SOVIET RECOMBINANT DNA RESEARCH: STATUS AND TRENDS

Created: 9/1/1978

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NATIONAL SECURITY INFORMATION LtiMuriwrind: DIkImwte Oimind SoncHom

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Soviet Recombinant DNA Status and Trends

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gtnevj 'INsHonet tvnign Amamnl Center

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. Keo Judgments

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recombinant DNA researchave impr^-ci rapidly,

but still lag Western state-of-the-art by several years. The scope of Soviet recombinant DNA research is limited because of the small number of qualified molecular geneticists to initiate research projectshortage of adequately equipped laboratories. The Soviet research enjoys high-level support,ontinuing high interest in the field is expected.

Taking advantage of continuing access to virtually all advanced Western recombinant DNA research which is neither classified nor proprietary, the Soviets should be able to establish within two to fiveasic research program using recombinant techniques that is of moderate size and high quality; it is improbable, however, that they will challenge the leadership of the best Western laboratories.

Soviet recombinant DNA research appears to be directed primarily toward agricultural, biomedical, and commercial applications. The Soviets probably will experience difficulties in adapting laboratory techniques to achieve these goals because of the still limited scope of their program and inadequate Support technologies in the biomedical

sciences, '

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military-sponsored recombinant DNA work has been reported, but it is improbable that this work is directed toward or is capable of achieving significant biological warfare applications.

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PREFACE

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The rectnl development of recombinant DNA technology has raised concern lhat the USSR will acquire recombinant capabilities from the West as well as through its own efforts and use them tu thc disadvantage of the United States. This paper assesses current Soviet research capabilities, likely trends in the scope and quality of future Soviet research, the importance to the Soviets of the various means through which they can obtain detailed information about advanced Western recombinant research techniques, and Ihc likelihood that the Soviets will derive meaningful benefits fromDNA techniques.j

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CONTENTS

Judgments

Preface

Introduction

Status of Soviet Recombinant DNA Research Soviel Military-Sponsored Recombinantechnology AcquisitionJ.

Soviet Capabilities To Assimilate Foreign Recombinant Techniques

Soviet Recombinant DNA Research: Status and Trends

The term "genetic engineering" often is used interchangeably with the term "recombinantut the two are not synonymous. Genetic engineering refers to advanced basic and applied research techniques that have evolved frombiology and related research ingenetics and cell physiology. Theseimpart the capability lo modify orpurposefully the genetic characteristics or the developmental sequences of cell* or organ* isms at the molecular or cellular level. Included within this restricted definition of geneticare such things as "test tube babies" as well as more exotic research directed toward producing hybrid (chimeric) organisms orhuman beings or other mammals. At times genetic engineering has been used somewhat inappropriately to refer to all applied genetic research, including such traditional areas ofas livestock breeding and developing new hybrid varieties of plants, ;

Recombinant DNA encompasses only onearea of genetic engineering; namely, Bpecific biochemical and microbiologicalto alter,elatively controlled and reasonably predictable manner, the molecules that encode the genetic characteristics of an organism, and to introduce specifically selectednew tu theanset of genetic Instructions.

The specific molecular manipulations that are made and the exact methods used to make them can vary widely from one recombinant DNA experiment to another. The basic process,usually involves the Initial isolation or synthesispecific set of chemically identical nucleic acid molecules (usuallyolecules are thenbonded orfccomblnnnt

specially prepared vectoia (carriers) that usually are plasmids. bacteriophages, or other virus-like infectious entities that can self-replicate in appropriate host cells. After the bonding has been completed, the modifiedcan be inserted into bacteria or other cells that lave been prepared biochemically to accept them. If the vectors have been "constructed" appropriately, tbe piece of initially selected DNA can give the recipientew geneticFor Instance, the host cell might be given the capability to synthesize an enzyme that il previously could not make. This enzyme in turn could permit the host cell to metabolize aundigestible food source or to become Immune to some previously lethal drug orAlternatively, these same procedures can be used to study the chemical structure (or other molecular biological properties) of the inserted DNA. In this case, the host cell is simply allowed to propagate, which in turn causes many copies of the inserted DNA sequence to be made (cloned) also. These cloned sequences then can be isolated biochemically in quantities andnot possible by other means.

: Starvf of Soviet Recombinant DNA Research

1 Most Soviet studies using recombinant DNA techniques have been initiated only within the past few years. The Soviets have advanced their recombinant DNA capabilities primarily byto exploit experimental techniquesin the West (mostly in the United States) and by acquiring specially modifiedand host cell-lines from Western colleagues. These Soviet efforts to obtain Westerntechnologies appear to be continuing. [I,. 41

Soviet recombinant research is conducted by competent scientists, but has not progressed suf-

ficicntly for their researchers lo hive specialized knowledge to offer in return for advancedtechniques obtained from the West. They have contributed somewhat toyew methods to change the chemical recognition specificity of several enzymes (restrictases) used during some recombinant]

Thc Sovirts are believed to have only aboul five research groups that have demonstrated reasonably advanced recombinant capabilities (seend these Soviet groups ere from one to two years behind most of the several hundred US groups. The best Soviet research

also trails that in numerous West European laboratories, which now rival the USther Soviet groups, some of which are listed In tableave conducted related (support or preparatory) research and couldrecombinant experiments soon.

A group headed by academician Aleksandr A. Bayev at the Institute of Biochemistry andof Microorganismsushchino. has investigated the fundamental processesin recombination phenomena usingcottost cell and several well-studied virus vectors. This work has included the study of molecular specificity and normal physiological

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Rtcofnbinont Roworeh ond FociUHt* In iho USSR

Leader

butllute of BtocSctnlMry and Phydolotv of MIcrooiaarUimi/Bayev |

All-Union SctenUflc Reaoarch Imtltute. Genetic* and Selection ot Industriali/Debabov

Ivanowkly Innilute ol Vlrokary/TlktwnenVc

Imlllulf ol Molecular Bloloay/CoortlveY InatUuM at Atomic

Irutllute ol GeneralInatHule of BoUny/AndrUnov

ftnearch

nd phageonMruclwI. lt.*ttttatlom fart boUted Colli rrtfrwttasr. Mudted mlttrfav ecUon. and mopped DNA hydrolyiU prod-Kt* Syv lerm Uudled Include only the well known bectrtlal and vlrutvector*

Hybrid plaamidi El-Rfik and RP4-ColEl (pASS) 4coHeen coratructed or reirruction and notion. trartnVrred by method of irantformaUon Inreetcdmi elonri -ere Hnbled by antlbtotkr rcabtance E. cef. and levrral phaar-ere obtained (rant IS artentiaii

I'- Glactaae oporon Iromal'm lieen Isolated ii'inf Hani Hi endonuclrase and Iranifrrred Inloby -ayector (bybrtd) plaamld pMPfl done* -era arlrcted by aaHbMK retbtance and ability lo mm gaUctcee al lhe only aourie of carbon Methodi and technique* had been etUbllihed lev. eral yr*nby Wertera reanarrhen

f>oaoeAlla nwlanofurer eenrt Have been Incorporated Into Lambdahaae.i

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andi lectin tour* and telrctrd by nucleic eckl hykridiiaiton; result Int hybrid clone* we lhe iulv irct of farther taeratkNttoa. Tht yector phaae -pcTJviflarviVfMaTTi arl^rrf tft

faa cWoroplajt DNAoll CBOO pliimldi (pSCIOI or RSFhai been tranaferrrd lo t. colt CnflOTraaatonaantl were arlrcted by antlhtollr. raff KM IU, wed In tolal In* Eco HItialbtained from a

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action of DNA mcdificatbn enzymes and basic capabilities hurt been established for these of recombinant DNA techniques. Noapplications have beenwo other laboratories at IBPM(see tablender the direction of Ya. I. Buryanov and A. M. Boronin, respectively, have investigated theific action of methylases during naturalination and have used classical genetications involving plasmids to producetrains that oxidize napthalcne at anate. No attempt has been made to usetechniques in Boronin's .

At the All-Union Scientific Researchf Genetics and Selection of Industrial(VIIaboratory under the direction of V. G. Debabov haseveral E. coll host-vector systems to transfer, specific genes between differing strains of E.ome of this research has been done

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in collaboration with personnel from the Institute of Bioorganic Chemistry.elated research also has been performed by another laboratory at VII Genetika. headed by S. I. Alikhanyan. This group has mapped the location of specific genes on plasmids by using restriction enzymes to generate deletion

Under the direction of T. I.aboratory at the Ivanovskiy Institute ofMoscow hasene that confers the ability to utilize the sugar galactoseource of carbon. This was accomplished by isolating the geneambda virus and transferring itaboratory-modified ptasmid. Clones of E. colt containing the transferred gene were selected by antibiotiche techniques used represent only slightof methods developed several years earlier in the West.

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Reseorth ond Focllitle* In th* USSR

Leader

Institute of Biochemistry and Hiyrtoloiycroonn nilnu/ Borortl n

/Butwnov

All-Union Scientific Research Institute of Ot*ltcf. and Selection of Industriall ya n

Atl-Unlnn IrWHiHr of SynlhnU of

N.I. ftronv Second Moscow Mrdlcal] j

Research

apthalcne calanollim Include production of plwmld mulanti by classical means wllh (he InienI of producing Ptmdomonat strains capalilelth cWrea o( napthilene turnover

Research centers on DNA met hy lam in E. tall.

Hybrid pLumtd pASS, constructed by Debabovd in tenetlc arulysit of pfasmld RF4 Other related research center) on rrarilomhlp between platmlds and ipore formation tn Bectltm strain*

ocus on the feneOc euhanne betweenmkroorganhmt To date, ptasmld DNA from E. collas been trunsferrrd lo B. mbtllltnd Iranrfwmsnts arlected by antibiotic resistance.

Invest lotion K> optimise conditions for abwrtrina tram.-form tne vecton In several E. toll strains Tram, formibillly achieved for Umolnaniii fC (oil CfiflO) strains; heterointous Uralm rahlbltrd low tramformablllly.

ud-Vnkij

Rllentm nn different i'l'.iir.ir.) In itudy of antibiotic resistance.

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The onl> examples of Soviel experiments lhat have transferred gensa from higherave come from the Institute of Molecular Biol'B),offshoot of the Kur-chatov Institute of Atomicndoint project of thef General Genetics in Moscow, and the Institute of Botany in Alma, P. lGcorp;ycv's group at 1MB transferred genes from the fruit fly Drosophila tocoil and then isolated specific clones using standard nucleicn the joint. M.lea chloroplast gene to E. coll. Standard antibiotic-resistance techniques were used tohost cells carrying the inserted gene.

No Soviet groups have reported the successful transfer via recombinant techniques of any DNA sequence that has immediate commercial or other applied use. The types of material being transferred (for example, chloroplastowever, are consistent with reported Soviet intentions to use recombinant techniques inulture to produce new nitrogen-fixing plants and in the food industry to improve thequality of single cell protein

lthough these Soviet researchers are highly capable and technically competentheir efforts to develop recombinant capabilities rapidly have been hamperedack of:igh-quality modern laboratoryeadily available commercial (or othersource of needed restrictioneliable source of high-quality biochemicals;arge cadre of qualified molecular biologists (many still are aitcn-r'ing to recover from the effects of the Lysenkohoy have been able to give postdoctoral and graduate-level trainingew individualsui they do notufficient number of personnel or facilities to develop independently andarge, highly advanced

Manpower and space limitations also severely restrict current Soviet capabilities to exploit moreew potential applications oftechniques. It probably will take several

years for this situation to change significantly, even though thc Soviets already are reported to be building several newleast one of which is tohigh containment)to be upgradingny successful applications ofDNA techniques achieved by the Sovieis probably would not be accomplished quickly enough lo place their researchers eitheror apparently at the forefront ofDNA research woildwidc.

SoviatRaiaarch

Several military-funded, closed,research institutes L ' *

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reportedly were established ounng the. The missions of these institutes included conducting research directed toward possibleapplications of recombinantonetheless, the Soviet military is not known to be using recombinant tcchni,or biological warfare (BW) purposes. Military-funded Soviet research instituies probably would use recombinant techniques for basic biomedical studies. For instance, projects could be oriented toward developing prophylactic agents suitable for use against infectious diseases. Such work probably would include the development ofvaccines for dysentery and typhoid fever, as well as vaccines for more exotic viralas those in Africa.

Soviet military-sponsored recombinant DNA research nrobably is not advanced technically. Except for Nikolay Matvienko, who reportedly has transferredilitary] thc most capable Soviet recombinant DNAare believed to be conducting unclassified basic research and to have published freely in the open literature. Thc research sophistication of even these prominent researchers, who have been working in thc best Sovielis. those that are reasonably well-equipped and fullylags that of most Western groupsear or more. Newly established military research institutes probauly could not havestaffs of cqunl or superior competence. Furthermore, these institutes probably could noi

have successfully Initiated advanced research projects on topics lacking both domestic and foreign sources of directly relevant research data.

Information regarding Soviet recombinant DNA research by military*funded institutes has been meager. One such Institute waa reported to be in or near Protvlnoown near Moscow) and another in or nearJ The Push-chino institute couldisidentificationigh containment facility, reportedly being built for IBP at Pushchlno. Nofacility is known lo exist near Protvino.

Nikolay Matvicnko, who conductedDNA research previously at 1MB inand at IPBM Ins believed to be the deputy director of the Protvino Institute. The quality of the researchers atis not known, but Matvicnko is the only technically competent bacterial geneticist known to have been hired out of the academyA secondraduate student who was judgedource to have rather poor capabilities, reportedly was hired to work at Protvino]

It is not yet clear if recombinant techniques can be useful for BW research. Some US experts have argued that traditional techniques toBW agents arc more cost effective. Also, they felt lhat recombinant techniques probably could not be used to enhance meaningfully theof existing agents or toew "super"] Others have argued that the developmentsuper" bug is not necessary. The simple transfer of debilitating diseases, such as dysentery, to normally nonpathogenicsuchommon inhabitant of the human digestivebe sufficient to make identification of the causative agent and effective treatment of the induced pathologies extremely difficult. The counter argument to this has been that several decades of testing uiually is required to understand sufficiently the ecology and epidemiology of any new "bug" to sanction its useredictable military weapon.

Two basic categories of Western recombinant DNA information which are potentially relevant

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to the Soviet military include: recombinantinvolving the transfer of factors that arc pelbogenic to man or that can increaseovel way the virulence of organisms infectious to humans; and procedures and equipment used lo support biologically hazardous recombinant DNA research.

The conduct of biologically hazardousinvolves traditional microbiological safely equipment and techniques that have been used in the biomedical handling and study of pathogenic organisms. Although some of the techniques for constructing advanced protection equipment (or "high containment" facilities in general) have become somewhat of an art, most of theand equipment designs have beenopenly. Much of the equipment iscommercially.

Recombinant DNA research involving factors pathogenic lo humans has been severely limited by the safety restrictions governing moslresearch. Thus, little information currently isubstantial amount of information should become available in the future as the number of high containmentthat permit experiments to be undertakenSuch information probably will be made available in the open literature.

Technology Acquisition Channel*

The Soviets can acquire information useful to their recombinant DNA research effortsumber of sources. Virtually all US and most foreign research data and techniques have been published or are being prepared for publication in the open literature. Even the detailsrocedure recently submitted for US patent rights have been published] Two of the coauthors on this patented research project are now conducting research in West European laboratories.

Most advanced Western scientists arc free lo communicate research activities and procedures to foreign scientists both through writtenand al internationalJ The distribution of samples and supplies of newly developed vectors or host cells also has been left

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to the discretion of the scientists possessing them, for non-Communist nations have [neitherorced regula ions that exist (such asf the US unilateral Commodity Control List) nor issued guidelines concerning theof research information or specimen transfers.

Although the US remains at the forefront of recombinant research worldwide, many foreign researchers, particularly ir Europe are capable of providing, and in some cases have provided, the Soviets with experimental supplies that were both adequate and as good as could have been obtained from US sources (seeany of the specialized enzymes also are now available commercially from numerous Western suppliers.

:|As the number of researchers and research

i groups conducting advanced recombinant DNA studies in West European countriessubstantial number existeasier it should become for Soviet scientists to obtain needed technical data from professional contacts.

International scientific me-*tings also havehannel for the rapid, multilateral

1 exchange of experimental data. Except forentatives of industrial firms, most scientists attending international meetings have exchanged

! information and answered questions

Although no formal agreement exists between the Uniied Stales and the USSR tuesearchers or research information either on genetic engineering in general or on recombinant DNA] the Soviets have begun to propose numerous exchanges involvingDNA techniques under the auspices of existing microbiological, health, and medical] Some exchange visits andcollaboration also can be expectedSoviet researchers and scientists in Europe and

All of these channels for information transfer have been suppo'ted by Sovicilch have been directed taward acquirinc advanced Western recombinantto support Soviet researcht least some Soviets who havecontacts, including those who would

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be involved in recombinant DNA-relatcdwill have been prebriefed and can be expected to attempt to service Soviet intelligence requirements,

Soviet Capability-mi.Ota Foreign Recombinant Technk-uo*

T'le Soviets traditionally have had littleat converting microbiological andlaboratory techniques into usefuloperations. This probably will be the case with Soviet attempts lo apply recombinant DNA techniques. For instance, the Soviets arc considered to be relatively unsophisticated in several fields of biological research (such as the genetic manipulation of plant cell proloplasis in tissue culture) that probably will be needed in conjunction with recombinant techniques to achieve certain industrial or aariculturalFurthermore, despite the extremely nigh quality of Soviet organic chemists, fewhigh-quality laboratory reagents have been produced in thet appears improbable thai the use of recombinantsuddenly would enable Soviet biochemical or pharmaceutical industries either to develop or toufficiently large number of high-quality products to compete meaningfully with Western Industries. Soviet capabilities to apply recombinant DNA techniques to military-oriented research projects should face similar constraints.

Despite ths problems anticipated with Sovici attempts to adapt recombinant techniques to commercial uses, over the next two to five yea's they should be able toidrc of competent, basic research scientists fully trained in the use of advanced recombinant DNAThe ready availability of Westerndata already has saved Soviet researchers several years of developmental research effort. The rate at which the Soviets arc able toimproving their recombinant capabilities should remainon the acquisition of advonccd Western work for atew years more.

The number of laboratories lhat ihc Soviets ore building or rcfurbishino to accommodate

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recombinantndicates that sufficient support will be provided to establish andoderate size recombinantprogram ofechnically sound research groups. The research efforts of these groups appear unlikely to be hampered byenforced research restrictions designed lolhat research activities do not pose inadver-tant health hazards, despite the fact lhat research guidelines have been adoptedhe Soviets are thus expected to attain recombinant research capabilitiesto many Western laboratories, but they arc not likely to challenge seriously the leadership of the most advanced Western laboratories.

If Soviet access to Western expertise were suddenly to be restricted, it would delayby as much as an additional fiveestablishmentophisticatedresearch program. Sufficient capabilities have been established by thc Soviets already, however, for them to piocccd on their own. Currently, Soviet recombinant DNA research dependence on the West probably is most tightly linked to Western biochemical supplies andlaboratoryas ultrnccn-trifuges and scintillationlthough inconvenienced by thc need to anticipate laboratory supply requirements atear in advance because of the long lag time frequently experienced between requesting and receiving material, Soviet biomedical ic* search would be dealt an even greater blow if only Soviet biochemicali and precisionwere available. Soviet biochemicalproduce onlyozen laboratory reagentsonsistently high quality (forfree fromnd Soviet-built precision laboratory equipment has beenpoor in

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Western scientific literature has been and continues to be important to thc advancement of Soviet recombinant DNAt hasather extensive list of those experimental techniques known to work, others that have not worked, and has detailed the procedures used to obtain the numerousvectors, and mutant cell lines found to be

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useful for recombinant procedures. Information of this type has permitted thewell as new laboratory groupsselectprocedures previously demonstrated lo be appropriate and to avoid proceduresfound to present difficulties or to be less efficient than otherubstantialof these types of generally applicabletechniques should continue to appear inWestern literature for the ncxl year or two. Thereafter, an increasingly greater portion of new recombinant techniques probably willrelatively project specific.

As Soviet laboratories begin inc:ca>ingly to narrow the focus of their research projects,they probably will establish unique projects of their own choosing rather than simplyor attempting to compete with advanced Western work. At this point lhe relativeof personal contacts should increaseto the information available in 'he open literature because the experimental problems that are encountered during specialized research projects usually are best solved through informal consultations with colleagues, and because ihc West will continue toubstantiallynumber of (echnially advanced scientists than will the USSR.

In the long term, when Soviet researchhave become quite specific, Informnlsuch as at international meetings, probably will be thc most useful form of personal contact to the Soviets, since such contaCvS provide accessroad cross-section of Western scientific expertise. Currently, however, formal research exchanges probablyore useful form of personal contact to the Soviets. Exchange visits bring technically competent peoplein the laboratory, where equipment andtechniques can be observed first hand and where tutored, practical experience can he obtained.ctors increase the value of thc technology transfeired, particularly in casesroblem in experimental procedure has been encounteredoviet laboratory (such as difficulty In replicating the work of arothcr laboratory) or where an individual who isuntrained In recombinant techniques dc-

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ormal training program. In the former case, taking an individualengthy proceduretep-by-step basis probably would identify the problem (that U, the difference in procedure, such asifferent brand of buffer orrecipitate toomuch more quickly than'could bethrough written correspondence or through trial and error deviations in laboratory procedures. In the latter case, the Soviets could benefit appreciably byraduate student or postdoctoral level scientist trained in aWestern laboratory. Where the trainee probably would be tutored by and be exposeduchmber of competent,qualified researchers than would be the case in the USSR and where the still limited Soviet laboratory space and experimental supplies

would not be strained further.

Nonetheless, it is improbable thatxchanges willignificant contribution to Soviet recombinant DNA capabilities In the near term. After returning to theoviet researcher trained during an exchange visitwould spend several monthsearesearch project,aboratory, or attempting to integrate any US-acquired skills into an already ongoing research projecl. The Soviets probably will benefit more over the long term from the personal contacts established during an exchange visit. Theseshould facilitate Soviet abilities to acquirepecialized reagent neededor torompt replyechnical inquiry.

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