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
Cricks 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
proteinpresumably with one amino acid added or
subtracted. But one or two mutations would result in
nothingpresumably 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 facteven
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
anymorehe 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, talksand,
lately, writeshis 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 Cricks 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.