By David N. Leff

Science Editor

Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.

Newborn babies tend to develop inner-ear infections after six months of age, because until then they are protected by antibodies carried over from their mothers. These antibacterial proteins are generated by the immune system’s B lymphocytes, which constitute 5 percent to 15 percent of the white blood cells in the peripheral blood of healthy people.

A person lacking B cells suffers from immunodeficiency – the disease notorious for the past two decades as the prime life-threatening feature of AIDS. However, the very first form of immunodeficiency was described in 1952. It’s now known as X-linked agammaglobulinemia (XLA). (Immunoglobulins are antibodies.) B cells make up less than 1 percent of the lymphocytes in the blood of XLA sufferers, who require life-time antibiotics and replacement gammaglobulin injections to stay alive. About 85 percent of individuals with early onset agammaglobulinemia are males – owing to the X-chromosome connection.

One such patient is the subject of a report in Science dated Dec. 3, 1999, and titled: “An essential role for BLNK in human B cell development.” This young man, now age 20, had his first bout of many inner-ear infections when eight months old. After two subsequent sieges of pneumonia, he was started on gammaglobulin replacement, and thereafter lived a normal life, except for recurrent otitis and sinusitis, plus hepatitis C acquired from the gammaglobulin shots. He had no detectable B cells or antibodies in his body. An older brother died at 16 months of age from pseudomonas bacterium sepsis

Both of these boys’ parents were healthy, with normal B cell concentrations. But both proved to be carriers of two mutations in a B-cell precursor molecule called BLNK – B-cell linker protein – and pronounced “Blink.”

Immunologists at Washington University in St. Louis, who pinned down these deleterious base-pair substitutions, have also authored a companion paper in the same issue of Science, titled, “Requirement for B cell linker protein (BLNK) in B cell development.” In this article, they analyzed the tissue and blood of mice that lacked BLNK, and determined that most of the animals’ progenitor B cells failed to pass through a key developmental stage, which prevented B lymphocytes from maturing into infection fighters. The co-authors detected a 50-fold reduction in the number of peripheral B cells in these mice, which had been kept in a germ-free environment. “Mutations in BLNK,” they concluded, “appear to have more severe consequences in the human as compared to the mouse.”

Mitochondria Perpetuate Mothers-Only Cells By Eradicating Mitochondria-Bearing Sperm Cells

A pitiless battle of the sexes takes place at the very outset of reproduction. Humans, like other mammals, inherit mitochondria only from their mothers, but father-donated spermatozoa contribute nearly 100 mitochondria to the fertilized egg. Presumably to keep the maternal line intact, these paternal interlopers are systematically wiped out by ubiquitin, the body’s debris-scavenging protein.

The consequences of this phenomenon, described in Nature dated Nov. 25, 1999, by scientists at the Oregon Regional Primate Research Center in Beaverton, may have dire, unexpected consequences. In their brief paper titled “Ubiquitin tag for sperm mitochondria,” the co-authors point out, “This imprint is a death sentence that is written during spermatogenesis, and executed after the sperm mitochondria encounter the egg’s cytoplasmic destruction machinery.”

They warn, “Learning more about this destruction pathway is important for understanding inherited mitochondrial diseases, and for evaluating the safety and efficacy of cloning, oocyte cytoplasm donation therapy,’ and fertilization assisted by spermatid or sperm microinjection.”

The paper describes experiments in rhesus monkeys and domestic cows that document this ubiquitin-enforced sperm die-off. But, alarmingly, when they looked at another bovine species, the Southeast Asian gaur (Bos gaurus), a large wild ox, they could see no ubiquitination of their sperm at all. “The inheritance of sperm and egg mitochondrial DNA,” the co-authors observed, “is thought to be solely sex-specific, but if it is also species-specific, then evolutionary clocks based on mitochondrial DNA may need to be recalibrated.”

Moreover, “The high death rate observed in cloned offspring could be due to heteroplasmy, the condition of mismatched mitochondria.” Overall, they concluded, “The implications of paternal mitochondria being selectively tagged for extinction may force a re-evaluation of procreative strategies.”

De Novo Deletion In Y Chromosome Explained Sperm Absence From Infertile Man’s Semen

On another spermatic front, biologists at the Massachusetts Institute of Technology in Cambridge were able to trace the infertility of a man totally lacking sperm production to a mutation on his Y (male-determining) chromosome. Their report in the December 1999 issue of Nature Genetics bears the title: “An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y

In the Y chromosome, any one of three regions – AZFa, b or c – disrupts spermatogenesis, causing infertility in otherwise healthy men. The MIT co-authors sequenced the AZFa region, and identified two functional genes, USP9Y and DBY. Screening both these sequences in 576 infertile and 96 fertile men, they found a 4-base-pair deletion – a de novo mutation –in the USP9Y gene of the man with no sperm in his semen. It was absent in his verifiably fertile brother, the father of two children.

Typing both siblings for Y-chromosome DNA polymorphisms (sequence variations), the co-authors found that the two men share a rare Y haplotype, including a T-to-A base-pair substitution not previously reported in the literature.

The USP9Y gene, they pointed out, “has a highly similar homolog, USP9X, on the X [female-determining] chromosome, and both genes are expressed throughout the body. Further work,” they concluded, “will determine whether USP9Y and USP9X perform the same function.”