October 20, 2015

Rewriting the fairy tale of science

By Eric Hamilton



“Once you see something, you can study it” –Marty Chalfie

Science has traditionally liked to tell the story of itself in a particular way, with predictable beginnings and ends, like a fairy tale. Hardworking and naturally brilliant upstart young scientist comes across a thrilling phenomenon in the natural world. He (and it’s usually a he) must know the truth! Logical, methodical, accurate experiments ensue, alone in the lab late at night, and at just the right time, the smart young man’s hypothesis is confirmed — eureka!

Marty Chalfie, one of the winners of the 2008 Nobel Prize in Chemistry for his establishment of green fluorescent protein, or GFP, as a biological marker, directly contradicted this Hollywood version of science during his keynote address to the Cell and Molecular Biology program’s annual mini-symposium in September. Through the story of how GFP was discovered and put to work inside cells, Chalfie spoke of the serendipity, mistakes, frustration and teamwork behind any major (or minor) scientific advance.

In fact, he began his engaging and funny presentation with the myths as the scientific process was seemingly taught in the 1960s: scientists are innate geniuses who are always purposeful; experiments always work; scientists work alone, and are white men.

Reality: GFP’s necessary precursor, aequorin, was discovered by throwing away a sample of purified jellyfish protein into a sink in frustration; the calcium in the water caused the protein within to glow blue for the first time outside of the living animal. And only then could Osamu Shimomura — who survived the bombing of Nagasaki as a young man — realize that another protein must exist that converts the blue light from aequorin to the green color jellyfish emit. Thousands of pulverized jellyfish later, and GFP was extracted as well. Unlike its predecessor, GFP required only blue light to glow.

The scientific method says nothing about throwing samples away into the sink.

Chalfie’s realization that GFP could be used to great effect in the transparent nematodes he studied could be called a eureka moment. But the following two years of miscommunication with a collaborator and chance failures of competitors who envisioned the same technique were anything but. Those years were how science really proceeds: haltingly slow, with far less agency than you would ever like to admit.

Ultimately, his team demonstrated that GFP could be safely expressed in living cells, while his wife, Tulie Hazelrigg, showed that GFP could be attached in whole to other proteins and preserve their function. That allowed researchers to track for the first time functional proteins inside living cells and see their dynamics. In exchange for preparing the Saturday morning coffee for two months at home, Hazelrigg gave Chalfie permission to mention the protein work in his landmark Science paper.

(Science, by the way, asked Chalfie if they could change the color of the glowing worm on the cover to a more design-friendly red or blue. He declined.)

Since then, GFP has revolutionized how biology is done. I use GFP literally every week; my most vital experiments absolutely require it, largely for locating my proteins of interest and getting a sense of how much protein there is by eye. The first time I personally transformed a fluorescent protein into my pollen and saw tiny cellular structures glow brightly under the microscope, my breath caught in my throat. It actually worked, like it was supposed to (for once!), and I saw in that moment things nobody else had ever seen before.

Bookending his talk, Chalfie reiterated many of the truths, rather than myths, about how science is actually performed. First of all, it’s done by real, normal people — rarely geniuses. And those people work together, closely and distantly, to build on years, decades, and centuries of prior knowledge in order to learn just a little bit more about how nature works. Ignorance, stubbornness, and a willingness to try are usually more important than innate intelligence.  

And he spoke of the importance of basic research, albeit not just on model systems, or pioneer organisms as he called them. On communicating about science, Chalfie made a suggestion I haven’t heard much of before, which is to tell non-scientists not just how science is done, but how it’s funded. Because a grant-based system, rather than one of contract funding, is fundamental to how basic research is conducted in an intellectually open way.

I’ve now seen two-thirds of the 2008 Nobel Prize in Chemistry speak at Washington University. A year-and-a-half ago, Roger Tsien spoke about his work permuting GFP and other fluorescent proteins into better, more versatile compounds for scientists to manipulate and work with. Chalfie noted in passing that Tsien had won the Intel Science Talent Search (known as the Westinghouse STS at the time) as a young man, speaking only a day after Intel announced it would end its sponsorship. I have to wonder which promising young scientists might not get their best start with the support pulled on this prestigious competition.

My favorite sentiment of his talk reiterated how many, if not most, discoveries of note are accidental, and I’ll end with it:

“If you do an experiment and it confirms your hypothesis, you’ve made a measurement. But if you do an experiment and it contradicts your hypothesis, then you’ve made a discovery.”