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Epstein-Barr Virus May Play Role in Multiple Sclerosis Development

For decades, researchers have suspected that people infected with an exceedingly common virus, Epstein-Barr, might be more likely to develop multiple sclerosis, a neurological illness that affects a million people in the United States. Now, a team of researchers reports what some say is the most compelling evidence yet of a strong link between the two diseases.

The virus infects nearly everyone in their teen or young adult years, and very few go on to develop multiple sclerosis. The researchers also note that it is not the only known risk factor for people who develop the illness. But they say their data points to it being the clearest of them all. While it remains to be seen whether the finding will result in treatments or cures for multiple sclerosis, the study may further motivate research into therapies and vaccines for the condition.

In their study, published Thursday in Science, the group examined data from 10 million people on active duty in the United States Armed Forces over two decades. The strength of their study, said its principal investigator, Dr. Alberto Ascherio, an epidemiologist at the Harvard T.H. Chan School of Public Health, is that they were able to follow people for years and ask whether infections with Epstein-Barr preceded multiple sclerosis.

Among the service members in the study, 801 developed multiple sclerosis, a disabling disease that occurs when the immune system attacks the fatty insulation that protects nerves in the brain and spinal cord. Most who develop the disease are diagnosed between the ages of 20 and 50. The disease is rare, though — an individual’s chance of getting multiple sclerosis is half of one percent.

At the same time, the virus in question, Epstein-Barr, is common, infecting nearly everyone in the population at some point. Although few are aware that they were infected, some develop mononucleosis. The virus remains in the body for life.

Because so few who are infected with the virus get multiple sclerosis, it cannot be the sole cause of the disease. Other risk factors have been identified, including some, like low levels of vitamin D and smoking, that were seen previously by the Harvard group using the same data set. There also are genetic factors — 900 abnormal genes have been identified in patients with multiple sclerosis, said Dr. Anthony J. Reder, a multiple sclerosis expert at the University of Chicago, who was not involved in the new study. Gender also plays a role; most patients are women.

But, Dr. Ascherio said, no risk factor stands out like Epstein-Barr infections.

To ask how much the virus increases risk, the investigators studied the small proportion of people who were not infected with the virus early in their service careers but subsequently became infected. They detected infections by the presence of antibodies to the virus.

Among the multiple sclerosis patients, 32 out of 33 got infected with Epstein-Barr before they developed M.S.

As a control group for their study, the scientists tracked 90 individuals who were not initially infected with Epstein-Barr and who also did not get multiple sclerosis. Of them, just 51 subsequently became infected with Epstein-Barr.

That meant an Epstein-Barr virus infection increased the risk of multiple sclerosis over thirtyfold, Dr. Ascherio said.

But Dr. Reder cautioned that it could be hard to tease out cause and effect from an epidemiological study. People who develop multiple sclerosis have overactive immune systems that make them develop high levels of antibodies to viral infections. Multiple sclerosis might arise not because of the virus but because of the body’s response to it.

“Multiple sclerosis patients have fewer viral infections than normal,” he said, because their immune systems are so active that they effectively fight off viruses. “Multiple sclerosis patients often say, ‘I never get a cold.’ When I hear that, my ears perk up.”

The drugs currently used to treat multiple sclerosis suppress the immune system, Dr. Reder noted. So far, he added, anti-viral drugs have not helped patients with multiple sclerosis.

The Harvard group tried to control for the possibility that the immune system’s response, not the virus itself, increases the risk of multiple sclerosis in those infected with Epstein-Barr. They asked if antibodies to another common virus, cytomegalovirus, also were linked to a greater risk of multiple sclerosis. They were not.

But cytomegalovirus, Dr. Reder said, for unknown reasons, seems to protect against multiple sclerosis. So the fact that those infected with it did not have a higher risk of multiple sclerosis might not be surprising.

Others said the study was convincing evidence of cause and effect.

“The way it was done is quite compelling,” said Dr. Michael Davin Kornberg, a multiple sclerosis specialist at Johns Hopkins. “It really is the most convincing data we’ve had for a causal association.”

That leaves the question of what to do now.

Dr. Bruce Cree, a multiple sclerosis researcher at the University of California, San Francisco, noted that it might be difficult to treat multiple sclerosis by going after Epstein-Barr because it can be difficult to find the actual virus in patients. Even though multiple sclerosis is a disease of the brain and spinal cord, he could not find the virus in patients’ spinal fluid.

But patients do seem to harbor cells in their brains that produce antibodies to Epstein-Barr virus. Dr. Cree is researching whether he can treat multiple sclerosis patients by eradicating those cells, which are infected with Epstein-Barr.

And Dr. Lawrence Steinman, a multiple sclerosis researcher at Stanford, who wrote a perspective accompanying the Harvard group’s paper, said an experimental mRNA vaccine against Epstein-Barr was one of a number of approaches being designed to stop the virus from affecting the brain.

The question now, he said, is, “Can we make multiple sclerosis go away?”

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Ciencias

How The mRNA Vaccines Were Made: Halting Progress and Happy Accidents

“I said, ‘I am an RNA scientist. I can do anything with RNA,’” Dr. Karikó recalled telling Dr. Weissman. He asked her: Could you make an H.I.V. vaccine?

“Oh yeah, oh yeah, I can do it,” Dr. Karikó said.

Up to that point, commercial vaccines had carried modified viruses or pieces of them into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions — encoded in mRNA — that would allow the body’s cells to pump out their own viral proteins. This approach, Dr. Weissman thought, would better mimic a real infection and prompt a more robust immune response than traditional vaccines did.

It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were not impressed, either. His lab had to run on seed money that the university gives new faculty members to get started.

By that time, it was easy to synthesize mRNA in the lab to encode any protein. Drs. Weissman and Karikó inserted mRNA molecules into human cells growing in petri dishes and, as expected, the mRNA instructed the cells to make specific proteins. But when they injected mRNA into mice, the animals got sick.

“Their fur got ruffled, they hunched up, they stopped eating, they stopped running,” Dr. Weissman said. “Nobody knew why.”

For seven years, the pair studied the workings of mRNA. Countless experiments failed. They wandered down one blind alley after another. Their problem was that the immune system sees mRNA as a piece of an invading pathogen and attacks it, making the animals sick while destroying the mRNA.

Eventually, they solved the mystery. The researchers discovered that cells protect their own mRNA with a specific chemical modification. So the scientists tried making the same change to mRNA made in the lab before injecting it into cells. It worked: The mRNA was taken up by cells without provoking an immune response.

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Ciencias

Howard Solomon, 94, Dies; His Business Success Had a Personal Connection

“Forest Pharmaceuticals deliberately chose to pursue corporate profits over its obligations to the F.D.A. and the American public,” Carmen Ortiz, the U.S. attorney for Massachusetts, said when the settlement was announced.

The company denied the allegations. In a statement at the time, Mr. Solomon said, “We remain dedicated to ensuring that we operate in full compliance with all laws and regulations.”

In 2011, Forest Labs won a proxy fight against the shareholder activist Carl C. Icahn, who had argued that the company had, among other things, lost billions of dollars of shareholder value over the previous decade. Mr. Icahn continued to pursue Forest Labs with a second proxy fight in 2012, which ended with one of his nominees elected to the company’s board.

In a letter to Mr. Icahn during that fight, Mr. Solomon wrote: “Your discourse thus far has shown a striking lack of strategic ideas. Instead, it has been replete with wild and baseless accusations, innuendo and distortion of facts.”

Still, at some point, Mr. Solomon reached out to Mr. Icahn, and they had a series of dinners.

“We got friendly,” Mr. Icahn said in a phone interview. “I thought he was a nice gentleman, a courtly guy.” He added: “I didn’t agree with the way he ran the business necessarily, but he was a nice guy who was thrilled with the outcome. He made a lot of money.”

In 2013, Mr. Solomon announced his retirement as chief executive and was replaced by Brent Saunders, an executive friendly with Mr. Icahn. Then, in early 2014, Actavis (now Allergan) paid $25 billion to acquire Forest Labs. Mr. Solomon, still the chairman, left after the acquisition and formed a family investment firm with his younger son, David, who had been a Forest Labs executive.

In addition to his sons, Mr. Solomon is survived by his wife, Sarah Billinghurst Solomon, a former assistant general manager of artistic affairs at the Metropolitan Opera, and five grandchildren. His first wife, Carolyn (Bower) Solomon, died in 1991.

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Ciencias

The Kunga Was a Status Symbol Long Before the Thoroughbred

In ancient Mesopotamia 4,500 years ago, long before horses arrived in the region, another spirited member of the equine family, the kunga, took a starring role in pulling four-wheeled wagons into battle.

Archaeologists had suspected that these animals — depicted in art, their sales recorded in cuneiform writing, their bodies sometimes laid to rest in rich burial sites — were the result of some kind of crossbreeding. But proof was lacking.

On Friday, a team of researchers reported on more than a decade of research in the journal Science Advances, concluding that studies of ancient DNA showed the kunga was a cross between a female donkey (Equus Africanus asinus) and a male Syrian wild ass (Equus hemionus hemippus).

The kunga is the first known instance of a human-engineered hybrid of two species, a production far beyond the traditional processes of the domestication of animals, the researchers found.

Eva-Maria Geigl, a specialist in ancient genomes at the University of Paris, and one of the scientists who did the study, said the breeding of kungas was really “early bioengineering” that developed into a kind of ancient biotech industry.

Like mules, which are hybrids between horses and donkeys, and which were created much later, the kungas were sterile. Each new kunga was a one-off, a mating between a wild ass stallion and a donkey.

The stallions had to be captured and kept in captivity, even though they were highly aggressive, as modern records have indicated. Dr. Geigl said that the director of a zoo in Austria, where the last captive Syrian wild asses died, described them as “furious.” Archaeological records show that a breeding center in Nagar (now Tell Brak, Syria) shipped the young kungas to other cities. They were costly animals, status symbols, and were used in war and military ceremonies.

Kungas held their high status for at least 500 years, Dr. Geigl said. Horses did not appear until around 4,000 years ago to take their place in battle and ceremony, and to contribute to the creation of other hybrids. Before the current research, the oldest known hybrid was a mule from a site in Turkey dating to 3,000 years ago. Members of the same team reported on that find in 2020.

The research team had to cope with the very poor preservation of fossils from desert areas, but used a variety of techniques to examine ancient DNA. Laurent Frantz, a paleogenomics expert at Ludwig Maximilian University of Munich, who was not involved in the study, said that despite these difficulties, the “results were very convincing,” showing that people “were experimenting with hybrid equids long before the arrival of the horse.”

Fiona Marshall, an archaeologist at Washington University in St. Louis, who has researched the prehistory of donkeys and their domestication, said the study was “enormously significant” partly because it showed that the breeders had clear intentions. The early process of domestication was always murky — probably part accident, part human intervention — but this research showed what the ancient Syrians were after.

“People wanted the qualities of a wild animal,” she said. Donkeys might have been tamer than their ancestors, the African wild ass, but the breeders in Mesopotamia wanted to back breed to other wild asses for strength and speed — and perhaps size. Although the last known living examples of the Syrian wild ass were very small, a little more than three feet at the withers, older animals of the same species were larger.

Dr. Geigl — who collaborated on the research with Thierry Grange at the University of Paris, E. Andrew Bennett, now with the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing, Jill Weber at the University of Pennsylvania Museum of Archaeology and Anthropology and others — said that the team sequenced DNA from numerous sources, including modern donkeys, horses and several species of wild asses, and museum samples.

Of particular importance were the bones of 44 kungas interred at a rich burial site in Syria called Umm el-Marra. Those skeletons had earlier led Dr. Weber and others to hypothesize that they were hybrids and that they were the kungas described in tablets and represented in art.

Their teeth showed bit marks and indicated they had been fed a special diet. The new research used DNA from those kungas to compare to other species and determine that these animals were, as suspected, the result of breeding female donkeys and male Syrian wild asses.

The research team also sequenced DNA from a Syrian wild ass found at Gobekli Tepe in Turkey, an 11,000-year-old site where humans gathered for purposes still being studied, and from two of the last animals of the species, held at a zoo in Vienna.

It is a species that no longer exists. The kunga can’t be recreated, Dr. Bennett said. Donkeys are plentiful, of course, but the last known Syrian wild asses died in the late 1920s. One was shot in the wild and the other died in a zoo in Vienna.

“The recipe for making the kunga was unknown for thousands of years,” Dr. Bennett said. “And we finally decode it not even 100 years since one element has become extinct.”

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