Bacteria that was sent into space on the shuttle came back to Earth genetically altered and significantly deadlier.
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Salmonella, the bacterium that causes food poisoning, was sent in special test tubes as a payload on the space shuttle Atlantis in September 2006. When it returned, scientists found the bugs were three times more deadly to laboratory mice than the same germs grown in identical containers and at the same temperature and humidity as on the spacecraft.

Researcher James Wilson, lead author of a report on the phenomenon in Tuesday’s edition of the Proceedings of the National Academy of Sciences, said the bacteria grown in space showed altered protein production arising from 167 of their estimated 4,000 genes, which made them far more virulent than their Earth-bound counterparts.

After the shuttle touched down on terra firma 12 days later, the researchers gave lab mice varying doses of the salmonella. After 25 days, 40 per cent of the animals given bacteria that had stayed home were still alive, compared with only 10 per cent of rodents given the space-travelling germs.

Furthermore, Wilson said, it took about one-third as much of the bacteria from the orbiting shuttle to kill half the mice, compared with the salmonella on Earth.

So what is it about space that so alters bacteria and what does that mean for astronauts or future space travellers?

“The answer is we don’t know, ” Wilson, a research assistant professor at the Biodesign Institute at Arizona State University, said Monday from Tempe, Ariz.

But he believes the bacteria reacted to what’s called “low fluid shear,” caused by microgravity’s effect on the liquid inside the test tubes aboard the space vehicle.

When new salmonella cells grow in microgravity, the force of the liquid passing over the cells is reduced, likely causing them to change, said Wilson.

That fluid shear effect also occurs in humans, in certain areas of the gastrointestinal tract, where salmonella can take up residence and cause illness, he noted.

“A major goal of the study was to see how space flight affects a bacteria and particularly a pathogen, because those pathogens (disease-causing germs) will be up there with astronauts. With all the quality control we do and efforts to prevent that, it will happen.”

“We do want to apply the results we have here to crew safety,” he said. “And seeing how these changes affect their (bacteria’s) ability to cause disease, we can also use that information to fight infections here on Earth.”

“So this is not just space-type stuff. It does also help humankind on Earth as well.”

Microorganisms may soon be efficiently and inexpensively producing novel pharmaceutical compounds, such as flavonoids, that fight aging, cancer or obesity, as well as high-value chemicals, as the result of research being conducted by University at Buffalo researchers.

In work that could transform radically the ways in which many of these compounds are produced commercially, the UB researchers are genetically engineering microorganisms, such as E. coli, into tiny, cellular factories.
Several patents related to this work have been filed by UB. The team also is in discussions with companies in the U.S. and abroad.

First Wave Technologies, Inc., a technology development company based in UB’s New York State Center of Excellence in Bioinformatics and Life Sciences, which is collaborating with the UB group, recently received a highly competitive Phase I Small Business Innovation Research (SBIR) grant from the National Science Foundation to focus on the biosynthesis of a popular group of flavonoids called isoflavonoids.

“Ultimately, we want to be able to take a designed E. coli off of the shelf and drop into it the enzymes that constitute a particular biosynthetic pathway in order to make exactly the product we want,” said Mattheos A. G. Koffas, Ph.D., assistant professor of chemical and biological engineering in the School of Engineering and Applied Sciences and leader of the UB team.

The UB approach to synthetic chemistry addresses some of the major challenges in conventional industrial production of specialty chemicals.

Through the use of specially adapted bacteria, specialized enzymes and natural feedstocks, microbial biosynthesis reduces or eliminates the need for petrochemical sources, elevated temperatures, toxic heavy metal catalysts, extremes of acidity and dangerous solvents, Koffas said.

In addition, the natural enzymes the UB researchers are using can facilitate chemical reactions that are difficult to accomplish through conventional chemistry, such as chiral synthesis, glycosylations and targeted hydroxylations, common but challenging steps in many syntheses.

“We are finding out how we can actually ‘train’ microbial systems to produce high yields of chemicals to be used as pharmaceuticals and to make production processes more efficient, less expensive and more environmentally friendly,” Koffas said.

As with any commercial endeavor, process efficiency is a critical concern, he noted.

In work published in Applied and Environmental Microbiology in June, Koffas and his colleagues produced about 400 milligrams of flavonoids per liter of cell culture, far above the next highest yield of about 20 milligrams per liter produced by other microbial synthesis efforts.

“We have done this by increasing the amount of precursor available and re-engineering the native microbial metabolism,” he explained, adding that they have taken different approaches to identifying the pathways that lead to the biosynthesis of precursors for desired compounds.

“Further improvement of production yields are possible and various approaches are being pursued by our team at this time,” he said.

Another major challenge for microbial biosynthesis is that the enzymes required for certain chemical steps have special requirements that the host cell cannot meet efficiently, Koffas said. In some cases, the enzyme needs to be re-engineered, while in others the host cell needs modification.

Koffas’ lab recently achieved the functional expression in E. coli of P450 monooxygenases, enzymes that are used widely in nature, but are not readily expressed in most industrially important microorganisms.
“P450 is very important in the synthesis of natural products,” said Koffas. “For example, both Taxol, the breast cancer drug that is currently produced from plant cultures, and artemisinin, the anti-malaria drug, have P450 enzymes in their biosynthetic pathways.”

The Koffas lab has introduced ways to modify both the P450 monooxygenase enzymes and the host cell, thereby improving their yield of flavonoids.

Microbial biosynthesis methods also are making it easier to create analogs of existing drugs, as well as new molecules for a broad range of therapeutics.

The UB researchers are particularly interested in developing novel molecules that can be used to treat chronic diseases, such as type II diabetes and obesity.

They also are using the methods to produce specialty compounds, such as natural pigments, that could replace chemical dyes in food.

Koffas’ goal is to employ these microbial synthesis methods for a wide variety of applications.
Flavonoids, which are of interest to pharmaceutical companies because of their antioxidant and anti-carcinogenic properties, are difficult to produce using currently available methods.

Microbial synthesis strategies also are being adapted by the UB researchers for the biosynthesis of other commercially significant classes of compounds, including vitamins, anti-cancer drugs, anti-parasitic drugs, dyes and food supplements.

The UB group is working on boosting yields further and hopes to achieve pilot scale production of flavonoids by the end of this year.

For further information on commercialization of this technology, you may contact Mike Fowler, commercialization manager for bioinformatics and health sciences, in UB’s Office of Science, Technology Transfer and Economic Outreach.

Koffas’s research has received funding from the National Science Foundation, UB’s New York State Center of Excellence in Bioinformatics and Life Sciences and the Independent Research and Development Fund of the UB Office of the Vice President of Research.

This story has been adapted from a news release issued by University at Buffalo.

Investigators at the University of British Columbia, have found a way to turn on the brakes of a cell, and thus halt abnormal blood-cell growth in a range of 1) ___ and autoimmune disorders, and blood cancers. The immune system relies on white blood cells called, 2) ___, to defend the body against infectious pathogens such as bacteria and viruses. In a healthy body, leukocytes are strictly controlled and turned off when no longer needed. This off-switch is controlled by a 3) ___ called “SHIP” – standing for SH2-containing inositol 5’phosphatase. SHIP, which is only present in 4) ___ cells, was discovered in 1997 by, a senior scientist at the BC Cancer Research Center. It regulates the PI3 kinase (PI3K) pathway which is essential for cell growth, survival and 5) ___ cell activation. Inappropriate or persistent activation of the PI3K pathway, can result in serious inflammatory/immune diseases or blood cancers such as multiple 6) ___, leukemia and lymphoma. Aiming to find new drugs for treatment of blood borne diseases, a team searched for drugs that could modulate SHIP. The team screened a library of sea sponge extracts for molecule compounds that can turn SHIP on. Sea sponges are a rich source of novel bio-active 7) ___, created by nature, to protect themselves against marine predators. Interestingly, many of these compounds possess important medicinal properties. The sponge library has already produced other agents with interesting biological properties on 8) ___ cells, some of which are in clinical development as potential drugs for treatment of human diseases. The researchers identified a compound, now known as AQX-MN100. It is able to inhibit immune and blood cell activation both in the test tube and in mouse models of human inflammatory disease and lymphoma by activating SHIP. This is an entirely new paradigm for controlling run-away cells. Previous research efforts were aimed at trying to control the cells through blocking stimulation 9) ___. In a run-away train analogy, this would be like taking your foot off the accelerator and the train will eventually stop when it runs out of fuel vs. this new approach of directly applying the brakes. Since SHIP is only found in 10) ___/___ cells, side-effects of SHIP-based therapy on other cells of the body, are expected to be limited. The AQX-MN100 discovery has been validated by proof-of-principal grants from the Canadian Institutes of Health Research (CIHR) aimed at translating basic research findings into clinically applicable therapy. This research is highlighted in the Sept. 15 edition of Blood, Journal of the American Society of Hematology.

ANSWERS: 1) inflammatory; 2) leukocytes; 3) protein; 4) blood; 5) immune; 6) myeloma; 7) compounds; 8) mammalian; 9) signals; 10) immune/blood