Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (21 page)

His experiments were set up so that blood substitutes flowed through the blood vessels of rabbit thyroid glands that were being kept alive in a glass chamber. At one point Dr. Folkman noticed that tumor cells implanted into the glands stopped growing when they were still quite small and then became dormant. However, when the
dormant tumor was transplanted into a living mouse, the tumor grew rapidly. This observation led Folkman to develop a new theory about cancer. He hypothesized that in order to grow beyond 2 or 3 millimeters (slightly larger than the head of a pin), tumors had to form their own blood vessels. Folkman began to suspect that tumors recruited blood vessels by releasing factors that stimulate the sprouting of minute capillaries from nearby vessels.
²

He pursued his idea, termed “angiogenesis,” with investigations over a period of forty years in the hope of answering a number of questions: How are these new blood vessels recruited? What factors bring about their formation? Does angiogenesis enhance the tumor's capability to expand and infiltrate locally, and to spread to distant organs in the process called metastasis? Can the tumor growth be controlled by combating these factors?

As detailed by Robert Cooke in his 2001 book
Dr. Folkman's War,
³
the successful answers to these basic questions took Folkman through diligent investigations punctuated by an astonishing series of chance observations and circumstances. Over decades, Folkman persisted in his genuinely original thinking. His concept was far in advance of technological and other scientific advances that would provide the methodology and basic knowledge essential to its proof, forcing him to await verification and to withstand ridicule, scorn, and vicious competition for grants. Looking back three decades later, Folkman would ruefully reflect: “I was too young to realize how much trouble was in store for a theory that could not be tested immediately.”
⁴

At the age of thirty-four, Folkman accepted the position of surgeon in chief at Boston's Children's Hospital and professor of surgery, the youngest in the history of Harvard University. Despite the honor, Folkman was considered “just a surgeon” and certainly not in the mainstream of bench research, and therefore had trouble getting published. His quest was out of step with the National Cancer Institute's march toward chemotherapy, viral and chemical causes of cancer, and tumor immunology. Besides, blood vessels were then generally considered “just plumbing,” bringing nutrients in and wastes out, unlike today, when the blood vessel system is appreciated as a dynamic organ in itself.

Capillaries are essentially tiny tubes—thinner than a strand of hair—of one layer of endothelial cells (the lining cells of all vessels). In order to understand what stimulates the new growth of capillaries toward a tumor, scientists had to be able to culture endothelial cells in the laboratory. But conventional wisdom held that this was not possible. Studies by a Japanese team in the mid-1960s had been unsuccessful in culturing human endothelial cells. Then fortune intervened.

Researchers at the University of California at San Francisco, working on factors that initiate cell division (not specifically in the linings of vessels), had success in growing endothelial cells from cow aortas in culture dishes. “Serendipitously,” a member of the team explained, “cow and pig turned out to be very easy endothelial cells to grow.”
⁵
Encouraged by their success, Folkman's group was able to culture large numbers of endothelial cells from human umbilical cords and, by altering the nutrient fluid, found that they could control human blood vessel growth.
⁶
This five-year effort provided the keystone to the purification of factors that stimulate development of new blood vessels.

G
RISTLE FOR THE
M
ILL

Virtually all tissues in the human body require blood vessels to provide nutrients for their metabolism and function. Notably, one substance that has no blood vessels is cartilage. Cartilage is present between the segments of the spine, where the disks act as shock absorbers, and at the ends of long bones, where it provides a bearing surface to reduce the friction between moving parts. In the first week of an embryo's life, blood vessels are found in cartilage tissue to help it grow, but then a fascinating change occurs. Later in fetal development these blood vessels shrink and ultimately disappear. For Folkman, this phenomenon raised a crucial question: Is there an intrinsic property of cartilage that makes this happen? Is it a source, in other words, of an angiogenesis inhibitor?

A member of Folkman's team, Robert Langer, a chemical engineer, searched for two years for such a biochemical blocker. Eventually he worked with large amounts of cartilage, which is abundant in
sharks. The skeletons and fins of sharks are made of pure cartilage, and traversing it are tough strands of large proteins. From these, Langer, in an exciting breakthrough, was able to extract a protein mixture that inhibited angiogenesis,
⁷
but it proved in time to be too weak to develop into clinical use.

Much to the dismay of Folkman and Langer, the large international chemical company W. R. Grace chose to exploit the finding relating proteins from shark cartilage to the inhibition of angiogenesis by marketing a food supplement product made from shark cartilage through health food stores, despite the fact that any active ingredients would not be absorbed by the body. The FDA prohibits food supplements (other examples include vitamins, minerals, fiber, garlic, and unsaturated fish oils) from making any therapeutic or prophylactic claims. The so-called remedy was promoted later by a widely distributed book,
Sharks Don't Get Cancer,
⁸
further raising false hopes in cancer victims.

The Laetrile Hoax

The most notorious of commercially driven, unorthodox therapies was Laetrile, whose benefits as a cancer treatment were proclaimed by its advocates from the 1950s into the 1970s. This was abetted by the widely publicized quest of the movie star Steve Mc-Queen, who was dying from cancer. Laetrile was a concentrated extract of a cyanide-containing substance, amygdalin, prepared from the kernels of apricot pits and bitter almond, after which amygdalin is named (
amygdale
is the Greek word for “almond”). Incredibly, its use in cancer therapy was based on the idea that cancer cells are much richer than normal cells in an enzyme that breaks down Laetrile to release toxic cyanide, which would then destroy the cancer cells. It was also trade-named “vitamin B-17,” despite not being a vitamin and being nutritionally worthless. Laetrile became a billion-dollar-a-year industry, and the Laetrile cult was branded as “perhaps the most bizarre, ruthless, deceptive, misleading, and dangerous health cult to come along this
century.”
⁹
In November 1977 the FDA mailed a warning notice to every doctor and a total of nearly a million health professionals in the United States, placing them on notice that Laetrile was worthless and poisonous. The results of clinical trials conducted for the National Cancer Institute in 178 patients at four major medical centers were published in the
New England Journal of Medicine
in 1982 with the conclusion that Laetrile not only was ineffective as a treatment for cancer but frequently resulted in cyanide toxicity approaching a lethal range.
¹⁰

A totally unexpected finding led remarkably to the isolation and purification of the first factor that specifically stimulated the growth of new blood vessels. Two biochemists in Folkman's laboratory had worked intensively on the chemically complex fluid derived from cartilaginous tumors grown in a number of rats. Expecting it to inhibit endothelial cell growth, they saw that the substance actually did the opposite: it truly stimulated growth of endothelial cells. This was dramatic support of Folkman's concept that tumors send out chemical signals that cause blood vessels to grow and extend new branches to nourish them. This natural and potent growth-stimulating protein was subsequently isolated by Napoleone Ferrara, a scientist working for a biotechnology company, and named VEGF (pronounced “VEJeff”), for vascular endothelial growth factor.

I
NSPIRATION FROM
C
ONTAMINATION

Another major chance event occurred in November 1985 to a biologist in Folkman's laboratory: a fungus contaminated a culture dish of endothelial cells. Rather than discarding the dish, he paused to examine it and found that the endothelial cells at the site had stopped growing. (One can only marvel at the resemblance of these events to Alexander Fleming's accidental experience leading to penicillin.) Extracts of the fungus were then shown to arrest the growth of tiny blood vessels in
chicken embryos. Investigation had failed to turn up an angiogenesis inhibitor, but accident now provided one. This finding resulted in the production of a compound called TNP-470. In animals, the drug blocked a wide range of tumors, slowing growth by as much as 70 percent. Clinical trials undertaken in the United States indicated by the mid-1990s that it worked best in humans in combination with chemotherapy or radiation.

“T
HIS
G
UY
's R
EALLY
O
N TO
S
OMETHING
!”

For more than a century, physicians had puzzled over a particular phenomenon that had been observed repeatedly. The biologic aggressiveness of tumors varies enormously: some cancers, once they become evident, grow slowly, whereas others spread readily to distant organs. And some metastatic colonies grow to only a small size and then lie dormant. Yet sometimes, following surgical removal of a primary tumor, its metastasis loses any restraint and grows explosively. Could there be an innate mechanism? Could the influences of angiogenesis and possible inhibitory agents explain the phenomenon?

The solution came through a fortuitous chain of events upon which even a Hollywood screenplay could not improve. At a bustling annual meeting of the American Association for Cancer Research in 1987, Noël Bouck, a molecular biologist at the Northwestern School of Medicine in Chicago, who was suffering in a new pair of high heels, sought respite for her tired feet in an empty lecture hall. Before she realized it, the room quickly filled up with other attendees, there to hear a presentation on angiogenesis by none other than Judah Folkman. Bouck had not heard of him, since her cancer research work was directed along other lines, but she could not gracefully escape. As she listened to him, against her will, she began to think “this guy's really on to something!” She quickly became a convert to his theory on cancer. Returning to her laboratory, she redirected her own research to focus on angiogenesis and, within two years, she and her colleagues discovered the first angiogenesis-inhibiting substance produced by a tumor.
¹¹

Bouck's discovery pointed the way to solving the riddle of metastatic dormancy for Folkman. It propelled his thinking that the primary tumor's secretions might be harnessed as cancer drugs to suppress the growth of both the primary and small metastases.

Painstaking work over the next several years led to the identification of an inhibitor of endothelial cell growth. Calling it angiostatin (from the Greek, meaning “to stop blood vessels”), Folkman's team showed that it inhibited the development of metastases. Thirty-two years of perseverance at last not only validated and extended his original insight but also pointed the way to a new approach to cancer management. The findings were published in the fall of 1994 as the cover article in
Cell
and were widely cited as a landmark contribution.
¹²
One year later, his research team found another inhibitor they named endostatin that was shown to be a powerful agent against a variety of tumors implanted into mice. The news spread like wild-fire, publicized in the national media in the spring and summer of 1998. The National Cancer Institute undertook the planning of clinical trials.
¹³

Folkman's long years of persistence led to a new era in which dozens of pharmaceutical and biotechnology companies are now actively pursuing angiogenesis-related therapies. At least twenty-four inhibitors are being clinically tested at more than a hundred medical centers in the United States. One of these, Avastin, was approved in February 2004 for colorectal cancer and was shown to also be effective against breast cancer and lung cancer. It is given along with a generic chemotherapy drug. Avastin, marketed by the biotechnology company Genentech, is the first approved cancer drug that works by choking off the supply of blood that tumors need to grow. It blocks the protein in the body called vascular endothelial growth factor (VEGF) that promotes blood vessel growth. Avastin had sales in the United States of $676 million in its first twelve months on the market, the highest first-year sales of any cancer drug ever up to that time. As of early 2006 it appeared to be on its way to becoming the best-selling cancer drug ever.

The hope is that, as knowledge of tumor angiogenesis progresses, cancers can be detected through elevated levels of angiogenic molecules
in the blood long before clinical symptoms appear. Folkman's perseverance in the face of determined skepticism and often outright opposition by colleagues was finally rewarded with acclaim and general acceptance. His work represents one of the major breakthroughs in cancer research in the twentieth century.

15

Aspirin Kills More than Pain

A vibrant new hope arose among cancer specialists in the early 1990s and continued throughout the beginning of the new millennium. It offered something perhaps better than a cure: the possibility of preventing cancers from even forming. Such promise came from a humble nonprescription drug found in medicine cabinets across America. For over a century, people have reached for aspirin to relieve headaches or back pain. In the 1990s a host of studies affirmed that aspirin might also lower the risk of developing colon cancer by as much as 40 percent.