Taylor and Alimta’s long road to success Miriam Bocarsly '06 tells how
a "shockingly good drug" was developed
three years ago, Edward Taylor was anxiously awaiting FDA approval
of an anticancer drug that had spent about 12 years in clinical trials. Since
its FDA approval, the drug, Alimta, has been
a major success, stopping the growth of a variety of solid tumors
while easing suffering and extending life. Taylor was recently the
recipient of a Heroes in Chemistry award from the American Chemical
Society, and royalties from Alimta will provide significant funding
for the chemistry building that will soon begin construction next
to Princeton Stadium.
The following piece, written nearly three years ago, reflects
back on the time when Taylor was eagerly anticipating the impending
FDA approval of Alimta. This piece was the winner of the University’s
Pope Prize for Science Writing. The author, Miriam Bocarsly ’06,
is currently working at Drexel University on a research project
that addresses eating disorders, weight gain, and obesity in college
By Miriam Bocarsly ’06
A veteran of more than a half-century of research, Edward Taylor
sits in his office, swirling a pen between his hands. The office
is immaculate, everything in its place, every book filed neatly
on the floor-to-ceiling shelves. With a huge smile on his face,
one of those ear-to-ear grins, Taylor is sitting, playing with his
pen and waiting. He turns sideways every few minutes to take a quick
glance at his e-mail, then returns to fiddling with his pen.
“Any moment now, any moment now,” he says checking
his e-mail yet again, “but not yet.” Ted Taylor, professor
emeritus of chemistry at Princeton University, has discovered what
has proven to be a cancer treatment markedly more effective than
any currently available drug. The list of cancers his new drug,
Alimta, attacks is more than a foot in length, including virtually
all solid tumors. Taylor is imminently expecting approval for Alimta
from the U.S. Food and Drug Administration, the final hurdle standing
between his drug and the market.
Taylor, a small-framed man, sitting cross-legged behind a large
desk, is the definition of brilliance. But he’ll tell you,
over and over again, that the success he has experienced is pure
fate – a result of serendipity.
Equally serendipitous is the way that Taylor became a professor
of chemistry. A much-younger Taylor attended Hamilton College in
Clinton, N.Y., where he intended to major in English, a subject
he loved. “I loved to write essays, learn poetry and debate,”
he reminisces. “I had a good friend who would join me in this
enterprise, and we would write essays on various topics we assigned
to each other. It was nothing to do with our school work, it was
just fun.” However, in order to fulfill a distribution requirement,
he was forced to take a science class. “The only science I
took in high school was physics, and I hated physics. So when I
learned I had to take a science class, it was either biology or
chemistry. So I flipped a coin, and ended up taking chemistry,”
he explains. And something clicked. In two years Taylor had taken
every chemistry course the school offered, and had to transfer to
Cornell to continue his undergraduate education.
In 1946, nearly 60 years ago, Taylor began his Ph.D. work at Cornell.
As was the custom and still is, he was looking around in multiple
disciplines to see what the interesting problems were when a professor
sent him down to the library to read a paper. The paper was a piece
in Science Magazine about a strange compound that had been
isolated from liver. As research continued, the same structure was
also found in spinach leaves and fermentation broths, and was deemed
an essential growth factor, or protein necessary for normal development
What interested Taylor the most was that the strange compound
he read about had a unique ring structure, a loop of carbon and
hydrogen atoms, which had been seen before only in the wing pigments
of butterflies. “Butterflies, imagine that!” he says,
still fascinated and intrigued by the obscure relationship.
Taylor found himself entranced; there was something really bizarre
about that ring system. “What is the connection between butterflies,
liver, and spinach?” he asked. And before long, Taylor was
in the lab, doing all he could to learn as much as possible about
the recurring ring structure. He knew it wouldn’t be easy.
He was tackling a problem that had already caused other scientists
many headaches. “Just to figure out the ring structure in
the butterfly took 50 years and frustrated two Nobel Prize winners,”
he relates with a smile. And Taylor’s goal was to go farther
and learn more than those scientists before him. Little did he know,
his entire career, and a very successful one at that, would take
flight from those butterfly wings.
While Taylor slaved away during those early years, attempting
to understand everything he could about the structure and qualities
of his much-beloved ring, other scientists also were working feverishly
on the same ring system. In 1948, researchers at another institution
determined that modifying the ring’s structure slightly could
change it from being necessary for microorganism growth to a compound
that could stop the growth of microorganisms. In other words, these
scientists created an antibacterial agent. And by complete accident,
while testing the antibacterial agent in patients, it was discovered
that the chemical also brought about remissions of acute lymphoblastic
leukemia, a lethal type of cancer in children.
“Now there is something that was really exciting, because
you don’t cure leukemia with an antibacterial. Something else
was happening here,” Taylor says, beaming like a child before
opening a wrapped present.
The mysterious ring compound was named folic acid, and over the
next 30 years, its role as a key component for life was elucidated.
“It is now understood to be requisite for every form of life
on this planet: microorganisms, birds, trees, mammals – man,
the list keeps going,” Taylor says, explaining that it is
necessary for DNA production, as well as a number of other cell
Leaving Cornell with his Ph.D. and moving on to teach at the University
of Illinois, and then transferring to Princeton University in 1954,
Taylor expanded his repertoire from the single ring to an entire
family of similar structures called heterocyclic compounds, on which
he became the world’s recognized expert. As a matter of fact,
to the right of his desk stand nearly 100 red-covered books –
each edited by Taylor, and each exploring some aspect of heterocyclic
But no matter how far Taylor’s mind wandered, he kept on
coming back to folic acid. “I just wanted to know what caused
this cancer remission in the chemical derived from folic acid,”
Even more importantly, however, the antibacterial that caused
the cancer to go into remission was not only powerful, but also
terribly toxic. It killed cancer cells very efficiently and effectively,
but it also killed healthy body cells. There was very little distinction
between an effective dose and a lethal dose; if the chemical were
ever to be used in patients, something would have to be modified
to make it less toxic. Taylor was ready to take on that challenge,
and in the late 1970s, his lab developed a compound that looked
as if it might be a more potent, less toxic anti-tumor agent.
At this point, Taylor realized that he couldn’t go about
the task of developing a cancer treatment alone. “I am a trained
synthetic organic chemist, and although I minored in biochemistry,
that doesn’t make me a biochemist. And I knew I needed an
expert,” he recalls.
Taylor contacted Eli Lilly, a pharmaceutical company located in
Indianapolis, and asked them to evaluate the compound synthesized
in his lab. Lilly scientists agreed to test his compound, but wrote
back shortly thereafter saying that there was something wrong with
their tests, and it must be the fault of a less-practiced summer
crew. They asked Taylor to wait for the normal scientists to return
in the fall. However, in the fall, when the normal crew returned,
the results of the tests did not change.
As it turns out, Taylor’s compound was so efficient, powerful,
and versatile that Lilly had never seen such positive results before,
and was therefore convinced that there was a flaw in the tests.
But the results were correct. And Lilly was willing to take a chance
and embark on a collaborative mission with Princeton University
in hope that Taylor might be on to something.
The beginning of the collaboration was exciting for Taylor, but
in no way the end of his story. Rough roads and bumpy chemistry
still paved the future. Taylor’s compound is horribly complicated
to make. “It is like a rock, and how do you do chemistry on
a rock?” he asks, referring to his compound. But rock-like
compounds were the least of Taylor’s complications. He ran
full-force into a major chemical problem: “There was a bugaboo,”
he says, looking back with a smile. The compound was so insoluble,
so rigid, and so difficult to work with that Taylor experienced
a problem of geometry. Synthesis of his organic compound created
two varieties, which were barely distinguishable, except for the
fact that one worked to fight cancer, and the other didn’t.
A chemist at Lilly was able to create a way to separate the active
form from the inactive form, but it limited the amount of the compound
that could be collected and would have made it as expensive as gold,
But Taylor, a dedicated scientist, was not ready to give up, and
decided to look at the problem in a different way. Instead of working
to separate the two forms of the compounds, he decided to chemically
eliminate the part of the molecule responsible for the geometric
differences. Unfortunately, to do so would involve eliminating some
of those features that had already been established as essential.
“We took a chance; we figured, ‘Why not?’ ”
It took years, and the new ring system seemed to be going off in
a direction with no positive leads, but luck comes to those who
least expect it. “We hit the jackpot,” Taylor quietly
and simply states.
That is how Alimta, the summation of a decade of work, was born.
Whether it was luck or genius, or a delicate mixture of both,
Taylor’s drug moved on to clinical trials. “The facts
are sobering,” he says. Only one out of every 15,000 possible
drug candidates makes it into clinical trails. Of those, only one
out of five makes it through the first round of tests. By the time
a drug makes it on to the market, it has cost about $1.7 billion
in development costs. All that sums up to a lot of work, a lot of
gambles, and a lot of money. “It’s tough out there,”
Taylor says, but he was lucky; his drug survived.
While the compound was going through the first round of trials,
Taylor’s lab went on to develop hundreds and hundreds of similar
molecules, looking for an even more effective structure. But they
couldn’t find one. “It was as if nature was sitting
around waiting for us to find this molecule,” Taylor marvels.
Alimta is taken into cells by a specific protein that acts, like
a car, as a transportation device. This protein happens to be over-expressed
by all tumor cells, causing Alimta to be taken into tumor cells
more frequently than normal cells. Once in the cell, the drug works
by eliminating the function of folic acid in the host cell. "We
are completely clobbering the folic acid in the cell, which is needed
for cell survival," Taylor explains. But there was still one
more hurdle to jump: Patients were still showing high levels of
toxicity in normal cells. Through the work of hundreds of scientists
and statisticians at Lilly, it was discovered that co-administering
vitamin B12 with Alimta eliminates the toxic effects in normal cells.
Yet, cancer cells are destroyed just as before, thus overcoming
that final crucial hurdle.
Clinical trials have proven Alimta to work in a wide range of
tumors – such as mesothelioma, cancer of the lining in the
lungs – that have up until now resisted every type of therapy.
The drug is administered intravenously for a 10-minute period only
once every three weeks, making it more convenient than other chemotherapeutic
agents. Additionally, while up to 50 percent of patients suffer
life-threatening side effects with conventional cancer drugs, only
5 percent have similar adverse reactions to Alimta.
After 11 years of extensive clinical trials, six months ago the
FDA approved Alimta for compassion use, meaning that seriously ill
patients could obtain the drug free from Lilly before it had been
approved for the market. So far the results of treatment with Alimta
have been overwhelmingly positive. Mesothelioma, a cancer that kills
most patients within six months of diagnosis, will be the first
cancer for which Alimta is approved. In clinical trials, mesothelioma
patients have survived up to three years with Alimta therapy –
six times longer than expected. Moreover, patients report that when
treated with Alimta, they feel better and can lead normal lives.
“It is spectacularly successful,” Taylor says, “but
it isn’t a cure. Nobody claims a cure, because the cancer
can come back. But if you have someone who is supposed to be dead,
and he is out mowing the lawn, or going on bike rides, that is a
Although the imminent FDA approval will only authorize Alimta
for treating mesothelioma, there are around a hundred clinical trials
under way, and as the results come back, Taylor expects the drug
to be approved for many more forms of cancer. Additionally, once
the FDA has approved the drug for a single type of cancer, doctors
can use it in any situation they think appropriate, a practice known
as “off-label use.”
It has been a long road for Taylor, but one full of success and
fulfillment. “In 1980, I started working on an idea, and it
led to all this. And looking back now, I see it was a crappy idea,
but what difference does it make? Find what is interesting and seems
to be a curious phenomenon, and keep your eyes open and see what
results. And what came out of it was an awful lot of neat stuff
in chemistry,” Taylor says with excitement.
“It took a long time, and the fact that it turned out the
way it did was serendipity, it was really luck. The luck would not
have come if we were not working in the area, and we wouldn’t
be working in this area if these hints pointing to something really
important, weren’t there,” Taylor says. “It’s
going to be a shockingly good drug.”
Now, nearly 60 years after it all started and six years after
his retirement, Taylor still comes in to work every morning. He
isn’t teaching classes or running a research lab, but he is
still writing papers, consulting, and editing a series of books.
“Once I discovered organic chemistry, that was it –
I loved it. And I have loved it ever since. I still do it every
day, even though I am retired.” Although Taylor has not been
able to leave chemistry behind, he finds his farm in Vermont a much
more relaxing environment for writing, and has scheduled plenty
of time for family and grandchildren. And, Taylor added, he has
more time to perfect one of his other loves: golf. Checking his
e-mail one last time, Taylor hopes that he will hear from the FDA
before leaving Monday with his wife Ginny, to play golf in Arizona.