Art of the Soluble

Art of the Soluble

WE THE CURIOUS vol.2 no.2

"Most of all, of course, I was lucky to survive," writes Clifton Leaf, the executive
editor at Fortune. In 1978, at the age of fifteen, Leaf was admitted to a clinical trial
at the National Cancer Institute and cured of Hodgkin's disease. "So it makes the
question I am about to ask sound particularly ungrateful: Why have we made so
little progress in the War on Cancer?"

The science of cancer -- our understanding of the disease -- has clearly progressed.
We are now, in the words of Harold Varmus, head of Memorial Sloan-Kettering,
"pretty damn knowledgeable" about how cancer arises. Altogether the cancer
research community has published 1.56 million papers, largely on the genes and
"signaling pathways" that go haywire in a cancer cell. "You get a paper where you
change one gene ever so slightly and you have a drastic effect of cancer in the
mouse," explains Jean-Pierre Issa, a leukemia researcher, "and that paper gets
published in Science or Nature, and in your best journals. That makes your
reputation. Then you start getting grants based on that. Open any major journal and
80% of it is mice or drosophila [fruit flies] or nematodes [worms]."

But, according to the head of cancer research and clinical investigation at Eli Lilly,
mouse models are "woefully inadequate" for determining whether a cancer drug
will work in humans. "If you look at the millions and millions and millions of mice
that have been cured and you compare that to the relative success, or lack thereof,
that we've achieved in the treatment of metastatic disease clinically, you realize
that there just has to be something wrong with those models." Somehow, our
understanding of how cells can become cancerous -- and might be cured -- in the
lab has not brought us the cure we need.
In his article Why We are Losing the War on Cancer (and How to Win It), Clifton
Leaf gives this stark summary: "In 1971, when the war on cancer began, 50% of
people diagnosed with the disease went on to live at least five years. Today, 33
years and some $200 billion later, the five-year survival rate is 63%, a modest 13-
point gain. But a look behind the numbers for the four biggest killers -- lung, colon
and rectal, breast, and prostrate cancer -- reveals that progress isn't being made
where you might think it is. With the help of early detection and treatment, more
patients are living longer. Once a cancer has spread, however, chances of survival
are scarcely better now than they were three decades ago."

If only we could assess our progress in terms of scientific knowledge gained

instead of the metric that really counts: lives saved. But we can't. Nor is it clear
that the knowledge we have gained is the knowledge we need most to win this
"war." Take, for instance the problem of metastasis. We talk about breast or colon
cancer as the "big killers," but the original tumors in these areas are not, ultimately,
what kill people with cancer. It is cancer's ability to spread -- to reach like "the
arms of crab" -- into vital organs that causes death. "In the end," writes Leaf, "it is
not localized tumors that kill people with cancer; it is the process of metastasis --
an incredible 90% of the time." Since the founding of The National Cancer
Institute (NCI) in 1972, less than 0.5% of NCI grants focus on understanding the
process of metastasis. In 2003, only 8% of the NCI grant proposals awarded even
mentioned the word metastasis.

As one Dana-Farber researcher has pointed out, "It is as if one World Trade Center
tower were collapsing on our society every single day." And yet, even as this goes
on day after day, a proposal by an accomplished researcher to study the gene
function of metastases vs. primary tumors is now in its third resubmission to the
NCI. "I mean, there is nothing known about that," he says. "But somehow I can't
interest people in funding this!"

Andy Grove, the chairman of Intel and a prostrate-cancer survivor, calls it "a Greek
tragedy. Everybody plays his individual part to perfection, everybody does what's
right by his own life, and the total just doesn't work." Leaf blames the "cancer
culture," which he describes as "a groupthink that pushes tens of thousands of
physicians and scientists toward the goal of finding the tiniest improvements in
treatment rather than genuine breakthroughs; that fosters isolated (and redundant)
problem solving instead of cooperation; and rewards academic achievement and
publication over all else."

Leaf is right; it is a "groupthink." It is a tragedy. But there is another word for it as

well. It is science -- this is how science works.

In 1962, nearly a full decade before the War on Cancer began, Thomas S. Kuhn
published his landmark essay, The Structure of Scientific Revolutions. It is from
that work that we get the expression "paradigm shift." Kuhn would not be shocked
by how little meaningful progress we have made in the fight against cancer. In fact,
he could have predicted it. "One of the reasons why normal science seems to
progress so rapidly," he explains, "is that its practitioners concentrate on problems
that only their own lack of ingenuity should keep them from solving."

As laymen, we tend to perceive science in terms of all that it has done for us -- the
technology, the progress, the immense breakthroughs in our knowledge of and
control over the world. Kuhn cuts through such misconceptions: "The scientific
enterprise as a whole does from time to time prove useful, open up new territory,
display order, and test long-accepted belief. Nevertheless, the individual engaged
on a normal research problem is almost never doing any one of these things."
Scientists, Kuhn argues, are puzzle-solvers.

Like jigsaw puzzles and crossword puzzles, a puzzle in science is a problem where
the existence of a solution is assured. This certainty that a solution must exists -- if
only the researcher is clever enough to find it -- arises from the scientists' shared
base of knowledge, assumptions, and practices that Kuhn calls the "shared
paradigm" of a scientific community. Researchers can commit years, even decades,
of their career to studying puzzles and can martial great resources with confidence
because such problems, as long as the paradigm is taken for granted, are assumed
to have solutions.

"To a great extent," writes Kuhn, "these are the only problems that the community
will admit as scientific or encourage its members to undertake." For example, the
MAP kinase pathway can be broken down into lots of puzzles: How it is affected
by the Ras gene? How does it make transfected NIH 3T3 cells behave the way they
do? Scientists have the understanding and the tools to attack such problems. Given
the current paradigm, however, there are very few puzzle-like problems for the
process of metastasis. "It's tough. Okay?" says M.D. Anderson's Josh Fidler.
Metastasis is an organism-wide phenomenon that is very poorly understood; it may
involve dozens of different process and hundreds of variables; and it is very hard to
do the kind of experiments that generate reproducible results. "And," continues
Fidler, "individuals are not rewarded for doing tough things."

As Kuhn wrote in 1962, "It is no criterion of goodness in a puzzle that its outcome
be intrinsically interesting or important. On the contrary, the really pressing
problems, e.g., a cure for cancer or the design of a lasting peace, are often not
puzzles at all, largely because they may not have any solution."
That is the paradox of science's power. On the one hand, we can justifiably expect
science to make great progress; every day more and more puzzles are solved by
scientists from around the globe. But, despite this reliable and remarkable progress,
we cannot expect that science will make progress on those problems that most
urgently need resolving, the problems we most care about. To forget this is to
make a terrible mistake -- a tragic mistake.

P. B. Medawar, a Nobel laureate in Physiology and Medicine, has said that science
research is "the art of the soluble." To solve a puzzle, you need only to be patient
and clever; and, given enough time and enough brains, science reliably finds a
solution. To solve the seemingly insoluble, however, is to be alert and lucky.
Nothing is assured. The possibility of failure is real, but so too is the possibility of
success. Again and again, the alert and lucky have found ways to save lives --
millions upon millions of lives.

"The history of medicine is replete with examples of cures obtained years, decades,
and even centuries before the mechanism of action was understood for these cures
-- from vaccination, to digitalis, to aspirin," Sidney Farber told congress in 1972.
Farber, a Boston physician known as the "godfather" of cancer research, argued
that the government should fund a structured, coordinated assault against cancer --
a centralized approach on the scale of the Manhattan Project or the Apollo
missions. "We cannot wait for full understanding; the 325,000 patients with cancer
who are going to die this year cannot wait; nor is it necessary, in order to make
great progress in the cure for cancer, for us to have the full solution of all the
problems of basic research." Farber didn't want solutions to puzzles; he wanted the
cure within his lifetime. He lost.
COMING UP THIS MONTH
The Screwball Division solves a mystery

REFERENCES
Why We're Losing the War on Cancer (and How to Win It) by Clifton Leaf
Fortune March 22, 2004

The Structure of Scientific Revolutions by Thomas S. Kuhn

On the MAP by Karen Hopkin

The Scientist, June 2009

Advice To A Young Scientist by P. B. Medawar

WE THE CURIOUS, the free newsletter for people who love learning
By Mackenzie Hawkins

SUBSCRIBE TO WE THE CURIOUS (It's free!)

sign up at www.glyphco.com/we-the-curious

RSS FEED
subscribe to an RSS feed of We the Curious
GLYPHCO
We the Curious is a Glyphco project.
"Knowledge creatively employed."
www.glyphco.com