By David N. Leff

Two of the most devastating death-dealing pandemics in recorded human history scourged vast populations during and right after World War I.

Most statistics say the great influenza pandemic that swept the globe in 1918-1919 took the lives of 20 million to 40 million men, women and children — 675,000 in the U.S. alone.

Epidemic typhus, which raged in Russia and Eastern Europe, infected an estimated 25 million, of whom 3 million died between 1917 and 1921.

Russians knew typhus all too well. A century earlier, in 1812, Napoleon invaded the Czar's domain with his Grande Armie, 600,000 strong. When he turned tail and fled, all but a remnant of that army remained behind, slain by typhus.

By an irony of history, the great typhus pandemic of World War I began in Serbia just where the war itself began — in Sarajevo — in 1914. That same year, typhus flared up in Serbia, with 10,000 cases for starters, and reached 150,000 by 1915.

The infection was virtually endemic in louse-ridden battle areas. In fact, it was known as "camp fever."

Among the many physicians who investigated typhus was a young American pathologist, Howard T. Ricketts, who died of the infection in 1910 at the age of 39. In 1915, typhus took the life of a German zoologist named Stanislav Prowaze, also 39.

Both researchers gave their name to the parasite, Rickettsia prowazekii, that transfers the infection from the human body louse (Pediculus humanus) to its preferred host, Homo sapiens.

Actually, typhus is only one of the rickettsial diseases, which grow in lice, mites, fleas and ticks. The louse-borne infection begins with a fever that can spike to 104 degrees Fahrenheit, an unrelenting headache and a distinctive rash. It may go on to a swollen and darkened face, gangrene of fingers and toes, stupor, and all too often, death.

"R. prowazekii has a very curious epidemiology," said biochemist Charles Kurland, a professor of molecular biology at Uppsala University, in Sweden. "The interesting thing is that for other rickettsia there is a reservoir in nature, which consists of these arthropods. "The organism passes through lice," he noted, "but the lice die after a couple of weeks. So it seems that we humans are the reservoir of typhus infection."

Once a body louse drills its tiny hole in the skin, through which the parasite enters, along with the louse's feces, that injection site begins to itch maddeningly. Scratching it with filthy fingernails drives the typhus inward.

Kurland is senior author of a paper in today's Nature, dated Nov. 12, 1998. Its title: "The genome sequence of Rickettsia prowazekii and the origin of mitochondria." He and his co-authors report that the parasite's total, smallish genome amounts to 1,111,523 base pairs, containing 834 protein-coding genes.

"It's been thought since the nineteenth century," Kurland told BioWorld Today, "that the cell's mitochondrial organelle originated in bacteria. I felt that the most likely ancestor of an organelle," Kurland continued, "would be an ancestor of a pathogen. Because both had to solve the same problem: They had to get into the cell and take up residence.

Identity With A Difference

"The one difference between the organelle and the pathogens," he noted, "is that the organelle works out a mutually satisfactory modus vivendi with this host cell, whereas the pathogen goes in and does its business, and eventually kills the host."

Sequencing the R. prowazekii genome yielded a long laundry list of evidence that the parasite and the power-station mitochondria share enough DNA characteristics to make their cellular symbiosis plausible. Kurland counted some of the ways:

"If we look at the total capacity of the organism as a biochemical machine, to do the metabolism, it turns out that the carbon metabolism is remarkably similar to that of mitochondria. It can only do oxidative phosphorylation; it can only respire. It can't do anaerobic fermentation — just like the mitochondria.

"The other thing that struck us," he said, "was that when we took out the genes responsible for oxidative phosphorylation — for example, the respiratory chain — when we took protein synthesis genes, and did phylogenetic [family-tree] reconstruction, we found that the rickettsias are the organisms most closely related to the mitochondria."

By an extrapolation from mutation at a fixed rate, Kurland's colleagues were able to estimate the divergence of the proto-parasite and proto-organelle back in time 1.8 billion years. As for the presumed nature of the host cell in those days when it didn't have a mitochondrion, he allowed, "We don't know. That's the $64,000 question. People talk about a 'primitive eukaryotic cell,' whatever that might be. It could be, but there are problems with any scenario you work out now."

Prospective Payoffs - Obvious And Otherwise

Besides the gratification of adding another genome to the increasing number coming off the sequencing assembly lines, Kurland sees "a lot of practical applications" in laying bare rickettsia's secrets.

"The most obvious one," he pointed out, "is that if you are interested in making vaccines, or designing antibiotics, you now have access to receptors and appropriate antigens to do modern drug-discovery work. Of course, the availability of the genome means that you have the genes involved in pathogenicity and virulence, etcetera. That's very obvious. There's a not-so-obvious application also, which is a little further downstream.

"In the rickettsia, 24 percent of the genome's sequence is non-coding. We think that this is the remains of fossil genes that have been thoroughly mutated, but not eliminated yet. And some of the most well-characterized genetic diseases in humans are associated with mutations in mitochondria."

Among these, he cited "sudden blindness, forms of epilepsy, neuromuscular dysfunction. For example, a young man may wake up at the age of 20-something and be completely blind without any warning, with no cure, no treatment in sight."

Kurland concluded: "Now I believe that this kind of mutation-based disease is an expression of the peculiar genetic circumstances for the mitochondria, and which are also expressed in the rickettsia genome. They're accumulating harmful mutations faster than the nuclear genes. In consequence, they are the source of genetic problems for humans. Studying this process in the rickettsia, we may be able to get at it in the human mitochondria." n

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