New Bug Bagged: Subtle is the Genome

New Bug Bagged: Subtle is the Genome

by Dr. Jeremy Cherfas

WHAT'S HOT IN BIOLOGY...

Rank	Paper	Citations This Period Nov- Dec 98	Rank Last Period Sep- Oct 98
1	S. F. Altschul, et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs," Nucleic Acids Res., 25(17):3389-3402, 1 September 1997. [NIH, Bethesda, MD; Pennsylvania St. U., University Park] *XU793	95	1
2	R.M. Kluck, et al., "The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis," Science, 275(5303):1132-6, 21 February 1997. [La Jolla Inst. Allergy and Immunol., San Diego, CA] *WJ503	68	2
3	J. Yang, et al., "Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked," Science, 275(5303):1129-32, 21 February 1997. [Emory U., Sch. Med., Atlanta, GA:] *WJ503	66	3
4	F.R. Blattner, et al., *"The complete genome sequence of Escherichia coli* K-12,"** Science, 277(5331):1453-74, 5 September 1997. [U. Wisconsin, Madison; U. Michigan Sch. Med., Ann Arbor; FMC Bioproducts, Rockland, ME; U. Natl. Autonoma Mexico, Moreles] *XV429	50	4
5	J.-F.Tomb, et al., *"The complete genome sequence of the gastric pathogen Helicobacter pylori,"* Nature, 388(6642):539-47, 7 August 1997. [6 U.S. and Swedish institutions] *XP722	49	8
6	P. Li, et al., "Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade, " Cell, 91(4):479-89, 14 November 1997. [Howard Hughes Med. Inst., U. Texas Southwest. Med. Ctr. Dallas; Thomas Jefferson U., Philadelphia, PA] YG492	48	6
7	H. Zou, et al., "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3," Cell,90(3):405-13, 8 August 1997. [U. Texas Southwestern Med. Ctr. Dallas; Genentech, South San Francisco, CA] *XQ063	45	9
8	V.V. Ogryzko, et al., "The transcriptional coactivators p300 and CBP are histone acetyltransferases," Cell, 87(5):953-9, 29 November 1996. [NIH, Bethesda, MD] *VV774	42	5
9	F. Kunst, et al., *"The complete genome sequence of the Gram-positive bacterium Bacillus subtilis,"* Nature, 390(6657):249-56, 20 November 1997. [46 institutions worldwide] *YG667	39	†
10	M. Enari, et al., "A caspase-activated Dnase that degrades DNA during apoptosis, and its inhibitor ICAD," Nature, 391(6662):43-50, 1 January 1998. [Osaka U. Med. Sch., Japan; Kirin Brewery Co., Kanagawa, Japan; Osaka Biosci. Inst., Japan] *YP888	38	†

SOURCE: ISI's Hot Papers Database. the full legend.

Whoopee! Another complete genome sequence bursts onto the scene at #9. A giant team, encompassing no fewer than 151 researchers at 46 separate locations, has disentangled the 4,214,810 base pairs and roughly 4,100 genes of the bacterium Bacillus subtilis. That makes B. subtilis the eighth bacterium to be sequenced, but gains importance partly because it is the first Gram-positive bacteria to be decoded, and Gram-positive bacteria are important in industry and medicine.

It is fast becoming a truism that genome sequences illuminate aspects of an organism's modus vivendi, but how could it be otherwise? Obviously genes will have been selected by lifestyle. But the subject is still sufficiently novel to surprise, and this genome is no exception. B. subtilis is a survivor. If growth stops, it responds by increasing its metabolic diversity. It develops the ability to move and is attracted towards different chemicals that might be food. It secretes enzymes that might make more food available and antibiotics that get rid of competitors. If all that fails, it forms spores that are resistant to drying out and irradiation and withstand chemical attack, sitting it out until conditions improve. Its genome is starting to show how.

For example, B. subtilis is widely used in industry because of its ability to secrete proteins at gram-per-liter concentrations. Look at its genome and you find five signal peptidase genes, as compared to only one in E. coli. B. subtilis can make use of a large menu of foods, and is able to grow aerobically and anaerobically. Its genome reflects these catholic tastes, with almost one in five of the genes devoted to intermediary metabolism.

Remarkable, too, is the way in which some gene families have expanded hugely. There are 77 different ABC transporter proteins, for example. These are pumps that import nutrients and signals and export metabolic by-products. Why B. subtilis needs 77 of them will doubtless be answered soon, but in the meantime one can marvel at the elaboration of its system for communicating chemically with its environment.

ABC transporters can also be the basis of resistance to antibiotics. Mutants are active enough to pump antibiotics out of the cell before they can do any harm. As most medically important infections are caused by Gram-positive bacteria—examples include tuberculosis, pneumonia, diphtheria, scarlet fever, botulism and listeriosis—and as these are becoming increasingly resistant to ever more antibiotics, knowing the sequence of B. subtilis may well help researchers to understand resistance and, more importantly, how to overcome it.

The flip side of that coin is B. subtilis's ability to secrete antibiotics. About 30 genes seem to be involved in the production of antibiotics, including one polyketide pathway that occupies 2% of the genome. These pathways are similar to those of other Gram-positive bacteria, such as Streptomyces. Knowledge of the genome of B. subtilis may allow scientists to engineer more effective antibiotics and perhaps, coupled with new-found information about the ways in which Gram-positive bacteria build their complex cell walls, entirely new classes of antibiotic.

The 4,100 genes have already provided new insights into the lives of bacteria and whetted the scientists' appetites for more. About 42% of the genes have no known function—yet. But a consortium of 19 European and 7 Japanese laboratories has embarked on a program systematically to analyse the genome, which will have important repercussions for the use of B. subtilis in research and industry.

Moving, briefly, to another genome, hovering in the lists at #15 is a thin paper on the fat gene: the first demonstration that humans too use leptin to regulate appetite and energy expenditure (see C.T. Montague et al., Nature, 387:903-8, 1997; 33 citations this period). Stephen O'Rahilly, Professor of Metabolic Medicine at Cambridge University, assembled a team to sequence the DNA of two very obese children, cousins in a closely related family. Both children shared the same mutation in their Ob gene, their leptin levels were so low as to be almost undetectable, and both are very fat: case proven. Recombinant leptin is now available, and the older child has had 18 months of treatment that resulted in weight loss. So leptin works to reduce body weight, at least in very severe cases.

The public excitement that greeted the first results on leptin will probably not be re-kindled by this result, but will have to await more general availability. That, however, is far from frivolous. As O'Rahilly tells Science Watch, "Trying to turn oneself into a waif-like model is stupid and unnecessary," but given that one in five Americans is sufficiently obese to run a two-to-three-fold increase in death rates from cardiovascular disease, "a successful treatment for moderate obesity would undoubtedly be life-saving. Whether leptin itself might represent that remains to be seen."

Science writer Dr. Jeremy Cherfas
works with the Biotechnology and Biological Sciences
Research Council of the U.K., Swindon.