CHAPTER 2
Genetics
A person’s genetic makeup is a complete set of instructions on how the body is “supposed” to be built. The body’s genetic material consists of genes, made up of coils of deoxyribonucleic acid (DNA). Genes are contained in chromosomes, which are mainly in the cell nucleus.
Chromosomes and Genes
A gene is a segment of DNA containing the code used to synthesize a protein.
A chromosome contains hundreds to thousands of genes.
Every human cell contains 23 pairs of chromosomes, for a total of 46 chromosomes.
A trait is any gene-determined characteristic and is usually determined by more than one gene.
Some traits are caused by abnormal genes that are inherited or that are the result of a mutation.
Proteins are probably the most important class of material in the body. Proteins are not just building blocks for muscles, connective tissues, skin, and other structures. They also are needed to make enzymes. Enzymes are complex proteins that control and carry out nearly all chemical processes and reactions within the body. The body produces thousands of different enzymes. Thus, the entire structure and function of the body is governed by the types and amounts of proteins the body synthesizes. Protein synthesis is controlled by genes, which are contained on chromosomes.
The genotype is a person’s unique combination of genes or genetic makeup. Thus, the genotype is a complete set of instructions on how that person’s body synthesizes proteins and thus how that body is supposed to function and be built.
The phenotype is the actual structure and function of a person’s body. The phenotype typically differs somewhat from the genotype because not all the instructions in the genotype may be carried out (or expressed). Whether and how a gene is expressed is determined not only by the genotype, but also by the environment (including illnesses and diet) and other factors.
Genes
DNA: Genes consist of deoxyribonucleic acid (DNA). DNA contains the code, or blueprint, used to synthesize a protein. Genes vary in size, depending on the sizes of the proteins for which they code. Each DNA molecule is a long double helix that resembles a spiral staircase containing millions of steps. The steps of the staircase consist of pairs of four types of molecules called bases (nucleotides). In each step, the base adenine (A) is paired with the base thymine (T), or the base guanine (G) is paired with the base cytosine (C).
Synthesizing Proteins: Proteins are composed of a long chain of amino acids linked together one after another. There are 20 different amino acids that can be used—some come from the diet, and some are made by enzymes in the body. As a chain of amino acids is put together, it folds upon itself to create a complex three-dimensional structure. It is the shape of the folded structure that determines its function in the body. Because the folding is determined by the precise sequence of amino acids, each different sequence results in a different protein. Some proteins (such as hemoglobin) contain several different folded chains. Instructions for synthesizing proteins are coded within the DNA.
Coding: Information is coded within DNA by the sequence in which the bases (A, T, G, and C) are arranged. The code is written in triplets. That is, the bases are arranged in groups of three. Particular sequences of three bases in DNA code for specific instructions, such as the addition of one amino acid to a chain. For example, GCT (guanine, cytosine, thymine) codes for the addition of the amino acid alanine, and GTT (guanine, thymine, thymine) codes for the addition of the amino acid valine. Thus, the sequence of amino acids in a protein is determined by the order of triplet base pairs in the gene for that protein on the DNA molecule. The process of turning coded genetic information into a protein involves transcription and translation.
Transcription and Translation: Transcription is the process in which information coded in DNA is transferred (transcribed) to ribonucleic acid (RNA). RNA is a long chain of nucleotides just like a strand of DNA, except that the base uracil (U) replaces the base thymine (T). Thus, RNA contains triplet-coded information just like DNA.
When transcription is initiated, part of the DNA double helix splits open and unwinds. One of the unwound strands of DNA acts as a template against which a complementary strand of RNA forms. The complementary strand of RNA is called messenger RNA (mRNA). The mRNA separates from the DNA, leaves the nucleus, and travels into the cell cytoplasm (the part of the cell outside the nucleus). There, the mRNA attaches to a ribosome, which is a tiny structure in the cell where protein synthesis occurs.
Structure of DNA
DNA (deoxyribonucleic acid) is the cell’s genetic material, contained in chromosomes within the cell nucleus and mitochondria.
Except for certain cells (for example, sperm and egg cells and red blood cells), the cell nucleus contains 23 pairs of chromosomes. A chromosome contains many genes. A gene is a segment of DNA that provides the code to construct proteins.
The DNA molecule is a long, coiled double helix that resembles a spiral staircase. In it, two strands, composed of sugar (deoxyribose) and phosphate molecules, are connected by pairs of four molecules called bases, which form the steps of the staircase. In the steps, adenine is paired with thymine, and guanine with cytosine. Each pair of bases is held together by a hydrogen bond. A gene consists of a sequence of bases. Sequences of three bases code for an amino acid (amino acids are the building blocks of proteins) or other information.
With translation, the mRNA code (from the DNA) tells the ribosome the order and type of amino acids to link together. The amino acids are brought to the ribosome by a much smaller type of RNA called transfer RNA (tRNA). Each molecule of tRNA brings one amino acid to be incorporated into the growing chain of protein, which is folded into a precise shape under the influence of nearby molecules (“chaperone” molecules).
Control of Gene Expression: There are many types of cells in a person’s body, such as heart cells, liver cells, and muscle cells. These cells look different, act differently, and produce very different chemical substances. However, every cell is the descendant of a single fertilized egg cell, and as such contains the exact same DNA. Cells acquire their very different appearances and functions because different genes are expressed in different cells (and at different times in the same cell). The information about when a gene should be expressed is also coded in the DNA. Gene expression depends on the type of tissue, the age of the person, the presence of specific chemical signals, and numerous other factors, many of which are still poorly understood.
The mechanisms by which genes control each other are very complicated. Genes have markers to indicate where transcription should begin and end. Various chemical substances (such as histones) in and around the DNA block or permit transcription. Also, a strand of RNA called antisense RNA can pair with a complementary strand of mRNA and block translation.
Replication: Cells reproduce by splitting in two. Because each new cell requires a complete set of DNA molecules, the DNA molecules in the original cell must reproduce (replicate) themselves during cell division. Replication happens in a manner similar to transcription, except that the entire double-strand DNA molecule unwinds and splits in two. After splitting, nucleotides on each strand bind to complementary bases (A with T, and G with C) floating nearby. When this process is complete, two identical double-strand DNA molecules exist.
Mutation: To prevent mistakes during replication, cells have a “proofreading” function to help ensure that bases are paired properly. There are also chemical mechanisms to repair DNA that was not copied properly. However, because of the billions of base pairs involved in and the complexity of the protein synthesis process, mistakes can happen. Such mistakes can occur for numerous reasons (including exposure to radiation or drugs) or for no apparent reason. Minor variations in DNA are very common and occur in most people. Most variations do not affect subsequent copies of the gene. Mistakes that are duplicated in subsequent copies are called mutations. Mutations that affect the reproductive cells may be passed on to offspring. Mutations that do not affect reproductive cells die out with the affected person.
Mutations may involve small or large segments of DNA. Depending on its size and location, the mutation may have no apparent effect, or it may alter the amino acid sequence in a protein or decrease the amount of protein produced. If the protein has a different amino acid sequence, it may function differently or not at all. An absent or nonfunctioning protein is often harmful or fatal. For example, in phenylketonuria, a mutation results in the deficiency or absence of the enzyme phenylalanine hydroxylase. This deficiency allows the amino acid phenylalanine (absorbed from the diet) to accumulate in the body, ultimately causing severe mental retardation. In rare cases, a mutation introduces a change that is advantageous to the cell.
Did You Know…
Not all gene abnormalities are purely harmful—the gene that causes sickle cell disease also provides protection against malaria.
People carry an average of six to eight abnormal genes.
Natural selection refers to the concept that mutations that impair survival in a given environment are less likely to be passed on to offspring (and thus become less common in the population), whereas mutations that improve survival progressively become more common. Thus, beneficial mutations, although initially rare, eventually become common. The slow changes that occur over time from mutations and natural selection in an interbreeding population collectively are called evolution.
Chromosomes
A chromosome is made of a very long strand of DNA and contains many genes (hundreds to thousands). The genes on each chromosome are arranged in a particular sequence, and each gene has a particular location on the chromosome (called its locus). In addition to DNA, chromosomes contain other chemical components that influence gene function.
Pairing: Except for certain cells (for example, sperm and egg cells or red blood cells), the nucleus of every human cell contains 23 pairs of chromosomes, for a total of 46 chromosomes. Normally, each parent contributes one chromosome to each of the 23 pairs.
There are 22 pairs of nonsex (autosomal) chromosomes and one pair of sex chromosomes. Paired nonsex chromosomes are, for practical purposes, identical in size, shape, and position and number of genes. There are two types of sex chromosomes, X and Y, each very different from the other. Because each member of a pair of nonsex chromosomes contains one of each corresponding gene, there is in a sense a backup for the genes on those chromosomes.
Sex Chromosomes: The pair of sex chromosomes determines whether a fetus becomes male or female. Males have one X and one Y chromosome. A male’s X comes from his mother and the Y from his father. Females have two X chromosomes, one from the mother and one from the father. In certain ways, sex chromosomes function differently than nonsex chromosomes.
The Y chromosome carries relatively few genes other than the ones that determine male sex. The X chromosome contains many more genes than the Y chromosome, many of which have functions besides determining sex and have no counterpart on the Y chromosome. In males, because there is no second X chromosome, these extra genes on the X chromosome are not paired and virtually all of them are expressed. Genes on the X chromosome are referred to as sex-linked, or X-linked, genes.
Normally, in the nonsex chromosomes, the genes on both of the pairs of chromosomes are capable of being fully expressed. However, in females, most of the genes on one of the two X chromosomes are turned off through a process called X inactivation (except in the eggs in the ovaries). X inactivation occurs early in the life of the fetus. In some cells, the X from the father becomes inactive, and in other cells, the X from the mother becomes inactive. Thus, one cell may have a gene from the person’s mother and another cell has the gene from the person’s father. Because of X inactivation, the absence of one X chromosome usually results in relatively minor abnormalities (such as Turner’s syndrome—see page 1728). Thus, missing an X chromosome is far less harmful than missing a nonsex chromosome.
If a female has a disorder in which she has more than two X chromosomes, the extra chromosomes tend to be inactive. Thus, having one or more extra X chromosomes causes far fewer developmental abnormalities than having one or more extra non-sex chromosomes. For example, women with three X chromosomes (triple X syndrome) are often physically and mentally normal (see page 1729).
Mitochondrial Chromosomes: Mitochondria are tiny structures inside cells that synthesize molecules used for energy. Unlike other structures inside cells, each mitochondrion contains its own circular chromosome. This chromosome contains DNA (mito-chondrial DNA) that codes for some, but not all, of the proteins that make up that mitochondrion. Mito-chondrial DNA usually comes only from the person’s mother because, in general, when an egg is fertilized, only mitochondria from the egg become part of the developing embryo. Mitochondria from the sperm usually do not become part of the developing embryo.
Chromosomal Abnormalities: There are several types of chromosomal abnormalities (see page 1726). A person may have an abnormal number of chromosomes or have abnormal areas on one or more chromosomes. Many such abnormalities can be diagnosed before birth.
Abnormal numbers of nonsex chromosomes usually result in severe abnormalities. For example, receiving an extra nonsex chromosome can be fatal to a fetus or can lead to abnormalities such as Down syndrome, which commonly results from a person having three copies of chromosome 21. Absence of a nonsex chromosome is always fatal to the fetus.
Large areas on a chromosome may be abnormal, usually because a whole section was left out (deletion) or mistakenly placed in another chromosome (trans-location). For example, chronic myelogenous leukemia is sometimes caused by translocation of part of chromosome 9 onto chromosome 22. This abnormality can be inherited or be the result of a new mutation.
Traits
A trait is any gene-determined characteristic. Many traits are determined by the function of more than one gene. For example, a person’s height is likely to be determined by genes affecting growth, appetite, muscle mass, and activity level. However, some traits are determined by the function of a single gene.
Variation in some traits, such as eye color or blood type, is considered normal. Other variations, such as albinism, Marfan syndrome, and Huntington’s disease, harm body structure or function and are considered disorders. However, not all such gene abnormalities are uniformly harmful. For example, the sickle cell gene causes disease (sickle cell anemia) but also provides protection against malaria.
Genetic Disorders
A genetic disorder is a detrimental trait caused by an abnormal gene. The abnormal gene may be inherited or may arise spontaneously as a result of a mutation. Abnormalities of one or more genes are fairly common. Humans carry an average of six to eight abnormal genes. However, most of the time the corresponding gene on the other chromosome in the pair is normal and prevents any harmful effects. In the general population, the chance of a person having two copies of the same abnormal gene (and hence a disorder) is very small, but in children of close relatives, the chances are higher. Chances are also high among children of parents who have married within an isolated population, such as the Amish or Mennonites.
Inheritance of Single-Gene Disorders
The traits produced by a gene can be characterized as dominant or recessive. Dominant traits can be expressed when only one copy of the gene for that trait is present. Recessive traits carried on autosomal chromosomes can be expressed only when two copies of the gene are present (because the gene on the paired chromosome is usually expressed instead). People with one copy of an abnormal gene for a recessive trait (and who thus do not have the disorder) are called carriers.
How Genes Affect People: Penetrance and Expressivity
People who have the same gene may be affected differently. Two terms explain these differences: penetrance and expressivity.
Penetrance refers to whether the gene is expressed or not. That is, it refers to how many people with the gene have the trait associated with the gene. Penetrance is complete (100%) if everyone with the gene has the trait. Penetrance is incomplete if only some people with the gene have the trait. For example, 50% penetrance means that only half the people with the gene have the trait.
Expressivity determines how much the trait affects (or, is expressed in) a person. A trait may be very pronounced, barely noticeable, or in between. Various factors, including genetic makeup, exposure to harmful substances, other environmental influences, and age, can affect expressivity.
Both penetrance and expressivity can vary. People with the gene may or may not have the trait, and in people with the trait, how the trait appears varies.
With codominant traits, both copies of a gene are expressed to some extent. An example of a codominant trait is blood type. If a person has one gene coding for blood type A and one gene coding for blood type B, the person has both blood types (blood type AB).
Whether a gene is X-linked (sex-linked) also determines expression. Among males, almost all genes on the X chromosome, whether the trait is dominant or recessive, are expressed because there is no paired gene to offset their expression.
Penetrance and Expressivity: Penetrance refers to how often a trait is expressed in people with the gene for that trait. Penetrance may be complete or incomplete. A gene with incomplete penetrance is not always expressed even when the trait it produces is dominant or when the trait is recessive and present on both chromosomes. If half the people with a gene show its trait, its penetrance is said to be 50%. Expressivity refers to how much a trait affects a person—whether the person is greatly, moderately, or mildly affected.
INHERITANCE PATTERNS
Many genetic disorders, particularly those involving traits controlled by multiple genes or those that are highly susceptible to environmental influences, do not have an obvious pattern of inheritance. However, some single-gene disorders display characteristic patterns, particularly when penetrance is high and expressivity is full. In such cases, patterns can be identified based on whether the trait is dominant or recessive, and whether the gene is X-linked or carried on a mitochondrial chromosome.
Non–X-Linked Inheritance
Dominant Disorders: The following principles generally apply to dominant disorders determined by a dominant non–X-linked gene:
When one parent has the disorder and the other does not, each child has a 50% chance of inheriting the disorder.
People who do not have the disorder usually do not carry the gene and thus do not pass the trait on to their offspring.
Males and females are equally likely to be affected.
Many people with the disorder have at least one parent with the disorder. However, sometimes the disorder arises as a new genetic mutation.
Recessive Disorders: The following principles generally apply to recessive disorders determined by a recessive non–X-linked gene:
Virtually everyone with the disorder has parents who both carry the abnormal gene, even though usually neither parent has the disorder (because two copies of the abnormal gene are necessary for the gene to be expressed).
Single mutations are less likely to result in the disorder than in dominantly inherited disorders (because expression in recessive disorders requires that both genes be abnormal).
When one parent has the disorder and the other parent carries one abnormal gene but does not have the disorder, half of their children are likely to have the disorder. Their other children will be carriers with one abnormal gene. If the parent without the disorder does not carry the abnormal gene, none of the children will have the disorder, but all of the children will inherit and carry an abnormal gene that they may pass on to their offspring.
A person who does not have the disorder and whose parents do not have it but whose siblings do have it has a 66% chance of being a carrier of the abnormal gene.
Males and females are equally likely to be affected.
Non–X-Linked Recessive Disorders
Some disorders represent a non–X-linked recessive trait. To have the disorder, a person usually must receive two abnormal genes, one from each parent. If both parents carry one abnormal gene and one normal gene, neither has the disorder but each has a 50% chance of passing the abnormal gene to their children. Therefore, each child has a 25% chance of inheriting two abnormal genes (and thus of developing the disorder), a 25% chance of inheriting two normal genes, and a 50% chance of inheriting one normal and one abnormal gene (thus becoming a carrier of the disorder like the parents). Therefore, among the children, the chance of not developing the disorder (that is, being normal or a carrier) is 75%.
X-Linked Inheritance
Dominant Disorders: The following principles generally apply to dominant disorders determined by a dominant X-linked gene:
Affected males transmit the disorder to all of their daughters but to none of their sons. (The sons of the affected male receive his Y chromosome, which does not carry the abnormal gene.)
Affected females with only one abnormal gene transmit the disorder to, on average, half their children, regardless of sex.
Many X-linked dominant disorders are lethal among affected males. Among females, even though the gene is dominant, having a second normal gene on the other X chromosome offsets the effect of the dominant gene to some extent, decreasing the severity of the resulting disorder.
More females have the disorder than males. The difference between the sexes is even larger if the disorder is lethal in males.
Dominant X-linked severe diseases are rare. Examples are familial rickets (familial hypophosphatemic rickets—see page 287) and hereditary nephritis (Alport’s syndrome—see page 273). Females with hereditary rickets have fewer bone symptoms than do affected males. Females with hereditary nephritis usually have no symptoms and little abnormality of kidney function, whereas affected males develop kidney failure in early adult life.
Recessive Disorders: The following principles generally apply to recessive disorders determined by a recessive X-linked gene:
Nearly everyone affected is male.
All daughters of an affected male will carry the abnormal gene.
Normally, an affected
male does not transmit the disorder to his sons.
Females who carry the gene do not have the disorder (unless they have the abnormal gene on both X chromosomes or there is inactivation of the other normal chromosome). However, they transmit the gene to half their sons, who usually have the disorder. Their daughters, like their mothers, usually do not have the disorder, but half are carriers.
EXAMPLES OF GENETIC DISORDERS
| GENE | DOMINANT | RECESSIVE |
| Non-X-linked | Marfan syndrome | Cystic fibrosis |
| Huntington’s disease | ||
| X-linked | Familial rickets | Red-green color blindness |
| Hereditary nephritis | Hemophilia |
X-Linked Recessive Disorders
If a gene is X-linked, it is present on the X chromosome. Recessive X-linked disorders usually develop only in males. This male-only development occurs because males have only one X chromosome, so there is no paired gene to offset the effect of the abnormal gene. Females have two X chromosomes, so they usually receive a normal or offsetting gene on the second X chromosome. The normal or offsetting gene normally prevents females from developing the disorder (unless the offsetting gene is inactivated or lost).
If the father has the abnormal X-linked gene (and thus the disorder) and the mother has two normal genes, all of their daughters receive one abnormal gene and one normal gene, making them carriers. None of their sons receive the abnormal gene because they receive the father’s Y chromosome.
If the mother is a carrier and the father has the normal gene, any son has a 50% chance of receiving the abnormal gene from the mother (and developing the disorder). Any daughter has a 50% chance of receiving one abnormal gene and one normal gene (becoming a carrier) or a 50% chance of receiving two normal genes.
An example of a common X-linked recessive trait is red–green color blindness, which affects about 10% of males but is unusual among females. In males, the gene for color blindness comes from a mother who usually has normal vision but is a carrier of the color-blind gene. It never comes from the father, who instead supplies the Y chromosome. Daughters of color-blind fathers are rarely color-blind but are always carriers of the color-blind gene. An example of a serious disease caused by an X-linked recessive gene is hemophilia.
Abnormal Mitochondrial Genes
Several rare diseases are caused by abnormal genes carried by the chromosome inside a mitochondrion. An example is Leber’s hereditary optic neuropathy, which causes a variable but often devastating loss of vision in both eyes that typically occurs during the teenage years. Another example is a disorder characterized by type 2 diabetes and deafness.
Because the father generally cannot pass mito-chondrial deoxyribonucleic acid (DNA) to the child, diseases caused by abnormal mitochondrial genes are almost always transmitted by the mother. However, not all mitochondrial disorders are caused by abnormal mitochondrial genes (some are caused by genes in the cell nucleus that affect the mitochondria). Thus, the father’s DNA may contribute to some mitochondrial disorders.
Unlike the DNA in the nucleus of cells, the number of abnormal mitochondrial DNA occasionally varies from cell to cell throughout the body. Thus, an abnormal mitochondrial gene in one body cell does not necessarily mean it will cause disease in another cell. Even when two people seem to have the same mitochondrial gene abnormality, the expression of disease may be very different in the two people. This variation makes genetic testing and genetic counseling of limited value in making predictions for people with known or suspected mito-chondrial gene abnormalities.
Gene Technology
Gene technology is rapidly improving. The polymerase chain reaction (PCR) is a laboratory technique that can produce large numbers of copies of a gene, which makes studying the gene much easier. A specific segment of deoxyribonucleic acid (DNA), such as a specific gene, can be copied (amplified) in a laboratory. Starting with one DNA molecule, at the end of 30 doublings (only a few hours later) about a billion copies are produced.
Did You Know…
Obtaining detailed information about one’s own genotype may be commercially feasible in the foreseeable future.
A gene probe can be used to locate a specific part of a gene (a segment of the gene’s DNA) or a whole gene in a particular chromosome. Probes can be used to find normal or mutated segments of DNA. A DNA segment that has been cloned or copied becomes a labeled probe when a radioactive atom or fluorescent dye is added to it. The probe will seek out its mirror-image segment of DNA and bind to it. The labeled probe can then be detected by sophisticated microscopic and photographic techniques. With gene probes, a number of disorders can be diagnosed before and after birth. In the future, gene probes will probably be used to test people for many major genetic disorders simultaneously.
Microchips are powerful new tools that can be used to identify DNA mutations, pieces of ribonucleic acid (RNA), or proteins. A single chip can test for 30,000 different DNA changes by using only one sample.
Uses of Genetics
The potential for understanding human genetics increased greatly when the Human Genome Project successfully identified and mapped all the genes on human chromosomes in 2003. Genetic techniques can be used to study individual genes to learn more about specific disorders. For example, some kinds of disorders that have been classified based on what symptoms they caused have been reclassified based on what the genetic abnormality is.
Genetic tests are used to diagnose certain disorders (for example, hemochromatosis and chromosomal disorders such as Down syndrome and Turner’s syndrome). Genetics is also increasing the ability to predict what disorders a person is likely to develop. For example, women with certain abnormalities in the BRCA genes are prone to develop breast and ovarian cancers. These predictions may allow disease prevention and screening to be tailored much more to each person. Advances in techniques that assess people’s genetic characteristics and increased understanding of human genetics have improved diagnosis of genetic disorders before birth. Genetic screening can be used to counsel parents about the risks of passing on a genetic disorder to their offspring (see page 1607). Screening can also be used to detect fetal abnormalities (see page 1608).
Increased understanding of human genetics has the potential to predict how people, depending on their precise genetic makeup, will respond to certain treatments. For example, specific genes can predict how much warfarin, a blood thinner, a person is likely to require. This prediction is important because taking too much warfarin can cause serious bleeding and taking too little makes the drug ineffective, which is also risky. Gene analysis can also predict whether a person will have intolerable or only minor side effects when taking irinotecan, an anticancer drug. People likely to have intolerable side effects can be treated with a different drug.
Did You Know…
Genetics may be able to help predict what disorders a person is likely to develop or how the person will respond to certain treatments.
Gene Therapy
Although gene therapy is defined as any treatment that changes gene function, it is often thought of as the insertion of normal genes into the cells of a person who lacks such normal genes because of a specific genetic disorder (gene insertion therapy). The normal genes can be manufactured, using polymerase chain reaction (PCR), from normal deoxyribonucleic acid (DNA) donated by another person. Currently, such gene insertion therapy is most likely to be effective in the prevention or cure of single-gene defects, such as cystic fibrosis.
The transfer of the normal DNA into a person’s cells can be done by several methods. One method is to use a virus, because certain viruses have the
Cloning
A clone is a group of genetically identical cells or organisms derived from a single cell or individual. Cloning (the producing of clones) has been commonplace for many years in agriculture. A plant can be propagated (cloned) by simply taking a small piece of the original plant and growing a new one from it. The new plant is thus an exact genetic copy of the original one. Such propagation is also possible with simple animals such as flatworms: cut a flatworm in two, and the tail grows a new head and the head grows a new tail. However, such simple techniques do not work with higher animals, such as sheep or humans.
In the now-famous “Dolly” experiments, cells from a sheep (donor cells) were fused with unfertilized sheep eggs from another sheep (recipient cells) from which the natural genetic material was removed by microsurgery. Then the genetic material from the donor cells was transferred into the unfertilized eggs. Unlike unfertilized eggs, these laboratory-made eggs had a complete set of chromosomes and genes. Unlike eggs fertilized naturally (with sperm), the laboratory-made eggs received genetic material from only one source. The eggs then started to develop into embryos. The developing embryos were transplanted into a female sheep (the surrogate mother), where they developed naturally. One of the embryos survived, and the resulting lamb was named Dolly. As expected, Dolly was an exact genetic copy of the original sheep from which the donor cells were taken, not of the sheep that provided the eggs.
Research on cloning continues, but cloning of humans is technically difficult and ethically controversial. Studies suggest that cloned higher animals (and thus humans) are more likely to have serious genetic defects than normally conceived offspring. Governments have attempted to make cloning humans illegal. However, cloning need not only be used to create a whole organism. It can, theoretically, also be used to create a single organ. Thus, one day a person may be able to receive “spare parts” manufactured in the laboratory, using the person’s own genes.
Whether a cell used for a clone produces a specific type of tissue, a specific organ, or an entire organism depends on the potential of the cell—that is, how highly the cell has developed into a particular type of tissue. For example, certain cells (stem cells) have the potential to produce a wide variety of tissue types or even possibly an entire organism. They have not yet differentiated into specific types of tissues. Other cells have differentiated and can develop into only those specific tissue types. Stem cells have stimulated interest because of their potential to generate tissue that can replace diseased or damaged tissues. Because stem cells tend to be less differentiated, they can thus potentially replace a wide or unlimited variety of types of tissue.
ability to insert their genetic material into human DNA. The normal DNA is inserted by a chemical reaction into the virus, which then infects (transfects) the person’s cells, thereby transmitting the DNA into the nucleus of those cells. One of the concerns about insertion using a virus is potential reactions to the virus, similar to an infection. Another concern is that the new, normal DNA may become “lost” or may fail to be incorporated into new cells after some period of time, leading to the reappearance of the genetic disorder. Also, antibodies may develop against the virus, causing a reaction similar to the rejection of a transplanted organ.
Another method for inserting genes uses liposomes, which are microscopic sacs containing the DNA that are absorbed by the person’s cells, thereby delivering their DNA to the cell nucleus. Sometimes this method does not work because the liposomes are not absorbed into the person’s cells, the new gene does not work as intended, or the new gene is eventually lost. A third method is called naked plasmid DNA injection, in which plasmid DNA (a special circular form of DNA) is injected into a person’s muscle.
A different method of gene therapy uses antisense technology, in which, rather than inserting normal genes, the abnormal genes are simply switched off. Using antisense technology, drugs can combine with specific parts of the DNA, preventing the affected genes from functioning. Antisense technology is currently being tried for cancer therapy but is still very experimental. However, it seems to have the potential to be more effective or safer than gene insertion therapy.
Another approach to gene therapy is to increase or decrease the activities of certain genes by modifying chemical reactions in the cell that control gene expression. For example, modifying a chemical reaction called methylation can change the function of a gene, causing it to increase or decrease production of certain proteins or to produce different kinds of proteins. Such methods are being tried experimentally to treat certain cancers.
Gene therapy is also being studied experimentally in transplantation surgery. By altering the genes of the transplanted organs to make them more compatible with the recipient’s genes, the organ recipient is less likely to reject the transplanted organ. Thus, the recipient may not need to receive drugs that suppress the immune system, which can have serious side effects. However, this type of treatment is usually unsuccessful.
Ethical Controversies
With the new genetic diagnostic and therapeutic capabilities come many controversies about how they should be used. Concerns have been raised that knowledge of a person’s genetic information might be used improperly. For instance, people whose genetic characteristics make them prone to particular disorders might be denied employment or health insurance coverage.
Prenatal screening for genetic abnormalities that cause serious disorders is widely supported. However, concern exists that screening could also be used to select for traits that are desirable (for example, physical appearance and intelligence).
Cloning of humans is highly controversial. Creating a human being by cloning is still technically impossible. Animal studies suggest it is much more likely than natural methods to result in severe defects that are lethal or cause serious health problems. Creating a human by cloning is widely seen as unethical and is usually illegal.