By David N. Leff

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

Unless the Y2K bug interferes, Homo sapiens should complete the total sequencing of the human species' own genomic endowment by or about the year 2003. A multinational consortium took the first bite out of this enormous apple by announcing in Nature dated Dec. 2, 1999, "The DNA sequence of human chromosome 22."

Three laboratories - in Britain, Japan and the U.S.- shared this ground-breaking feat, with most of the work done by Britain's Sanger [Gene-Mapping] Center, backed financially by the Wellcome Trust. The other two sequencing powerhouses were the Advanced Center for Genome Technology, in Norman, Okla., and Tokyo's Keio University School of Medicine. But the unabridged list of co-authors numbered 216 contributors from nine centers in five countries - UK, U.S. (five centers), Japan, Canada and Sweden.

Of the 23 paired chromosomes in the human karyotype, chromosome 22 is the second smallest, comprising only 1.6 percent to 1.8 percent of genomic DNA. But it's one of the more meaningful ones in its complement of disease-linked genes.

"The completed sequence," as reported in Nature, "covers 33.4 megabases of 22's long arm, with 11 gaps, and has been estimated to be accurate to less than 1 error in 50,000 bases." The DNA on that long arm covers 679 gene sequences, ranked in descending order of the evidence validity used to identify them:

¿ 247 "known genes" - identical to known human gene or protein sequences;

¿ 150 "related genes" - homologous to such sequences from human or other species;

¿ 148 "predicted genes" - homologous only to ESTs (expressed sequence tags) - not entire genes;

¿ 134 "pseudogenes" - similar to known genes, but with disrupted open reading frames.

The complete genes on 22's long arm range in sequence length from a single kilobase to the largest one found, which stretches across 583 kb. (The chromosome's short arm apparently contains no protein-coding regions.) The Nature paper estimates that "if the distribution of genes on the other chromosomes is similar, the minimum number of genes in the entire human genome would be at least 61,000." Common guesstimates bandied about to date have ranged from 30,000 to 120,000.

Highlighting the potential clinical applications of total genomic sequencing, the report noted that "part of chromosome 22's long arm is responsible for the etiology of a number of human congenital anomaly disorders." These include cat eye syndrome, DiGeorge syndrome, schizophrenia, congenital heart disease, chronic myeloid leukemia and some breast, ovarian and colon cancers, as well as spinocerebellar ataxia. It's also the site of several genes encoding immunoglobulins of the immune system.

The consortium made the point that, as in this case, it will release full data on genome sequences to the public domain as they are completed, so that the research community can begin making use of them in timely fashion, rather than waiting for the future sequencing of the entire project.

Zebrafish Elucidate How Chordin Protein Keeps Bone-Building From Going Too Far

Knowing how to build a vertebrate skeleton is one thing; knowing when to stop construction is another.

A skeletogenetic work crew - equipping developing embryos with the complex structure of a bony skeleton - consists of transforming growth factors called bone morphogenetic proteins (BMPs). These molecules stimulate the formation of cells that deposit the bone matrix where it should go, and when.

But if BMPs didn't know when to shut down that process, cartilage and bones would go right on growing. A couple of genes called noggin and chordin express proteins that step in to prevent that osseous overgrowth. (The BMPs may, however, make a comeback in the event of a bone injury requiring repair.)

Last year, researchers determined in mice that noggin protein antagonism to BMP put a crimp in mouse osteogenesis at the site of joint formation. This year, to clarify what chordin does, required the good offices of zebrafish. Embryologists at the Carnegie Institution of Washington in Baltimore raised schools of knockout zebrafish lacking functioning chordin genes. These mutants expressed BMPs aberrantly, and developed stunted fins and tails. Injections of chordin messenger RNA into early-stage embryos corrected those defects.

Nature Genetics for December 1999, tells this tale in an article titled: "Patterning the zebrafish axial skeleton requires early chordin function."

Transplanted Embryonic Stem Cells Repair Spinal Cords In Rats Nine Days After Injury

Anywhere from 250,000 to 500,000 people in the U.S. alone suffer spinal cord injuries every year. Most of these strike the young, who are disproportionally exposed to sports and vehicular accidents. Neurons in the central nervous system (CNS) put out axons that may project for several feet down the body's trunk and limbs. When such nerves in the spinal cord are severed or crushed, little can be done to repair them, and victims are often condemned to a lifetime wheelchair sentence - unless new therapies can be developed.

Mammalian CNS isn't programmed to generate enough nerve cells to replace those lost through injury. This suggests cell transplantation as therapy, but pieces of adult spinal cord don't survive such measures. Embryonic neurons do survive, but they don't divide to supply enough replacement cells.

So neurosurgeons at Washington University in St. Louis, tried embryonic stem cells, potentially capable of differentiating into neurons specific to the spinal cord. The December 1999 issue of Nature Medicine reports their results in an article titled: "Transplanted embryonic stem cells survive, differentiate, and promote recovery in injured rat spinal cord."

The researchers delivered about 1 million precursor cells to the injury sites of rats that had had the spinal nerves that control hind-leg motion crushed nine days earlier. By two weeks later, some of the cells had filled the injury cavity, and migrated a centimeter in both directions from the crush site. By one month, the hind legs of transplanted rats had regained some coordinated movement, and could partly support the animals' body weight.