By David N. Leff

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

A ¿brief communication¿ in today¿s Nature, dated May 17, 2001, casts doubts on the accuracy of the fruit fly¿s total genome sequence, as reported last year by Celera Genomics, of Rockville, Md.

The one-page article, by Stanford University bioinformatics mathematician Samuel Karlin, bears the terse title: ¿Annotation of the Drosophila genome.¿ However, in its first paragraph, his paper notes ¿numerous and significant discrepancies¿ between Celera¿s published genome and the SwissProt database. (See BioWorld Today, April 7, 2000, and April 10, 2000.)

(SwissProt is a database for proteins, located in Lausanne, Switzerland. It has been overseeing the collection of all possible proteins for the last 15 to 20 years, and works together with GenBank in Washington.)

The fruit fly, Drosophila melanogaster, was reported as having a genome totaling 120 million base pairs of DNA, containing 13,601 protein-encoding genes. Karlin and his co-authors ¿extracted 1,049 Drosophila sequences created before 1999 from the SwissProt database, and compared them with the Celera proteome.¿ They found that ¿45 percent had sequence differences of more than 1 percent, including mismatches, insertions and deletions ¿ small and large ¿ spread over the protein¿s length.¿

The total human genome sequence was announced by Celera¿s founder, president, CEO and chief scientific officer, J. Craig Venter, Feb.13, jointly with the International Human Genome Sequencing Consortium. (See BioWorld Today, Feb. 13, 2001.)

Without casting aspersions on Celera¿s accuracy in this much larger endeavor, Karlin wrote, ¿Proteomic studies using the present Drosophila genome sequence have significant limitations and the same will be true of the human genome.¿

In a telephone interview with BioWorld Today, Karlin commented: ¿Celera has lots of good people. The bacterial genomes they produced have been more than 98 percent accurate, and lent lots of insights into how bacteria compare with each other, how they operate.

¿My article in Nature,¿ he continued, ¿was meant to be just a general caveat ¿ that one had to be careful in using the sequences, particularly in these recently published genomes ¿ that¿s all. They¿re being put out much too fast. Therefore, automatically, they¿ll have more errors. I didn¿t mean it to be negative, as the press seems to be reacting.

¿The higher eukaryotes,¿ he explained, ¿things like flies and humans, are much more complicated than bacteria. Their genomes are made up of pieces. They use all the pieces in various ways in different combinations. And one of the arguments with the human genome ¿ why there are so few genes ¿ is because they can take one gene of many pieces and produce lots of proteins from them, just combining different parts.¿

Smoking, Obesity, Diet, Infectious Bugs, Genetics Indicted As Future Cancer Risks, Scientist Warns

It was probably Mark Twain who said, or wrote, ¿There are three degrees of lying ¿ plain lies, damn lies and statistics.¿

Today¿s issue of Nature, dated May 17, 2001, carries an ¿Insight progress¿ article, which lays out what amounts to damn truths about cancer. Its title: ¿Cancer epidemiology in the last century and the next decade.¿ Its sole author is the eminent epidemiologist Julian Peto, at the Institute of Cancer Research, Surrey, England.

Combatants who were killed or died in World War I (1914-18) totaled, officially, 8,528,831. Of this global body count, British casualties were 908,371. However, the smoke of battle reflected in that figure was only the beginning. British deaths from the Great War went on for decades.

¿The large increase in male cigarette smoking in Britain,¿ Peto¿s paper recounts, ¿caused an unprecedented epidemic among men born around 1900. By 1955 the rate among British men aged under 55 was the highest in the world.¿

Then came the merciful backlash: ¿Over the five decades since British and American epidemiologists reported that cigarette smoking is an important factor in carcinoma of the lung,¿ there has been a marked reduction in tar levels of British cigarettes, and in smoking among British men. As a result, their lung cancer rate below age 55 has fallen by more than two-thirds since 1955. It is now among the lowest in the developed world, and still declining. Similar changes,¿ the article added, ¿occurred 20 years later in America, where cigarette smoking increased rapidly during the Second World War.

¿The most important discovery in the history of cancer epidemiology.¿ Peto¿s paper states, ¿is the carcinogenic effect of tobacco.¿ He makes the point, ¿For many years these effects were thought to be restricted largely to the lung, pancreas, bladder and kidney, and [synergistically with alcohol] the larynx, mouth, pharynx and esophagus. More recent evidence indicates that several other types of cancer, of which the most important worldwide are stomach, liver and [probably] cervix, are also increased by smoking.¿

Next on this rap sheet come ¿the effect of diet and overweight.¿

¿Cancer risks in old age,¿ it points out, ¿may also depend as much on diet in early life as on current habits. Apart from drinking alcohol,¿ it goes on, ¿consumption of various foods contaminated with aflatoxin (a metabolite of Aspergillus fungi), and a few local customs (such as feeding Chinese-style salted fish to infants, which causes nasopharyngeal cancer), no single dietary factor shows a strong enough effect to establish it as an important carcinogen or anti-carcinogen.¿

The obesity indictment continues: ¿There is now a consensus that cancer is commoner in those who are overweight. The evidence is strongest for post-menopausal breast cancer and cancers of the endometrium, gall bladder and kidney, but several other sites contribute to the overall cancer risk.

¿Radical changes in national dietary habits would not be easy to achieve even if there were a consensus on which foods are relevant,¿ the article observes. ¿Dietary supplements such as vitamins or other micronutrients seem an attractive alternative, but they may not have the same effects as the foods that contain them, and some may even be harmful.¿

Incidence of breast cancer, the paper points out, is transiently increased by pregnancy, and permanently lowered by late menarche (puberty), early first childbirth, high parity (number of births) and extended breast feeding.

But that¿s not all. The Nature paper goes on to inculpate such recently revealed cancer perpetrators as viruses, bacteria and parasites ¿ enhanced by modern immunosuppression therapy ¿ as well as occupational and environmental carcinogens, plus inherited genetic risk factors. All of the above, it foresees, will make cancer one of the commonest causes of death in the just-begun 21st century.

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