03.2019 | THE SCIENTIST 61READING FRAMESI
n 1971, Judah Folkman, then a 38-year-
old surgeon at Boston Children’s
Hospital, proposed a radical idea:
tumors in the body send out signals that
trick surrounding tissues into helping
them grow. The signals instruct these
tissues to sprout new blood vessels, which
can deliver oxygen and other nutrients to
cancer cells. He suggested designing a new
kind of drug, one that would block those
signals, preventing or destroying the new
blood vessel growth and starving tumors.
Cancer at the time was treated
mainly by flooding the body with poison
(chemotherapy) or searing it with radiation.
Folkman’s idea of subtly targeting some
mysterious communication channel
between tumor and host was met with
scorn. When he spoke about his idea at
scientific meetings, Folkman said, the
room would empty out: “Everybody had
to go to the bathroom at once.” One year,
the criticism was so intense that Boston
Children’s Hospital convened an external
committee to review his research. The
committee judged his work to be of little to
no value. He was asked to resign as chief of
surgery should he choose to continue the
studies. He resigned and, fortunately for all
of us, continued his research.
Today, Folkman’s thesis underlies nearly
all modern approaches to treating cancer,
from anti-angiogenesis therapy to cancer
immunotherapy. The work has resulted in
dozens of FDA-approved drugs that have
helped hundreds of thousands of cancer
patients, and has inspired the development of a
broad new category of drugs, VEGF inhibitors,
that can reverse a certain form of blindness
(that caused by macular degeneration).
Tasked with writing this essay about
pursuing “ideas that are outside the boundaries
of what some would call rational thinking,”
adapted from my forthcoming book,Loonshots,I hardly knew where to start. So many great
breakthroughs in drug discovery were initially
considered crazy.
In the 1970s, when Japanese biochemist
Akira Endo sought to develop a compound
to lower blood cholesterol, the research
community wrote off the concept, reasoning
that every cell contains cholesterol, so any
such drug must harm every cell. Fortunately,
he persisted. The statins he developed have
prevented millions of heart attacks and
contributed significantly to a three-decade
decline in deaths from heart disease.
In the 1990s, chemist Julian Adams
insisted on developing a cancer drug
known as PS-341, which blocked
proteasomes—the waste receptacles of
cells. Every cell, like every home, needs
waste disposal. Blocking that system is
a crazy, irrational idea. Except that it
worked. The drug became a revolutionary
new treatment for multiple myeloma.
Folkman liked to include a slide in
some of his presentations with a clip from
a 1903 New York Times article. The article
described yet another failed attempt at
building a flying machine and explained
exactly why any such machine could never
work. Nine weeks later, two brothers took
off from Kitty Hawk, North Carolina, in the
world’s first successful airplane.
Overconfidence in accepted wisdoms
discourages true innovation. The recent
proliferation of spectacular scientific
tools—from full-genome sequencing
to CRISPR—increases this danger, by
encouraging the pursuit only of rigorously
validated targets. But complex systems
such as human cells and tissues often
produce results that can’t be predicted
from simple laboratory analyses.
If we want great breakthroughs, we
need to encourage crazy—even irrational—
ideas, whose logic might defy our bestcurrent models. Doing so requires humility:
the willingness to question our beliefs.
Former US Vice President Joe Biden
declared a moonshot against cancer in- Similar goals may soon be set against
other diseases. It’s important to keep in
mind that a moonshot is just a destination.
Nurturing loonshots—the neglected ideas
whose champions are often dismissed as
crazy—is how we get there.g
Safi Bahcall is a physicist, a former biotech
CEO, and author of Loonshots: How to
Nurture the Crazy Ideas that Win Wars,
Cure Diseases, and Transform Industries.St. Martin’s Press, March 2019Many of the truly transformative innovations in science
were initially met with scorn.BY SAFI BAHCALLIn Praise of Crazy Ideas