Actually, the Newsweek articles are also on the front page. Here's the one on Folkman:
For years, researcher Judah Folkman was scorned by peers. Last week he became
famous--for a breakthrough that may, or may not, help conquer our most-feared
killer.
By Sharon Begley and Claudia Kalb
In his gold wire-rimmed glasses and white lab coat, Dr. Moses Judah
Folkman doesn't look anything like a man in the eye of a media storm. Leaning
forward in the conference-room chair on the 10th floor of Boston's Children's
Hospital, Folkman is deep in earnest conversation about his long-scorned
theory of cancer when his beeper goes off. CBS is asking him to appear on the
evening news. Folkman, 65, politely excuses himself and, returning the call,
declines--as he has most of the 2,000 other interview requests that flooded
in last week. This was Folkman's moment, his chance for the cliched 15
minutes of fame, for seven-figure book deals and glowing newspaper profiles.
And he was having none of it. An intensely private man, Folkman blew off Dan
Rather, Peter Jennings and Ted Koppel, refused TV offers from Australia and
Israel and France and Italy, canceled a long-scheduled speech before a
prostate-cancer group to avoid paparazzi--and wished the whole thing had
never happened. "We were just minding our own business," he says in
bemusement.
But a front-page story in The New York Times last week described Folkman's
years-old discovery of a cancer treatment as so promising that it might "cure
cancer in two years," as James Watson, Nobel laureate and the codiscoverer of
DNA, was quoted as saying. The article became the media equivalent of a
virulent flu. It infected television broadcasts, newspapers, magazines and
radio with the idea that researchers could actually cure the disease that
Americans fear more than any other. Desperate patients flooded help lines,
Internet chat rooms, hospitals and doctors' offices with questions and pleas
for the drugs, and many angrily asked why they had to stay on toxic
chemotherapy if a benign and effective therapy was available. Where patients
saw hope, investors saw gold: even before the stock market's opening bell
Monday they had placed thousands of "buy" orders for shares of EntreMed Inc.,
the Rockville, Md., company with the patent rights to Folkman's two
anti-cancer compounds. The stock price roller-coastered from $12 to $85 and
back down to $52. For a few days, the word angiogenesis was more ubiquitous
than the name Lewinsky.
Then came the backlash. By midweek, editorials and op-ed pieces were
emphasizing that while the two drugs discovered by Folkman's lab--endostatin
and angiostatin--had cured a bunch of mice, they had helped exactly zero
humans. And then the Times story, whose front-page placement belied the fact
that it contained little that had not been reported already, itself became
The Story. Jim Watson denied his hyperbolic "cure cancer" quote. Rival
newspapers published accusations that reporter Gina Kolata's story was an
attempt to stir up interest in, and get more money for, a book she was
shopping around. Within a day her agent withdrew the proposal "after
[Kolata's] discussion with her editors after the difficulties became clear of
staying with the story after she acquired a financial stake in it." (In fact,
Kolata's book proposal came after, not before, her article.)
If last week demonstrated anything, it was that hope is long but memory is
short when it comes to "cures" for cancer. In 1983, the renowned biologist
Lewis Thomas foresaw "the end of cancer before this century is over." Yes,
angiostatin and endostatin, which tame tumors by preventing the growth of
blood vessels that feed them, had successfully treated mice. And other
anti-angiogenesis agents have even shrunk tumors in human trials. But the
history of cancer treatment is full of shooting stars, experimental
treatments that have glowed with the promise of ultimate success only to
crash and burn. Taxol, interferon, interleukin-2--oncologists still prescribe
them. Some patients live because of them; others die despite them. "I know
this as well as everybody else," says Folkman. Even in his boldest dreams he
does not expect anti-angiogenesis agents to slay cancer on their own. But he
also thinks that, for some people, they could mean the difference between
surviving with a tumor and dying because of it, and he has thought so through
decades of snickers and hostile silence.
Folkman's first lightbulb-above-the-head moment came in 1960, when he was
all of 27. Drafted by the Navy, he was assigned to the Naval Medical Research
Institute in Bethesda, Md., where he studied blood substitutes. One day he
injected cancer cells into a rabbit thyroid gland that was being kept alive
in a blood-free solution inside a corked glass chamber. Tiny melanomas
sprouted. But they never grew larger than a pencil tip. "That was the first
time we saw that, in the absence of blood vessels, there was no tumor
growth," Folkman recalled last week as he pointed to the old glass tube in a
display case. He and colleague Frederick Becker published their observations.
But they didn't present their truly radical idea: that tumors, in order to
grow, need to hook up to blood vessels.
Over the next few years Folkman became convinced of his hunch. Tumors that
he implanted in rabbits' eyes did not grow at all until blood vessels,
spreading from the cornea, reached them. It was just like a pioneer town that
didn't grow until the railroad tracks got there. But when the blood vessels
did arrive, the tumor grew as fast as a Western boomtown: more than 100 times
their original size in 10 to 15 days. Now Folkman realized something even
more revolutionary: tumor cells must secrete some natural compound to induce
blood vessels to sprout tiny capillaries. Without the come-hither molecule,
capillaries do not connect to a tumor; without a custom-grown blood supply,
the tumor stays dormant.
That observation offered several fat targets for treatment. Theoretically,
you can interfere with the tumor cell so it does not secrete the molecular
signal that summons blood vessels. Or you can throw a biological monkey
wrench at the blood vessels so they cannot receive this signal, or cannot
respond to it. Either way, the tumor should shrink. But the possibilities
were even greater, because blood vessels are not one-way streets. Besides
bringing oxygen and nutrients to tumors, they serve as escape routes. Cancer
cells break off from the tumor, enter the bloodstream and colonize distant
points to produce secondary tumors. It is these metastases, not the primary
tumor, that often kill. Without blood vessels, there is no railroad out of
town; without a railroad, there are no metastatic escapees.
Folkman submitted his first major paper laying out the theory of blood
vessels and cancer to "many good journals." All rejected it, saying his
conclusion was not supported by the data he submitted. The New England
Journal of Medicine finally ran it, in 1971. Throughout the 1970s, "the
reaction was mainly hostility and ridicule," recalls Folkman. "People would
ask me [at scientific meetings], 'You really don't believe that, do you?' "
An application for a research grant from the government was denied; the
reviewer deemed the subject "just in your imagination."
Joining Folkman's lab seemed like professional suicide. "People warned me
not to hook up with him," says cell biologist Bruce Zetter, who nevertheless
agreed to join Folkman's search for ways to grow capillary cells in a dish
and who now heads his own lab at Children's. Dr. Henry Brem, who worked with
Folkman in 1973 and is now a neurological oncologist at Johns Hopkins
University, recalls his first-year pathology professor's catching flak "just
for mentioning Folkman's hypothesis that angiogenesis plays a role in tumor
growth. The biggest names at Harvard were saying it didn't belong in the
med-school curriculum." Conventional wisdom held that angiogenesis was an
inflammatory process having nothing to do with tumor progression. For 10
years, whenever Folkman got up to speak at a scientific meeting, he would
"hear people laughing in the corner," he says. Or the room would empty out.
"Everybody had to go to the bathroom at once," he says.
The nadir came in 1974. "A lot of people who worked for us just left,"
Folkman says. "They said, 'We're not making any progress'." Biology had
become so focused on genes and the proteins they made that if a theory didn't
fit this paradigm, it was dismissed. "At Harvard there was almost this rule
that if you didn't come up with a molecule in five years it must not exist,"
says Dr. Steven Brem, a brother of Henry's and now a neurosurgeon at the H.
Lee Moffitt Cancer Center in Tampa, Fla. Folkman's five years were almost up.
Low on research money, he and a colleague accepted an unheard-of 12-year, $23
million grant from the Monsanto Co. It created a firestorm at Harvard Medical
School, where Folkman had (and has) a joint appointment. No one there had
ever before accepted that kind of industry money. Now, of course, corporate
money flows like distilled water into America's university labs.
At national meetings, scientists would greet one of Folkman's
presentations with a knowing "Oh, I see Folkman has cured cancer--again." "I
would always come home very depressed," Folkman says. His wife, Paula, an
alto who sings with the Boston Symphony at Tanglewood and is the daughter of
a doctor who made house calls, was his source of strength. He often had her
read his manuscripts, and, except when he was traveling, would walk home to
have dinner with her and their two daughters, one now an elementary-school
teacher and one a modern dancer. His students remember his lectures on how to
keep a marriage intact (he wed in 1960) almost as well as they remember his
seminars on angiogenesis.
The Monsanto grant got Folkman's experiments back on track. In 1981 he
quit his position as surgeon-in-chief at Children's (and one third of his
salary) to devote himself full time to research. Someone who combines
research and surgery never has it easy, he once said: "His counterpart in
basic science thinks he is a dilettante researcher, his clinical colleagues
think he is unsafe and his mother-in-law says, 'He's 35 years old and still
working with animals. When will he be a real doctor?' "
Folkman was determined to identify the substances that ooze out of tumors
and attract capillaries. In 1983, two of his scientists, Michael Klagsbrun
and Yuen Shing, isolated such a substance. It was named "basic fibroblast
growth factor." Finally there was an actual molecule, not just a nifty idea,
and researchers who had been standing (or carping) on the sidelines climbed
on the angiogenesis bandwagon. Even serendipity smiled on Folkman. A culture
of blood-vessel cells that Donald Ingber had been growing in Folkman's lab
got contaminated. A yeast fungus had apparently blown in. Standard procedure
is to chuck a contaminated cell line. But Ingber had a hunch. In a replay of
Alexander Fleming's noticing that bacteria did not grow near penicillin mold,
Ingber saw that the blood vessels had retreated from the fungus. He had
discovered an angiogenesis inhibitor, now called TNP-470.
Many fields of science are infamous for professors who work their students
like galleon slaves and hog all the credit. Folkman is famous for the
opposite. He was inspired to pursue a career in medicine by visits he made to
the sick with his rabbi father. Students recall Folkman's hints that he once
had not been treated well by a superior, "and he vowed then and there that he
would be different," says Zetter. Folkman is generous with colleagues and
competitors alike, mailing samples of cell lines to anyone who asks. He won't
add his name to papers reporting research that others did in his lab (many
professors take full credit merely for running the place).
After Ingber and Folkman's discovery of the anti-angiogenesis agent in
fungus, other researchers suggested that a tumor secretes not only a
substance that stimulates angiogenesis, but one that inhibits it, too. That
would explain why, when a surgeon removes a primary tumor, little satellite
tumors sometimes start acting up, like kids whose teacher has stepped out.
The teacher here is the tumor that secretes an anti-angiogenesis molecule
that keeps smaller tumors in check; absent the tumor, the smaller tumors can
grow--and kill. In 1994, Dr. Michael O'Reilly in Folkman's lab isolated such
an angiogenesis inhibitor; he called it angiostatin. He discovered a second,
endostatin, in 1996. Endostatin so stifles blood-vessel growth that human
cancers grafted onto mice actually shrink, as O'Reilly, Folkman and
colleagues reported last November. Those results were the spark that flamed
into last week's hype, and hope, about a cure for cancer.
Folkman once said that treatment based on the angiogenesis model would be
available within five years. That was in 1972. Now he points to dozens of
books in the conference room. "All those books, those red books," he says.
"Those are all experiments [of ours] that didn't pan out." According to a
1997 editorial in the journal Science, by the early years of the next decade
cancer will overtake heart disease as the nation's No. 1 killer.
Everyone--doctors, scientists and, most of all, today's patients and
tomorrow's--hopes that Folkman's current lab book does not wind up on the
shelf of failures.
With Theodore Gideonse in New York
Newsweek 5/18/98 Lifestyle/ One Man's Quest to Cure Cancer
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