As reported by The Hartford Courant, October 6, 2005.

Scientists Resurrect Deadly Flu Virus

By William Hathaway

Scientists have resurrected one of the world's great killers in the laboratory, hoping that the genetic secrets within the 1918 influenza virus will help them predict and combat the next major microbial threat to mankind.

In a contained laboratory at the federal Centers for Disease Control and Prevention in Atlanta, scientists used reverse genetics to re-create the 1918 flu virus that killed 20 million to 50 million people, according to studies released Wednesday. Scientists say that although the 1918 strain probably does not represent a significant human health threat today, it can provide insight into dangerous types of contemporary influenza, such as the highly lethal avian strain now circulating among birds, which some scientists fear could evolve into the next catastrophic pandemic.

"This is truly a spectacular event," Dr. John Shanley, professor of medicine and director of infectious diseases at the University of Connecticut Health Center, said of the studies published in the journals Nature and Science. "To resurrect a virus and gain useful scientific information from it is remarkable."

An analysis of the genetic structure of the 1918 strain, also known as Spanish flu, reveals that it was an avian influenza, like the current H5N1 strain that has infected poultry and migratory birds in Asia and caused scores of human deaths.

The 1918 virus's jump from birds to humans, perhaps through intermediary animals such as pigs, was different from the two other outbreaks of pandemic influenza that occurred in the 20th century. Those pandemic strains in 1957 and 1968 occurred when novel influenza genes mixed with existing human influenzas.

Initial comparisons with the 1918 strain show that the H5N1 strain seems to have already made some of the molecular changes it needs to become a pandemic strain - a virulent flu capable of being readily transmitted from person to person, said Dr. Jeffrey K. Taubenberger, a researcher with the Armed Forces Institute of Pathology in Rockville, Md., and author of one of the papers.

However, the H5N1 strain still needs to make several evolutionary leaps before it becomes a widespread threat to human health, he said.

A decade ago, Taubenberger began his quest to track down the 1918 virus - and to solve the long-standing mystery of why it spread so quickly at the end of World War I and why it was so deadly, especially to young and otherwise healthy people.

Taubenberger's team examined samples of lung tissue preserved from autopsies and also from the body of a 1918 female flu victim who was buried in the Alaskan permafrost. Those samples gave scientists the raw material needed to decode the flu's RNA, the single strand of genetic information that contains instructions for the virus to attach to the surface of a cell, penetrate the cell and then hijack cellular machinery to replicate itself.

The genetic sequence of five of the eight segments of the flu virus previously had been decoded. The new research published Wednesday in Nature details the final three segments.

The researchers and government scientists said they had held lengthy discussions about whether to publish the data, which in theory could be used by terrorists intent on engineering a deadly form of influenza. The U.S. National Science Advisory Board for Biosecurity, formed after the terrorist attacks of Sept. 11, 2001, to advise government agencies and scientists on security issues, agreed that the benefits of publication outweighed the potential risks.

The knowledge can be used to help identify which influenza strains might be dangerous and to develop new flu vaccines and treatments that could be effective in combating a new pandemic flu, said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

Scientists at the CDC took the information, and using a technique called reverse genetics, actually created the virus in a contained laboratory designed to handle potentially dangerous pathogens.

Dr. Julie Gerberding, director of the CDC, said that the 1918 virus is no longer considered a significant health threat but that as a precaution it still was handled as such.

The 1918 flu was an H1N1 virus, a type that most of the world had never been exposed to at that time, just as people today have developed no immunity against the H5N1 strain. Most people today have antibodies to H1N1, meaning that they have some immune protection against the 1918 strain, Gerberding said. Also, the 1918 strain seems susceptible to anti-viral drugs currently on the market, she said.

When examined in the lab, the 1918 virus appeared to be especially deadly to mice and chicken embryos and also grew readily in human lung tissue. However, although most influenza viruses need an enzyme called trypsin to replicate, the 1918 virus did not. That means the 1918 strain could infect more cell types than a typical influenza strain, which could help account for its virulence, the scientists said.

Taubenberger said that by comparing the 1918 virus to other flu strains, including H5N1, scientists hope to create a checklist of molecular changes that a flu virus needs to make before it can infect humans and be passed from person to person.

"Knowing what the virulence determinants are would be a tremendous benefit for us," said Dr. Brian Cooper, chief of the infectious disease division at Hartford Hospital.

Even a few months' head start knowing that a lethal new human strain was evolving into a pandemic would be invaluable in helping the world prepare for what could be a medical health catastrophe, Cooper said.

"I think [a pandemic flu strain] is the scariest thing biologically that I could dream up," Cooper said. "This is a very, very serious risk."

Although H5N1 has not been shown to jump from human to human, it has killed almost half of the people known to be infected through contact with birds. Cooper said that the real percentage of fatalities is probably much lower because of non-lethal cases that have not been reported.

Also, as a virus becomes more easily transmitted, it loses some of its virulence.

Cooper noted, however, that Spanish flu killed only about 3 percent of its victims but still was one of the greatest scourges ever to afflict mankind.