Cui Chengbin, a Ph.D and a researcher of pharmacology at Ocean University of Qingdao, East China's Shandong Province, declared at an international symposium last week that his team has succeeded in making some once-inactive microbes produce bioactive metabolites that may be used as a source of future medicines.

Their research, once successfully completed, may lead to a revolution in the pharmaceutical industry, experts said.

Microbes are very small living things that can only be seen under a microscope.

Cui did not name the microbes they've cultured, but said the experimental results were quite "encouraging" and proved their approaches applicable. "Present results suggest our research strategy is in the right direction and feasible, although some techniques are yet to be improved," he said in a keynote speech at the symposium on molecular science held by the university in Qingdao.

New medicines that have as a miraculous effect as that of penicillin may be developed using their new approaches in the long run, he predicted.

Derived from metabolites of a microbe called penicillium, penicillin was the first and probably the best-known drug produced with microbes and used to treat bacterial infections in humans.

Despite the great success of penicillin, the majority of microbes in the world remains away from human use.

The reason lies with the traditional processing techniques in extracting medically useful substances from microbes, according to Cui.

Ever since its discovery more than 70 years ago, penicillin, like many other antibiotics subsequently discovered, has remained little changed in terms of production techniques, most of which are based on the culture of penicillin-producing molds rather than chemical synthesis.

The making of penicillin, as well as its magical effect, has inspired scientists to look for other microbes that may function as biological medicine factories.

Yet it has been found that less than 5 percent of the microbes in the world are culturable like penicillium. But Cui believed that was too optimistic to be accurate.

"The real number, in my opinion, is less than 1 percent." he said. And even less can be developed as medicine, he added.

"A major parameter of their medical value is to see if the extracts from the microbes are bioactive against certain bacteria," Cui explained. "Unfortunately most of the extracts obtained by humans to date show no bioactivity and are therefore called useless microbes."

Cui believes they could be extremely valuable if new approaches are found to culture those non-culturable microbes and isolate and purify the bioactive substance from them.

Ribosome Engineering

One of his approaches is based on a newly emerging technology called "ribosome engineering," with which the scientists hope to transform the target microbe itself into a working machine against bacteria.

Ribosomes constitute one of the most essential components of the cell, the basic proposition of life. Ribosomes are important because they are tiny molecular machines responsible for translating the genetic code and synthesizing proteins. Thus, scientists also liken ribosomes to the miniature factories that build new proteins.

But recent studies found that it may serve more than just as a venue for protein synthesis; it "may also control genes dynamically by themselves," according to Kozo Ochi, the leading Japanese scientist who started ribosome engineering.

Cui and his colleagues noticed that altering certain parts of ribosomes can activate certain genes and awaken the potential functions of micro-organisms that lead to the production of new antibiotics and bioactive substances.

This process is generally known as "ribosome engineering."

In their experiment, some "useless microbes" were selected to undergo ribosome engineering and then were cultured, under the same conditions as that of the original strains.

Analysis of the cultured strains after their ribosomes were altered showed they contained bioactive substances in the metabolites, which proves the approach is feasible.

Cui disclosed that they have screened out several such microbial strains and are now engaged in the isolation of medically useful substances, a key step towards practically usable medicine.

"In fact, we've got the bioactive compounds," he disclosed.

But he denied any overnight success of a new magic medicine, saying many technical obstacles remain to be cleared.

For one thing, what they are doing is mainly focusing on basic research. Provided everything goes smoothly, it will take further clinical trials before a new medicine can be approved.

For another, ribosome engineering, as a newly emerging technology, is still immature.

The technology was initiated by a Japanese research team led by Kozo Ochi of the National Food Research Institute of Japan, who discovered in the late 1990s the novel gene-controlling functions of the ribosome.

Their discovery became precursor of a large-scale project started in 1998 in Japan called "Origin of Ribosome Engineering," for which Ochi serves as chief scientist.

The project with a five-year term, according to Ochi, is aimed at altering ribosomes in a controlled manner in order to produce desired microorganisms or proteins.

Cui got his inspiration from the project when he was a contract-researcher at the Institute of Physical and Chemical Research of Japan from 1994-97, a major participant of the project.

With the technology still under development, there remains uncertainties in its application in the field of medical research, Cui admitted.

Ribosome engineering is not the only approach Cui and his colleagues have adopted. Another approach Cui's team is now working on is like leasing a new machine to produce the desired substance.

Using genetic engineering technology, they extracted the genomic DNA from a non-culturable microbe and inserted it into a host microbe that is culturable but does not produce any bioactive substances.

Then the genetically engineered microbial strains were cultured and fermented under the same conditions as those of the host strains until sufficient microorganisms were produced for evaluation of their bioactivity.

Evaluation was also carried out to see if the inserted DNA of the target microbe has been working in the host microbe.

They have obtained several such engineered strains that produced bioactive substances and have isolated two bioactive compounds so far.

(China Daily July 26, 2002)