SCIENCE NOTES 2002 ¦ University of California, Santa Cruz Science Communication Program

WHEN I WAS A GRADUATE STUDENT, I would see him while walking to and from the Salk Institute parking lot, perched on the cliffs above La Jolla. Of course, his car, parked in the "reserved" spot closest to the Institute, was a little more distinctive than mine. The gleaming white Mercedes had California tags that read "AT GC," the bases that made up the double helix of DNA, which he and James Watson discovered more than a half century ago. Francis Crick's full head of white hair would always alert me to the fact that I was sharing the sidewalk with one of science's living legends. I never mustered the courage to speak up, but every time our paths crossed I would wonder, "Does he appreciate this beautiful afternoon the same way I do?" Surely, now that he is immersed in the problem of human consciousness, he must be thinking about how our brains process appreciation for hang gliders at sunset.

Francis Crick thinks, reads, talks–and, lately, writes–his way through ideas.

The encounters with Crick had me pondering what distinguishes a great scientist from the good ones. I thought of the question as grist for the mill of my graduate school self-education. If I could establish a pattern, then perhaps I could tap into the formula for success and at least bump myself up from "floundering" to "mediocre." As far as I could determine, the pattern was that these scientists had not just one or two good ideas, but a lifetime of them. So, on a more fundamental level, I wanted to know where those ideas came from.

Maybe, I thought, certain researchers had been graced by God-given genius. Others might simply work harder and spend more hours thinking about problems. And some individuals possessed the ability to contemplate problems in drastically different ways. Was there some magical combination of traits? The answer would require some deeper digging. Since Crick and his work made appearances throughout my studies, I decided his lifetime of ideas would make a good case study.

Like every other obedient biology undergraduate, I had read The Race for the Double Helix, so I roughly knew the story of how Crick and Watson solved the structure of DNA. Later, I would recognize that Crick used all of his creative and critical thinking skills during this race. But what struck me at an impressionable young age was that he and Watson weren't just mere biologists who stumbled upon a chance discovery. Rather, they knew physics and chemistry in such detail as to synthesize the bits of data scattered across various fields. They had to translate the X-rays of DNA crystals into a 3-D structure. Their knowledge of the laws governing hydrogen bonds told them that A's paired only with T's and C's only with G's. They tried each piece in different configurations, until through trial and error, they found a model that fit the physical data and made sense biologically. In an interview 36 years after their discovery, Crick asserted, "We deserve credit for learning about a lot of different subjects so we could put it all together. And not many people were prepared to do that."

Today scientists are more narrowly specialized than in Crick’s time, so even fewer aspire to be a jack-of-all-trades. But those who do make big discoveries. Biochemist Roger Tsien is one of them. I was a rotation student in a neighboring lab when Tsien was inducted into the National Academy of Sciences. The champagne flowed as the elder scientists congratulated him on his achievements. His lab had solved the structure of Green Fluorescent Protein (GFP) and then modified it to study the inner workings of the cell. GFP, a protein found in jellyfish, glows green owing to a unique physical structure. Tsien's enhanced version of the GFP protein is one of the most important research tools in cell biology today. Scientists attach GFP to any unknown protein and then simply look through a microscope to find out where that protein acts inside the cell.

At different times in his career, Tsien has belonged to departments of chemistry, physiology, pharmacology, and cell and molecular medicine. His lab continues to design new molecules that will light up under different cellular conditions, such as pH or calcium concentration. To do this design work, lab members must apply chemistry and physics at the submicroscopic level of the GFP molecule and within the dynamic confines of the cell. This is an example of how, by crossing multi-disciplinary techniques, Tsien develops unique methods for answering his next set of research questions.

I came across more of Crick's creative work the next year of graduate school in my critical reading class. His landmark 1961 paper established the genetic code as sets of three bases (A, T, G, or C) coding for each amino acid as it was added to a protein chain. We studied the paper as a classic example of using deductive reasoning to arrive at the best possible hypothesis.

One elegant experiment showed that triplets of bases were the most likely configuration. A pair would only have given 4 (A, T, G, or C) X 4 (A, T, G, or C) = 16 different amino acids and Crick knew that at least 20 amino acids existed. The researchers used a specific mutation-causing chemical that either adds or subtracts one base at a time from DNA. Then they could use combinations of mutations such as (+, +) or (-, -, -) to discover how the mutations affected the protein building. Mutations in sets of three resulted in a protein–presumably with one amino acid added or subtracted. But one or two mutations would result in nothing–presumably because the code had been shifted by one or two and was now unreadable.

Next, they criticized their hypothesis against every other piece of available data. In the paper, Crick marches through all of the reasons why overlapping codes, codes of two and three, and nonlinear codes do not fit the observed evidence. Because their hypothesis withstood this trial of ideas, it was accepted almost as fact–even before it could be proven beyond a doubt with experimental techniques.

Crick used critical thinking to advance his own ideas at a time when the laboratory methods to solidify those ideas did not yet exist. A similar phenomenon occurs in lab meetings in which scientists play a brainstorming game. Thinking out loud about a piece of experimental evidence, they challenge each other to prove that their ideas are both feasible, given other data, and testable. They hone their critical thinking skills so that they carry out only rigorous experiments. Crick explained that the candor between himself and Watson allowed for this relentless back-and-forth critical reasoning. "If one of you gets an idea which is a cul-de-sac, or which gets you off on a false trail, the other one will pull you back and get you out of it," he said in a 1989 interview.

Crick made his last appearances in my graduate career during the Salk Institute's weekly seminars. He would frequently be sitting in the front row of the half-filled lecture hall. Typically, he would have a brilliant question for the speaker at the end of the lecture. His questions would always be broad, yet astute, and the speaker would smile and say, "Yes, well, that will be our next experiment."

Crick listened thoughtfully to whatever lectures came through the auditorium, from HIV vaccine design to the genetics controlling floral patterning. By keeping up with these widely disparate areas of research, he expanded his horizons and gained insights into areas far beyond his expertise. Crick does not run a lab at Salk anymore–he only keeps a study with a spectacular ocean view. Nevertheless, I suspect that he talks to more people about his ideas each day than do most investigators running 20-person labs. Crick thinks, reads, talks–and, lately, writes–his way through ideas.

Crick's creative genius comes from a mixing of the following three ingredients: knowing many fields of study, being critical of each idea, and keeping in close and frequent contact with other brilliant minds. Toward the end of my graduate school days, many of my friends had left or were leaving shortly to start their own labs. In a rookie version of Crick’s broad-based yet highly focused networking, these young scientists spent their days on the phone or shooting email messages to each other. While a substantial portion of this communication revolved around last night's Simpsons episode, an important process was nevertheless at work. These young investigators were forging new alliances with people in other fields. They were trotting out new hypotheses for testing. And they were keeping one another honest by razzing a poorly formed game plan. Collectively, they were brewing the next generation of scientific discoveries.