By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Your ideal bioterror weapon is not a high-mortality pandemic such as plague or smallpox. It¿s a highly contagious infection that prostrates its human victims for long periods, on and off, thus demanding unremitting medical attention but rarely killing. Its relapsing symptoms may range from chills and (very high) fever to headache, pain, fatigue, nosebleed, dementia and arthritis.
Such a candidate pathogen-of-war is a relatively obscure bacterium, Brucella melitensis, better known as Malta fever. Both of those monikers go back to the Crimean war (1853-1856) ¿ remember ¿The Charge of the Light Brigade?¿ Many of the British sick and wounded were shipped to the Mediterranean island of Malta to recover. Instead, they came down with a mysterious ailment that featured very high fever and a panoply of symptoms that hit them from head to feet, and in between. Forbidding the British garrison from drinking goats¿ milk produced a dramatic drop in the disease.
In 1887, a British army surgeon, David Bruce (1855-1931), isolated the causative agent of Malta fever. The disease now bears his name, Brucellosis, coupled to melitensis ¿ Latin for Malta. It tracked back to domestic livestock ¿ bovine, porcine and ovine ¿ in which fetal stillbirth is the hallmark. Goats in particular were prime vectors of Malta fever, now more correctly called ¿undulant fever.¿ This reflects the fact that a patient¿s temperature chart spikes and falls over days and weeks in febrile waves ¿ like today¿s aberrant stock market highs and lows.
Unpasteurized goat¿s milk and cheese are the main conveyors of undulant fever. It¿s an occupational disease in rural people the world over who come in contact with those domestic animals. They¿re mainly meatpackers, veterinarians, hunters, farmers, livestock handlers and children. The merest scratch or pinprick carrying traces of contaminated goats¿ milk or urine can transmit the debilitating, flu-like infection. Though rare in the U.S., Canada and Europe, brucellosis is still reported in the Mediterranean regions, the Middle East and Central America.
Although the disease caused by B. melitensis rarely kills humans, it spreads ferociously (especially among lab staff), is hard to treat, and lacks a vaccine. Animal vaccines are pathogenic to people. Therefore, B. melitensis occupies a place on the U.S. Centers for Disease Control and Prevention¿s ¿B¿ list of potential bioterrorist weaponry. This in turn led the Department of Energy to fund the total sequencing of the bug¿s genome by Integrated Genomics Inc., of Chicago. That company, together with a multinational consortium of co-authors, announced completion of their assignment in Wednesday¿s Proceedings of the National Academy of Sciences (PNAS), dated Dec. 26, 2001. Its title: ¿The genome sequence of the facultative intracellular pathogen Brucella melitensis.¿
That versatile, virulent vector tipped the genomic scales at 3,294,931 base pairs, comprising two chromosomes, one 2,117,144 bp long; the other, 1,177,787. Of its 3,197 genes with open reading frames, 2,487 ¿ 78 percent ¿ had assigned functions. The PNAS report notes that the bacterium can survive and thrive with or without oxygen. The co-authors suggest that the next step in researching how the bug harms its host depends on identifying the types of toxic molecules the pathogen secretes.
Rounding Out Year Of The Genome,¿ Chromosome 20¿s 59,421,637 Base Pairs Completely Sequenced
A rather more significant feat was total sequencing of human chromosome 20, which harbors the genes that cause Creutzfeldt-Jakob disease, severe combined immunodeficiency, Type II diabetes, obesity, cataract and eczema, among other maladies. It took 127 co-authors at the Wellcome Trust Sanger Center, Cambridge University, UK ¿ a leader of the international consortium that announced completion of the entire human genome early this year ¿ to report in Nature dated Dec. 20/27 2001: ¿The DNA sequence and comparative analysis of human chromosome 20.¿
This is the third chromosome to be scoped as part of the Human Genome Project. Chromosome 22 was published in December 1999 and 21 in May 2000. Number 20, at 59,421,637 base pairs determined, comprises about 2 percent of the human genome.
Offspring Of Mice Sans New Gene Expressed Genes Not Normally Encoded By Mom¿s Copy
Many a clinical gene therapist has tried to treat a cancer by delivering healthy genes into tumor tissue of the patient ¿ only to find out that those genes were asleep. What happened? Did the gene-therapy constructs get methylated and silenced? Methylation increases the information content of DNA, and can be used to keep genes in the inactive state. Besides inheriting the 30,000 to 50,000 genes carried by the 23 pairs of chromosomes in every cell of the human body, 100 to 200 special-purpose genes carry an extra mark ¿ or imprint ¿ that identifies them as having come from either Mom or Dad. That mark is usually an add-on to the DNA of a methyl group. The parental-fingering process is called genomic imprinting.
Geneticists and developmental researchers at Columbia University in New York have identified a gene ¿ Dnmt3L ¿ that chemically marks certain parts of the mouse genome as being inherited from the mother. Their discovery was originally published in Science Express, released Nov. 22, 2001, under the title: ¿Dnmt3L and the establishment of maternal genomic imprints.¿ Genomic sequencing of DNA from oocytes and embryos showed that removal of the gene prevented methylation of sequences that are normally maternally methylated.
The Dnmt3L gene is the first ever shown to play a role in establishing imprinting during egg development. As a potential new tool in the growing field of tissue and cell engineering, it may break that logjam in cancer gene therapy. The university¿s department of science and technology ventures, its director stated, ¿will be developing a relationship with industry to translate these research discoveries into therapies for patient care.¿