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Genetic Engineering and Biotechnology - The Promise And Progress Of Genomicmedicine

cells therapy stem human

Progress in understanding the genetic basis of disease has arrived at a rapid-fire pace. Genetic and genomic information gained from the Human Genome Project promises to revolutionize prevention and treatment of disease in the twenty-first century. Physicians will be able to accurately predict patients' risks of acquiring specific diseases and advise them of actions they may take to reduce their risks, prevent disease, and protect their health. There are equally promising therapeutic applications of genetic research including custom-tailored treatment that relies on knowledge of the patient's genetic profile and development of highly specific and effective medications to combat diseases.

According to Dave Carpenter in "Biotech: Practical Genomics" (Hospitals & Health Networks, vol. 77, no. 5, May 2003), the genomics revolution has already arrived in some U.S. hospitals. Carpenter found more than just the traditional genetic screening of newborns. He described cardiovascular patients screened via sophisticated genetic analysis technology that employs computer software to determine patients' risk of complications, such as deep-vein thrombosis (blood clots in the leg veins). For example, Aurora Health Care, which operates thirteen hospitals in Wisconsin, has partnered with a clinical genetic information systems company and a biotechnology company on an application of genetic medicine for cardiovascular care.

The Wisconsin program is on the leading edge of advanced patient-specific programs for detecting and preventing cardiovascular disease. The collaborative effort illustrates what industry observers have termed the shift from reactive patient care to predictive, preventive, and personalized care. Treatment can begin earlier and medication will be custom tailored for each patient. Physicians, administrators, and consumers anticipate that such genetic applications will prevent costly and potentially adverse surgical complications.

Molecular Farming Harvests New Drugs

Molecular farming or "biopharming"—genetically engineered crops—runs the gamut from tobacco plants harboring drugs to treat acquired immune deficiency syndrome (AIDS) to plants intended to yield fruit-based hepatitis vaccines. An example of a plant with the potential to produce a GM pharmaceutical is corn grown by researcher Andy Hiatt at his biotechnology firm Epicyte Pharmaceutical in San Diego, California. According to the article "Cures on the Cob" (Time, May 19, 2003), a human gene that codes for an antibody to genital herpes—a sexually transmitted disease that affects about sixty million Americans—is being grown in the corn plants. The biotechnology firm plans to use the corn to develop a topical gel for herpes. Epicyte is also developing plant-grown spermicide and antibodies to combat respiratory viruses, treat Alzheimer's disease, and counter Ebola, should the virus be used as a weapon in an act of bioterrorism.

Opponents term molecular farming "Pharmageddon," and environmentalists fear that the artificially combined genes will have unintended, untoward consequences for the environment. Consumer advocates, wary about the proliferation of GM foods, dread the possibility that plant-grown drugs and industrial chemicals will end up in food crops. To prevent such a scenario, the FDA issued new regulations to safeguard the food supply during the last quarter of 2003.

Preclinical Disease Detection

At the close of the twentieth century, technological advances offered opportunities to identify diseases at stages before they were visible, in terms of biochemical or symptomatic expression. Termed "preclinical detection," this ability to predict and as a result intervene to prevent or avert serious disease involves an understanding of three levels of disease detection involving genomes, transcriptomes (the transcribed messenger RNA complement), and proteomes (the full range of translated proteins).

In "Genomes, Transcriptomes, and Proteomes: Molecular Medicine and Its Impact on Medical Practice" (Archives of Internal Medicine, vol. 163, January 27, 2003), Ivan Gerling, Solomon S. Solomon, and Michael Bryer-Ash used diabetes mellitus (DM) as an example of how a common and serious medical disorder might be treated using these three levels of analysis. Gerling, Solomon, and Bryer-Ash proposed that in the foreseeable future diabetes will be described using more than simply its predominant clinical and biochemical abnormalities. Instead, it will be described in terms of molecular abnormalities. Since many different genetic defects and molecular pathways produce virtually indistinguishable clinical symptoms, disorders such as diabetes may become known as large numbers of molecularly distinct diseases with treatment targeted at the specific molecular defect causing each one.

Gerling, Solomon, and Bryer-Ash described a model in which genomic screening for type 1 DM could be instituted, followed by intervention and transcriptomic and proteomic monitoring to look for evidence of early molecular markers. They wrote that gene therapy or other targeted interventions such as immunization would likely be effective at this very early, preclinical stage of disease. They also observed that genetically based identification and classification of type 2 diabetes will be more complex than for type 1 DM because they would involve environmental influences on the transcriptome imposed by factors such as diet, obesity, and lack of exercise. Still, the authors contended that a change in the proteome of the cell that preceded metabolic abnormalities could help to formulate and administer gene-based therapy. Gerling, Solomon, and Bryer-Ash concluded that genetic information is rapidly becoming precise and detailed enough to offer physicians and patients opportunities to prevent diseases and that pre-clinical molecular defects will enable prompt initiation of individualized, genetic, and molecular-based treatment.

Genes Explain Disease and Drug Resistance, Treatment
Failures and Success

Recent research suggests that some people possess genes that enable the immune system to act unusually quickly. This may explain how about 20% of infected patients fend off or completely cure themselves of hepatitis C—a virus that causes serious and often fatal liver disease—without any medical treatment. U.S. and U.K researchers posit that a specific gene combination allows the body to quickly let loose its frontline defense—natural killer cells. Natural killer cells are continually ready to counter an invading virus. Inhibitory receptors restrain natural killer cells between infections, to ensure they do not attack healthy tissue. The researchers identified a particular gene combination that controls one inhibitory receptor, and the molecule attached to it was twice as common in recovered patients as in patients who remained infected with hepatitis C. To find the genes involved in this immune response, the researchers analyzed the DNA of 1,037 hepatitis C patients, 352 of whom spontaneously recovered. The researchers concluded that, "In the long term, whether we can use this information to modulate the body's immune system to improve therapeutics or vaccine design—that is the ultimate goal" (Salim I. Khakoo et al., "HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection," Science, August 5, 2004).

In 2004 researchers identified a set of genes linked to either resistance or sensitivity to the anticancer drugs commonly used to treat acute lymphoblastic leukemia (ALL). The researchers tested leukemia cells from 173 children newly diagnosed with leukemia for sensitivity to four chemotherapy drugs used in leukemia treatment. They found a particular group of genes that when present in leukemia cells determined their sensitivity or resistance to the drugs. The study also showed that these genes predicted treatment success or relapse in the 173 children as well as another group of ninety-eight children with leukemia who were treated with the same drugs. The researchers asserted that the presence or absence of these genes may explain why nearly 20% of children with leukemia do not respond to drug treatment (Amy Holleman et al., "Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment," New England Journal of Medicine, vol. 351, no. 6, August 5, 2004).

In the February 24, 2005, issue of the New England Journal of Medicine researchers reported that gene mutations explain why some lung cancer tumors become resistant to treatment with new cancer drugs meant to disrupt a molecular target that helps tumors grow. They found that mutations in the EGFR (epidermal growth factor receptor) gene are associated with favorable responses to treatment. They also found that the tumor stops responding to the cancer drugs if or when a secondary mutation in the same gene develops—three of six patients in the study who had this secondary mutation experienced a recurrence of their tumors. The researchers hypothesized that the anticancer drugs may give cancer cells that have the second mutation a growth advantage (Susumu Kobayashi et al., "EGFR Mutation and Resistance of Non-Small-Cell Lung Cancer to Gefitinib," New England Journal of Medicine, vol. 352, no. 8, February 24, 2005).

Human Stem Cell Research

Human stem cell research—investigations performed using embryonic and adult human stem cells that have varying degrees of "plasticity" (the potential to give rise to cells)—may be applied to address a range of medical problems. It may also be used to test new drugs. For example, new medications could be tested for safety and efficacy on differentiated cells generated from these stem cell lines, in much the same way that cancer cell lines are used to test new antitumor drugs.

The most exciting and potentially lifesaving application of human stem cells is to generate cells and tissues that may be used for cell-based therapies. Presently, donated organs and tissues are often used to replace diseased or damaged tissue, but the need for tissues and organs for transplant far exceeds the supply. Stem cells, which are able to differentiate into all cell types, present the possibility of a renewable source of replacement cells and tissues to treat a wide range of disorders such as Huntington's, Parkinson's, and Alzheimer's diseases; spinal cord injury; stroke; burns; heart disease; diabetes; and arthritis. For example, neurons could be produced to treat neurodegenerative diseases such as Parkinson's and Alzheimer's; muscle cells could be produced to treat muscular dystrophies and heart disease; and hematopoietic (blood-forming) stem cells could be produced to treat leukemias and AIDS. It is anticipated that further research into gene therapy of human stem cells during development and differentiation may result in the successful correction of a defective gene in a human stem cell, which might be applied to treat conditions such as cystic fibrosis.

Along with medical therapy, stem cells could be equally important in basic biological research such as examining the development of human and other species. Many new techniques and technologies—such as directed differentiation, gene trapping, lineage marking, cell ablation, and lineage selection—may now be applied to human cells. Using these techniques, investigators plan to create a complete gene-expression road map showing how different cell types are formed, survive, proliferate, differentiate, and migrate during development. This information will also enhance the understanding of how problems occur during embryogenesis (the development of the embryo from the fertilized egg). Additionally, it may help explain the effects of teratogens (agents that cause fetal malformations) and improve screening for new teratogens.


There are several types of stem cells. The bone marrow contains three types of stem cell populations and they are particularly desirable for stem cell research because they are readily obtained from animal and human sources and have been shown to develop into several types of cells within the body. Their replication outside the body is limited, and the most effective mode of delivery is still under investigation.

Stem cells isolated from adult human blood have demonstrated the capacity to differentiate into heart, skin, and smooth muscle cells. Researchers are investigating the optimal dose and timeframe of administration of these stem cells. Stem cells from umbilical cord blood are easily obtained, have the potential for enhanced self-renewal and differentiation, and may be stored for use at a later time.

Embryonic stem cells are the most primitive of all populations of stem cells. They can undergo an unlimited number of cell doublings and retain the capacity to differentiate into any cell type. Embryonic stem cells are not approved for use in humans, in large part because of the need to suppress recipients' immune systems to prevent rejection of the transplanted cells and the possibility of development of a teratoma (a tumor consisting of a mixture of tissues not normally found at that site). Culturing human embryonic stem cells involves generating feeder layers of animal cells, generally mouse fibroblasts and human fibroblasts, which creates the risk of contamination with pathogens (disease-causing microorganisms). The risk of contamination will likely be sharply reduced in the future. In March 2005 researchers described a new way to culture human embryonic stem cells that uses a medium that does not contain animal or human cells (Irina Klimanskaya et al., "Human Embryonic Stem Cells Derived without Feeder Cells," The Lancet, March 8, 2005). The investigators asserted that "This system eliminates exposure of human embryonic stem cells and their progeny to animal and human feeder layers, and thus the risk of contamination with pathogenic agents capable of transmitting diseases to patients." The moral, ethical, and political debates about the use of embryonic stem cells in medical research have sharply curtailed research in the United States and have inspired scientists to seek other sources of stem cells.

In February 2005 researchers at the University of California, San Diego, reported that they had found heart stem cells in human newborns, rats, and mice. In the laboratory the researchers were able to grow these stem cells into fully functioning heart cells. This discovery is promising because it means that patients might be able to receive their own cardiac stem cells to correct a range of heart diseases including infants born with heart defects (Karl-Ludwig Laugwitz et al., "Postnatal isl1+ Cardio-blasts Enter Fully Differentiated Cardiomyocyte Lineages," Nature, February 10, 2005).

Another challenge is how best to deliver stem cells to the site of an injury. If, for example, stem cells intended to help repair injury to the heart are not able to reach the site of injury they will not be able to improve heart function. Several modes of delivery have been investigated, including direct intramuscular injection to deliver the cells directly to a damaged heart muscle.

Gene Therapy

Gene therapy aims to correct defective or faulty genes by using one of several techniques. Most gene therapy involves the insertion of functioning genes into the genome to replace nonfunctioning genes. Other techniques entail swapping an abnormal gene for a normal one in a process known as homologous recombination, restoring an abnormal gene to normal function through selective reverse mutation, or changing the regulation of the gene—influencing the extent to which a gene is "turned on" or "turned off." In 2002 gene repair of faulty messenger ribonucleic acid (mRNA) was used by researchers at the University of North Carolina to treat blood disorders such as thalassemia and hemophilia as well as cystic fibrosis and some cancers. In March 2003 University of Iowa investigators reported preliminary success with a related technique, known as RNA interference or gene silencing, to turn off production of an abnormal protein involved in Huntington's disease (, October 11, 2002, and March 13, 2003).

Early work in gene therapy focused on replacing a gene that was defective in a specific well-defined genetic disease such as cystic fibrosis. Recent research has revealed that gene therapy technology may be more helpful in treating several nongenetic diseases for which there are no available effective treatments. Gene therapy clinical trials are currently underway for pancreatic cancer and sarcoma (a malignant tumor arising from nonepithelial connective tissues); end-stage (advanced) coronary artery disease, in which factors that improve blood supply to the heart may be lifesaving; and macular degeneration, for which loss of sight might be prevented.

To treat each of these disorders, the appropriate therapeutic genes are inserted by using in vivo (in a living organism, rather than the laboratory) gene therapy with adenoviral vectors. (Adenoviruses have double-stranded DNA genomes and cause respiratory, intestinal, and eye infections in humans.) A vector is a carrier molecule used to deliver the therapeutic gene to the target cells. The most frequently used vectors are viruses that have been genetically altered to contain normal human DNA. Researchers exploit viruses' natural abilities to encapsulate and deliver their genes to human cells. An unanticipated benefit of this type of gene therapy is that highly specific immunity could be induced by injecting into skeletal muscle DNA manipulated to carry a gene encoding a specific antigen. Since this form of therapy does not lead to integration of the donor gene into the host DNA, it eliminates potential problems resulting from disruption of the host's DNA, a phenomenon that was observed by FIGURE 9.6
Complex manufacture of a gene therapy product
SOURCE: Philip D. Noguchi, "Slide 7. Complexity of a Gene Therapy Product," in Simple Complexity in an Evolving World: Rising to the Challenge, U.S. Food and Drug Administration, Center for Biologic Evaluation and Research, Office of Cellular, Tissue and Gene Therapies, October 2002, (accessed March 10, 2005)
investigators using ex vivo (outside a living organism, usually in the laboratory) gene therapy. Figure 9.6 shows how ex vivo cells are used to create a gene therapy product.

Figure 9.7 shows the steps involved in gene therapy using a retrovirus as the vector. In this process the vector discharges its DNA into the affected cells, which then begin to produce the missing or absent protein and are restored to their normal state. In this example the patient's own bone marrow cells are used as the vector to deliver SCID-repaired genes (SCID is the acronym for severe combined immune deficiency) to restore the function of the immune system.

In addition to virus-mediated gene delivery, there are nonviral techniques for gene delivery. Direct introduction of therapeutic DNA into target cells requires large amounts of DNA and can be used only with certain tissues. Genes can also be delivered via an artificial lipid sphere, called a liposome, with a liquid core. This liposome, which contains the DNA, passes the DNA through the target cell's membrane. DNA can also enter target cells when it is chemically bound to a molecule that in turn binds to special cell receptors. Once united with these receptors, the therapeutic DNA is engulfed by the cell membrane and enters the target cell. In May 2002 researchers at Case Western Reserve University created tiny liposomes able to transport therapeutic DNA through the pores of the nuclear membrane. In March 2003 researchers at the University of California at Los Angeles successfully inserted genes into the brain using a liposome. This was a significant accomplishment because, FIGURE 9.7
Fundamentals of gene therapy
SOURCE: "Fundamentals of Gene Therapy," in Gene Therapy, U.S. Department of Energy Office of Science, Office of Biological and Environmental Research, Human Genome Program, October 19, 2004, (accessed March 11, 2005)
previously, viral vectors were too large to cross the "blood-brain barrier." The ability to transfer genes into the brain bodes well for patients suffering from neurological disorders such as Parkinson's disease (, May 12, 2002, and March 20, 2003).

In 1999 the death of American teenager Jesse Gelsinger after he participated in a clinical gene therapy trial for ornithine transcarbamylase deficiency shocked and saddened the scientific community and diminished enthusiasm for technology that promised that healthy genes could replace faulty ones. He died from multiple organ failures four days after beginning the treatment, and his death was attributed to a severe immune response to the adenovirus carrier. Since then other adverse outcomes have been reported. In 2002 an international team of scientists reported curing a child with severe combined immunodeficiency using gene therapy (Judy Siegel-Itzkovich, "Scientists Use Gene Therapy to Cure Immune Deficient Child," British Medical Journal, vol. 325, no. 7,354, July 2, 2002). The child spent the first seven months of her life inside a plastic bubble to protect her from all disease-causing agents because she totally lacked an immune system. After suppressing her defective bone marrow cells, the researchers introduced, using a genetically engineered virus, a healthy copy of the gene she was missing (for adenosine deaminase) into her purified bone marrow stem cells. The baby recovered quickly; within a few weeks she was no longer in isolation and went home well. Researchers credited the gene alteration treatment with the cure.

Unfortunately, two other children with similar conditions who received comparable gene therapy subsequently developed conditions resembling leukemia. As a result, in January 2003 the FDA temporarily stopped all gene therapy trials using retroviral vectors in blood stem cells. The FDA reconvened its Biological Response Modifiers Advisory Committee in February 2003 to determine whether to permit retroviral gene therapy trials for treatment of life-threatening diseases to proceed with additional safeguards. The Committee indefinitely suspended such trials and as of March 2005 they have not resumed in the United States.

In October 2004 the Biological Response Modifiers Advisory Committee was renamed the Cellular, Tissue, and Gene Therapies Advisory Committee to describe more accurately the areas for which the committee is responsible. The FDA described the function of the renamed committee as evaluating "data relating to the safety, effectiveness, and appropriate use of human cells, human tissues, gene transfer therapies, and xenotransplantation products." Xenotransplantation is any procedure that involves transplantation, implantation, or infusion into a human recipient of live cells, tissues, or organs from a nonhuman animal source; or human body fluids, cells, tissues, or organs that have had any contact with live nonhuman animal cells, tissues, or organs. It has been used experimentally to treat certain diseases such as liver failure and diabetes, where there are insufficient human donor organs and tissues to meet demand.

In the United States the FDA and the National Institutes of Health (NIH) jointly oversee regulation of human gene therapy. The FDA focuses on ensuring that manufacturers produce quality, safe gene therapy products and that these products are adequately studied in human subjects. The NIH evaluates the quality of the science involved in human gene therapy research and funds the laboratory scientists involved in development and refinement of gene transfer technology and clinical studies.


In September 2004 the FDA granted Acuity Pharmaceuticals permission to conduct the first human test of RNA interference (called RNAi) on patients suffering from macular degeneration—a deterioration of the retina that is the leading cause of blindness in older adults. The disease was chosen because the RNA can be directly injected into the eye, overcoming problems associated with delivering the RNA to the affected cells. Although RNAi has demonstrated efficacy in the laboratory, it is not yet known whether it will work in people. Other techniques once considered promising ways to turn off genes have not produced effective drugs. Other companies are investigating the use of RNAi to treat Huntington's and Parkinson's diseases, hepatitis C, and HIV, the virus that causes AIDS. In an article in the New York Times, Natasha Caplen, a gene therapy expert with the National Cancer Institute, said the FDA had not yet determined how it would regulate RNAi drugs. Until such regulations are in place, companies will be unable to begin clinical trials (Andrew Pollack, "Method to Turn Off Bad Genes Is Set for Tests on Human Eyes," New York Times, September 14, 2004).

In December 2004 investigators in the United Kingdom reported successful gene therapy to correct the cause of X-linked severe combine immunodeficiency (SCIDX1) and restore immunity. Bone-marrow stem cells were infused with human gamma-c cloned into an ape gamma-retroviral vector and then returned to the young patients, who ranged in age from four to thirty-three months. The investigators concluded that "gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity" (H. Bobby Gaspar et al., "Gene Therapy of X-Linked Severe Combined Immunodeficiency by Use of a Pseudotyped Gammaretroviral G-vector," The Lancet, vol. 364, no. 9,462, December 18, 2004). By March 2005 eighteen cases of SCID had been treated with a retroviral-mediated gene-transfer protocol and, of these, seventeen realized clear and lasting health benefits.

Genetically Enhanced Athletes

In the article "Gene Therapy May Be Up to Speed for Cheats at 2008 Olympics" (Nature, vol. 414, no. 6,864, December 6, 2001), David Adams reported that gene therapy may enable athletes to genetically modify themselves to boost their performances. Athletes might target performance-enhancing genes such as those encoding growth factors capable of building muscle strength or widening blood vessels, or a hormone called erythropoietin that increases the number of oxygen-carrying red blood cells. Furthermore, the researchers Adams interviewed said such modifications might be impossible to detect and that artificial genes "can and most likely will be abused by healthy athletes as a means of doping." The International Olympic Committee has established an advisory group to monitor progress in gene therapy and to prevent a GM athlete from competing in the 2008 Olympic Games in Beijing.

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