By David N. Leff
Babies are born naked - inside and out.
That is, from a newborn's mouth, designed for suckling and yelling, to its anal aperture, intended for excretion, its food-processing digestive tract is lined with a moist smooth mucous layer of seamless epithelial cells. A parallel airway passage - which handles breathing - runs from mouth and nose to lungs. And the male and female internal and external reproductive organs are similarly surfaced, as is the neonate's baby skin. They all serve as barriers, defending the helpless newcomer against the pathogens of the cruel world out there.
"There are certain times in a human being's life," observed molecular biologist Michael Zasloff, "when these barrier defenses are down, and that human in consequence is potentially susceptible to a bacterial invasion. This, for example, is the situation in the newborn infant. The neonate has not yet acquired the strong barrier defenses that it will have some days later. It is very likely, for this reason, that children die of infectious diarrhea throughout the world, particularly the third world."
Zasloff is the founder and a director of Magainin Pharmaceuticals Inc. in Plymouth Meeting, Pa. "Over the last 15 years," he recalled, "we've come to realize that all animals must live in harmony, in some way, with the microbes in their environment. To achieve this relationship, we humans have evolved very powerful chemical defenses, which include antimicrobial peptides, such as defensins, in our body.
"When our epithelia are assaulted, when bacteria try to invade them, when we are wounded, these surfaces have the capacity to produce more of these defensive substances that man the first-line immune defense barricade."
Wanted: New Tool To Control Innate Immunity
"Five or six years ago," Zasloff recounted, "we at Magainin began a search for substances that could stimulate these barrier defenses, and in principle permit them to do pharmacologically what normally takes place following bacterial invasion. At the end of this study, we came across a variety of substances, which had this property of stimulating epithelial cells in a test system to produce antibacterial peptides. Among them, we discovered the essential amino acid, isoleucine."
Zasloff and his colleagues at Magainin report this finding in the current online issue of the Proceedings of the National Academy of Sciences (PNAS), dated Nov. 7, 2000.
"One of our initial motivations," he told BioWorld Today, "was to find something that could actually be used to boost the barrier defenses of babies. And we believe that a molecule, like isoleucine - which is a safe foodstuff that really falls into the category of a nutraceutical - potentially fulfills that role. We see a place for its application, for example, in the very early pediatric period, at home and in Third World countries.
"Another immediate application of isoleucine," he continued, "would be directed to the food-supply industry, primarily to those interested in animal husbandry. At the present time," he pointed out, "antibiotics as food supplements are being taken off the U.S. market - for example, recently in chickens. These are much more extensively prohibited in Europe.
"We don't really know why antibiotics are given to poultry - how they work when added to their feed - but they definitely provide a growth advantage. As a consequence, there's a great commercial need, or pressure, on the use of antibiotics for this purpose. For the past two years we have been exploring, with a number of companies, the feasibility of introducing isoleucine into the poultry food supply as an alternative to oral antibiotics as feed supplements. There's a major commercial need right now for some such substitution. It's our expectation that by stimulating the gut and airway to produce antimicrobial substances, we will give the chickens the selective advantage that antibiotics have formerly provided. I view it as a new direction in the treatment or prevention of infectious diseases."
Zasloff made the point, "Isoleucine will kill and eliminate many of the bad microbes in the environment. In contrast, it spares the good microbes - notably the Lactobacillus and Bifidobacteria of yogurt - which begin to predominate in the population of organisms in contact with our epithelia. And, in addition, these good microbes themselves stimulate the system to produce more of those antibiotic defenses."
Vagina To Gums To Borscht
"We will soon see it evaluated," he continued, "in such human health care products as vaginal agents to treat a sexually transmitted disease [STD]. That is, we see it as a substance - and this has yet to be proven - that could find use as a peculiar type of microbicide to prevent STDs, and it would be doing so by boosting the barrier defenses of the vaginal wall. The Population Council, in New York, along with Magainin, is planning a clinical trial that will involve the addition of isoleucine to an HIV microcidal vaginal gel. That trial is imminent; we are in its fairly late-stage planning. Because isoleucine is a food, basically - rated by the FDA as GRAS [generally recognized as safe] - it has fewer complexities in its development than a drug would have. So we don't really worry about its absorption.
"I'm sure it will also find use in oral health care," Zasloff added. "The gingiva of our gums have surfaces that are in contact with microorganisms, and restoring the normal flora that we were designed, to some extent, to live with, I think can be accomplished through the application of isoleucine."
Zasloff made an added point: "Nobody knows why, but isoleucine - along with a few other amino acids - is not made in the mammalian body, and must be recovered from the outside. It can come from a plant that other animals have gathered from the food chain. But isoleucine per se," he noted, "is an essential amino acid. It is not a part of a protein, but free isoleucine. When isoleucine is present in our digestive tract, it means that it has come from an external source, derived from a food that has been ingested. Most foods have isoleucine in them as protein.
"It occurs," he observed, "believe it or not, in beets. So borscht - widely eaten in many parts of the world - actually contains free isoleucine."