The Molecular Biology of Adenoviruses 3: 30 Years of Adenovirus Research 1953–1983

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Another method is to use a similar but not identical DNA sequence with less harsh experimental conditions than are normally used to identify related genes. These less stringent conditions allow the similar segments of DNA to hybridize without requiring perfect base pair matching. Finally, another method of isolating important genes is called expression cloning.

In expression cloning, a functional response for the encoded protein is tested and used as a guide to isolate specific DNA sequences that encode the protein of interest. Figure 4. Screening a DNA library. DNA is cut into fragments with restriction enzymes. These fragments are inserted into vectors, which are then replicated in bacteria. Colonies each contain a single type of recombinant DNA fragment. The colonies are transferred and fixed to a nylon filter.

A radioactive probe for the desired sequence can then be hybridized to the filter, locating the colony with the desired DNA. N Engl J Med ; Once the gene is identified, multiple copies need to be produced; the process of producing multiple copies of DNA is called amplification. One way a gene can be amplified is by using small circular pieces of DNA known as plasmids.

Both the plasmid and gene are cut with the same restriction enzyme, enabling the foreign gene to be placed ligated into the plasmid. Many plasmids contain antibiotic resistant genes that make them easy to identify. The newly created plasmid that contains the foreign DNA of interest is incorporated into bacteria, a process known as transformation. Only bacteria that have successfully incorporated the plasmid will grow in nutrients that contain antibiotic.

Transformed bacteria then replicate. Most plasmids used in molecular biology are "relax-control" plasmids, meaning that, in addition to replicating with each bacterial cell division, the plasmid also replicates many times within a single cell; the net result is rapid amplification of plasmid DNA. Messenger RNA and the encoded protein can be produced efficiently by using plasmid expression vectors that contain a highly active promoter region. Bacterial, yeast, or mammalian cells are then transfected with the recombinant DNA, resulting in large quantities of the desired protein being produced.

Cells are then lysed and the protein purified from other host cell proteins using various methods, one of which is chromatography. Many clinical advances can be attributed to general methods used in cloning. Tissue plasminogen activator is one example of a gene whose encoded protein is now mass produced using recombinant techniques.

Genes for many human diseases have been identified and cloned, including those important in hemophilia, Duchenne's muscular dystrophy, and cystic fibrosis. Insertion of cloned DNA and subsequent amplification in bacterial cells is not the only method available to amplify segments of DNA. To specify the region to be amplified, it is necessary to synthesize two short oligonucleotides primers , each complementary to one strand of each of the ends of the DNA of interest.

Denatured DNA, primers, all four nucleotides, buffer, and the enzyme DNA polymerase are cooled to 42 degrees degrees Celsius, the temperature at which primers anneal to complementary DNA. The temperature is then raised to 72 degrees Celsius, the optimal temperature for DNA polymerase.

The DNA polymerase used in PCR reactions is unique in that it is isolated from thermophilic bacterium and is stable at much higher temperatures than other polymerases. The temperature is then elevated back to degrees Celsius, where the double-stranded DNA denatures and now forms four new templates for the next cycle in the reaction. The cycle of denaturing double-stranded DNA helices, hybridizing primers, and then incorporating nucleotides to growing templates is repeated times.

Because this reaction is exponential, 30 cycles produce more than one million copies of the targeted DNA segment. Figure 5. The polymerase chain reaction. Polymerase chain reaction is a very powerful technique, with wide applications. It can be used to provide ample amounts of DNA from a known gene. By modifying primer sequences slightly, mutations can be introduced into genes and the functional result studied. Clinically, PCR amplification of small quantities of DNA can detect infectious agents or identify residual cancer cells.

Polymerase chain reaction amplification of DNA followed by restriction enzyme analysis enables diagnosis of diseases such as sickle cell anemia from a single sample of blood. Recently, PCR followed by DNA analysis has begun to be used to determine parenthood in paternity battles and identify perpetrators in rape and murder cases. Polymerase chain reaction is highly specific and can amplify a segment of DNA even if only one or two copies of the sequence are present in a sample, making it useful in many applications in medicine. Polymerase chain reaction is not without difficulties, including its high sensitivity.

Many genes have slightly different sequences that are of no clinical consequence. Such variations in the general population are called polymorphisms see section on Genetic Testing-Techniques for a more detailed discussion of polymorphisms. A further problem with PCR is the risk of contamination of the study sample; in this case, the resultant amplified DNA might be a contaminant rather than the targeted DNA, potentially leading to misdiagnosis.

However, PCR remains a valuable adjunct for molecular biologists and clinicians, being faster and easier than standard cloning methods. Whereas restriction enzyme analysis, cloning of genes, and PCR are used to study specific genes in detail, more general techniques such as Southern and Northern blotting can be applied to study DNA and RNA, respectively Figure 6. Southern blotting analyzes the structure and location of a gene.

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Genomic DNA is cut with restriction enzymes and the resulting fragments are separated by size on an agarose gel. The fragments are then transferred to a solid support nitro-cellulose or nylon using an electric field or more slowly with a buffer gradient. The presence and relative amount of a gene, as well as a physical map of the gene, can be produced by analyzing the resultant fragments. This restriction map can be used to compare the DNA sample with others and detect difference in genes between individuals. Southern blotting is used to identify major gene rearrangements and deletions and can be used to detect genetically inherited gene abnormalities in a patient or their family.

In the process of cloning a gene, Southern blotting provides a convenient method to identify a single gene within a larger-sized DNA fragment, and a method to compare genes between species. Northern blotting analyzes the size and expression of specific mRNA. Northern analysis is frequently used to identify the size of mRNA message for a known gene in various tissues and cells. Northern blotting also can be used to identify an increase in the expression of specific mRNA in response to various stimuli.

Figure 6. Southern Blotting. DNA is cut with restriction enzymes and separated by size, using gel electrophoresis. The resulting fragments are transferred onto a nylon filter which is then hybridized with a DNA probe specific for the sequence of interest. Nonhybridized probe is washed away, and the filter is exposed to x-ray film. A DNA sequence complementary to the probe is seen as a dark band on the developed film. N Engl J Med ; All of the molecular biology methods described thus far can be used with DNA or RNA isolated from a single tissue or cultured cells. However, none of these techniques maintains tissue architecture so that DNA or RNA can be localized to specific cells within a tissue.

Conditionally Replicating Adenoviruses for Cancer Treatment

In situ hybridization determines RNA expression at a cellular level Figure 7. In this technique, thin slices of tissue microns thick are fixed on slides and then incubated with labeled RNA or DNA probes.

Adenovirus life cycle

In this way, specific cells that contain the RNA of interest are highlighted, and may give insight into tissue function. However, because RNA expression may not equal protein expression, comparison with autoradiography or immunohistochemical approaches which label protein is important. A clinical use of in situ hybridization is to isolate virally infected cells Figure 7. Figure 7. In situ hybridization. A labeled DNA probe is hybridized with prepared tissue samples.

Visualization of the probe localizes specific cells. Reprinted with permission: Nabor S: Molecular medicine: Molecular pathology-Diagnosis of infectious disease. Genetic diseases traditionally have been diagnosed by clinical criteria or biochemical tests. Clinical diagnosis is often ambiguous because specific features of a disorder may take years to develop. Biochemical tests used to detect the presence or absence of a gene product may give equivocal results; in addition, prenatal testing and the identification of a carrier state are frequently difficult.

With the advent of new molecular techniques, specific genes and gene mutations can now be identified long before the appearance of clinical symptoms. Another benefit of new molecular biology-based diagnostic testing is that these tests require only a small sample of DNA such as found in a single tube of blood instead of tissue biopsies. Because of these advantages, molecular-based genetic testing has become commonplace. Frameshift mutations where a nucleic acid is added or deleted, causing the triplet code to be offset , premature termination of translation resulting in aberrantly small protein , and insertion of multiple repetitions of nonsense sequence, are mutations more likely to be pathogenic than simple base pair mutations.

Mutations that involve the simple change of one amino acid for another may or may not have clinical significance. The effect of an amino acid change may be able to be predicted based on the structure of the protein, or it may be necessary to reproduce the new phenotype in cell culture or even in an animal model to prove the pathogenicity of the substitution. Single amino acid changes without observable biologic consequence are known as benign polymorphisms, and are quite common in the general population. Therefore, geneticists must be able to distinguish pathogenic mutations from nonpathogenic polymorphisms, an often difficult task.

This differentiation is straightforward in a disease such as sickle cell anemia, which is homogeneous, in that all patients with the disease have a valine substituted for glutamic acid on the beta-globin gene in hemoglobin. However, genetic testing is complicated because many inherited diseases are not the result of a single mutation, but rather multiple mutations, all resulting in the same phenotype.

Figure 8. The 3-base-pair deletion in cystic fibrosis. The mutation Involves the deletion of CTT in the tenth exon of the gene. The sequence on the left is from a healthy individual and the sequence on the right is from a patient with cystic fibrosis. This 3-base-pair deletion results in the loss of phenylalanine from the protein. A further problem with current genetic testing is that very small deletions or additions in DNA that are responsible for disease remain extremely difficult to identify.

Even large deletions that involve long sequences of DNA may sometimes be difficult to detect. This is because nonsex chromosomes come in pairs, so even a large defect in one gene might be masked by a second normal gene. Although the normal gene should produce the expected hybridization band on a Southern blot, and this band should be less intense than if two normal genes are present, quantitative analysis by Southern blotting is difficult and only relative at best.

These problems help to explain why even though many genes and mutations have been identified as important in various diseases and genetic testing has become commonplace, thus far, relatively few diagnostic tests unequivocably diagnose disease. Identification of a specific mutation responsible for a given disease facilitates genetic testing. However, when the specific mutation is not known, direct testing is not possible. In this situation, alternative techniques such as linkage analysis may prove useful. Linkage analysis can be used in families where specific DNA sequences markers are always found in individuals with the disease, but not in those without the disease.

Difficulties involved in linkage analysis are that two or more generations of affected family members are required for study, and markers for each individual must be determined separately. Also, when a gene has a weak influence on disease expression, more families must be studied to draw meaningful conclusions. Therefore, linkage analysis cannot be performed in a single affected family member or when relatives are uncooperative.

Linkage analysis has been used in families to diagnosis Duchenne's muscular dystrophy, hemophilia, and spinal muscular atrophy. Two new methods have been developed to examine the entire genome instead of individual markers. Representational difference analysis compares the differences between two genomes, whereas genomic mismatch scanning GMS identifies identical sequences between two samples. Representational difference analysis uses hybridization techniques to pick out regions of DNA that differ from one another.

Genomic mismatch scanning screens DNA from affected relatives of unrelated families to identify similar gene sequences. These regions would be linked to the gene for the disease. These two methods offer new promise in mapping and identifying inherited disease. The ability to screen for genetic disorders raises many ethical questions, including the psychologic impact of screening on patients, consequences of results on health insurance benefits and employment, and, ultimately, decisions made that result from information obtained by prenatal screening. When screening for multiple genetic diseases becomes available, difficult decisions will be required in regard to whom to test and whether such individuals desire testing.

Information gained from screening must be used carefully and only in the appropriate context; although molecular testing may identify the presence of a defective gene, this does not prove the disease will occur, or give any insight as to the age of onset of the disease, the role the environment may play, or the severity of the disease in a specific individual.

All these issues have the potential to impact on society in terms of unemployment, education, insurance benefits, and how we view each other i. The unborn also may be affected, with results from prenatal genetic testing influencing whether a given genetic aberration is deemed acceptable, or even parents' potential desire to choose specific attributes for their offspring from hair color to intelligence to sex. Therefore, it remains imperative that, along with advances in our understanding of the human genome, work continues in the fields of ethics and sociology to help resultant new information be used in the best way possible for the overall good of humanity.

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Besides being useful in diagnosing disease, molecular biology techniques are important in disease treatment. Gene therapy can be defined as therapeutic intervention via molecular modification. Three major areas need to be addressed for gene therapy to be effective-identification of the specific gene of interest, identification and isolation of target cells for gene delivery, and determination of the method of transfer. Each of these areas will be addressed in the following section.

Before gene therapy can begin, it is important to have a comprehensive understanding of the molecular basis underlying a specific disease process. This is sometimes the most difficult aspect of gene therapy. Once a gene, or set of genes, has been determined as important in a disease, the genes must be individually cloned, including important regulatory sequences.

If the goal is simply to replace a missing gene or provide abundant amounts of a normal gene where disease occurs from abnormalities in the native gene, resulting in defective protein product function , then only the coding sequence may be required. However, regulatory sequences normally surrounding a gene of interest may be necessary for efficient RNA and protein production once the gene is transferred to a new cell. Specific promoter sequences that direct gene expression only in certain cells also may be used to target the gene to a specific tissue.

Once the gene is cloned, the next step is to identify and isolate target cells for gene delivery. Determination of a target cell or tissue for gene delivery is an important and complex task. The first cells used in gene therapy were lymphocytes. The altered lymphocytes were then reinjected into the patient, restoring partial immunity to the individual. However, this therapeutic "correction" of adenine-deaminase deficiency lasted only as long as the lymphocytes lived.

One way to circumvent this problem would be to target hematopoietic stem cells instead of lymphocytes, potentially curing the genetic disease permanently. However, stem cells only constitute a small proportion of cells in the bone marrow, are difficult to obtain, and are not readily susceptible to infection by retroviruses. Therefore, only a small subpopulation of stem cells can be altered genetically and might not be capable of producing the desired clinical effect. Another cell targeted for gene therapy is the hepatocyte.

Many genetic diseases involve the liver, including galactosemia, phenylketonuria, and familial hypercholesterolemia. Typically, hepatocytes are removed, cultured, infected with the desired gene, and then reinjected into the portal vein, where they migrate into the liver. The liver has tremendous regenerative capacity, and the new hepatocytes survive quite well once reintroduced.

However, currently, a large portion of the liver must be removed from the patient to obtain cells and to stimulate hepatocyte regeneration. In contrast to the earlier examples, not all targeted cells need to be removed from the body to be used for gene therapy. Aerosols that carry adenoviruses that contain the cystic fibrosis transmembrane receptor gene can be inhaled by patients with cystic fibrosis. Intravenous injection of a gene with a promoter that targets the specific tissue of cell of interest would be ideal, but current gene therapy technology is currently far from this ideal.

Once a gene has been identified as important in a disease, and the appropriate cell or tissue is targeted, the next step is to deliver the foreign DNA into the cell so it can be integrated into DNA in the nucleus, and ultimately expressed as the desired protein product. Transfer of DNA can occur within the patient in vivo or on living cells removed from the body ex vivo and subsequently returned to the patient. Several approaches have been taken in this regard. Transfer of DNA or RNA into cells using direct "physical" approaches microinjection, calcium phosphate precipitation, lipofection, and electroporation has been tried, with limited success.

Microinjection can be very efficient, but is extremely limited in clinical practice because of the small number of cells that can be injected. Each cell is injected individually, and for effective treatment, as many as 10 8 to 10 9 cells must be injected, a daunting task. Electroporation is a more efficient technique and uses brief, high-voltage electrical pulses to form transient nanometer-sized pores in the plasma membrane of cells; DNA directly enters the cells through these pores.

Electroporation is useful for transient expression of cloned genes and to establish cell lines with integrated copies of a given gene. Calcium phosphate precipitation is the most widely used method of cell transfection, even though its mechanism of action is not entirely clear. It is thought that the transfected DNA enters the cell by endocytosis and is then transferred to the nucleus. This method is useful, though, when large numbers of cells are required. In general, physical methods of DNA transfer do not result in integration of foreign DNA into the targeted cell's genome, which necessitates reinjection or repeat therapy.

In contrast, viruses have proved more efficient in delivering genes and stably incorporating foreign DNA into targeted cells. Advantages and disadvantages of viral transfer of DNA are explained later. Three types of viral approaches are generally used currently for gene therapy-retroviruses, adenoviruses, and adeno-associated viruses; a fourth approach herpes virus is also beginning to be examined.

Each of these viruses has distinct advantages and disadvantages in terms of gene therapy. Retroviruses are RNA viruses that produce viral DNA incorporated into the host cell genome, so any foreign DNA placed in a retrovirus should be expressed in the cell indefinitely. Retroviruses are easy to manipulate, and can infect a wide variety of cell types with a high degree of efficiency. Problems with retroviruses include the inability of the virus to accommodate large inserts of foreign DNA as well as the potential for oncogenesis due to random incorporation in the cell's genome, potentially resulting in disruption of regulatory DNA sequences required for normal cell growth.

Disrupted genes might then produce protein with abnormal activity. In addition, retroviruses can only infect replicating cells, limiting their use for in vivo treatment because most human cells are not actively replicating. In contrast to retroviruses, adenoviruses can infect nondividing cells and easily accommodate large fragments of foreign DNA. The major, current problem with using adenovirus in gene therapy is that expression of adenoviral proteins induces a vigorous host immune response, resulting in inflammation and decreased foreign gene expression.

This is the primary explanation for disappointing results in initial human trials that used adenovirus gene therapy in cystic fibrosis. However, very high titers of adenovirus were used in these trials, and newer, more highly infective and hopefully less immunogenic adenoviruses have been produced since. Only time will tell whether these newly engineered viruses will be effective in gene therapy.


Adeno-associated virus is a defective human parvovirus also capable of infecting various mammalian cells. Preliminary data suggests that this virus, like adenovirus, is capable of infecting nondividing cells. A distinct advantage with adeno-associated virus is that it expresses no viral antigens and, therefore, is nonimmunogenic. It also has never been associated with disease in humans. However, to replicate, adeno-associated viruses require a helper virus, usually adenovirus. Another difficulty with adeno-associated viruses is that only small pieces of foreign DNA can be incorporated.

The most direct method of gene transfer is simply to substitute a normal gene for an abnormal or nonfunctional gene by homologous recombination. This is analogous to organ transplantation at a molecular level. Enzymes known as site recombinases catalyze the excision and insertion of genetic material by recognizing specific nucleotide sequences.

Inserting a tissue-specific promoter with the new gene provides a method to localize the production of the gene product. Currently, this process has been successful only in cell lines and embryonic stem cells. Problems that limit the introduction of the artificial chromosome method into gene therapy include the need to identify sequences for both centromere and telomere function in mammalian cells.

Finally, in some cases, correction of a disease may not require physical transference of foreign DNA into cells. For instance, a defective gene could be bypassed by "turning on" genes that possess a similar function. One example of this approach would be the use of fetal gamma-globin genes to correct disorders of adult hemoglobin beta-chain synthesis in thalassemia and sickle cell disease.

The Recombinant DNA Advisory Committee has approved more than 60 protocols for human gene therapy, examples of which are shown in Table 2. Guidelines for clinical trials include life-threatening diseases, where current therapy is inadequate. The gene for the disease should have been isolated, cloned, and characterized. Along with continued trials to deliver the cystic fibrosis transmembrane conductance regulator gene to respiratory epithelium, trials have begun to treat alphaantitrypsin deficiency and phenylketonuria. Several approaches to cancer therapy are currently being investigated, including enhancement of the immune response to tumors, insertion of genes into tumor cells, which then invoke cell death, and methods to modify tumor suppressor genes.

It is still not clear whether it is safe to incorporate genes into nuclear DNA or whether it will ever be possible to produce stable extra chromosomes. In addition, the immune response to new gene products also needs to be evaluated. Although somatic gene therapy which affects only the individual being treated raises many ethical questions, as discussed previously, genetic modification of germ cells which affects future generations enters an entirely new realm of medical ethics.

Table 2. Current Clinical Gene Therapy Protocols. Application of Genetic Techniques to Malignant Hyperthermia. Although concepts of gene therapy and genetic testing can be simple, the actual application of these techniques to diagnose and treat human disease may be quite complicated. Malignant hyperthermia provides an example of a disease in which even identification of susceptible individuals is difficult.

Malignant hyperthermia is a clinical syndrome in which genetically susceptible individuals experience hypotension, tachycardia, skeletal muscle rigidity, metabolic acidosis, fever, and dysrrhythmias in response to inhalational anesthetics and depolarizing skeletal muscle relaxants. There is no recognizable phenotype of malignant hyperthermia-susceptible individuals, and current diagnostic tests are based on in vitro muscle contraction responses to caffeine and halothane. Difficulties with these tests include the invasiveness of the muscle biopsy required, expense of surgery and laboratory testing, and high sensitivity but low specificity.

Currently, a primary goal of malignant hyperthermia research is to develop a noninvasive, inexpensive, and accurate test for malignant hyperthermia. The primary genetic defect in malignant hyperthermia-susceptible individuals is an abnormality in the skeletal muscle release channel, the ryanodine receptor, whose gene is located in the q The most common malignant hyperthermia-susceptible mutation is a point mutation that results in a change from Arg to Cys at position of the ryanodine receptor gene.

Three other independent mutations glyarg, ilemet, arghis also have been identified, and a second malignant hyperthermia susceptibility locus has been identified and localized to the q Because known mutations account for only a small fraction of human malignant hyperthermia, the development of diagnostic tests and genetic therapy for human malignant hyperthermia will require extensive additional research. Throughout the past 20 yr, molecular biology has expanded the horizons of clinical medicine in both diagnosis and treatment.

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Maurice Green (virologist)

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