Using Antibodies In Research And Medicine

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In 1993 Serge Muyldermans and a team of researchers at Vrije University in Brussels, Belgium, had a lucky accident that may lead one day to promising new therapies involving antibodies. While performing an experiment, they used camel blood instead of serum taken from a mouse. The experiment had a strange outcome that did not make sense until the scientists took a close look at the camel's antibodies. They discovered that the molecules had an unusual structure: They only contained two heavy chains, rather than the heavy and light chains found in other mammals. Further study showed that this is also true for species such as llamas and alpacas, which are closely related to camels through evolution. This is interesting because antibodies have many applications in research and medicine, and in some of these cases camel antibodies may work better than those of other animals.

Their simpler structure makes them smaller, which means they can move through tissues more quickly. They are also more stable when subjected to heat. Several laboratories in Europe, the United States, and elsewhere are, therefore, beginning to use the molecules in their work. For example, Ulrich Wernery, a scientist at the Central Veterinary Research Laboratory in the Middle Eastern country of Dubai, is currently using them to make antidotes to snake venom. Currently, most such "antivenins" are made by exposing horses to small amounts of venom

Camel Antibody

and then extracting the antibodies that the horses make. Some people, however, have allergic reactions to these substances; the therapeutic antibodies themselves are regarded as foreign and rejected by the immune system. Antivenins made in camels are presently scheduled for clinical trials, and Wernery predicts that they will not provoke allergies because of their unique structure.

Camel antibodies are only the most recent in a long line of medical and biological applications of antibodies. One of the main uses is to detect diseases in patients, a process known as serology. Doctors take a sample of blood and measure whether it contains antibodies against particular infectious agents. High amounts of IgM antibodies are a sign that a person is infected with a particular virus or has been infected very recently. Antibodies are also used to look for signs of hepatitis or other liver diseases, including some autoimmune conditions. In pregnancy tests antibodies are used to check a woman's body for hormones produced by an embryo.

Antibodies contribute to a problem that arises during pregnancy when mothers and fetuses have differences in their blood involving Rhesus factors. The blood cells of some people produce the Rh protein, which appears on their surfaces (such people are called "Rh positive"), and the cells of Rh-negative people do not. This can potentially lead to disaster because the mother's body might build antibodies against the Rh proteins of her fetus. While the blood systems of the mother and child are kept separate during pregnancy, the baby's blood sometimes enters a mother's bloodstream during complicated pregnancies or childbirth.

If the fetus has Rh-positive blood, the protein acts as an antigen, and the blood stimulates an immune response. This can cause severe problems in both the mother and child. It also affects the next pregnancy; if the mother's body has antibodies against Rh, they can reach the placenta and attack the blood cells of the fetus. This problem was the cause of many deaths before scientists understood it. Now, doctors routinely screen the blood of mothers and administer anti-RhD treatments before the mother can produce antibodies. Even just a few decades ago, many states required blood tests before issuing marriage licenses in order to warn partners who were at risk of having such babies. Today's easy access to treatment has led nearly all states to drop the requirement.

Another application of antibodies involves giving them to patients when their own bodies fail to produce them in response to a disease, or when the body cannot make them fast enough to respond to an infection or a poison. This procedure is called passive immunity. The strategy is to transplant antibodies that have been made in another person (or an animal such as a horse) to someone suffering from an illness. Examples include antivenins against snakebites and early treatments for rabies. Passive antibody therapies have also been used to treat some types of cancer, multiple sclerosis, and rheumatoid arthritis. When the imported antibodies dock onto foreign substances, they summon macrophages and other white blood cells that wipe out the invader. This part of the immune response works the same as if the antibodies had been made by the patient's body. Yet, the introduction of foreign antibodies sometimes causes problems such as allergic or immune reactions; antibodies made in another body may be regarded as foreign. Additionally, unlike antibodies that develop naturally, the immune system does not develop memory cells, so a patient is not protected from repeated infections.

The fact that antibodies bind to very specific targets has made them valuable in research. They can be used as tools to track, identify, or purify proteins. These techniques require huge numbers of antibodies, which have to be made in cells. Usually the procedure begins by exposing an animal such as a rabbit, horse, or chicken to an antigen, the molecule that scientists would like to tag or study. The animal builds antibodies against the substance. The B cells are extracted, but before their antibodies can be harvested, extra steps are necessary. Just as one key might fit two doors, some antibodies recognize more than one antigen. Additionally, the body often builds more than one antibody against a specific antigen (two different keys that fit the same door). Either of these situations can confuse experiments or cause problems during therapies, so scientists had to find a way to isolate identical and extremely specific antibodies. This required isolating an animal cell that made the best possible antibody, then having that cell copy itself. This creates monoclonal antibodies, molecules that are the same because they come from a single parent cell.

The technique for producing this type of antibody was invented in 1975 by German biologist Georges Köhler (1946-95), his professor César Milstein (1927-2002) an Argentine working at the University of Cambridge in England, and the Danish immunologist Niels Kaj Jerne (1911-94). Their discovery led to their sharing the Nobel Prize in physiology or medicine in 1984. One notable problem they had to overcome was the fact that antibody-producing cells do not survive or reproduce well in the test tube. Their solution involved fusing the cells with a type of laboratory-cultured cancer cell called a myeloma. This cell grows readily in the test tube, reproduces very quickly, and is

A Devil in Distress: Can Cancer Be a Transmissible Disease?

It is not often that a cartoon character steps up to shed light on the immune system, cancer, and potential new therapies involving T cells. But the Tasmanian devil has suddenly caught the interest of scientists across the world. The real marsupial lives only on the island nation of Tasmania, where its odd shrieks startle tourists and keep people awake at night. Several hundred years ago the devil was also widespread on mainland Australia, but it became extinct there with the arrival of the dingo. Now it faces another threat. In 1996 scientists discovered an epidemic of cancer that was killing the animals in a northern region of the island. Since then the disease has spread so rapidly that researchers estimate it may have decimated half the entire species.

Tumors arise in the animal's mouth and on its face, eventually making it impossible or too painful for the devil to eat, and it starves to death. What has been so puzzling about the disease is that it seems to spread directly from animal to animal. The devils often have fierce fights in which they bite each other on the face, which explains how cancer cells might spread. But while cancer sometimes follows on the heels of an infectious disease (discussed in the next section), it is almost never directly transmissible. Cancer cells are not parasites; they arise through mutations in a person's cells and cannot transmit the disease on their own. If cells from a cancer patient were accidentally transplanted into another person, the immune system of the new host would wipe them out immediately. Only one exception was known, a rare sexually transmitted disease in dogs—and now perhaps in the Tasmanian devils.

In 2006 two Tasmanian scientists, Anne-Maree Pearse and Kate Swift, examined cells from animals with

The Tasmanian devil in defensive stance, at Tasmanian Devil Conservation Park, Tasman Peninsula (Wayne McLean)

the "devil-facial tumor disease." They discovered some extremely odd characteristics: The cancer cells were missing five of the normal devil chromosomes and had four extra ones. These particular aberrations had never been seen before in the animal's cells. Cells can undergo such massive changes, but the chances of it happening more than once are extremely small. As tumor cells taken from animals all over the country had the same features, it virtually proved that all of the cases could be traced back to one source, rogue cells that evolved in a single animal. Like parasites, they were being passed from one devil to the next in a bite.

Normally the immune system treats tumor cells like any other type of transplanted tissue and rejects them, but even other types of tissue transplanted between devils were not being rejected. Pearse and Swift proposed that this was due to heavy inbreeding within the population. A 2007 study by groups from Australia and Tasmania confirmed this and showed what aspect of the immune system was at fault. Existing devils produce very few types of MHC molecules ("vacuum sweeper" proteins on the surfaces of cells that combine with fragments of foreign molecules and are recognized by T cell receptors). Most species have



a wide variety of MHCs, which means that two animals are unlikely to have the same ones. This protects them from accidentally taking in diseased cells—such as cancer— from other members of their species. The devils are closely related to each other. It is strong evidence that the animals that live in Tasmania descend from a very small population that arrived on the island a few hundred years ago.

"immortal"; in other words, it goes on copying itself for generation after generation without becoming old or dying. Samples of the antibodies produced by each cell culture are extracted and tested to find one that binds to the antigen the best. It is then selected to produce the finished molecule.

In recent years genetic engineers have developed new techniques to make antibodies by inserting their genes into bacteria, yeast, and other microorganisms to turn them into antibody-production factories. These molecules remain one of the most important tools in biological and medical research.

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