Svanborg’s lab originally studied bacteria, not cancer.

Fortunately, much of Svanborg’s work has prepared her for this specific research. She and her group had studied the nature and function of epithelial cells, the gut-lining cells that come into contact with breast milk in nursing infants. And they had experimented with mothers’ milk many times. They had shown that it does a terrific job of blocking infection by pneumococcus bacteria, the cause of pneumonia, and that breast-fed children suffer significantly fewer ear and upper respiratory tract infections than babies who don’t nurse.

And her team had already done much of the homework that would be needed. They had tracked down studies showing that breast milk also protects against cancer (the relative risk of childhood lymphoma is nine times higher in bottle-fed infants, and the risk for carcinoma is also elevated). She wondered what accounted for that discrepancy. Now she had at hand the results that might provide an answer. “We felt sheer excitement and enthusiasm,” she says.

Alpha-lac may root out malignant …..cells

and encourage healthy ones 

It took more than two years before her team felt ready to share its discovery with the rest of the world. In August 1995 they announced that breast milk kills cancer cells and pinpointed the killer, which turned out to be one of the most abundant proteins in the milk. It’s called alpha-lactalbumin (alpha-lac for short), and it helps produce lactose, the sugar found in milk. Many scientists had already studied alpha-lac, but no one had ever noticed anything like this before. If the protein was persuading cancer cells to commit suicide, it must be the microscopic version of a comic-book superhero, leading a quiet life by day, transforming itself into a swashbuckling crime-fighter by night. Indeed, as Svanborg and her colleagues discovered to their astonishment, the protein was performing the decidedly unprotein-like trick of changing its shape (see “Protein Folding,” below). Now it was making cancer cells an offer they couldn’t refuse.

PROTEIN FOLDING

Proteins roll off cells’ assembly lines, the ribosomes, as long chains of links called amino acids. Amino acids come in 20 different varieties; proteins typically contain between 100 and a few thousand linked in different sequences. The links function like an alphabet, spelling out the form and function of the protein. Just as the 26 letters in the English alphabet can form a virtually infinite collection of words, the 20 amino acids combine to spell a mind-boggling array of proteins. Muscle, skin, hair, cartilage, antibodies, enzymes, and hormones are just a few of the structures made of proteins. The human body contains some 50,000 different kinds of proteins.

But as one-dimensional chains, proteins are useless. To carry out their varied functions, proteins bend and twist into intricate three-dimensional shapes. Imagine crushing a length of yarn in your hand—the tangled mass resembles a folded protein. Some regions coil into loops, some into spirals. Others bend into hairpins, and still others press into pleated sheets resembling accordions and washboards. Proteins depend on these shapes to carry out their functions. Their nooks and crannies interact with the proteins’ environment. For example, digestive enzymes trap starch molecules in their folds, placing them near chemicals that break them down into sugar. Similarly, antibodies hold tight to invading microbes while summoning help from the immune system’s bigger guns.

Then there are prions—proteins found in the brain. Prions, whose normal function is unclear, are the likely cause of mad cow disease and similar brain disorders in animals and humans. Prions seem to bring about destruction by unfolding from their normal helical shape and aggregating into relatively indestructible clumps. For reasons yet unknown, tissue around these clumps dies, leaving Swiss-cheeselike holes in the brain. No one knows what causes prions to change their shape.

Prions are a dramatic example of a protein that changes shape to perform different functions. Apha-lactalbumin seems to be another. In its completely folded state it helps produce lactose and nourishes babies, but when it’s partially unfolded, it forces cancer cells to burst open and die. These proteins, and a few others, offer evidence that a standard dogma in biology must fall. According to the old view, one DNA sequence produces one amino acid sequence that produces a particular structure that performs one function. But now biologists must recognize the existence of proteins with more than one structure that perform more than one function.

“The accepted scientific rule has been, ‘one structure, one function,’ ” says Svanborg. “But having multiple functions would be a very energy-saving, economical way for a protein to operate.” It’s altogether too practical for nature to pass up. —P. R.

The discovery also suggested a possible explanation of how breast milk protects against cancer. Perhaps, Svanborg reasoned, the errant cells that give rise to malignancies first show up in infants. The key is breakneck reproduction, a characteristic of the cells lining an infant’s gut. Some of these cells may proliferate out of control. That’s called cancer. Or they may never fully mature or stabilize, lurking in the system like time bombs, ever ready to burst forth into tumors. Transformed alpha-lac “targets not only cancer cells but all kinds of immature, rapidly growing cells, and leaves mature, stable cells alone,” Svanborg says.

Alpha-lac, then, may be conducting surveillance missions within the nursing child, rooting out potentially malignant cells and encouraging properly growing cells to mature. Because the lining of the gut, a prime meeting point between the inside of the body and the hazards of the outside world, is a headquarters of the immune system, the vigilance may help the child’s immune defenses develop.

APOPTOSIS

Recycling is the way of nature and apoptosis, or programmed cell suicide, is the linchpin of the body’s recycling program.

All healthy cells have a built-in mechanism for suicide; it’s switched on by signals received from their environment. (In contrast, cancer cells fail to respond to the environmental signals that regulate cell death. In cancer cells, the apoptosis machinery is short-circuited, allowing the cells to grow unchecked. The result can be the chaotic mass of cells called a tumor.) Once activated, the mechanism for programmed cell death shrinks the cell’s nucleus, decreases the cell’s fluid, or cytoplasm, and snips up the cell’s DNA. The cell literally falls apart, fragmenting into its constituent parts.

Catharina Svanborg and her group at Lund University in Sweden, in collaboration with scientists at the Karolinska Institute in Stockholm, are investigating how alpha-lac turns on the suicide mechanism in cancer and other immature cells. They now know that the protein can slip through the cells’ outer membrane. Once inside, the alpha-lac may light out toward the cell’s energy source, the mitochondria, or it may make a beeline for the cell’s nucleus, pass through the nuclear wall, and head directly to the DNA. Once there, it may activate DNA-destroying enzymes, in effect taking molecular scissors to the strands of genes, snipping them to bits.

That’s one scenario. Another possible one involves the mitochondria. Lurking within a cell’s cytoplasm, inactive, just waiting to be turned on, is a family of protein-cutting enzymes, or proteases, called caspaces. Like the Borgias, this family is not to be regarded lightly. Once persuaded to burst into action, caspaces can kill their host cells. Through what’s called a caspace cascade, the sequential activation of one enzyme after another, caspaces slash to pieces protein after protein, eventually bringing about the destruction of the cell’s DNA. In so doing the caspace cascade kills the cell—causing apoptosis.

Mitochondria can awaken these sleeping killers. They secrete a substance called cytochrome c that switches on a messenger protein that latches onto the caspaces and jars them awake. Alpha-lac, the Lund and Karolinska teams have demonstrated, can persuade mitochondria torelease cytochrome c. So alpha-lac may induce apoptosis by directly causing the destruction of DNA from within the cell’s nucleus, or it may instigate the suicide-generating caspace cascade through the mitochondria. Svanborg has a standing wager with co-researcher Anders Häkansson as to which strategy is the essential one. “He’s standing by the mitochondria,” she says. “I’m betting on the nucleus.” —P. R.

It was quite an exhilarating observation. But the excitement was not mirrored by cancer researchers. “There was . . . a mixed reception from the establishment,” Svanborg says dryly. “In our world, people don’t accept things as fact until they are proven over and over.” The laconic Håkansson is more pointed: “When there was a reception at all, it tended to be skeptical.”

Someone who did notice, however, was John Stevens, a vice president of grants at the American Cancer Society. After reading the Svanborg team’s research paper, he made a journey to Sweden. “I had not known of Lund University before, but we found Catharina and her team to be very talented researchers, very dedicated, and their work fascinating.” A $200,000 grant made Svanborg’s the only non-American lab with ACS support.

So she got back to work with renewed enthusiasm. “The grant gave us recognition,” says Svanborg. “We came into this from nowhere, and the cancer society gave us the stamp of quality. Now the weight was on us to prove that this is real and reproducible.”