Medical Frontiers -- Old and New

The Amish, who don't like drawing attention to themselves, were featured in two articles about medicine in the New York Times this week. One was titled "5 cases of Polio in Amish Group Raise New Fears" and is about the emergence of polio in a rural Minnesota community. The other, "A Doctor for the Future", Dr. Holmes Morton's work with rare genetic diseases at his Pennsylvania clinic. His group researchs and treats patients in the Amish and Mennonite communities in Lancaster County. The two stories show the promises and hopes of medical technology on one hand, and the eternal frustrations of bringing the promises to fruition for patients on the other.

Old Scourges

Health officials were surprised recently, to discover a case of polio in the U.S., where the last known of polio was 10 years ago, a case of vaccine derived polio (VDPV) in an immunocompromised patient. The World Health Organization (WHO) had set a goal to rid the world of polio in 1988. It's a difficult goal and the deadline is often frustrated, it was last moved to December, 2005, which will again be pushed back. Acronym Required wrote about the Global Polio Eradication Initiative last June. At that time, the December deadline was threatened by a polio strain from Africa that was detected in patients in new outbreaks in Yemen and Indonesia. Epidemiologists theorized that the African strain was given the opportunity to spread when several African countries stopped immunizations.

The Minnesota strain was recently isolated from stool samples of a hospitalized baby girl is a oral polio vaccine (OPV) derived strain that researchers estimate has been around for 2 years. Subsequently more children in the small Amish community have been tested and found to carry the same strain. Since OPV has not been used in the U.S. for 5 years and in Canada since 1997, its origin is still unknown.

After World War II, the thinking was that all disease epidemics could be stopped with widespread vaccinations, as well as antibiotics, sanitation, and pesticides. Specific to vaccination goals, there are well understood physical challenges to reaching outlying communities in order to give the vaccines. On top of those logistical challenges, some citizens are suspicious of vaccinations and link them to autism, despite the fact that the link has been routinely negated by research. Others, like some African communities, suspect that vaccines are given for malevolent purposes like sterilization -- they refuse to take them. These sporadic individual and community decisions give diseases the opportunity to find a host and spread through immunocompromised or unvaccinated individuals.

The history of successful vaccination efforts - for example smallpox, polio, and measles - proves that vaccinations can be the silver bullet of preventative medicine. However while vaccines confer immunity, worldwide education to maintain a critical mass of vaccinated individuals has proven challenging and increasing travel between populations heightens the risks of leaving some groups unvaccinated. Since the most devastating diseases like malaria and AIDS often gain a foothold because of public health and challenges to long term population behavior change, vaccines seem like the only feasible way to get ahead of the diseases. But vaccination success is just as accutely tied to population behaviors (albeit to a lesser extent), as the polio cluster in Minnesota shows. Even as the global vaccination goal of the polio initiative seems within our grasp, it remains elusive.

New Technology

While old scourges linger, the forefront of medicine promises that the new DNA sequencing techniques will give us unprecedented understanding of disease and ultimately lead to cures based on sequencing data. The doctors who treated the Amish were interested in working with the population because of the high incidence of rare metabolic and genetic diseases. For instance, Type I glutaric aciduria is an autosomal recessive disease that effects fewer then 100 people in the U.S. The mutation on chromosome 19 results in the replacement of one amino acid for another in the production of the glutaryl-CoA enzyme. This mutation in turn disables the ability of the body to metabolize two essential amino acids, lysine and tryptophan, with potentially devastating consequences to the affected starting in infancy. Management of various phenotypic manifestations is difficult, and requires strict dietary restrictions and periodic crisis management that has historically failed to stem progressive cognitive and physical damage.

The low incidence of the mutation makes the disease difficult to study because of limited available funding as well as a limited patient population. Disease clusters like this one in the Amish in Pennsylvania give researchers a significant population to study and the results can lead to progress in understanding the disease. For instance, with Huntington's disease, by studying families that were significantly affected in places where the mutation was found frequently, like Mauritius, researchers were able to determine the genetic mutation and as a result awareness, research and funding benefited from the knowledge.

Type I glutaric acidosis is linked to a single gene mutation, which looks like a good target for gene therapy. The molecular biology and biochemical tools used by the researchers in Lancaster County to research the disease offer far more sophisticated diagnostics then the techniques used in the painstaking work of decades ago. However while diagnostic efforts via technology progressed quickly relative to historic efforts, clinical treatment was slower. The doctors were thwarted in their attempt to enroll some of their patients into clinical trials because of medical safety concerns with gene therapy. Their trials were disallowed, because the treatment they were going to use apparently looked too similar to gene therapy.

While the new technology and genetic techniques didn't pan out as the researchers imagined, the group learned to manage the disease in ways that assure lower morbidity and mortality. The New York Times wrote that Dr. Morton realized that the future of "genetic medicine" was not on the horizon, but in his office, and he began working with the treatments he had, dietary supplementation, and attention to detecting disease early in order to interfere with catabolic processes that wreaked havoc on patients. He worked within the limits of cultural boundaries and mores, with technology that was in his lab.

Gene therapy arrived on the clinical scene with much fanfare and might expectations that far outweighed its proven potential. As clinical trials faltered, it then was roundly denounced by the press. Gene therapies are not the ballyhooed cure that they were made out to be before their clinical trials, but the technologies still offer much hope. The techniques will perhaps change, improve, and at times seem to sputter, but this type of research always takes longer then some are willing to admit.

As with gene therapies, vaccines hold the promise that once devastating disease will be history. Along with smallpox and polio, measles is another example of a disease that no longer affects people in western countries. The WHO announced this week that there has been a 60% reduction in cases in Africa. That's progress. However for many reasons; the cost of treating the last unvaccinated patients, suspicion about technology, or - conversely - overconfidence in technology, many diseases for which we have vaccines continue to thrive. Many other diseases, especially bacterial infections have acquired resistance against antibiotics. Infectious disease will always demand vigilance.

While we implicitly depend on technology to propel medicine to new frontiers of health, technology is no replacement for public health vigilance on the part of governments, physicians, communities and individuals. We need to continue to work with the simple tools we have at hand, although they may seem imperfect, while we pursue the horizons that technologists evangelize.


Update: CNN reports in "Polio Gone In 10 African Countries" that 10 of the 18 countries that had reported outbreaks since 2003 had been polio-free since June according to the WHO. Polio has been endemic in Nigeria, India, Pakistan, Niger, Afghanistan and Egypt since 2003. In addition polio has been reintroduced in Angola, Ethiopia, Eritrea, Nepal, Somalia and Sudan, plus the 8 African countries that are now once again polio-free, Indonesia and Yemen. In all countries except Angola, the strain was from Nigeria and related to that country's boycott of the vaccine.

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