By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
"Poorly understood," "unclear" and "unknown" are the terms most often applied to the cause and mechanisms of multiple sclerosis. This chronic autoimmune disease of the central nervous system usually strikes its victims in early adulthood. What MS strikes them with is a wall-to-wall spectrum of symptoms, from tingling and numbness in the arms and legs to blurred vision - optic neuritis - in one eye.
The single, salient, known hallmark of MS zeroes in on myelin. This layered lipoprotein sheaths the axons of normal CNS neurons. This axonal wrapping resembles electrical insulation around a wire. Myelination around an axon enhances that "wire's" conduction of neuroelectrical signals. Where the myelin is patchily gone, the denuded neurons inflict its victims with the protean signs and symptoms of MS.
But unlike the common run of disease pathologies, MS is a maddeningly unpredictable on-and-off ailment. It alternates been slight and severe disabilities, called flare-ups or relapses, to long or short disease-free periods. The fact that MS is seen as an autoimmune disease means that the body's own immune system is guilty of producing this disorder. That's where the "unknown" and "poorly understood" puzzles pop up.
One rough-and-ready explanation is that smoking guns of the immune defenses shoot off their "friendly fire" at the body's own tissues - in this case, myelin basic protein, the obvious antigenic target. But this assumption leaves more questions unanswered than answered: Which of the immune system's hordes of action-ready inflammatory molecules - antibodies generated by humoral immune B cells, cellular T lymphocytes, macrophages and complement, triggered by T cells, to name a few - go into action against their myelin antigenic targets?
One recently discovered Exhibit A is impounded as evidence in the Proceedings of the National Academy of Sciences (PNAS), dated Feb. 13, 2001. Its title recites the indictment: "Anti-DNA antibodies are a major component of the intrathecal [CNS-boundary membrane] B-cell response in multiple sclerosis." Its authors, neuroscientists and immunologists at the Scripps Research Institute in La Jolla, Calif., launched their inquiry with nerve cells from two young women with MS.
Their paper notes, "No single autoantigenic target of either humoral or cellular immunity has been linked directly with the development of MS, and no antibody specificity is diagnostic for disease."
They garnered their first axonal samples at autopsy from a woman with subacute MS. Her first hint of the disease came at age 17, marked by blurred vision in her left eye, which cleared up spontaneously. Then, at age 35, she experienced marked weakness in the lower limbs, and ataxia - loss of balance and staggering gait. Magnetic resonance imaging scans showed multiple demyelinating lesions in the brain and upper spinal cord.
In this MS patient, and one other, they found that the bulk of the antibody response "was driven by a limited antigen set." Further analysis suggested that "the antigenic targets of these molecules may be composed of nucleic acid [double-stranded DNA], rather than protein." This recalled to the co-authors that "antibodies binding specifically to DNA have long been recognized as a unique serological hallmark in individuals suffering from systemic lupus erythematosus [SLE], another prevalent chronic inflammatory disorder."
Indeed, SLE and MS frequently occur in the same patient, or in the same family.
Chances Of Overweight, Oversized Cloned
Mammals Clouds Outlook For Copying Humans
As the public furor over cloning humans heated up last week, scientists and ethicists in the field cautioned that genetic defects in cloned mammals are so frequent and severe as to contraindicate efforts at duplicating a human being. One little-mentioned developmental risk they cited was the likely birth of abnormally large and heavy newborns.
Scientists at Scotland's Roslin Institute, which gave the world Dolly the sheep, now provide a clue that accounts for this outsize growth and weight. Their brief communication in Nature Genetics for February 2001 bears the title: "Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture."
They compared the levels of the insulin growth factor receptor (IGF2R) between large fetal sheep from in vitro-cultured embryos with normal fetuses of the same age. The levels of the growth factor receptor were 30 percent to 60 percent lower in the former cohort than in the latter. Specifically, of 48 fetuses recovered at 125 days of gestation - two days before normal 147-day term - the largest IGF2R product weighed 8.2 kilograms, whereas the largest noncultured, control embryo tipped the scales at 4.5 kilos.
The co-authors went on to ascertain that the IGF2R gene lacks the property of methylation, known to be involved in fixing the "volume" at which some growth-influencing genes are set.
Mitochondrial Analysis Reveals Giant Moa's Evolution,
Plus How Southern Continents' Landmass Split Apart
In New Zealand, the moa (Dinornis giganteus) - a flightless running bird that stood 10 feet tall - became extinct around 400 years ago, wiped out by the Maori Polynesian people, who arrived about the turn of the second millennium. The moa's closest living avian relative is the ostrich. Both belong to the taxonomic group of ratite birds, which also include emus and cassorwries and kiwis, among many others.
Now biological anthropologists at the University of Oxford, UK, have extracted 0.1-gram samples of subfossil cortical (surface-layer) bones, 1,300 to 1,500 years old, from three moas and one Madagascan elephant-bird (Emeus crassus) specimen, another equally huge, long-extinct ratite.
From these meager DNA scrapings, they have achieved the first complete mitochondrial genome sequences of any extinct species. Besides unraveling the ratite evolution's family tree, this genomic insight shed light on how the ancient supercontinent of Gondwanaland broke up into the present-day southern lands of Australia, New Zealand, India, Madagascar and Antarctica.
Their report in Nature, dated Feb. 8, 2001, is titled: "Complete mitochondrial genome sequences of two extinct moas clarify ratite evolution." n