Science / Medicine : Learning More About Humans From Sharks : Research: The creatures have an unusual resistance to many human diseases, including cancer. Scientists are seeking clues to their immune system.

Before dense jungles covered the land, long before the Earth’s continents moved apart, and millions of years before the first amphibians crawled out of the sea, there were sharks. More than 400 million years ago, they were already stalking prey in the Earth’s warm, enormous primordial sea.

Sharks are among the most fabled and feared of the Earth’s creatures, and the subject of both popular lore and considerable misconception. They have survived several mysterious mass extinctions of ocean life and have outlived most other fish in the sea, except for a few ancient oddities, like hagfish and lampreys. From an evolutionary viewpoint they are one of the most successful creatures the world has ever seen.

Scientists have long regarded the shark as a living link to the marine origins of vertebrates, and recent studies of the shark immune system have shown it to be unlike that of any other animal. The discovery is considered a tantalizing clue to the evolution and workings of the mammalian immune system, a better understanding of which could ultimately benefit those working to combat various immune-system disorders in humans.

But the work also promises insights into the evolutionary process in general and a better explanation of why sharks seem to have unusual resistance to a number of diseases, including cancer. This latter fact has been known for more than 25 years and continues to be the subject of a few isolated, long-term research efforts aimed at developing a treatment for human cancer.

The recent immune-system studies were done at several marine laboratories in Florida and New York, where researchers are working with sharks, skates and rays, all of which occupy the same taxonomic subclass, called elasmobranchs. Compared to the immune systems of mammals and birds, which have received the most scrutiny so far, the elasmobranch immune system appears primitive but remarkably effective and highly adapted to its environment, according to Michael Sigel, who did pioneering work on the shark immune system at the University of Miami in the 1960s.

“Immunity seems to be much more effective in the shark than in man, horse or other mammals,” said Sigel, now chairman emeritus of the department of microbiology and immunology at the University of South Carolina Medical School.

A properly working immune system keeps its host alive by combating disease and infection. It does this by identifying antigens--potentially harmful foreign substances, mainly proteins--in the body and mounting an attack against them.

In humans and other mammals, a two-part system has evolved. One part, called the cell-mediated response, or T-cell immunity, eliminates cells with antigens on their surfaces. A virus-infected cell, for example, has viral protein (a form of antigen) on its surface, which initiates a cell-mediated response.

The other part of the immune system is the humoral antibody response, or B-cell immunity, which deals directly with antigens by releasing antibodies into the blood. These antibodies are other kinds of proteins that attach themselves to the antigen, either destroying it directly or enabling other cells to destroy it by ingestion. In humans, there are millions of possible antibodies, which fall within five classes, known as immunoglobulins.

In the mid-1960s, Sigel found that sharks have a peculiar immunoglobulin molecule called IgM that offers unusually versatile protection. Sigel later found that a large amount of the IgM is always circulating in sharks and ready to act. “It always seems ready to attack anything in sight,” Sigel said. In humans, on the other hand, the immune system is normally dormant, turning itself “on” in response to antigens.

Nonetheless, in the IgM discovery, Sigel established an interesting link between humans and sharks: human fetuses have mostly IgM immunoglobulin at first, and begin producing the other forms later on. Sigel interprets this coincidence as an example of “ontogeny recapitulating phylogeny,” or the development of an individual organism reflecting evolution itself.

Biologists believe that through evolution, the human immune system became complex and extremely flexible in order to cope with the huge number of different antigens that it must respond to. Every one of these antigens prompts a different set of antibodies, so B-cell immunity depends on a fabulous diversity of antibodies.

In virtually all animals, the very first wave of antibodies that responds to an antigen is IgM. But during this first response, some antibodies undergo a mutation that refines and improves the way they bind to that particular antigen. The next time the immune system encounters the antigen, it mounts a quicker and more effective attack based on a higher class of antibodies called IgG or IgA.

But since sharks cannot make these higher antibodies, they never experience an improved, or memorized, second immune response. Multiple exposures to the same antigen merely produce essentially the same response over and over again.

In the early 1980s, after the role of genetics in the mammalian immune system was uncovered, Gary W. Litman and Kristin R. Hinds at the Sloan-Kettering Institute for Cancer Research in Rye, N.Y., began exploring the antibody-gene system of the horned shark, which is found mainly in the Pacific off Southern California. The evolutionary line including sharks diverged from the line extending to mammals as many as 450 million years ago, and Litman and Hinds were looking for clues to the immune systems that existed at the time of that divergence.

What they found exceeded expectations. “At every twist and turn of evolution, we have documented evidence in this laboratory that there were sometimes major differences in the way that antibody genes were organized and functioned,” said Litman, now at the University of South Florida, in a recent interview. “That came very much to our surprise.”

For example, sharks do not have nearly the variety of gene segments that humans have, so their immune system is less flexible.

Litman says he and Hinds have found some evidence in sharks of antibody mutation, but it is not at all like the mammalian process that lays the foundation for a much-improved secondary response to an antigen.

To Litman, the shark immune system is evidence that “evolution doesn’t always work in a continuous way to improve. At some departure, a type or form may appear that doesn’t have to work anywhere else in evolution.”

The shark’s system, he notes, is less sophisticated than man’s, “but perhaps it leaves less to chance. Maybe it stayed less complicated because it doesn’t need capabilities like those of a higher, land-bound system.”

Litman’s theory is supported by past findings that the shark immune system seems to do an extraordinary job of protecting against cancer and other diseases.

More recent research in this area has focused on the ability of shark cartilage to inhibit tumor growth. Tumors need a large blood supply to survive, and it has been known for years that cartilage of all kinds--whether from mammals or fish--has no blood vessels, and indeed contains substances that prevent the formation of new blood vessels. For studies of this phenomenon, the shark is the ideal laboratory animal: It is cartilaginous from head to tail, without a bone in its body.

Carl A. Luer, a senior scientist at Mote Marine Laboratory in Sarasota, Fla., has been working in this area since 1979. Having shown that a group of proteins from shark cartilage does in fact inhibit blood-vessel growth, Luer is now trying to isolate the specific proteins involved and compare their effectiveness with proteins from mammalian cartilage.

In the last year, he narrowed the group of proteins from eight to three. His long-term goal is to identify, in these proteins, one or more active molecules that might lead to a tumor treatment lacking the harmful side effects of current treatments like radiation.

In related experiments, Luer has been trying to induce tumors in hundreds of clear-nose skates and nurse sharks (the only ones being kept as laboratory animals in the United States, Luer says). He has tried two chemicals known to cause cancer in human beings and other species. But he has not yet been able to cause a tumor in either a skate or a shark.

This comes as no surprise to Churchill McKinney of the University of Miami School of Medicine, another expert on shark immunity. “Whatever causes cancer in human beings probably does not cause cancer in sharks,” she said. Although skeptical of claims of extraordinary immunity in sharks, McKinney hopes that studies of the elasmobranch immune system may help researchers trying to understand mammalian immune systems, particularly humans.

Human Immunity

When the human immune system senses the arrival of microorganisms--identified by surface proteins called antigens--it produces two types of white blood cells, or lymphocytes. (1) T-cells orchestrate the immune response, releasing chemical signals that activate the inflmmatory response. Some also become killer cells that ingest and destroy the invaders. (2) B-cells secrete antibodies that bind to the antigens and target them for destruction. (3) “Memory” B-cells, sensitized to that invader, remain in the circulation to ward off future attacks, making the patient imune.

Shark Immunity

The shark’s immune system works differently. It does not produce specific antibodies against each intruder. Instead, an immunoglobulin molecule called IgM constantly circulates in the shark’s blood, binding to foreign antigens and marking them for destruction. Because the shark does not make antibodies, they do not become immune after an infection. Instead, the same immune response begins afresh with each new infection.