Дата публикации: 22 сентября 2021
Автор(ы): Alexander YANENKO →
Публикатор: Научная библиотека Порталус
Рубрика: БИОЛОГИЯ →
Источник: (c) Science in Russia, №5, 2011, C.4-8 →
Номер публикации: №1632299715
Alexander YANENKO, (c)
by Alexander YANENKO, Dr. Sc. (Biol.), Deputy Director of the Federal State Unitary Enterprise GosNIIgenetika (Moscow)
In 2011 the Russian government starts implementation of the program of regeneration of the biotechnological sector of economy. Strong scientific schools and world scale research results form a serious base for future steps. All this and the difficulties of the present-day situation are discussed by Alexander Yanenko, Dr. Sc. (Biol.), Deputy Director of the Moscow State Scientific Center, FSUE State Research Institute of Genetics and Selection of Industrial Microorganisms with our correspondent Yevgeniya Sidorova.
--Alexander Stepanovich, let me congratulate you on the occasion of getting an award of the RF Government in the sphere of science and technology for 2010. You received this prestigious award together with your colleagues for development and industrial use of the new biotechnology. What's the gist of this work ?
--Thank you for congratulations. This award was granted to specialists of several institutions for development and industrial use of biocatalytical technology of aspartic acid manufacture and for making innovation drugs on the basis of this acid. These are drugs for elimination of magnesium and potassium deficiency, developing in patients with cardiovascular diseases (infarction, hypertension, ischemic diseases).
I should like to emphasize that this prize differs from all other awards as to get it, it is not sufficient to develop a technology, an important thing is to organize the manufacture of ready products and produce them for at least one year. As you see, this extremely difficult work can be realized only on the condition of coordinated efforts of many scientists and practical workers. The work was coordinated by Vladimir Debabov, supervisor of studies of GosNIIgenetika, RAS Corresponding Member.
--In other words, the whole way from scientific development to commercial manufacture of the product has to be passed?
--And its starting point was our Institute, responsible for obtaining appropriate microorganism strains--L-aspartic acid producers. Our colleagues from ZAO Biomed in Sa-
ratov reproduced the process on a wide scale and then turned to commercial manufacture of the product. L-aspartic acid is manufactured in Penza at OAO Biosynthesis industrial complex. Of special importance are preclinical and clinical trials, an essential step in the development of drugs. Therefore, we asked specialists from the Volgograd State Medical University for collaboration. They carried out appropriate studies and proved that L-aspartic acid provided the best bioavailability of magnesium and potassium for the myocardium.
--Can aspartic acid exist in another form?
--This substance exists in the form of two isomers, L and D. Their racemic mixtures* are now mainly used in medicine. However, all biological systems utilize only the L-form, as the D-form for them is a xenobiotic, which they have to get rid of. Our goal was to obtain aspartates for compensation for potassium and magnesium deficiency on the basis of L-isomer only--a normal cellular metabolite involved in protein synthesis. The Volgograd scientists headed by Vladimir Petrov, member of the Russian Academy of Medical Sciences, experimentally proved its advantages as a carrier of magnesium and potassium ions. Their conclusion formed the base for the manufacture of a number of new drugs.
--Thus, the drugs created by your team can be considered original, though L-aspartic acid is a well-known active substance in many drugs, including imported ones. Then, why no attempts to replace the racemic mixture by L-isomer have been made up to date, either in our country or abroad?
--In our clinical practice magnesium deficiency has been traditionally liquidated by using a well-known cheap drug--magnesium sulfate (in solution). The bioavailability of the elements of this drug is by an order of magnitude lower than that of imported aspartates (panangin, asparcam) based on racemic mixtures. However, the pharmaceutical sphere is rather conservative: the drug does exist, it is certified, its manufacture and realization are well organized.
We started search on the base of some previous results: in the 1990s our Institute worked at creation of a sweetening agent aspartame (a more accurate name is L-aspartyl-L-phenylalanine methyl ester), and hence, we had microorganism strains for aspartic acid production. It is true, at that time our work ceased at the stage of laboratory studies. Now we had to continue them and create an industrial technology. We focused on the new task and increased the aspartase activity (capacity to transform ammonium fumarate into aspartic acid) of the strain 1,000-fold, in order to provide economic efficiency of the process. The Biomed specialists, headed by Sergei Voronin, Director
General, immobilized bacterial cells (limited their mobility) by inoculating them into the gel filling the column reactor for the manufacture of aspartic acid.
By the way, the traditional chemical production of aspartic acid racemic mixtures is ecologically rather unsafe: it involves the use of such substances as maleic acid and ammonium at a temperature of 140-150 ºC and excessive pressure of 0.25-0.3 mPa; the productivity does not exceed 74 percent, with great wastes. At the biotech-nological plant the microorganism enzymes in a column reactor work as catalysts in water phase at 30-37 ºC strictly specifically*--aspartase (asparta-ammoniumliase) adds ammonium to fumaric acid with the formation of L-aspartic acid. The substrate is introduced into the column from the top, and the product (acid) is released from the bottom, after which it is purified and transformed into salts. Conversion of ammonium fumarate in our technology reaches 98 percent! Chemical catalyzers fail to provide such efficiency.
In addition, this process can be easily realized in a required volume--1-2 or more columns can be used.
--Is it necessary to increase the production of new drugs at present?
--The sales curve for drugs for injections (asparcam-L solution) has shown steady increase over the last year. The first pilot lot was issued in 2008. It took some time to explain specific features of the new drug to medical work-
* Racemic mixture is a mixture of equal amounts of two optical antipodes of one substance.--Ed.
* See: A. Yanenko, "Priorities of Industrial Biotechnology", Science in Russia, No. 5, 2006.--Ed.
ers, to study the market, carry out advertising actions (conferences, publications of research results). In 2010, the demand reached hundreds of thousands of packages. Our colleagues from Biosynthesis say they can hardly satisfy the "appetites" of consumers. Hence, volumes of the column are to be increased.
--Do you mean the national market only? Has the drug attracted foreign specialists?
--In order to introduce the drug into the European pharmaceutical market, we have to carry out clinical trials there, and it is very expensive. Hence, at present we work for the Russian market and the CIS countries.
--State programs of national biotechnology development have been actively discussed in our country in recent time. It seems that the changes outlined in them should seriously stimulate new scientific studies, is that so?
--For us the creation of Pharma-2020 and Biotech-2030 programs is an event of paramount importance, as the biotechnological complex of the country degraded for the last two decades. The prospects of pharmaceutical industry development in accordance with the Pharma-2020 program are tremendous: our country will manufacture up to 50 percent of drugs at home. The state will finance creation of 5,000 drugs, and will pay for expensive clinical trials for the first time. It goes without saying that the first step will be competition of projects. Let us note that the cycle of getting a new product takes 5-10 years. In other words, no more than two generations of drugs can be developed till 2020.
I think that for effective solution of problems associated with the development of biopharmaceutical industry we should pay special attention to the manufacture of substances by bacterial synthesis. However, studies to create instruments for target modification of the genomes of microorganisms, producing substances essential for drug manufacture, were in fact not supported. And these studies are expensive and time consuming, and they determine final results. One more problem is virtually complete absence of industrial fermentation base in the country. The Biosynthesis company in Penza is a pleasant exclusion. As a result, Russia has to purchase an entire spectrum of substances for drugs in foreign countries, primarily in China. We completely depend on the import of substances.
It is obvious that the manufacture of the minimum set of vitally important drugs is to be organized in the country. True, it is assumed that there are no conditions for substance manufacture in Russia, but our colleagues from Biosynthesis have proved the opposite. The antibiotic substances they manufacture are now exported to Europe and even China.
--Hence, if the things are properly organized, we can win the world market as well?
--We can and should try to.
And now about Biotech-2030. It is not yet a program, but a technological platform, a sort of a strategy for the development of industrial biotechnology in Russia. We expect that the realization of this program will lead to
regeneration of microbiological industry, and fermentation plants. We think that if this program is not realized, this would hamper research, including, among other things, the pharmaceutical trend.
One of the priorities of industrial biotechnology development in Russia is vegetable raw material processing and getting of valuable products from renewable sources-biodegraded polymers, plastics, monomers for chemistry of high-molecular compounds, fodder additives (lysine, threonine, etc.). Recently huge volumes of undemanded grain excess formed in the country. Meanwhile, up to 10 mln tons of this raw material can be used in biotechnology, which will provide its guaranteed sales and stimulate further development of agriculture.
However, there are no appropriate plants. The enterprises which worked during the Soviet period and manufactured, for example, lysine, no longer exist, and their equipment was utilized as metal scrap long ago. They manufactured 40,000 tons of lysine, and now the country imports about 50,000 tons of lysine every year.
These problems attracted the attention of businessmen and the state in recent years. We can expect the appearance of new plants for grain processing and manufacture of biotechnological products on this base in the near future. Innovations in this sphere will be on demand.
--Despite the objective difficulties of the two last decades, your Institute remained an example of innovation activity. What are the research trends you are developing at present?
--We participated in the realization of an important innovation project of state significance "Manufacture of Recombinant Proteins for Medical Use, Based on Animal and Microorganism Cells, Using Highly Effective Technological Platforms", to create medical preparation specifically, an improved form of alpha-interferon (protein released by cells of the organism in response to virus). The interferon molecule synthesized by bacteria differs from the natural molecule by just an additional amino acid--methionine. This variant of the drug is prohibited for use in Europe, and many countries, including the CIS countries, direct their attention to these standards. In order to create favorable conditions for the Russian producer, our Institute has developed a unique process based on a bacterial synthesis for the manufacture of methionine-free interferon.
One more work within the framework of this project was a new technology for obtaining erythropoietin, an important drug for treatment of anemias. It is vitally important for all patients with renal failure treated by means of dialysis. It is now manufactured in Russia using the old technology--animal sera, and hence, there is a risk of viral infection of drugs. In order to rule out this risk, the traditional component should be replaced by new ones--of vegetable origin or synthetic.
But first of all we should "teach" cell cultures to utilize only synthetic substances. And to make them grow not only as monolayers on the vessel surface, but also in suspension, and then the productivity of the processes will be higher. We worked at these problems for several years and suggested an improved technology, due to which erythropoietin can be produced without raw material of animal origin, and cultivation is carried out in suspension. In a word, we have a methodological and scientific base for drug creation on the base of recombinant proteins. The institute has two grounds equipped with all necessary devices and the premises for the manufacture of test specimens for preclinical studies.
And one more important result of our studies. A unique device for substitute therapy* was developed, intended for patients with insufficient secretion of digestive enzymes. It is based on the appropriate bacterial enzymes. Mezym, kreon, and other drugs of the same profile are based on animal pancreatin, which, unfortunately, creates a potential risk of their infection by viruses and prions**. The drug we suggest is safe and effective; its clinical trials are now in progress.
--We started our conversation from studies resulting in creation of a technology for obtaining aspartates--drugs for cardiovascular patients. But aspartic acid is also used for parenteral nutrition, when essential substances are to be administered via a route other than the gastrointestinal tract. Have you analyzed your results in this aspect?
--The most important task of the Institute from the moment of its organization has been the development of biotechnologies for bacterial synthesis of amino acids, including those for parenteral nutrition. We obtained producer strains for some of them: lysine, threonine, tryptophan, etc. Today in many countries, the production of one more amino acid, threonine, is based on the strains created at our Institute. Unfortunately, these studies completely ceased in the 1990s because of the absence of financial support. And we are glad to witness the new interest of Russian businessmen to this problem in recent years. The Institute is ready to resume the studies; the first contracts have been concluded. We have started development of an industrial technology for lysine manufacture, ordered by the Prioskolye Company (Belgorod region), one of the major poultry producers in Russia.
--It is obvious that effective implementation of the above-mentioned state programs of bioindustry development implies that there is a sufficient number of qualified specialists. Will their number be enough for realization of such large-scale plans?
--The situation with specialists is really difficult--their number is insufficient. On the other hand, there are wonderful schools at research institutes and universities, which can train highly qualified professionals. Our Institute traditionally receives graduates from biological and chemical faculties of Lomonosov Moscow State University, Mendeleyev Russian Chemico-Technological University, and Lomonosov Moscow State Academy of Fine Chemical Technology. The main problem is to keep perspective scientists. More than a hundred of our young staff members left our country over the last 15 years.
But I hope that realization of these programs to develop biotechnology will contribute to the solution of present-day staff problems, to creation of a scientific reserve, and eventually break the negative situation by providing effective development of this promising industry in our country.
* Substitute therapy consists in administration of a substance, the natural production of which is reduced or ceased.--Ed.
** Prions are a special class of infectious agents, purely protein, containing no nucleic acids, causing severe diseases of the central nervous system in humans and in some higher animals.--Ed.
Опубликовано на Порталусе 22 сентября 2021 года
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