Site: Pacific Institute of Bioorganic Chemistry
Far East Branch, Russian Academy Sciences
Vladivostok, 690022, Russia
Phone: (4232) 222528, 223721
Fax: (4232) 314050

Date Visited: October 23, 1995

WTEC Attendees:

D. Walsh (report author), H. B. Ali, R. Blidberg, S. Chechin, M. J. DeHaemer, L. Gentry, J. Moniz, J. B. Mooney

Hosts:

Academician George B. Elyakov

Director, Vice President of RAS, Chairman FEB

Natalie M. Sheptova

Assistant Director for Foreign Relations

BACKGROUND

The Pacific Institute of Bioorganic Chemistry (PIBC) was founded as the "Institute of Biological Active Agents" in 1964. It was given its present name in 1975 and is part of the Far Eastern Branch of the Russian Academy of Sciences. Academician Elyakov has been its director for the past 30 years. He is also presently the chairman of the Far Eastern Branch of the Russian Academy of Sciences and a vice president of the academy.

The PIBC's activities are coordinated with those of similar institutes in Russia working on problems of physicochemical biology and biotechnology. In the Russian Far East there is a wealth of terrestrial and marine flora and fauna, some of it unique to this part of the world. While the institute works with both land and sea organisms, the primary research focus is on the study of marine organisms at the molecular level. This direction offers the greatest potential for discovery of bioactive substances that can used for the benefit of man. Some examples of the benefits are given below:

Products developed at PIBC have been awarded Russian patents; but due to the present severe economic conditions, the expensive process of obtaining foreign patent protection has not been attempted. Nevertheless, the work of this organization has attracted foreign interest from government organizations such as the U.S. National Institutes of Health (NIH) and major drug companies such as Glaxo and Hoffman LaRoche.

In addition to obtaining rights to both use and manufacture bioactive substances developed by the institute, foreign organizations are also very interested in the 8,000 strain reference collection developed here. The marine microorganisms collection alone contains 700 strains of bacteria, 500 of actinomycets, and 500 marine fungi. The institute has offered all, or parts of this documented collection for use by other research institutions through purchase or leasing for fixed periods of time. No transfers have yet taken place

The visibility of the organization was raised considerably a number of years ago when it was visited by then-Soviet Union Chairman Mikhail Gorbachev. During the visit he was briefed on heart medicines developed over a period of 10 years at PIBC. He was sufficiently impressed by this work that he personally ordered increased funding support for the biomedical research program.

At present, the institute, located in a research campus in the northern part of Vladivostok, has 350 workers, of whom 70 are Ph.D.s and 15 are doctors of science. Part of the support staff is associated with the maintenance and operation of the institute's dedicated research vessel, Akademik Oparin.

The institute's annual budget is about 2 billion rubles. The total budget for the Far Eastern branch of the Russian Academy of Sciences is 110 billion rubles. This is spread among 26 scientific institutions. Thus, PIBC gets about 1.8% of the total research support funds allocated to this region.

The WTEC team spent approximately two hours at this site. All of this time was spent in the director's conference room where he briefed us on the work of his organization. Some of the viewgraph transparencies he used are appended to this site report (Figs. 2.20 - 2.23, Table 2.4). No laboratories or other facilities in the institute building were visited.

Unfortunately, the PIBC did not have any publications in English available for the team. Therefore, this site report is largely built on the briefing provided by the director, a few viewgraph slides, and the author's slight acquaintance with the general field of marine bioactive substances.

The team also visited the oceanographic research ship Akademik Oparin. Details of this visit are the subject of a separate site report.

RESEARCH AND DEVELOPMENT ACTIVITIES

As Academician Elyakov pointed out, land and ocean organisms' paths of evolution divided hundreds of millions of years ago. Therefore, while plant and animal extracts have been used for medicinal purposes for thousands of years, it is only recently that the search for new substances has extended to the sea. Because of the diverse evolutionary paths, there is every reason to expect major new advances from bioactive substances extracted from marine organisms.

The following breakdown of the publications list of the institute gives a good idea of the present focus of the marine bioactive substances research effort:

     Organism       Percentage of PIBC publications
     -----------       -----------------------------------
     Seaweeds                   35%
     Sponges                    20%
     Echinoderms                18%
     Coelenterates              12%
     Fishes                     10%
     Microorganisms*             5%
    
          * (includes: bacteria, actinomycetes and marine fungi)

One major research direction in seaweeds lies in the investigation of polysaccharides. It is believed they may have biomedical activities that may provide relief for AIDS patients. The institute's studies in the field of molecular immunology have enabled scientists to extract from various species of mollusks and seaweeds substances that stimulate the immune system and react against tumors without toxic effects.

Techniques have been found for extracting from inedible marine materials and fisheries waste (a previously wasted byproduct of commercial fishing) substances such as antioxidants, fungoid antibiotics, and immune system stimulants. The heart medicine that impressed Chairman Gorbachev was derived from an inedible marine animal, the sea urchin.

Investigations of marine invertebrate microorganisms capable of biosynthesis of substances with antimicrobial and cytotoxicogenic activities are being actively pursued. Strains of marine microorganisms have been found that produce a number of unique enzymes that appear to be very promising in the field of genetic engineering.

The PIBC research program does not eventually point towards commercial harvesting of natural flora and fauna as sources for bioactive substances. Rather, they collect and analyze the natural organisms for bioactive properties. If the properties found are unique or superior to known substances, then the next step is to learn how to synthesize the natural bioactive compounds. The well-understood sequence of events is as follows:

  1. Isolation of the bioactive substance from the natural organism (plant or animal)
  2. Purification of the substance to make it 'free-standing' for further analysis
  3. Structural investigation of the substance's chemical makeup
  4. Creation of a bioassay to determine all of the possible activities
  5. Synthesis of the natural compound through creation of a man-made chemical compound.

The "Trends of Marine Biotechnology Development," according to Academician Elyakov, are shown in Figure 2.20. Here it can be seen how marine organisms and fish industry wastes contain the resource pool for bioactivity investigations. Further, the various applications and activities are indicated as they are derived from the natural substances. Some other viewgraphs presented by the hosts are also attached (Figs 2.21 - 2.23).

At present, the institute's ocean research activities do not include investigation of the chemosynthetic organisms associated with hydrothermal vent areas on the deep-sea floor.

PIBC scientists have worked on joint programs in bioactive substances with researchers from the Harbor Branch Oceanographic Institution at Fort Pierce, Florida. Scientists from each institution have shared research cruises on each other's vessels and have done work together at both laboratories on shore. There appears to be good cooperation and mutual respect between these two organizations.

COMMERCIAL ACTIVITIES

Academician Elyakov showed a series of three viewgraphs titled, "Medicinal Preparations Obtained at the Pacific Institute for Bioorganic Chemistry." These are reproduced as Table 2.4. The preparations of marine origin were as follows:

     Commercial name          Activity

     Zosterin                 Decreases toxicity of antitumor drugs; purges heavy
                              metals from human organisms
    
     Preparation "CD"         Strong immuno-stimulator; increases level of antibodies

     Histochrom               Cardioprotector and anti-inflammatory agent

     Collagenase              Treatment of wounds; removal of dead and scar tissue

     Translam                 Antitumor and immunostimulation

All these drug products are covered by active Russian patents. All these patents are owned by PIBC, with the exception of Histochrom. This patent ownership is shared with the State Medical Institute in Vladivostok and the Cardiology Research Center of the Russian Academy of Medicinal Sciences (Moscow). In addition to the marine-derived products, there are two others that are developed from terrestrial plants:

     Commercial Name          Activity

     Maxsar                   Natural antioxidant.

     Cetris                   Bacteriastat, may be good for prophylaxis of cancer.

Both of these products are protected by Russian patents owned by the institute. More extensive details on these marine and terrestrial-origin compounds are in Table 2.4.

Perhaps two of the more unusual products from PIBC are liquid medicines which have rather high alcohol contents (80-90 proof). One is called "Russian Balm" and the other, a vodka- type product, "Golden Horn." Both are made from extracts of various plants which are said to have medicinal value. These are not distilled liquor products: the alcohol is used to extract the medicinal oils from the plant materials. While Russian Balm contains several plant extracts, Golden Horn is derived from a single plant "Eleutherococc" (Eleutherococcus Maxim). The WTEC team had the opportunity to sample both products.

PIBC operates its own manufacturing facility in the basement of the institute building. Most of the products described here are made on site in limited quantities.

SUMMARY

Director Elyakov said the institute's "dream" is to be set up as a company, independent of the government. In this way a rational, profit-making enterprise could be organized to market the discoveries, reference collections, and products produced by PIBC. At present, any monies made are taken by the government, and there is little incentive to develop more commercial products.

If PIBC could become an independent organization, Academician Elyakov believes it could be profitable within three years. This could be done through joint ventures, direct sales of products manufactured locally, licensing of production to other companies, and payment of royalties for processes and products developed by PIBC but produced elsewhere.

As noted earlier, the WTEC team did not visit any of the laboratory or production facilities at the institute. Also, no printed materials were received describing the PIBC and its work. Therefore, this site report is based primarily on Director Elyakov's briefing to the team and on subsequent discussions with members of the institute staff during the visit to the Akademik Oparin on October 27.

[figure 2_20]
Fig. 2.20. Trends of marine biotechnology development.

[figure 2_21]
Fig. 2.21. The distribution of microorganisms producing physiologically active compounds.

[figure 2_22]
Fig. 2.22. Collection of marine microorganisms in Pacific Institution of Bioorganic Chemistry FEB RAS
(Official acronym in World Federation for Culture Collection [WFCC]).

[figure 2_23]
Fig. 2.23. Echinochrome synthesis.

Table 2.4
Medical Preparations Obtained

[table 2_4a]
[table 2_4b]
[table 2_4c]

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23 September 1996; WTEC Hyper-Librarian