Several previous studies have linked ingestion of red meat to cancer and heart disease, and possibly to some disorders involving inflammation. However, that research has primarily focused on the role of red-meat saturated fats and on products that arise from cooking. The UCSD study is the first to investigate human dietary absorption of a cell-surface molecular sugar called N-glycolylneuraminic acid (Neu5Gc), which is found in non-human mammals. Not produced in humans, Neu5Gc occurs naturally in lamb, pork and beef, the so-called "red meats". Levels are very low or undetectable in fruits, vegetables, hen's eggs, poultry and fish. (see * below)
Conducting laboratory studies with human tissue, followed by tests in three adult subjects, the UCSD team provided the first proof that people who ingest Neu5Gc absorb some of it into their tissues. In addition, they demonstrated that many humans generate an immune response against the molecule, which the body sees as a foreign invader.
The study's senior author, Ajit Varki, M.D., UCSD professor of medicine and cellular and molecular medicine, and co-director of the UCSD Glycobiology Research and Training Center, said that although it is unlikely that the ingestion of Neu5Gc alone would be primarily responsible for any specific disease, "it is conceivable that gradual Neu5Gc incorporation into the cells of the body over a lifetime, with subsequent binding of the circulating antibodies against Neu5Gc (the immune response), could contribute to the inflammatory processes involved in various diseases."
He added that another potential medical barrier related to Neu5Gc might occur in organ transplantation.
"Over the past decade, the number of patients waiting for organ transplantation has more than tripled, with little increase in the number of donor organs. This has led to an exploration of using animal organs for transplantation into humans, a process called xenotransplantation," Varki said. "However, the leading donor candidate is the pig, an animal in which Neu5Gc happens to be very common. The current study raises the possibility that human antibodies against Neu5Gc might recognize the Neu5Gc in the pig organ and facilitate its rejection."
In describing the research approach taken by his team, Varki explained that humans do not produce Neu5Gc because they lack the gene responsible for its production.** And yet, other researchers have reported small amounts of Neu5Gc in human cancer tissues.
To verify the existence of Neu5Gc in human cancers, Varki's collaborator, Elaine Muchmore, M.D., UCSD professor of medicine and associate chief of staff for education at the San Diego VA Healthcare System, developed an antibody that would be attracted by, and bind to Neu5Gc on tissue samples. The antibody was purified by Pam Tangvoranuntakul, B.S., the study's first author and a Ph.D. student in Varki's lab.
Working with Nissi Varki, M.D., UCSD professor of pathology and medicine, Tangvoranuntakul found that the antibody stained not only human cancers, but also some healthy human tissues. They found that small amounts of Neu5Gc were present in blood vessels and secretory cells, such as the mucous membranes. A further chemical analysis by Sandra Diaz, a Varki research associate, confirmed the presence of Neu5Gc in human tissue.
Meanwhile, an analysis of healthy human tissue by postdoctoral fellow Pascal Gagneux, Ph.D., and Tangvoranuntakul determined that most people had circulating antibodies in the blood that recognized Neu5Gc, and thus could potentially initiate an inflammatory immune response.
In the absence of any known molecular mechanism that would produce Neu5Gc in humans, the group reasoned that the small amounts of Neu5Gc found in human tissue could arise from human ingestion of Neu5Gc in dietary sources. Postdoctoral fellow Muriel Bardor, Ph.D., showed that when human cells in culture were exposed to Neu5Gc, they easily absorbed and incorporated it onto their own surfaces.
However, to study the possibility of dietary absorption, it was necessary to carry out an ingestion study in healthy people. Because the researchers were hesitant to give a potentially harmful substance to humans, Ajit Varki volunteered to be the first subject, followed by Muchmore and Gagneux.
When the three volunteers drank Neu5Gc purified from pork sources and dissolved in water, there were no immediate ill effects. An analysis of the volunteers' urine, blood, serum (the clear liquid that can be separated from clotted blood), hair and saliva, both before ingestion and regularly for several days after, determined that the human body eliminates most of the Neu5Gc, but retains and metabolically absorbs small amounts of the foreign sugar. At approximately two days following ingestion, the Neu5Gc levels were two to three times the baseline level prior to ingestion. By four to eight days following ingestion, the levels had dropped nearly to baseline.
The authors cautioned that a causal relationship between Neu5Gc expression in human tissues with any human disease would be premature and scientifically speculative at best. Instead, they said their findings point to the need for population-level analyses of the presence of Neu5Gc in human tissues in relationship to disease incidence, and the mechanisms of human incorporation and antibody response against this sugar.
The study was supported by grants to Varki from the National Institutes of Health (NIH) and the G. Harold and Leila Y. Mathers Charitable Foundation. Some human studies were done in the UCSD General Clinical Research Center, which is also supported by the NIH.
Questions about the study should be sent to Dr. Ajit Varki via email to firstname.lastname@example.org.
* Sialic Acid and Neu5Gc content of common food items
|Food||Neu5Gc intake if eaten at daily recommended servings Total milligrams|
|Milk (cow, 2%)||711|
|Milk (cow, raw)||711|
|Beef, lean portion||9,720|
In the late 1990s, the first example of a complete genetic and biochemical difference between humans and apes was reported by a group led by Ajit Varki, M.D., working closely with Elaine Muchmore, M.D. They showed that humans are different from chimpanzees and other great apes in not having the enzyme responsible for producing Neu5Gc, which is also found on the cell surfaces of other non-human mammals. The group showed that this biochemical difference was due to a human-specific mutation in the gene encoding the enzyme CMP-Neu5Ac hydroxylase (CMAH), which is responsible for synthesizing Neu5Gc in apes and other mammals.