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Biological Development and Cancer A sperm cell and an egg cell unite. This seemingly straightforward! event sets in motion one of the most awe-inspiring pro- cesses in all of biology. Within a short time the fertilizer! egg begins to divide, producing two cells, four cells, eight. The dividing cells form a ball, which then becomes hollow. Parts of the ball form climples and ridges, with layers of cells moving inside other layers. Soon these layers thicken, forming different kinds of tissues. Other cells leave their points of origin anc! migrate through the developing embryo, eventually to become vertebrae, muscles, nerves. Tissues fold ant! protrude to form organs and limbs. The outlines of a living creature take shape. Ant} already within the growing embryo, the sex cells that someday will repeat the entire process are growing. For centuries, biologists have been fascinated with the process by which a single fertilized egg gives rise to a complex organism. They have clescribed the process in elaborate detail, developing a formidable vocabulary to label a growing embryo's stages and features. But biol- ogists want to do more than describe the growth of an organism; they want to know how it occurs. What are the mechanisms responsible for the grand pageant of ~levelopment? Until recently, the vocabulary of developmental biologists "clid not have much immediate context in terms of mechanisms,' according to Marc Kirschner, professor of biochemistry at the University of California at San Francisco. But the rapid advances of molecular techniques have begun to bridge this gap. More ant! more, development is being ex- plained in terms of the expression of genes and the corresponding 33

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molecular properties of cells and their environment. ``We don't really expect that all our explanations of embryology are going to be in terms of linear sequences of nucleotides," says Kirschner. ``But we want to be confident that these concepts could be reduced to that level." Explaining the development of a fertilized egg in molecular terms is a daunting task, Kirschner concedes. Much of molecular biology has focused on purified components in well-defined environments. But de- velopmental biology is much more complex. '~What we're really lacking is a cell biology of multicellular populations," says Kirschner. '`The progress in the recent past has been in the quite Important area of single-cell biology. But if we're really going to understand development, we need to know how groups of cells behave in populations." Unifying Concepts Despite its overall complexity, developmental biology is built on a solid foundation of biological principles. Most important, it is clear that development is choreographed by the messages carried in an organism's genes. Nongenetic factors, including environmental factors, can also play a key role in development. But the genes establish development's basic pattern and timing. For this reason, a powerful form of experi- mentation in developmental biology is to look for genetic mutations that affect the way an organism develops. Because virtually every cell in an organism contains the same col- lection of genes' an organism is essentially a clone of a fertilized egg. But the cells in that clone are radically different. These differences reflect the expression of different sets of genes within each cell. in other words, the cells have differentiated into nerve cells, muscle cells, skin cells, and so on (there are about 200 roughly distinguishable types of cells in the human body). In turn, the differentiation of ~ call it the product of its history and its environment. ~^ ~-. . ~ The difference between a human being and, say, a chimpanzee, is not so much the kinds of cells each has. Rather, it is the number of those cells and the way in which they are organized. During the de- velopment of an embryo, cells must reach their designated locations and assume their differentiated states. The central problem of devel- opmental biology is to explain this process. How do cells know where to go? How do they know what to become? The puzzle at the center of developmental biology can be stated another way, according to Kirschner. How does the tremendous com- plexity of an adult organism arise from the relative simplicity of a 34 SHAPING THE FUTURE

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fertilized egg? Although an organism's genome contains large amounts of information, developmental biologists agree that development draws partly on information that is not located in an organism's DNA. This may seem to conflict with the concept that development occurs uncler the control of DNA. But development cannot be understooc] without recognizing other factors, even though these factors themselves may have genetic roots. C`The real complexity that occurs in clevelopment comes after the egg stage," says Kirschner. `'The egg provides a crude level of information, and very complex ant] exquisite mechanisms act to achieve higher levels of complexity." ~. 1] . . Development occurs in all organisms that originate from the union of an egg cell and a sperm cell' and many processes in development are common to all such organisms. Religious and ethical constraints severely limit the research that can be done with human embryos (as (lescribed in the essay following this chapter). But clevelopmental events that occur in other species are very similar to those that occur in humans, and often they can be studied more easily in other kincIs of organisms. `'Many of the same embryological problems that are confronted in ver- tebrate development are also confronted in invertebrate development," says Kirschner, ``and some fundamental problems are confronted in all development-plants as well as animals." Inside an Egg The fruit fly Drosophila met7ar~ogaster, long a favorite of geneticists' has also shed a great deal of light on development. Drosophila is small and has a short life cycle (Figure 2-~), so that many organisms can be producer! and studied in a short time. Drosophila also has a genome that is smaller than that of humans but still sophisticated enough to produce biological processes sharer! by many other organisms. (Each Drosophila cell has about one-twentieth as much DNA as a human cell, and its genome contains about one-tenth as many genes.) In addition, geneticists have developed powerful tools that have enabled them to <~7 ~ . .1 r 7/~ 7 7 . . . ..1 ~1 manipulate the genome of L,rosopulla lo a greater extent Inan wan any other animal. A major way of studying Drosophila is by screening adults or larvae for genetic mutations that affect some characteristic of the organism. Researchers can then work backward from the mutation to learn more about the genes responsible for the mutation. For example, one striking mutation, Antennapedia' causes Drosophila to grow a leg where an antenna should be (Figure 2-2~. The gene responsible for this mutation BlOEOGICAE DEVELOPMENT AND CANCER 35

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After 1 Day After 6 Days After 10 Days it' ~;~ / Egg First Larval Stage Pupa Adult FIGURE 2-1 The fruit fly Drosophila melar~ogaster develops from a fertilized egg into an adult in about 10 days. The egg forms an embryo that hatches into a larva in about a day. After several larval stages, Drosophila becomes a pupa and undergoes metamorphosis, giving rise to the adult fly. Reprinted, with permission, from G. Rubin, "Drosophila melanogaster as an Experimental Animal," Science 240~4858~: 1443-1447, 1988. @) 1988 by the American Association for the Advancement of cam ~ science. Eye-- ~ Antenna - ~94 Normal Leg Mutant FIGURE 2-2 The mutation Antennapedia causes Drosophila to grow a leg where it normally would grow an antenna. Mutations such as this offer valuable clues about the genetic controls over development. Reprinted, with permission, from B. Alberts et al., Molecular Biology of the Cell. New York: Garland Publishing, Inc., 1983. (it) 1983 by B. Alberts et al. 36 SHAPING THE FUTURE

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has been cloned and has been fount! to lie next to genes that control other aspects of Drosophila~s form. At this point, biologists have de- scribed and analyzer! mutations in over 3~000 Drosophila genes (out of a total of 5~000 to 10~000 genes). Fruit flies develop from eggs laid outside the mother's body. The early stages of development vary somewhat from the generic process described at the beginning of this chapter. Instead of undergoing suc ~ . . . ~ ~ . ~ ~ ~ cessive divisions to produce a muit~cei~uiar organism, the fertilized eggs of Drosophila take a shortcut (Figure 2-3~. First, the DNA in the egg replicates, until the egg contains about HOOD copies of its DNA. Then, about 3 hours after fertilization, cell walls form simultaneously around all of the nuclei in the egg, creating an embryo of about 5,000 cells. The embryo then undergoes a complicated set of invaginations before hatching as a larva. in many ways, the Drosophila egg right after fertilization may seem to be a relatively simple, homogeneous structure (with the exception of the DNA in its nucleus). But careful observations reveal a richer texture. Soon after the dividing nuclei have migrated to the surface of the egg' they form ~4 distinct bancis along its length. Each of these bands will eventually develop into a specific part of the embryo, anc! ultimately the adult organism. Some Mantis will contribute to the head, others to the thorax, and others to the abdomen. How clo the nuclei in each band know what segment of the embryo to make? There are two limiting possibilities. One is that each band is influenced by a different molecular substance prelocatized to that por- tion of the egg. These substances could cause the DNA in specific ~ -I\ . . 11 ~v. I/ at, -_ ~ Fertilized Egg Many Nuclei Nuclei Migrate CellWalls to Periphery Form Form FIGURE 2-3 After fertilization, the nucleus in a Drosophila egg divides many times, producing about 5,000 copies that eventually migrate to the periphery of the cell. Soon after cell walls form around the individual nuclei, the egg folds in upon itself to produce an embryo, which then hatches into a first-stage larva. Reprinted, with permission, from B. Alberts et al., Molecular Biology of the Cell. New York: Garland Publishing, Inc., 1983. (it) 1983 by B. Alberts et al. (After H. A. Schnei- derman, pages 3-34 in Insect Development. Oxford, England: Blackwell, 1976.) BIOLOGICAL DEVELOPMENT AND CANCER 37

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regions to express the genes appropriate for that position. The other possibility is that the dividing nuclei interact with some simpler spatial clue within the egg to produce the observed segmentation pattern. Biologists have begun to solve this problem by examining mutations that distort the segmentation of Drosophila. For instance, some muta- tions cause larvae to develop missing segments, or double heads or tails, or other unusual features (almost all of these mutations are lethal, so that development stops at a preadult stage). Using this information, researchers have concluded that the spatial clues in the egg are rela- tively simple. In particular, it seems that the segmentation patterns observed in Drosophila are caused by substances emitted from either end of the egg. The concentrations of these substances drop as they get farther from their points of origin' so they form smoothly varying gradients across the length of the egg. Somehow the dividing nuclei read these gradients to determine where they are in the egg and what genes they should express. The proteins produced by these genes then establish additional gradients, which further elaborate the develop- mental pattern. ``Rules are built into the genome and into the bio- chemistry of genes and their products that allow the expression of this very specific pattern of segmentally expressed genes," says Kirschner. '`This presages the segmentation pattern seen later in development." The segmentation of Drosophila (remonstrates the complex way in which DNA interacts with its chemical environment during develop- ment, according to Kirschner. DNA does not just passively issue com- mands that are then carried out by the cleveloping embryo. Rather, the expression of DNA is modified by its surroundings, first in the egg and later in the developing organism. The result is an intricate system of interrelated biological components that can produce complex devel- opmental events. `~} think this is the heart of the problem of embryology," says Kirschner, ``how complexity is generated." Segmentation is a basic feature of all advanced animals. In humans, segmentation can be seen in fingers and toes, arms and legs, backbones and ribs. By studying how segments develop in organisms like Dro- sophila, biologists hope to uncover mechanisms that govern similar processes in other organisms, including humans. Communication Among Cells Prelocalization of substances in the egg can be an important factor in early development (although in some animals, including humans, it seems to play a negligible role, as described in the box on pages 42 38 SHAPING THE FUTURE

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43~. But prelocalization is soon supersecled by other factors. Most im- portant, as cells divide' they begin to communicate among themselves. Without this communication, clevelopment would be impossible. Many important aspects of cell-cell communication have been stud- iec! in the African cIawec] toad Xertopus laevis. As with Drosophila, the eggs of Xerlopus develop outsicle the body, making the embryo com- paratively easy to study. Xerlopus eggs are also unusually large about twice the size of the period at the end of this sentence. Xer~opus is also like Drosophila in that prelocalization of substances within the egg shapes early (development. A Xerlopus egg has a larker hemisphere, known as the animal pole, and a lighter hemisphere, known as the vegetal pole. As the fertilLizec3 egg begins to clivi(le, this (1istinction between the two hemispheres remains. A Xerlopus egg undergoes a process of cell division and fol(ling very similar to the one described at the beginning of this chapter. About eight hours after fertilization, the egg has divided into a hollow ball of about 4,000 cells. Shortly thereafter, a group of ceils near the border of the animal and vegetal halves of the embryo move into the interior of the egg, where they come into contact with the animal pole of the embryo (Figure 2-4~. These adjoining layers of cells then differentiate into the three kinds of tissue that will eventually give rise to all the parts of the aclult hotly. The top layer of cells will form ectoderm, which will go on to form skin and the brain. The bottom layer of cells will form endoderm, which will procluce the lining of the gut and associate(1 organs, such as the lungs and liver. Between the two layers will form a third layer, the mesoderm, which will eventuality generate muscle, ligaments, blooc] vessels, bones, the heart, and bloo(1 ceils. Kirschner points out that it is possible to draw what is known as a fate map of the early embryo' when it is still a ball of ceils surrounclina --0 a hollow cavity (Figure 2-5~. Cells derived from the animal pole of the embryo will make ectoderm. Cells derived from the vegetal pole of the embryo will make endoclerm. It is then possible to isolate various parts of the embryo ant! see how they clevelop on their own. When cultured in solution, cells from the animal part of the embryo form tissues characteristic of ectoderm. Cells from the vegetal cap form tissues characteristic of endoclerm. Neither, however, when cultured on its own' can form tissues characteristic of meso~lerm. But if the two types of cells are placed in contact, the situation changes. Cells from the animal part of the embryo sullenly begin forming mesoclermal tissues, such as muscle and kidney tissues. ``These two crude regions, when mixed together in this manner, generate the complexity of BlOEOGICAE DEVELOPMENT AND CANCER 39

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the normal embryo'" Kirschner points out. The implication is that some kinc] of chemical messenger travels from the vegetal ceils to the animal ceils and induces them to differentiate. What is the nature of this messenger? It operates at very low con- centrations' and it has been impossible to isolate anc! characterize clirectly from the embryo. So clevelopmental biologists have tested other substances to see if they can cause cells from the animal portion of Xer~opus embryos to form mesoclermal tissues. Lithe problem'" according to Kirschner, ``was not so much the failure to find these substances, but the fincling that lots of things would have effects." Substances like fish swim bladders and guinea pig bone marrow and even nonspecific 1 .1 ~1 . it- 1 1 ~ Head Belly At Tail / FIGURE 2-4 By the time the Xenopus egg has divided into several thousand cells, the embryo has formed a hollow ball. The cells on the top of the ball (gray) are derived from the animal pole of the egg; those on the bottom of the ball (white) are derived from the vegetal pole. During a process known as gastrulation, cells at the boundary of the two halves of the embryo move into its interior. These cells will go on to form endodermal tissues (black), while cells from the top of the embryo will generate ectodermal tissues. Mesodermal tissues will form in a layer intermediate between these two. Reprinted, with permission, from R. Dulbecco, The Design of Life. New Haven, Conn.: Yale University Press, 1987. (it) 1987 by Yale University. 40 SHAPING THE FUTURE

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factors like ammonia and calcium turned out to have a mesoderm- inclucing effect. '`This got to be very discouraging," Kirschner says. More recently, Kirschner anc] his coworkers have been one of several ~ r- 1 . 1 research groups trying to Once tne substance that actually operates in the Xerlopus embryo. First, they reasoned that the substance might be one of the known growth factors, which are proteins that hind to receptors on cells and cause them to clivide. So Kirschner's team ``wheeled our cart down the hall at UCSF and collected] all the known growth factors to try them." The only one that hac] an effect was fibroblast growth factor, which performs a number of functions in the body, including causing blood vessels (a mesoderm-clerived tissue) to proliferate. But even fibroblast growth factor did not produce as powerful an effect as the unknown substance operating in the embryo. So Kirschner and his colleagues starter! combining growth factors. '~You can spenc] your whole life cloing this kind of thing," Kirschner says, but before long they found what they were looking for. When fibroblast growth factor was mixed with a particular kind of transforming growth factor, a protein that regulates cell differentiation, the combi- nation caused induction at levels comparable to those fount! in the embryo. The transforming growth factor, known as TGF-beta, had no inducing effect by itself. But with fibroblast growth factor it acted ~ ~ rr . synergistically, producing an eitect muon greater than fibroblast growth factor alone coup! produce. Ectodermal Animal Tissues ~ Pole Endodermal Tissues Mesodermal Vegeta; Pole Tissues l / FIGURE 2-5 When cells from the animal or vegetal poles of the Xenopus embryo are cultured separately, they form tissues characteristic of ectoderm and endoderm, . ~ If r ~ ~ T 1 respectively tieit'. However, wnen cells from the two poles are cultured together, they produce mesodermal tissues (right). Reprinted, with permission, from I.B. Dawid and T.D. Sargent, `'Xenopus Levis in Developmental and Molecular Biology," Science 240~4858~: 1445. A) 1976 by the American Association for the Advancement of rat science. BIOLOGICAL DEVELOPMENT AND CANCER 41

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Fiat this point we could justifiably ask whether we had gotten our hands on the most expensive, most purified nonspecific factor avail- able,'' Kirschner points out. Maybe this was just another form of fish swim bladcler." But new findings indicatecI otherwise. Another re- searcher had cloned DNA copies of a messenger RNA that is prelo- calized in the vegetal pole of Xer~opus eggs. When the DNA was sequenced' it was fount] to be very similar to the gene that produces TGF-beta. In addition, Kirschner's team found that Xenopz~s eggs contain high con- centrations of a protein very similar to fibroblast growth factor. This evidence does not prove that fibroblast growth factor and TGF- beta together cause cells in the animal part of the Xer~opus embryo to produce mesoderm' Kirschner cautions. '`But it seems very likely that they're responsible," he contencls. Work is continuing to identify the actual factors involvecI' and conclusive identifications are expecter] within a few years. The inflection of mesodermal tissues in Xer~opus embryos is an ex- ample of a process that is critical in development. The chemical and Is Information Prelocalized in Human Egg Cells? Although prelocalization of substances in the egg shapes the early development of Drosophila, Xenopus, and many other species, it seems to play no part in the de- velopment of mammals, including hu- mans. In mammals, the fertilized egg first cleaves into several dozen cells and then forms a hollow ball. A thickening of cells within one end of the ball, known as the inner cell mass, will eventually form the embryo. The outer sphere of cells, known as the trophoblast, will form the placenta. Up to the eight-cell stage, the cells of a mammalian embryo appear to be identical. One way to demonstrate this is to separate a single cell from an eight-cell embryo and place it either inside or outside another eight-cell embryo. If inside the embryo, the introduced cell will form part of the fetus. If outside, it will form part of the placenta. This suggests that it is the position of cells 42 SHAPING THE FUTURE either inside or outside the developing em- bryo, rather than any intrinsic feature of the cells, that determines whether they will become part of the fetus or the placenta. Another way to demonstrate the simi- larity of cells in an early embryo is by sep- arating them completely from one another and putting them back together in a dif- ferent configuration. Despite this jumbling of position, the cells still produce a normal embryo. A variant on these experiments dem- onstrates a remarkable capacity of early mammalian embryos. If two embryos at the eight-cell stage are pushed together under the proper conditions, they can fuse to form a single embryo (see figure). If implanted into a foster mother, such an embryo can develop into a so-called chimeric animal consisting of genetically different groups of cells. Such a chimera has four parents, with cells derived from each set of parents scattered throughout its body.

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physical messages that a cell receives from its surroundings help it determine how to behave. It also demonstrates a common feature of chemical messengers. As with fibroblast growth factor ant] TGF-beta, the messengers active in development often function in the aclult or- ganism as well. Development Gone Awry: Cancer Development does not end after birth. Ceils continue to grow, clivide, and differentiate as the holly grows and as old cells wear out. The attainment of sexual maturity during aclolescence is a developmental process. So are many of the changes, such as milk production, that occur during pregnancy. Even aging and death can be thought of as a process of controlled development. Some cells in the adult body, including nerve cells, the muscle cells of the heart, and the lens cells of the eye, cannot reproduce. Once 8-Cell Mouse 8-Cell Mouse Embryo Whose Parents Embryo Whose Parents Are White Mice Are Black Mice Embryos Are Pushed Together and Fuse Troahoblast ~ Inner Cell ,,~ Embryo Transferred to Foster Mother The Baby Mouse Has 4 Parents (But Its Foster Mother Is Not One of Them) Two mouse embryos at the eight-cell stage can be fused to produce a chimeric mouse with four parents. The cells on the inside of each embryo form the inner cell mass, even- tually to become the fetus, while those on the outside form the trophoblast, which becomes the placenta. Reprinted, with permission, from B. Alberts et al., Molecular Biology of the Cell. New York: Garland Publishing, Inc., 1983. is 1983 by B. Alberts et al. BIOLOGICAL DEVELOPMENT AND CANCER 43

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established, they function until they die or the organism of which they are a part cries. Other cells multiply by simple replication. For instance, when liver cells die, other liver cells divide to make up for the toss. The same process occurs in bloocI vessels, in the pancreas and in other belly tissues. A third category of cells originate from undifferentiated cells known as stem cells. When a stem cell clivides, each of its two daughter cells has two choices. It can remain a stem cell, or it can differentiate into another cell type. For instance, all blood cells white cells as well as red cells originate from a single type of stem cell. According to Barry Pierce, professor of pathology at the University of Colorado, the unchecked proliferation of cancer cells bears an uncanny resemblance to the process of cell renewal. Cancer is a C`caricature" of cell renewal, Pierce says, with C`caricature meaning overproduction or gross exaggeration." In cancer, a stem cell or some other kind of cell capable of division is somehow transformed into a malignant stem cell, one that produces many cancerous offspring. Differentiation into other cell types may be blocked, with malignant stem ceils producing more stem cells in an uncontrolled avalanche of proliferation. Pierce has deciclec] to take a clevelopmental view of this process. C`Cancer is a tissue," he says, C`it7s composed of cells. Does it obey the laws of developmental biology?" By viewing cancer in this light, it is possible to envision some striking alternatives to current cancer treat ments. One common misconception about cancer. Pierce notes in Chat Or . ~ 7 _. A _. ~ ~ ~ ~ At_ ~_, A cells always beget cancer cells. C`This has had an unfortunate impact on developing alternatives to current therapies," he contends, ``because it implied that unless cancer cells were eradicated from the body or destroyed, the host will die. " Treatment have th~r~f.mrm {called ~ ~ . . . ellmlnatlng cancer cells entirely through surgery, chemotherapy, or radiation therapy. These procedures have met with some remarkable successes, Pierce points out, but they can exact a high toll on n~tient~ rL~L ~ ~ 1 - . - .1 1 . w11~;111~1~-~py or raOlallOn Inerapy do not Just destroy cancer cells they also destroy normal cells. C`Oncologists must poison the patient and then rescue that individual," Pierce says. C`Then they administer another dose of poison followed by rescue, with the hope that through repeated cycles the patient will recover and the tumor will suffer in- cremental damage, resulting in a cure." It is a C`hair-raising" situation, Pierce observes, Hand T think that doctors who do this are probably the best physicians in the world, because they walk such a narrow line, with death on each side." 44 SHAPING THE FUTURE

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But the dogma is wrong: cancer cells do not always give rise to cancer cells. There are a number of situations' Pierce notes, in which cancer cells differentiate into apparently normal cells. For instance' terato- carcinomas are cancers that arise from malignant sex cells. In the body7 these cancers share the characteristics of both cancers and embryos. The tumors contain both undifferentiated! cancerous stem cells and differentiatecI cell types found in embryos' including tissues derived from ectoderm7 mesoderm, and endoclerm. The important feature of these tumors is that the differentiated cell types are derived by differentiation from the cancerous stem cells and are usually not cancerous. If extracted from the tumor and grown in culture' most of these differentiated tissues behave normally. In the Making Cancer Cells Into Normal Cells One way to demonstrate that cancer cells do not always remain cancer cells is through an elegant experiment using mouse em bryos. If a malignant sex cell known as a teratocarcinoma cell is grown in culture, it will typically go on to produce a tumorous mass. But if such a cell is placed into an early mouse embryo (see figure), it often will lose its cancerous characteristics, and the embryo will develop normally. Even more striking is the fate of the in jected cell. If the cell is implanted into the inner cell mass, it will become part of the developing fetus and eventually will con tribute to tissues throughout the body. If the cell is implanted into the trophoblast, , it will contribute to the placenta. Not only Trophoblast does the cell lose its malignancy, but it is regulated by the embryo in such a way that it acts as a normal embryonic cell. Even though such a cell may have chromosomal abnormalities, it responds to external stim uli in the proper way and can be consid ered normal. Other kinds of cancerous cells, including leukemia and melanoma cells, can also lose their malignancy if inserted into specific parts of developing embryos at specific times. Despite being cancerous, the cells have the ability to respond to some factor produced in the embryo that can cause them to revert to normal cells and become a part of the growing embryo. It is at least pos- sible that every kind of cancer cell could be regulated this way, although the mecha- nisms of this regulation remain unknown. Inner Cell Mass `.,' Cancer cells can be introduced into mouse embryos through extremely small injecting pi- pets. The larger tube (at left) is a pipes that holds the embryo in place through suction. Reprinted, with permission, from G. B. Pierce et al., Cancer Research 44:3987-3996, 1984. ~ 1984 by the American Association for Can- cer Research. BIOLOGICAL DEVELOPMENT AND CANCER 45

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process of differentiating, the cancer cells have somehow shed their malignancy. There are other cases in which cancer cells have been shown to differentiate into nonmalignant cells. For instance, leukemia, colon cancer, and breast cancer cells can be chemically induced to differ- entiate into nonmalignant cells. Most remarkably, if certain kinds of cancer cells are inserted into embryos at Dartio',l~r timers once nl~r~c ~ ~ __ 1 ~ 1 1 1 1 Dilly me Inelr malignancy and become part of the embryo (see box' page 45). The ability of cancer cells to differentiate into normal cells points toward an entirely new approach to cancer therapy. If it were possible to induce cancer cells to differentiate, it might be possible to eliminate cancer cells without harming other cells in the body. These differen- tiation agents would have to be sDen~ifin for the n~rtir~,l~r Nor m^~] _ _ . . 1 . 1 1 1 r r ~ since agents tnat caused all normal stem Levis to differentiate would be disastrous for an individual. The differentiated cancer cells must also remain benign, a condition that current examples c30 not always meet. But if these criteria can be met, differentiation therapy could offer a less toxic, more precise treatment for cancer than surgery, chemother- apy, or radiation therapy. Pierce and other researchers are looking at two categories of potential differentiation agents. The first category consists of chemical sultan. ~:~:1 ~ 1_ _ 1 1 1 ~l~lllar ~o Nose usea in chemotherapy. Researchers have shown that various chemicals can convert a variety of cancer cells to differentiated states. However, many of these substances are toxic. raising the come problems associated with chemotherapy. The other category consists of substances that the body uses to signal cells to differentiate during development. For instance, TGF-beta, the transforming growth factor active in Xer~onus embryos also Chili . ~ _ ~ _ 1 - - ~ _ _ 7 a_ _ _ _ __~ _ ~ ~ ~ ~ ~ . ~ 1 ~ ~ . . .. _ _ the dliterent~ation of particular cells in humans. Its effects on cancers have not yet been tested. But as biologists learn more about how cells are normally renewed in the body, they may be able to better control the diseases caused when cell renewal runs amok. 46 SHAPING THE FUTURE