Asking why also led to one of the iconic sounds of 1980s pop music: in 1979, musicians Peter Gabriel and Phil Collins, former members of the Genesis band, were recording Gabriel’s third solo album. Collins was drumming, and he noticed that his drumming was accidentally picked up by one of the audio engineer’s microphones, where it was recorded in a strange way. Collins and Gabriel asked why this seemingly inconsequential and strange sound was recorded. They found that the microphone had been set to suppress loud sounds and record soft sounds, and to cut off recorded sounds quickly using a noise gate, as it was meant for the audio engineers to speak quietly to each other. It was a fluke combination that they never would have designed, and would never have understood unless they investigated why it had happened. The combination of these effects results in a transient and lonely beating sound that was made famous in Collins’ In the Air Tonight, and became a classic of 1980s music.
I learned the importance of asking why which my lab technician accidentally shattered a giant bottle of oil of wintergreen on the floor of the lab. We were looking for a better way to test drug candidates quickly for their effects on cells.
Our idea was to print microscopic sized spots of each drug embedded in a polymer that would allow the drug to be slowly released into surrounding cells, which would grow on top of the polymer. We would print these drug spots on glass microscope slides, just like the kind used in high school biology classes. We explored this strategy extensively, but we kept encountering a major problem — we couldn’t find a solvent that would dissolve both the drugs and the polymer to allow us to spot them out on the slide. We even went to talk to the prolific inventor and world leader in drug polymer technology Bob Langer, across the street at MIT, and even with Bob’s help, we couldn’t come up with an answer.
We were continuing to mull over this problem in my lab one afternoon, when another young technician in my group was working on the bench next to us. He had his headphones on, and was reaching up for a box on the shelf above the lab bench, when he accidentally knocked his arm against a one-gallon bottle of methyl salicylate on the bench. I wondered in that moment why I had a one-gallon bottle of methyl salicylate sitting on the benchtop. Methyl salicylate is oil of wintergreen and was one of the thousands of chemicals sold by Sigma that I had acquired in my ransacking of the Sigma chemical collection upon starting my lab. When he bumped the bottle, I saw it start falling, in slow motion, knowing that nothing could be done to avert the coming catastrophe. The bottle crashed to the floor, shattered into dozens of pieces, and sprayed the contents across the lab floor. We immediately cleared out of the lab and called the Environmental Health and Safety Office, whose staff arrived in full hazmat suits and respirators to clean up the spill. The lab had a minty fresh smell after that.
Upon returning to the lab, I noticed that the floor tiles on which the methyl salicylate bottle had landed were spotless. The rest of the lab tiles had the usual grungy, dirty appearance, as various mysterious substances accumulated on the floor over time. But the site of the accident looked as though it had been vaporized with an atomic bomb, leaving behind pristine white floor tiles brighter and cleaner than your dentist’s teeth.
In staring at our sparkling new floor, I asked why it was so clean. As we pondered and discussed this seeming bit of trivia, I realized that the answer to this why question was that methyl salicylate was really amazing at dissolving everything! Indeed, methyl salicylate was the solution to our scientific problem, dissolving drugs and polymer, allowing us to create the screening system we had envisioned.
There was an undeniable element of serendipity to this experience, but asking why played a key role. I was thinking about the drug solubility problem constantly, and it was in the back of my mind when I saw the unnaturally clean floor tiles. This is a way in which asking why can pay off — by asking and answering the why question, more often than not, you may make an impactful discovery.
