Rethinking Thalidomide
New research indicates that the controversial drug thalidomide, which caused severe birth deformities when taken as a sedative and hypnotic by pregnant women in the 1960s, may be useful in treating diseases that cause blindness.
Robert D'Amato, a researcher at the Children's Hospital at Harvard Medical School, came across thalidomide while searching for drugs to treat two diseases that cause blindness, macular degeneration and diabetic retinopathy. Both diseases cause excess growth of blood vessels which burst in the eye and destroy vision.
D'Amato, an ophthalmologist with a Ph.D. in neuroscience, said that in looking for a drug that stops blood vessel growth, or an angiogenesis inhibitor, he realized such a drug would have left a trail of clues. It occurred to him that an angiogenesis inhibitor would cause menstrual periods to stop, as well as cause birth defects. He conducted a medical literature search for drugs that caused these side effects, and hit upon thalidomide. "Thalidomide was one drug that fit the profile, because it had the appropriate side effects for an angiogenesis inhibitor," he said.
Eyes on thalidomide. New research suggests the drug may be used to treat diseases such as macular degeneration.
D'Amato theorized that the reason thalidomide causes birth defects is that it acts during angiogenesis to affect blood vessels of fetuses. He said that for 30 years, scientists had been trying to figure out how thalidomide affects fetuses, but no one had studied blood vessels. It has only been in the last 10 years that scientists have been able to grow blood vessels in cultures to study them. D'Amato set out to prove that thalidomide is indeed an angiogenesis inhibitor, and as such may present a possible treatment for macular degeneration and diabetic retinopathy.
Diabetic retinopathy results from high blood sugar levels that lead to a scarcity of blood in the retina. To compensate, the retina produces factors that encourage blood vessels to grow into a tangled mass, interfering with vision. The disease can be treated with lasers, which burn away the excess vessels, but only if the vessels haven't reached the retina.
Macular degeneration, which mostly affects people over the age of 65, results from a blood vessel growing under the macula, the center of the retina, that blocks vision. Some cases can be alleviated by treating the blood vessel from the side with a laser, but the process still affects vision.
D'Amato teamed up with Michael Loughnan, an Australian ophthalmologist, to test thalidomide on rabbits. They surgically implanted a substance that encourages blood-vessel growth in a pocket of the rabbits' corneas, causing a stream of vessels to grow across the cornea. The researchers then administered thalidomide and various compounds of thalidomide orally, to see if any of the drugs could halt the blood-vessel growth. The only successful compounds were the ones that inhibited blood vessel growth and caused birth defects, thus supporting D'Amato's theory. D'Amato said that thalidomide alone worked the best to halt blood vessel growth. The eyes of the rabbits that were given thalidomide had only a scattering of blood vessels around the growth pocket.
Since this discovery in December 1992, the researchers have conducted tests on mice and found similar results. The FDA granted D'Amato approval for clinical trials to begin in January 1995. The researchers will test men and postmenopausal women with macular degeneration. D'Amato said results will not be seen for at least a year. If the tests prove successful, however, a widespread treatment for macular degeneration would most likely be available around January 1996.
And, if the tests go well, the researchers would then begin testing thalidomide for treatment of diabetic retinopathy. However, D'Amato said they would first test diabetic men only. If success is seen in the male diabetics, they will begin testing women. D'Amato said, "If we were going to use thalidomide in premenopausal women, we would have to be assured that they wouldn't get pregnant."
D'Amato said the reaction to the new therapy has been tremendous. "The idea of taking a pill to relieve this is novel," he said.
Fighting for Air
Air pollution must be turned into the public nemesis that cigarette smoking has become. This underlying tenet from a conference sponsored by the National Association of Physicians for the Environment (NAPE) on November 18 will be developed into a major public education campaign targeting both the scientific community and the public.
In fact, much of the material for NAPE's anti-air pollution campaign will be drawn from the November conference detailing the impact of air pollution on body organs and systems. During that conference, scientific experts warned that lack of overt symptoms does not mean lack of adverse effects, and that the ravages of air pollution are not limited to the respiratory tract. "It's not just the lungs and lower respiratory tract, but also the eyes, the ears, the nose, and the skin that are exposed to environmental pollution," noted conference chair G. Richard Holt, who is also chair of NAPE's air pollution committee. Hearing loss, for example, may be linked to toxic materials such as heavy metals, and exposure to certain hydrocarbons can lead to smell and taste dysfunction. High levels of ozone and other air pollutants can result in both cancerous and noncancerous mucosal lesions. Humans are climbing up the ladder leading to severe physical effects from air pollution, warned Richard Trevino, president of the American Academy of Otolaryngic Allergy, and the absence of identifiable symptoms should not be a source of comfort.
Conference speakers were unanimous in calling for more research into the adverse effects of air pollution--both subtle and direct--and in urging the medical profession to become more attuned to the possibility of pollution as the cause of patient distress. Trevino, for example, said he believes air pollution is directly responsible for the rising incidence of hay fever, not only irritating the nasal mucosa but also making people more susceptible to allergens and toxicants. Data have been collected from numerous sites linking increased asthma incidence with rises in ground-level ozone concentrations.
The effects of air pollution are often hidden, insidious, and long-term, speakers pointed out during the conference. Lowell Goldsmith, chair of the American Academy of Dermatology's Environment Committee, said even the morning shower is not risk-free. Goldsmith has calculated that showering with chlorinated water leads to inhalation of chloroform, which causes cancer in animals, at levels that exceed current EPA standards. Fortunately, he added, most people don't spend extended periods of time showering. Air pollutants may also be absorbed by the body and recycled, in essence, later in life. Joan McGowan, chief of the bone biology and bone diseases branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, reported that as women enter menopause, the process of bone remodeling in which calcium and minerals are released by bone speeds up. Along with calcium, heavy metals such as lead that have been stored in bone may also be released by bone back into body systems.
A major concern of the conference was the effect of air pollution on special populations such as women, the poor, minorities, and children--populations often ignored in research. Citing a need for environmental justice, NIEHS Director Kenneth Olden said the institute has commissioned special studies to focus on health problems among the poor that might be linked to air pollution. The poor, he noted, tend to live in inner-city areas where pollutants are concentrated or work in argicultural areas where direct exposure to pesticides, herbicides, and fertilizers is prevalent.
Terri Damstra, associate director for international programs at NIEHS, pointed out that toxins which imitate estrogens, such as DDT, dioxin, and PCBs, are ubiquitous in the environment. These compounds, which have been associated with cancers and with breast, uterine, and bone disease, are disbursed in the atmosphere and subsequently enter the food chain. Damstra said 90% of the PCBs in the Great Lakes come directly from the atmosphere. Kathy Bryant, associate director of government relations for the American College of Obstetricians and Gynecologists, noted that these estrogen imitators are stored primarily in fat, and may have a disproportionate effect on women because women naturally have higher percentages of body fat than do men. Bryant called for an interagency review at the federal level to examine risk-assessment policy and its impact on women's health.
Animals and plants are not spared the devastating effects of pollution, according to one session at the conference. Acid rain, ground-level ozone concentrations, and other ambient air toxins are depleting the world of 50,000 plant species annually, destroying nature's ecological balance and narrowing forever the array of plants that might produce beneficial pharmaceuticals, warned Christopher T. Moore, chair of the environmental council of the Wilderness Medical Society. Air pollution knows no political boundaries, Moore pointed out, and even the most pristine areas show signs of environmental distress.
Included in the NAPE campaign's arsenal will be white papers, "scientific position" papers and educational videos that describe the impact of air pollution on each body organ and system. "The same tools that were used successfully against cigarette smoking--research, public health education, and advocacy--can be used against air pollution," urged conference co-chair Alfred Munzer, former president of the American Lung Association.
NAPE, organized just two years ago, has grown to include dozens of medical and environmental organizations, as has the worldwide affiliate it helped to organize, the International Society of Doctors for the Environment. In April NAPE will sponsor a conference on biodiversity loss, and subsequent plans include a conference addressing the impact of water pollution on body organs that parallels the air pollution conference.
Safe to Eat
Last September, the U.S. General Accounting Office released two reports that called for restructuring the federal food safety system. The reports cited extensive problems with the current system of monitoring amounts of unsafe chemical residues and environmental contaminants in food. Among GAO's findings are inconsistencies in assessing chemical risks and lack of prosecutions for violations of chemical limits in food.
Food feud. Two GAO reports call for restructuring the federal food safety system, but industry disputes the findings.
The FDA, the USDA, and the EPA all share the responsibility for monitoring chemicals that enter the food supply. These include chemical residues that result from the use of pesticides, animal drugs, and food additives, as well as environmental contaminants, such as lead and mercury, that enter the food supply through their occurrence in the environment, naturally or as a result of pollution. The agencies' responsibilities include approving food-use chemicals before they can be used; sampling and testing food products to ensure their safety, or end-product testing; and taking regulatory actions when violations occur.
The GAO examined the federal programs and identified several fundamental weaknesses. First, the efforts to determine the risks of chemicals are inconsistent because the agencies do not assess risks in the same way. Therefore, they may arrive at different risk estimates for the same chemical.
The GAO found that the USDA's National Residue Program, which is supposed to ensure that hazardous levels of drugs, pesticides, and other industrial chemicals do not contaminate meat and poultry, is inadequate because testing is not comprehensive and the methodology for collecting samples is flawed. The Food Safety and Inspections Service (FSIS), within the USDA, administers the program, which is designed to identify and select chemicals that could pose human health hazards, conduct residue tests in poultry and meat for those chemicals, and take enforcement action against those who market products containing dangerous levels of the chemicals. FSIS receives assistance from the EPA, which establishes residue limits and provides information on pesticides approved for domestic use, and the FDA, which does the same for approved animal drugs. FSIS collects samples of meat and poultry from slaughter plants and U.S. ports of entry and analyzes them. Any violations are referred to the FDA for investigation and enforcement action.
The GAO found that FSIS does not adjust its testing for imported meat and poultry to include problems with heavy metal residues or animal drugs and pesticides not allowed in the United States but used by exporting nations. Thus, FSIS does not know the extent to which potentially harmful residues may or may not exist in imported meat and poultry. Also, said GAO, FSIS does not always have complete information on chemicals that are not used in the United States or on new chemicals that are created each year.
The GAO also examined the input from the EPA and the FDA and found that these agencies are not able to provide all the information and assistance the FSIS needs for the program. One problem is that questions have been raised about the health and environmental effects of many of the pesticides previously approved by the EPA, as well as about the regulatory limits set for their residues in foods. The EPA is reevaluating these pesticides, but it estimates that it will not complete the reregistration process until 2006.
The GAO also points out that problems exist with the FDA's handling of violations due to limited resources and legislative restrictions. The FDA investigated only about 20% of the 21,439 violations that the FSIS reported to it from 1989 to 1992. Only one prosecution resulted from these investigations.
Rather than improving the current system, the GAO suggested that an alternative regulatory system for meat and poultry be developed. The report discussed an industry-operated risk-based system, overseen and monitored by the federal government. The GAO made other recommendations for the current food safety system, but the office feels that a better approach is for Congress to create a single agency responsible for carrying out a cohesive set of food safety laws.
The GAO obtained comment from the USDA, EPA, and HHS, as well as two industry trade groups that represent over 80% of the meat and poultry industry. All agreed that a process-oriented, risk-based approach that tries to prevent residue problems from occurring would be more effective than the current system that relies on limited testing of end products to detect residues.
The GAO also found problems with the regulatory laws because of inconsistencies within the overall federal structure and systems for controlling chemicals in all foods. For example, chemicals posing similar risks are in some cases regulated differently under different laws. Also, the laws do not require periodic reevaluations of compounds against the most current scientific standards, nor do the laws specifically require the agencies to monitor environmental contaminants in food.
The GAO also concluded that end-product testing and interagency referrals cannot detect and prevent contaminated food products from entering the food supply and do not effectively penalize violators and deter future violations. The GAO says that agencies do not have enough resources to effectively carry out end-product testing, which requires extensive resources to obtain comprehensive information on chemicals and develop test methods to detect all chemicals of concern.
To mitigate the problems with the current fragmented system, the GAO recommends that Congress enact uniform food safety laws that resolve differences in chemical standards and provide agencies with adequate oversight authorities, as well as direct agencies to develop systems that prevent problems, rather than simply identify them. The report also recommends that Congress should require that all foods eligible for import be produced under equivalent food safety systems.
The GAO received comments on these recommendations for changes in the system from USDA, the Department of Commerce, EPA, and FDA. USDA and the Department of Commerce generally concurred with GAO's recommendations. The EPA disagreed with the recommendation that a single food safety agency is needed and suggested that an interagency council be created instead. FDA did not concur with the report, saying that the information is outdated and does not support the conclusions and recommendations. However, the GAO said in response to FDA's comments that the information in the report was compiled from reports issued from 1990 to 1994.
The reports, "USDA's Role under the National Residue Program Should Be Reevluated" and "Changes Needed to Minimize Unsafe Chemicals in Food," were requested by the Subcommittee on Human Resources and Intergovernmental Relations of the House Committee on Government Operations.
French Fry Fuel
French fry grease and potatoes may fuel trucks and buses in the future. Research by the University of Idaho and the J.R. Simplot Company, which producers french fries in Idaho, is examining the possible use of waste vegetable oil and fermented waste potatoes to fuel diesel engines.
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Fries to go. Waste french fry oil may become a fuel of the future. |
The idea of recycling the waste of french fry plants into fuel sprang from 20 years of research at the University of Idaho. Researchers at the university have been investigating the use of waste vegetable oil as an alternative fuel since, "back in the energy crisis days," said Charles Peterson, a professor of agricultural engineering and a researcher at the university. Researchers speculate that the diesel fuel substitute, called biodiesel, could alleviate the country's reliance on imported oil. They estimate that converting 10% of America's cropland to the production of biodiesel could provide all the diesel fuel used in U.S. agriculture.
In addition, the environmental benefits of biodiesel are numerous, and research at the university has found that it is much more environmentally friendly than diesel. Use of vegetable oil and alcohol-based fuels could lead to a zero net gain in oxides of carbon emissions, scientists say, because they are part of the natural cycle of assimilation of carbon dioxide by plants for growth and development. Also, because vegetable oil has negligible levels of sulfur, its emissions of sulfur dioxide are lower than those of diesel fuel, thus reducing the potential for acid rain.
Biodiesel has also been found to be less threatening to the environment and wildlife than diesel in the case of spills. The fuel is biodegradable and breaks down quickly, preventing long-term damage to soil and water. Tests show that water bugs that succumbed to only minimal diesel spills survived biodiesel spills 70 times greater, Peterson said.
In addition, the production of biodiesel could help with another environmental problem: crowded landfills. Excess waste oils and animal fats generated from various plants and companies could be used in creating fuel, rather than taking up space in landfills.
Converting vegetable oil to biodiesel involves a process called transesterification. This process uses alcohol, methanol, or ethanol, in the presence of a catalyst such as sodium hydroxide or potassium hydroxide, to chemically break the molecule of the raw vegetable oil into a methyl or ethyl ester of vegetable oil and glycerol. Researchers at the University of Idaho have been successful in producing biodiesel from raw vegetable oil, and are now looking at using waste vegetable oil, such as that used in the production of french fries.
If they can develop a fuel that is comparable to the biodiesel made from raw vegetable oil, the Simplot Company will look at marketing and selling the product. According to Paul Mann, Simplot's manager of production planning and ethanol sales, the company began talking to the university researchers about a year ago. Simplot seemed like a good candidate for manufacturing biodiesel because it produces waste vegetable oil and ethanol, both of which are needed in transesterification.
The waste vegetable oil that is left over after producing french fries has been sold for use in cattle feed or pet food, Mann said. The ethanol is produced by grinding the waste starchy parts of the potato solids and fermenting them, and is also sold, he said.
Both the waste oil and the ethanol currently have markets, so they are not ending up in landfills. If they could be used in the production of biodiesel, Simplot may agree to change their current uses in order to serve a better purpose, Mann said.
Mann said that the company's original concern was whether there would be a market for biodiesel. However, after looking at the research and discussing the possibilities, Mann said he and others have decided that most likely, "if it could be made, it could be sold." One of the problems that the company would face in trying to sell the fuel is its high price tag, which is due to production costs and feedstock costs, or costs of the materials needed for production, according to Mann.
But much more research needs to be done before these issues are decided. Simplot will continue to follow the research on biodiesel, while the University of Idaho tries to work out the problems. Mann said the major problem the researchers now face involves the differences between raw vegetable oil and waste vegetable oil. He said that the oil used in the production of french fries is chemically modified in its raw state in order to raise its melting point, thus improving its ability to cook french fries. At the same time, this chemical modification also raises the oil's cloud point, the temperature at which solids begin to form. This poses a problem when used in biodiesel, because the fuel has to be kept at a certain temperature to prevent it from crystallizing. If the fuel has a high cloud point, it will crystallize at low temperatures during the winter. Researchers are now trying to lower the cloud point of the biodiesel made from waste vegetable oil.
If Simplot markets biodiesel, the company would focus on the environmental benefits of the fuel, marketing it for use by trucks, buses, and heavy machinery in environmentally sensitive or smog-prone areas. The success of biodiesel would depend on whether potential consumers believe the environmental benefits outweigh the costs. New air quality regulations and national mandates are being introduced that urge government and industry to begin using alternative fuels. Such regulations could raise interest in biodiesel. Because of the high price, however, biodiesel would probably not be sold at the corner pump, Mann said. Simplot will await the outcomes of this research before making any decisions about investment. "We're not going to jump in with both feet tomorrow," Mann said. "But it could be an opportunity in the future because we do have two of the major ingredients."
The Waning War on Cancer
The ongoing war on cancer, declared by President Nixon in 1971, needs to be revitalized or it will be lost, says a subcommittee of the National Cancer Advisory Board. Unless changes are made in the current strategy, cancer will become the nation's top killer in just five years, the subcommittee says.
The subcommittee to evaluate the National Cancer Program (NCP) prepared a report at the request of Congress members, who wanted to know why cancer is still on the rise, despite spending more than $23 billion on cancer research since 1971. The report outlined a strategy to renew the war and recommend direction for the NCP. "We have a schizophrenic system," said Paul Calabresi, chair of the National Cancer Advisory Board. "New direction is urgently needed."
The subcommittee identified several problems with current efforts to fight cancer. One problem is that despite the progress that has been made in cancer research, many researchers do not have the money to convert their breakthroughs in the lab into treatment. Also, the subcommittee said that half of all cancer patients could be cured if their tumors were discovered early enough, but 38 million uninsured Americans do not get routine cancer tests.
The major changes that the subcommittee recommends for the program include the establishment of a cabinet-level cancer director, universal access to cancer treatment, sufficient financing for cancer research, and an end to government support of tobacco, which the National Cancer Institute says causes one-third of all cancer deaths.
In the report, "Cancer at a Crossroads: A Report to Congress for the Nation," the subcommittee recommended that three major goals be pursued in fighting cancer: applying current knowledge about cancer prevention and care to all people; increasing support for translational research that develops basic cancer knowledge into preventive strategies, new technologies, and effective treatments; and increasing support for basic cancer research to maintain excellence and accelerate progress.
To reach these goals, the subcommittee said that six major issues must be addressed. The report identifies each of the issues and advises Congress how to address each one. First, the subcommittee points out that current health care reform proposals are devastating to the war on cancer because they deny resources for research and quality cancer care. To address this issue, the report says, Congress should include universal access to cancer care coverage in any health care reform plan that includes quality preventive, diagnostic, treatment, and rehabilitative services, including services provided in qualified clinical trials.
Second, the report says, the NCP suffers from an absence of coordination of cancer-fighting efforts in the public, private, and voluntary sectors. The 1971 National Cancer Act that established the NCP also mandated that the director of the National Cancer Institute develop a coordinated cancer research program encompassing the NCI programs, related programs of other research institutes, and other federal and nonfederal programs. But several years later, the responsibility for federal and nonfederal programs was taken from the NCI director and given to the general authorities of all national research institutes. The subcommittee feels that the scope of the NCP includes all nonresearch, nongovernmental, and community constituents who have an impact on cancer. The subcommittee recommends that Congress reestablish the 1971 legislative authority for coordinating the NCP and implement coordination of research and cancer care activities throughout the public, private, and voluntary sectors.
The third issue that the subcommittee points out is that many people currently receive inadequate cancer care, especially the poor, elderly, and uninsured. The subcommittee advises Congress to stabilize and strengthen the research infrastructure and cancer care delivery system, including NCI-designated cancer centers, community clinical oncology programs, and clinical trials cooperative groups.
Fourth, the report says that current laws, public policy, and governmental regulation undermine cancer prevention, treatment, and control efforts. Among such regulations are those regarding clinical trial design, the approval process for additional uses of established cancer therapies, and excessive documentation requirements, all of which discourage industry from undertaking anticancer drug and technology development. Also, the subcommittee says there is a lack of appreciation of the potential hazards of environmental and food source contaminants and that laws, policies, and regulations protecting and promoting tobacco use worsen the cancer problem and drive up health care costs. The subcommittee advises Congress to change such policies and industry practices.
The fifth issue that the subcommittee says warrants attention is that a failure to support translational research, which converts research findings into cancer care products and services, hinders the development of cancer-fighting advances. The subcommittee advises Congress to strengthen essential mechanisms, funding, and other support for translational research.
Finally, the subcommittee identifies current investment as insufficient to capitalize on unprecedented opportunities in basic science research. These opportunities have become available as a result of an ongoing revolution in molecular and cellular biology and offer the possibility to lead to a better understanding of the process of cancer development. In addition, the subcommittee says that inadequate resources now jeopardize continued basic science discoveries. The subcommittee advises Congress to intensify support for basic research to identify the mechanisms of cancer onset and spread, which are the foundation for future cancer preventive and therapeutic advances.
Dioxin Review Blues
The document itself was more than three years in the making, and it looks as if finding a review panel for the EPA's reassessment of dioxin could also become a marathon process. Efforts to appoint a balanced panel are being stymied by the recusals of panel members concerned about potential conflicts of interests.
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Mystery member. EPA's committee on environmental health effects of dioxin is looking for a few good men and women. |
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According to Sam Rondberg, executive secretary of the EPA's Science Advisory Board (SAB), which is responsible for filling the two committees-exposure and environmental health effects- that will review the dioxin reassessment, the problem is finding scientists to fill the growing number of vacancies on the environmental health effects committee left by members who have recused themselves from the review. Said Rondberg, "These people have taken very public positions on [dioxin] and they feel it would be improper for them to review the document." For example, Frederica Perera, the chair of the standing environmental health effects committee, has declined to participate because she sits on the board of the Natural Resources Defense Council which has legal actions pending against the EPA concerning dioxin. Although there is no a legal conflict of interest, Perera stated in her letter of recusal that she wished to avoid such a perception. Said Perera, "This is particularly important in light of the difficulty previous committees have encountered in achieving consensus on the health risks of dioxin."
Apparently many others share Perera's sentiments. Committee members Richard Monson of the Harvard School of Public Health, Donald Mattison of the University of Pittsburgh, and Michael Gallo of the Robert Wood Johnson Medical School in New Jersey have all declined to participate because of their public stands on dioxin. Ironically, Gallo and Mattison have gone so far as to sign a letter, along with many other leading dioxin researchers from outside government, criticizing the lack of outside scientists in the development of the risk characterization portion of the reassessment and calling for "careful scrutiny by the scientific community" of these conclusions. Commenting on the letter, Rondberg said that these scientists clearly want a careful review of the risk assessment, "they just don't want to be the ones doing it for the agency."
An impartial panel may be all but impossible, given that most of the country's dioxin experts were involved in some way in producing the eight "State of the Science" chapters of the reassessment. In fact, some committee members, including George Lucier, the federal liaison consultant to the committee, have declined to participate on the basis of their active involvement in preparing the document. The SAB is aiming instead for a balance of positions among reviewers that should deflect some potential criticism by proponents on both sides of the dioxin debate.
According to Rondberg, a factor that may help establish the credibility of the committee's review is a clear and specific charge. Unfortunately, until a committee chair is recruited, completion of the draft charge will be delayed. Rondberg said, however, that the committee is considering 1012 major issues for the review panel to consider, including toxic equivalency factors and the question of mass balance in terms of exposure.
Rondberg said the SAB is hoping to have a public meeting in March at which the exposure and environmental health effects committees will meet to review the reassessment. After this meeting, a report will be prepared and circulated for comment, and, after being finalized, it will be sent to the EPA administrator.
Mismatch Mania
Scientists are excited about recent studies on mismatch repair. No, it's not a new method for regrouping stray socks from the dryer. Mismatch repair is one of the two major types of DNA repair pathways. Researchers are studying mismatch repair for clues about how this process operates and about the consequences of repair pathway breakdown.
During mismatch repair, errors that occur while DNA is being replicated, including mismatched nucleotides, are fixed. Mismatch repair occurs in species from bacteria to humans. In fact, scientists have found that the proteins encoded by mismatch repair genes are similar throughout the evolutionary chain. Recognition of this similarity and subsequent research on the bacteria Escherichia coli led to the discovery that mutations in the DNA repair genes of humans can cause hereditary nonpolyposis colon cancer (HNPCC), one of the most common hereditary cancers. HNPCC may account for as many as 15% of the 20,000 cases of colon cancer in the United States every year.
Recently, Thomas Kunkel and colleagues at the NIEHS found evidence that, although mismatch repair systems among species may be similar, humans may have a far more advanced repair pathway. Kunkel's group looked specifically at a phenomenon called microsatellite instability. Microsatellite DNA is made up of short sequences of nucleotide bases repeated throughout a person's genome. These sequences may vary in length from person to person, but they should be the same within one individual. In HNPCC tumors, however, microsatellite DNA varies in length within the same person. Errors may occur during replication of DNA when the two strands of DNA fail to line up directly, resulting in a new strand that is longer or shorter than the old one and a new double-stranded molecule with a small loop of unpaired DNA. Because microsatellite instability is one of the defects mismatch repair is supposed to correct, researchers believe mutations in mismatch repair genes may be responsible for this alteration in genes, eventually leading to tumor formation.
In E. coli, researchers have found that mismatch repair cannot correct microsatellite defects of more than four consecutive unpaired bases. In humans, microsatellite DNA may result in far more than four unpaired DNA loops. Kunkel's group was interested in seeing whether human mismatch repair genes can repair DNA containing more than four unpaired nucleotides. Kunkel found that in at least one colorectal carcinoma cell line, extracts repaired DNA containing loops of 5, 8, or 16 unpaired bases, although the same extracts did not correct loops of four or less unpaired bases, suggesting that humans may have a far more evolved system for repairing DNA than other species. Researcher Richard Fishel of the University of Vermont in Burlington said in a November 4 article in Science that evolution of such a repair system "makes a lot of sense from an organism's standpoint. Since the bacterial genome has very few of these [larger loop] repeats, the bacterial enzyme doesn't have to recognize these errors." According to Kunkel, mutant cell lines that are defective in some but not all forms of loop repair probably exist, since quantitative and qualitative differences in stability of microsatellite alleles are found in a variety of tumor cell lines. Further identification of specific alleles of mismatch repair genes might prove useful in future studies of individual tumor susceptibility.
Last Update: April 21, 1998