Biotechnology tools and techniques open new research avenues for discovering how healthy bodies work and what goes wrong when problems arise. Knowing the molecular basis of health and disease leads to improved methods for treating and preventing diseases. In human health care, biotechnology products include quicker and more accurate diagnostic tests, therapies with fewer side effects and new and safer vaccines.
We can now detect many diseases and medical conditions more quickly and with greater accuracy because of new, biotechnology-based diagnostic tools. A familiar example of these benefits is the new generation of home pregnancy tests that provide more accurate results much earlier than previous tests. Tests for strep throat and many other infectious diseases provide results in minutes, enabling treatment to begin immediately, in contrast to the two- or three-day delay of previous tests.
Biotechnology also has created a wave of new genetic tests. Today there are almost 1,000 such tests, according to genetests.org. Many of those tests are for genetic diseases, while others test predisposition to disease. Emerging applications include tests to predict response to medicines and assist with nutritional planning.
Biotechnology has lowered the costs of diagnostics in many cases. A blood test developed through biotechnology measures low-density lipoprotein ("bad" cholesterol) in one test, without fasting. We now use biotechnology-based tests to diagnose certain cancers, such as prostate and ovarian cancer, by taking a blood sample, eliminating the need for invasive and costly surgery.
In addition to diagnostics that are cheaper, more accurate and quicker than previous tests, biotechnology is allowing us to diagnose diseases earlier in the disease process, which greatly improves a patient's prognosis. Proteomics researchers are discovering molecular markers that indicate incipient diseases before visible cell changes or disease symptoms appear. Soon physicians will have access to tests for detecting these biomarkers before the disease begins.
The wealth of genomics information now available will greatly assist doctors in early diagnosis of hereditary diseases, such as type I diabetes, cystic fibrosis, early-onset Alzheimer's Disease, and Parkinson's Disease-ailments that previously were detectable only after clinical symptoms appeared. Genetic tests will also identify patients with a predisposition to diseases, such as various cancers, osteoporosis, emphysema, type II diabetes and asthma, giving patients an opportunity to prevent the disease by avoiding triggers such as diet, smoking and other environmental factors.
Biotechnology-based diagnostic tests are not only altering disease diagnosis but also improving the way health care is provided. Many tests are portable, so physicians conduct the tests, interpret results and decide on treatment literally at the patient's bedside. In addition, because many of these diagnostic tests are based on color changes similar to a home pregnancy test, the results can be interpreted without technically trained personnel, expensive lab equipment or costly facilities, making them more available to poorer communities and people in developing countries.
Physicians will someday be able to immediately profile an infection being treated and, based on the results, choose the most effective antibiotics. But the human health benefits of biotechnology detection methodologies go beyond disease diagnosis. For example, biotechnology detection tests screen donated blood for the pathogens that cause AIDS and hepatitis.
Biotechnology will make possible improved versions of today's therapeutic regimes as well as innovative treatments that would not be possible without these new techniques. Biotechnology therapeutics approved by the U.S. Food and Drug Administration (FDA) to date are used to treat many diseases, including leukemia and other cancers, anemia, cystic fibrosis, growth deficiency, rheumatoid arthritis, hemophilia, hepatitis, genital warts, and transplant rejection.
The therapies discussed below share a common foundation. All make use of biological substances and processes designed by nature. Some use the human body's own tools for fighting infections and correcting problems. Others are natural products of plants and animals. The large-scale manufacturing processes for producing therapeutic biological substances also rely on nature's molecular production mechanisms.
Here are just a few examples of the types of therapeutic advances biotechnology now makes feasible.
USING NATURAL PRODUCTS AS THERAPEUTICS
Many living organisms produce compounds that have therapeutic value for us. For example, many antibiotics are produced by naturally occurring microbes, and a number of medicines on the market, such as digitalis, are made by plants. Plant cell culture, recombinant DNA technology and cellular cloning now provide us with new ways to tap into natural diversity.
As a result, we are investigating many plants and animals as sources of new medicines. Ticks and bat saliva could provide anticoagulants, and poison-arrow frogs might be a source of new painkillers. A fungus produces a novel, antioxidant enzyme that is a particularly efficient at mopping up free radicals known to encourage tumor growth. ByettaTM (exenatide), an incretin mimetic, was chemically copied from the venom of the gila monster and approved in early 2005 for the treatment of diabetes. PRIALT® (ziconotide), a recently approved drug for pain relief, is a synthetic version of the toxin from a South Pacific marine snail.
The ocean presents a particularly rich habitat for potential new medicines. Marine biotechnologists have discovered organisms containing compounds that could heal wounds, destroy tumors, prevent inflammation, relieve pain and kill microorganisms. Shells from marine crustaceans, such as shrimp and crabs, are made of chitin, a carbohydrate that is proving to be an effective drug-delivery vehicle.
REPLACING MISSING PROTEINS
Some diseases are caused when defective genes don't produce the proteins (or enough of the proteins) the body requires. Today we are using recombinant DNA and cell culture to produce the missing proteins. Replacement protein therapies include
factor VIII-a protein involved in the blood-clotting process, lacked by some hemophiliacs.
insulin-a protein hormone that regulates blood glucose levels. Diabetes results from an inadequate supply of insulin.
USING GENES TO TREAT DISEASES
Gene therapy presents an opportunity using DNA, or related molecules such as RNA, to treat diseases. For example, rather than giving daily injections of missing proteins, physicians could supply the patient's body with an accurate instruction manual-a nondefective gene-correcting the genetic defect so the body itself makes the proteins. Other genetic diseases could be treated by using small pieces of RNA to block mutated genes.
Only certain genetic diseases are amenable to correction via replacement gene therapy. These are diseases caused by the lack of a protein, such as hemophilia and severe combined immunodeficiency disease (SCID), commonly known as the "bubble boy disease." Some children with SCID are being treated with gene therapy and enjoying relatively normal lives, although the therapy has also been linked to leukemia. Hereditary disorders that can be traced to the production of a defective protein, such as Huntington's disease, may be best treated with RNA that interferes with protein production.
Medical researchers also have discovered that gene therapy can treat diseases other than hereditary genetic disorders. They have used briefly introduced genes, or transient gene therapy, as therapeutics for a variety of cancers, autoimmune disease, chronic heart failure, disorders of the nervous system and AIDS.
In late 2003, China licensed for marketing the first commercial gene therapy product, Gendicine, which delivers the P53 tumor suppressor gene. The product treats squamous cell carcinoma of the head and neck, a particularly lethal form of cancer. Clinical trial results were impressive: Sixty-four percent of patients who received the gene therapy drug, in weekly injections for two months, showed a complete regression and 32 percent attained partial regression. With the addition of chemotherapy and radiation, results were improved greatly, with no relapses after three years.
Approximately 18 people die each day waiting for organs to become available for transplantation in the United States. To circumvent this problem, scientists are investigating ways to use cell culture to increase the number of patients who might benefit from one organ donor. Liver cells grown in culture and implanted into patients kept them alive until a liver became available. In one study of patients with type 1 diabetes, researchers implanted insulin-producing cells from organ donors into the subjects' livers. Eighty percent of the patients required no insulin injections one year after receiving pancreatic cells; after two years, 71 percent had no need for insulin injections. In another study, skeletal muscle cells from the subject repaired damage to cardiac muscle caused by a heart attack.
Drugs for suppressing the immune response must be given if the transplanted cells are from someone other than the patient. Researchers are devising new ways to keep the immune system from attacking the transplanted cells. One method being used is cell encapsulation, which allows cells to secrete hormones or provide a specific metabolic function without being recognized by the immune system. As such, they can be implanted without rejection. Other researchers are genetically engineering cells to express a naturally occurring protein that selectively disables immune system cells that bind to it.
Other conditions that could potentially be treated with cell transplants are cirrhosis, epilepsy and Parkinson's Disease.
STIMULATING THE IMMUNE SYSTEM
The immune system is made up of different branches, each containing different types of "soldiers" that interact with each other in complex, multifaceted ways.
For example, the cytokine branch, which stimulates other immune system branches, includes the interleukins, interferons and colony-stimulating factors-all of which are proteins. Because of biotechnology, these proteins can now be produced in sufficient quantities to be marketed as therapeutics. Small doses of interleukin-2 have been effective in treating various cancers and AIDS, while interleukin-12 has shown promise in treating infectious diseases such as malaria and tuberculosis.
Researchers can also increase the number of a specific type of cell, with a highly specific function, from the cellular branch of the immune system. Under certain conditions, the immune system may not produce enough of the cell type a patient needs. Cell culture and natural growth factors that stimulate cell division allow researchers to provide or help the body create the needed cell type.
Cancer vaccines that help the immune system find and kill tumors have also shown therapeutic potential. Unlike other vaccines, cancer vaccines are given after the patient has the disease, so they are not preventative. They work by intensifying the reactions between the immune system and tumor. Despite many years of research, cancer vaccines have not yet emerged as a viable strategy to fight cancer. Nonetheless, researchers are optimistic that this kind of approach to battling cancer would be a major improvement over the therapies used today.
SUPPRESSING THE IMMUNE SYSTEM
In organ-transplant rejections and autoimmune diseases, suppressing our immune system is in our best interest. Currently we are using monoclonal antibodies to suppress, very selectively, the type of cell in the immune system responsible for organ-transplant rejection and autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Patients given a biotechnology-based therapeutic often show significantly less transplant rejection than those given cyclosporin, a medicine that suppresses all immune function and leaves organ-transplant patients vulnerable to infection.
Inflammation, another potentially destructive immune system response, can cause diseases, such as ulcerative colitis. Two cytokines, interleukin-1 and tumor necrosis factor, stimulate the inflammatory response, so a number of biotechnology companies are investigating therapeutic compounds that block the actions or decrease production of these cytokines.
Organ transplantation provides an especially effective treatment for severe, life-threatening diseases of the heart, kidney and other organs. According to the United Network of Organ Sharing (UNOS), in the United States more than 92,000 people were on organ waiting lists as of May 19, 2006.
Organs and cells from other species-pigs and other animals-may be promising sources of donor organs and therapeutic cells. This concept is called xenotransplantation.
The most significant obstacle to xenotransplantation is the immune system's self-protective response. When nonhuman tissue is introduced into the body, the body cuts off blood flow to the donated organ. The most promising method for overcoming this rejection may be various types of genetic modification. One approach deletes the pig gene for the enzyme that is the main cause of rejection; another adds human genetic material to disguise the pig cells as human cells.
The potential spread of infectious disease from other species to humans through xenotransplantation needs close attention. However, a 1999 study of 160 people who had received pig cells as part of treatments showed no signs of ill health related to this exposure. In addition, scientists have succeeded at deleting the gene that triggers immune activity from a type of pig that cannot be infected with the virus that causes the most concern.
USING BIOPOLYMERS AS MEDICAL DEVICES
Nature has also provided us with biological molecules that can serve as useful medical devices or provide novel methods for drug delivery. Because they are more compatible with our tissues and our bodies absorb them when their job is done, they are superior to most man-made medical devices or delivery mechanisms.
For example, hyaluronate, a carbohydrate produced by a number of organisms, is an elastic, water-soluble biomolecule that is being used to prevent postsurgical scarring in cataract surgery, alleviate pain and improve joint mobility in patients with osteoarthritis and inhibit adherence of platelets and cells to medical devices, such as stents and catheters. A gel made of a polymer found in the matrix connecting our cells promotes healing in burn victims. Gauze-like mats made of long threads of fibrinogen, the protein that triggers blood clotting, can be used to stop bleeding in emergency situations. Adhesive proteins from living organisms are replacing sutures and staples for closing wounds. They set quickly, produce strong bonds, and are absorbed.
In the future, our individual genetic information will be used to prevent disease, choose medicines and make other critical decisions about health. This is personalized medicine, and it could revolutionize healthcare, making it safer, more cost-effective and, most importantly, more clinically effective.
Pharmacogenomics is a key term, referring to the use of information about the genome to develop drugs. Pharmacogenetics is also used to describe the study of the ways genomic variations affect drug responses.
The variations affecting treatment response may involve a single gene (and the protein it encodes) or multiple genes/proteins. For example, some painkillers work only when body proteins convert them from an inactive form to an active one. How well these proteins do their jobs varies considerably between people. As another example, tiny genetic differences can change how statin drugs work to lower blood cholesterol levels.
Biotechnology researchers are interested in the use of gene-based tests to match patients with optimal drugs and drug dosages. This concept of personalized medicine-also called targeted therapy-is beginning to have a powerful impact on research and treatment, especially in cancer.
The biotech breast cancer drug Herceptin® is an example of a pharmacogenomic drug. Initially approved in 1998, Herceptin® targets and blocks the HER2 protein receptor, which is overexpressed in some aggressive cases of breast cancer. A test can identify which patients are overexpressing the receptor and can benefit from the drug.
New tests have been launched recently that identify patients likely to respond to Iressa®, Tarceva®, Gleevec® and Campath®, and patients developing resistance to Gleevec®. Tests are available to choose the correct dosage of a powerful chemotherapy drug for pediatric leukemia-the tests have saved lives by preventing overdose fatalities.
One of the most exciting new tests is Genomic Health's Oncotype DXTM, which examines expression of 21 genes to quantify risk of breast cancer recurrence and predict the likelihood that chemotherapy will benefit the patient. Impressed with the product's results in recent studies, the NIH in May 2006 launched a large new study called TAILORx (Trial Assigning Individualized Options for Treatment [Rx]) that will utilize Oncotype DXTM to predict recurrence and assign treatment to more than 10,000 women at 900 sites in the United States and Canada.
Many more pharmacogenomic cancer products-both medicines and tests-are in development. In fact, oncology may be entering an era when cancer treatment will be determined as much or more by genetic signature than by location in the body.
The idea is simple, but the project is monumental, given the variety of genetic tools cancer cells use to grow, spread and resist treatment. The National Institutes of Health in December 2005 announced it was taking on this challenge through The Cancer Genome Atlas. The project aims to map all gene variations linked to some 250 forms of cancer, not only the variations that help cause cancer, but also those that spur growth, metastasis and therapeutic resistance.
In December 2004, the FDA approved Roche and Affymetrix's AmpliChip® CYP450 Genotyping Test, a blood test that allows physicians to consider unique genetic information from patients in selecting medications and doses of medications for a wide variety of common conditions such as cardiac disease, psychiatric disease, and cancer.
The test analyzes one of the genes from the family of cytochrome P450 genes, which are active in the liver to break down certain drugs and other compounds. Variations in this gene can cause a patient to metabolize certain drugs more quickly or more slowly than average, or, in some cases, not at all. The specific enzyme from this family that is analyzed by this test, called cytochrome P4502D6, plays an important role in the body's ability to metabolize some commonly prescribed drugs including antidepressants, anti-psychotics, beta-blockers, and some chemotherapy drugs.
AmpliChip® was the first DNA microarray test to be cleared by the FDA. A microarray is similar to a computer microchip, but instead of tiny circuits, the chip contains tiny pieces of DNA, called probes.
RACE- AND GENDER-BASED MEDICINE
In 2005, the FDA for the first time approved a drug for use in a specific race: BiDil®, a life-saving drug for heart failure in black patients. In the 1990s, the drug had failed to beat placebo in a broad population but showed promise in African Americans. Further testing confirmed those results.
Although BiDil® thus far is the only drug to win a race-based approval, it's far from unique in its differential effects across populations. Many drugs, including common blood-pressure medicines and antidepressants, exhibit significant racially correlated safety and efficacy differences.
For example, in a large study of one of the most common blood pressure medications, Cozaar®, researchers found a reduced effect in black patients-a fact that has been added to the prescribing information for the drug. Interferon, likewise, appears to be less effective in blacks with hepatitis than non-Hispanic white patients (19 percent vs. 52 percent response rate), according to a recent study in the New England Journal of Medicine.
One such study found Japanese cancer patients are three times more likely to respond to Iressa®, apparently because of a mutation in a gene for the drug's target, epidermal growth factor receptor.
Genetic variations-mutations that affect drug receptors, pathways and metabolizing enzymes-are thought to underlie most of the racial, ethnic and geographic differences in drug response, making the field ripe for biotech-style personalized medicine. NitroMed, for example, is collecting genetic material with the hope of developing a test to identify all patients-irrespective of race-likely to respond to BiDil®.
Some companies are exploring the concept of gender-based medicine to take into account the differences in male and female response to medicine. Aspirin, for example, prevents heart attacks in men but not in women. At least one biotech company is developing a lung cancer drug that shows greater promise in women.
Biotechnology permits the use of the human body's natural capacity to repair and maintain itself. The body's toolbox for self-repair and maintenance includes many different proteins and various populations of stem cells that have the capacity to cure diseases, repair injuries and reverse age-related wear and tear.
Tissue engineering combines advances in cell biology and materials science, allowing us to create semi-synthetic tissues and organs in the lab. These tissues consist of biocompatible scaffolding material, which eventually degrades and is absorbed, plus living cells grown using cell culture techniques. Ultimately the goal is to create whole organs consisting of different tissue types to replace diseased or injured organs.
The most basic forms of tissue engineering use natural biological materials, such as collagen, for scaffolding. For example, two-layer skin is made by infiltrating a collagen gel with connective tissue cells, then creating the outer skin with a layer of tougher protective cells. In other methods, rigid scaffolding, made of a synthetic polymer, is shaped and then placed in the body where new tissue is needed. Other synthetic polymers, made from natural compounds, create flexible scaffolding more appropriate for soft-tissue structures, like blood vessels and bladders. When the scaffolding is placed in the body, adjacent cells invade it. At other times, the biodegradable implant is seeded with cells grown in the laboratory prior to implantation.
Simple tissues, such as skin and cartilage, were the first to be engineered successfully. Recently, however, physicians have achieved remarkable results with a biohybrid kidney that maintains patients with acute renal failure until the injured kidney repairs itself. A group of patients with only a 10 to 20 percent probability of survival regained normal kidney function and left the hospital in good health because the hybrid kidney prevented the events that typically follow kidney failure: infection, sepsis and multi-organ failure. The hybrid kidney is made of hollow tubes seeded with kidney stem cells that proliferate until they line the tube's inner wall. These cells develop into the type of kidney cell that releases hormones and is involved with filtration and transportation. In addition to carrying out these expected metabolic functions, the cells in the hybrid kidney also responded to signals produced by the patient's other organs and tissues.
The human body produces an array of small proteins known as growth factors that promote cell growth, stimulate cell division and, in some cases, guide cell differentiation. These natural regenerative proteins can be used to help wounds heal, regenerate injured tissue and advance the development of tissue engineering described in earlier sections. As proteins, they are prime candidates for large-scale production by transgenic organisms, which would enable their use as therapeutic agents.
Some of the most common growth factors are epidermal growth factor, which stimulates skin cell division and could be used to encourage wound healing; erythropoietin, which stimulates the formation of red blood cells and was one of the first biotechnology products; fibroblast growth factor, which stimulates cell growth and has been effective in healing burns, ulcers and bone and growing new blood vessels in patients with blocked coronary arteries; transforming growth factor-beta, which helps fetal cells differentiate into different tissue types and triggers the formation of new tissue in adults; and nerve growth factors, which encourage nerve cells to grow, repair damage and could be used in patients with head and spinal cord injuries or degenerative diseases such as Alzheimer's Disease.
Vaccines help the body recognize and fight infectious diseases. Conventional vaccines use weakened or killed forms of a virus or bacteria to stimulate the immune system to create the antibodies that will provide resistance to the disease. Usually only one or a few proteins on the surface of the bacteria or virus, called antigens, trigger the production of antibodies. Biotechnology is helping us improve existing vaccines and create new vaccines against infectious agents, such as the viruses that cause cervical cancer and genital herpes.
BIOTECHNOLOGY VACCINE PRODUCTION
Most of the new vaccines consist only of the antigen, not the actual microbe. The vaccine is made by inserting the gene that produces the antigen into a manufacturing cell, such as yeast. During the manufacturing process, which is similar to brewing beer, each yeast cell makes a perfect copy of itself and the antigen gene. The antigen is later purified from the yeast cell culture. By isolating antigens and producing them in the laboratory, it is possible to make vaccines that cannot transmit the virus or bacterium itself. This method also increases the amount of vaccine that can be manufactured because biotechnology vaccines can be made without using live animals.
Using these techniques of biotechnology, scientists have developed antigen-only vaccines against life-threatening diseases such as hepatitis B and meningitis.
Recently researchers have discovered that injecting small pieces of DNA from microbes is sufficient for triggering antibody production. Such DNA vaccines could provide immunization against microbes for which we currently have no vaccines.
Biotechnology is also broadening the vaccine concept beyond protection against infectious organisms. Various researchers are developing vaccines against diseases such as diabetes, chronic inflammatory disease, Alzheimer's Disease and cancer.
VACCINE DELIVERY SYSTEMS
Whether the vaccine is a live virus, coat protein or a piece of DNA, vaccine production requires elaborate and costly facilities and procedures. And then there's the issue of injections, which can sometimes be painful and which many patients dislike. Industrial and academic researchers are using biotechnology to circumvent both of these problems with edible vaccines manufactured by plants and animals.
Genetically modified goats have produced a possible malaria vaccine in their milk. Academic researchers have obtained positive results using human volunteers who consumed hepatitis vaccines in bananas, and E. coli and cholera vaccines in potatoes. In addition, because these vaccines are genetically incorporated into food plants and need no refrigeration, sterilization equipment or needles, they may prove particularly useful in developing countries (see also "Plant-Made Pharmaceuticals").
Researchers are also developing skin patch vaccines for tetanus, anthrax, influenza and E. coli.
The flexibility provided by biotechnology presents many opportunities for using plants in new ways. Advances in biotechnology have made it possible to genetically enhance plants to produce therapeutic proteins essential for the production of a wide range of pharmaceuticals-such as monoclonal antibodies, enzymes and blood proteins.
Plant-made pharmaceutical production is regulated under stringent requirements of the U.S. Department of Agriculture (USDA) and the Food and Drug Administration (FDA). The primary agency that regulates and monitors this technology is USDA's Animal and Plant Health Inspection Service (APHIS). APHIS requires companies to obtain permits for field trials for therapeutic protein production. The agency announced new permit conditions in March 2003. Prior to issuing a test permit, APHIS reviews all plans for seed production, timing of pollination, harvest, crop destruction, shipment, confinement, and the storage and use of equipment. Permits are issued for the importation, interstate movement and field testing of the plants. Field sites are inspected at least five times in a single growing season by APHIS or state officials, with those inspections corresponding to critical times in production, such as preplanting site location evaluation, planting, midseason, harvesting and postharvesting.
In 2004, 16 federal permits for growing plant-made pharmaceuticals were issued in 18 states governing 24 field sites for a total of 277 acres.
Therapeutic proteins produced by transgenic plants to date include antibodies, antigens, growth factors, hormones, enzymes, blood proteins and collagen. These proteins have been grown in field trials in a wide variety of plants, including alfalfa, corn, duckweed, potatoes, rice, safflower, soybeans and tobacco. Field trials with protein-producing plants are providing the essential building blocks for innovative treatments for diseases such as cancer, HIV, heart disease, diabetes, Alzheimer's disease, kidney disease, Crohn's disease, cystic fibrosis, multiple sclerosis, spinal cord injuries, hepatitis C, chronic obstructive pulmonary disease, obesity and arthritis.
In addition, scientists have made excellent progress in using plants as vaccine-manufacturing and delivery systems. They have used tobacco, potatoes, tomatoes and bananas to produce experimental vaccines against infectious diseases, including cholera, a number of microbes that cause food poisoning and diarrhea (e.g., E. coli and the Norwalk virus), hepatitis B and the bacterium that causes dental cavities. A cancer "vaccine" (which is therapeutic and not preventative) to non-Hodgkin's lymphoma has also been produced in plants.
Since most proteins cannot be chemically synthesized, there are very few options for protein production for pharmaceutical purposes: mammalian and microbial cell cultures and plants. More than $500 million and five years are required to build a facility for mammalian cell cultures. Using plants to produce therapeutic proteins lowers facility and production costs associated with plant-made pharmaceuticals.
One of the companies developing plant-produced antibodies estimates that this production method is 25 to 100 times less expensive than cell-fermentation methods. Standard fermentation methods can produce 5 to 10 kilograms of a therapeutic antibody per year, while this company reports that it can produce 10,000 kilograms of monoclonal antibodies per year. Using plants as factories to produce therapeutic proteins also enables researchers to develop novel and complex molecular forms that could not normally be grown in mammalian cell cultures.
Because protein-producing plants require relatively little capital investment, and the costs of production and maintenance are minimal, they may provide the only economically viable option for independent production of therapeutic proteins in underdeveloped countries.