Swords to Plowshares

"We took a Russian delivery system, a rocket as it were, and put an American warhead on it," says Jeffrey A. Gelfand, international director of the Center for Integration of Medicine & Innovative Technology.

Under the auspices of the BioIndustry Initiative (BII), a new program sponsored by the U.S. State Department's Office of Proliferation Threat Reduction (OPTR), the consortium of Massachusetts medical research institutions is making use of a drug delivery system from Russia's Research Center of Molecular Diagnostics & Therapy (RCMDT).

The Massachusetts consortium hopes to apply the system to an immunizing agent that targets an antigen first identified and cloned at Massachusetts General Hospital. The agent, which targets a protein expressed in malignant tissue, is in the early stages of development at RCMDT. The partners plan to move production to a BII-funded, current Good Manufacturing Practices (cGMP)-certified facility in Russia for preclinical production.

Gelfand's weapons analogy is well chosen in that RCMDT, like all of the laboratories and production facilities BII deals with, is a former Soviet biological weapons operation. The two-year-old State Department program, born of the Joint Statement on U.S.-Russian Cooperation Against Bioterrorism, signed by Presidents George W. Bush and Vladimir V. Putin in November 2001, aims to convert such facilities into self-sustainable, peaceable biotech businesses.

"Post 9/11, the State Department received emergency funds from Congress to expand our efforts," says Jason E. Rao, chemical and biological engagement officer at OPTR and director of BII in the U.S. "Congress asked the State Department after the anthrax attacks to accelerate drug and vaccine development for highly infectious diseases and also help redirect the former biological production facilities that were in the former Soviet Union."

BII picks up where a 12-year-old program, the State Department-sponsored International Science & Technology Center (ISTC), leaves off. While ISTC works with Russian research institutes to redirect the efforts of scientists--preventing them from pursuing biological warfare research in North Korea, Iraq, and elsewhere--BII aims to foster actual business ventures at labs and production facilities.

According to program administrators, the business angle adds to the complexity of securing biotechnology in the former Soviet Union, where science and research were well funded for decades but where an infrastructure for science-based business is completely lacking. Standards for everything from the growing of laboratory animals to the manufacture of pharmaceuticals need to be established, and scientists have to learn business basics--perhaps a bigger culture shock in the former Soviet states than anywhere else.

PARTICIPANTS in the effort, however, claim that significant headway has been made in the past two years. "The quality of Russian science, I have found, is absolutely superb," Gelfand says. "I have found a gold mine of new ideas that I'm excited to bring to Western academic labs and Western pharmaceutical companies."

For Evgenii S. Severin, general director and head of biochemistry at RCMDT, cooperation with U.S. agencies is bringing Russian science into the light. "Before BII, you could not invest in production for the international market in Russia," Severin says. "We lacked the mechanism. Vaccines need international certification for financial support. Now we have certification, international patents, and production. We are bringing in Russian science in a real way, not just in publishing papers."

RCMDT is a small-molecule research facility that traditionally focused on entities the body generates, such as interferon and cytokines, to turn on or turn down the immune response system. With the help of funding from BII, the group formed a partnership with the Moscow Medical Academy aimed at employing its polymeric nanoparticle drug delivery technology in treatments for drug-resistant tuberculosis and cancer.

BII brokered a collaboration between RCMDT and Antigenics, a U.S. biotechnology company, to develop a delivery system for tuberculosis and cancer drugs, and BII also landed RCMDT a grant from the National Institutes of Health for a collaborative project on new approaches to disease research.

Another Russian institute, the State Research Center of Virology & Biotechnology, known as Vector, in Novosibirsk, focuses on virology, molecular biology, and genetic engineering. BII has funded an independent validation of Vector's novel HIV vaccine and has assisted with patent filing on the institute's approach to hepatitis C and influenza. BII has also brokered collaboration with Wyeth Vaccines and Aventis Pasteur on AIDS vaccines.

In addition, BII has provided grants for RNA-based antiviral research being done by Vector and the U.S. biotech firm SomaGenics. The initiative will also fund a joint antiviral therapeutics production scale-up project planned by Vector and SiBioPharm, one of the four largest biotech plants in Russia.

Much of BII's groundwork in scouting out sites and planning for business development is done in partnership with the U.S. Civilian Research & Development Foundation (CRDF). Among its recent projects is the conversion of a vaccines plant to a feed mill in the former Soviet state of Georgia.

"The facility had been closed. It was antiquated and there were dangerous pathogens," says James Wolfram, senior scientist with CRDF. "There are still scientists there, and we are offering a way of making the facility sustainable through a different operation." CRDF is also upgrading a St. Petersburg facility called the Institute of Highly Pure Biopreparations, where pilot-scale cGMP manufacturing is now in place.

Wolfram says many research and production facilities in the Soviet Union were used for both industrial and weapons purposes. "Some agricultural facilities had a dual use, producing vaccines and also looking for virulent organisms in whatever diseases they were developing vaccines for," he says.

Many of these facilities have fallen on hard times. "We maintain we can redirect their efforts," Wolfram says. The first step is bringing operations up to international standards. BII reached a milestone recently with the establishment of an animal breeding facility at the Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry in Pushchino, Russia, producing special pathogen-free (SPF) rodents for the first time in Russia. By 2005, Wolfram says, Russia will require SPF rodents in all biomedical research, a standard that was set in the U.S. in the 1960s.

Simply moving from research to commercial production is a far tougher hurdle, however. "They have no experience with a market economy," says Ronald F. Lehman II, director of the Center for Global Security Research at Lawrence Livermore National Laboratory and chairman of the governing board of ISTC.

"We work hard to make sure Russian institutes get good value for their intellectual property, but we've had to work very hard to get them to understand that IP is an economic good," Leh man says. "The joke is that when you get a patent here, you hang it on the wall next to your Soviet medals. It's treated like an award. The fact that it is actually something to hold on to as a financial resource seems somewhat alien."

Lehman and others say that while Russian researchers were initially suspicious of U.S. interest in their operations, most resistance has evaporated. Lehman attributes this change partly to bonding between U.S. and Russian scientists. "The scientific community--I hesitate to say it--is a very friendly band of brothers," Lehman says. "There is a long history of ties, and they have grown rapidly. There are cultural differences, but scientists tend to get along well with scientists."

MORE IMPORTANT than the cultural differences, according to CRDF's Wolfram, are the differences in science and technology that evolved in parallel in the Soviet Union and the West. "We are learning a lot on aspects of disease that we have never spent much time on in the U.S.," he says. "Scientists in this country live off grants. And since we don't get Ebola in the U.S., there wasn't any kind of an effort on this disease, whereas Russians have worked on it for decades."

Natalya V. Savinova, project manager for BII in Moscow, is typical of the researchers employed at many of the biotechnology institutes in the former Soviet Union. Working at first on vaccines at the Obolensk Institute of Applied Microbiology, Savinova was among the researchers who formed Serpukhov, a preclinical research operation near Moscow in 1993. She began working as an interpreter for the State Department in 1993 and took the position at BII in 2002.

Savinova maintains that researchers were often not aware that their work was being channeled into biological weapons. In the 1980s, she recalls, she studied the physical chemical properties of "powderlike preparations." She was also involved in research on vaccines targeting various pathogens. "We never talked about bioweapons," she says. "Maybe we were not informed."

Now Savinova is focused on redirecting biotech facilities, arranging liaisons between Russian institutes and U.S. companies such as Eli Lilly, Diversa, and Dow Chemical. She says trust is building. "The production facilities are open to new relationships and interested in starting new businesses."

According to Barbara A. Miller, Dowpharma's research manager for vaccines and peptides, BII is a useful resource, even to a company like Dow, which has established its own contacts with researchers in the former Soviet Union. "BII is good at identifying your needs and finding possible partners in Russia," Miller says. "They are an excellent matchmaker."

Dow has submitted a proposal to Vector and the State Research Center for Applied Microbiology for possible collaboration on the development of plant-derived vaccines, according to Miller.

While progress is being made, observers agree that commercialization of Russian biotech is still in its early days. "Much of this is a brave new world," Lehman says. "Any kind of economic, political, or social turmoil will complicate commercialization." And while the top priority is nonproliferation of biological weapons, BII and its partners are trying to push as much science as possible from Russian lab benches into production.

Lehman acknowledges concern that underutilized Russian scientists might lose their cutting edge, but he is optimistic that links with the West will help. "They are incredibly talented, bright people," he says. "They are still inventive, learning more and more about how to engage the outside community. Some of it is leading to commercialization."