Page 1 of6
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`ILMN EXHIBIT 1038
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`
`
`Page 1 of 6
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`ILMN EXHIBIT 1038
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`

`
`Issu 0036-8075
`3 JUNE 1994
`VOLUME 264
`NUMBER 5164
`
`Chasing after
`b-mesons
`
`146
`
`Liquid crystals in cells
`
`AMERICAN
`ASSOCIATION FOR THE
`ADVANCEMENT OF
`SCIENCE
`
`NEWS & COMMENT '_..'
`
`f _..._.'.__._ .
`
`‘
`
`'
`
`Mystery Ailtnent Strikes Serengeti Lions 1404
`
`The Race to Understand Matter
`
`Case Closed for a. Giant Black Hole
`
`1405
`
`1996 U.S. Science Policy: Memo Backs
`Basic Research With Words, Not Cash
`
`Space Science: Europe Lays Plans to
`Shoot the Moon
`
`Panel Presents a Vision for Physics
`After the Supercollidcr
`Competition Looms for :1 Linear Collider
`
`RESEARCH NEWS
`
`Running Rings Around a Supernova
`
`1405
`
`1395
`
`1397
`
`Secrecy Runs Amolt
`G. T. Seaborg
`
`1410
`
`PERSPECTIVES ~'__._‘. _L;_'.‘__'_f.§I__..;
`
`..
`
`.'_..'_'.'_."_‘L1fZ1I
`
`Community Unity?
`J. B. C. Jackson
`
`1412
`
`VJ
`
`Drug Discovery on the Assembly Line
`Putting Genes on a Chip
`
`1399
`
`A Biochemical Function for Ras— E 1413
`At Last
`A. Hall
`
`Atmospheric Chemistry: A High-Flying
`Fix for Ozone Loss
`
`1401
`
`._._._.-.__._..
`ARTICLES . ~~
`
`._...J
`
`AIDS Vaccines: Immune Response
`Corp.—Talre Two
`
`Cemetery Reveals Complex
`Aboriginal Society
`
`1402
`
`1403
`
`Jal<—STAT Pathways and Transcriptional 1415
`Activation in Response to IFNs and Other
`Extracellular Signaling Proteins
`J. E. Darnell Jr., I. M. Kerr, G. R. Stark
`
`Genome Mapping: Closing in on Human 1404
`and Mouse Maps
`
`DEPARTMENTS
`
`THIS WEEK IN SCIENCE
`
`1331
`1 333
`
`EDITORIAL
`Continuing Evolution of U.S. Agriculture
`1385
`LETTERS
`Agricultural Research at Berkeley: K. R. Farrell; B.
`O. Schneeman; A. P. Gutierrez-, A. H. Goldstein;
`M. Barinaga I Blood Type and the Risk of Gastric
`Disease: A. E. l-lallstone and E. A. Peter; T. Borén
`and P. Fall-r
`
`SCIENCESCOPE
`
`1391
`
`1398
`RANDOM SAMPLES
`I Bringing
`Rugged Family Planning for Ticks
`Home the Bacon * Crack on the Wane in New
`York 0 Mathematical March on Washington
`1479
`BOOK REVIEWS
`The RNA IX/orlci, reviewed by H. D. Robertson 0
`Tlie Quark and the Jaguar, 5. Coleman 0 The Urulc
`World System, S. Pollock 0 Vignettes ' Books
`Received
`
`PRODUCTS 8. MATERIALS
`
`1484
`
`1......
`
`.7.
`
`.-.1
`
`Frederick W. Alt
`Don L Anderson
`Michael Ashburner
`Stephan J. Benkovic
`David E Bloom
`Floyd E Bloom
`Fist Bots!
`Henry R. Eourna
`Michael S. Brown
`James J. Bull
`
`Kath ryn Gala me
`C. Thomas Caskey
`Dennis W. Choi
`John M. Coiiin
`Paul J. Crutzen
`Robert Desimone
`Bruce F. Eldridge
`Paul T. Englund
`Richard G. Fairbanks
`Douglas T. Fearon
`
`Harry A. Fr.-zzaid
`Klaus Friedrich
`Theodore H. Gehalie
`John C. Gorhan
`Roger I. M. Glass
`Stephen P. Gail
`Peter N. Goodiallow
`Corey S. Goodman
`Ira Harsiuowilz
`Eric F. Johnson
`
`__iBoard of Reviewing Editors
`Roger A. Nicol!
`Stephen M. Kosslyn
`Sluarl L. Fimm
`Michael Lafiarbara
`Nicole Le Douarirl
`‘feshayau Poclxor
`Dennis A. Powers
`Charles S, Lsrvings ll
`Alexander Lavitzki
`Ralph S. Ouairano
`V. Ramanathan
`Harvey F. Lodish
`Richard Lnaink
`Douglas C. Rees
`T. M. Rice
`Diane Mathis
`David C. Rubia
`Anthony H. Means
`Erkki Ruaelahti
`Shiguiada Nalcanishi
`
`Gollfried Schaiz
`Jozef 3Cl'|E‘lI
`Ronald H. Schwartz
`Terrence J. Sejnowski
`Eiian Solomon
`Thomas A. Steilz
`Michael P. Sirykur
`Robert T. N. Tjian
`Emil R. Unanue
`Gearat J. Vermeij
`
`Bari Vogulsloin
`Harold Wainlraub
`Arthur Weiss
`Zena Warb
`George M. Whileaidea
`Owen N. Willa
`William A. Wulf
`Keith Yamamoio
`
`SCIENCE 0 VOL. 264 ' 3 JUNE 1994
`
`
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`Page 2 of 6
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`

`
`Plant Arabidopsis thaliana because of the discovery of
`the quartet mutations. Shown are pollen grains lrom
`Plants with a quarrel mutation, which. unlike wild-type
`P0i|en grains, are released in fused melotictetrads. See
`Page I 458. [Photo : Daphne F-‘reuss and Sung Y. Rhee]
`
`A Protein Phosphatase ZC Involved in
`ABA Signal Transduction in Arabidopsis
`thctiiana
`
`1452
`
`K. Meyer, M. P. Leuloe, E. Grill
`
`Estrogen Recepl:or—As5ociated Proteins:
`Possible Mediators of Hormone-Induced
`Transcription
`S. Halachmi, E. Martlen, G. Martin, H.
`MacKay, C. Abbondanza. M. Brown
`
`1455
`
`Tetrad Analysis Possible in Aralaidopsis
`with Mutation of the QUARTET (QRT)
`Genes
`
`D. Preuss, S. Y. Rhee, R. W. Davis
`
`1 458
`
`Liquid-Crystalline Mesophascs of Plasmid 1460
`DNA in Bacteria
`2. Reich, E. ]. Wachtel, A. Minslqr
`
`Activation of Raf as a Result of
`Recruitment to the Plasma Membrane
`D. Stolcoe, S. G. Macdonald, K. Caclwallader,
`M. Symons, ]. F. Hancock
`
`E 1463
`
`Reversal of Terminal Differentiation
`Mediated by p10? in Rb"' Muscle Cells
`J. W. Schneider, ‘W. On, 1.. Zhu, V. Mahdavi,
`B. Nadal—Ginard
`
`'14-57
`
`Inhibition of Hepatic Chylomicron
`Remnant Uptake by Gene Transfer of a
`Receptor Antagonist
`T. E. Willnow, Z. Sheng, S. Ishibashi, J. Hera
`
`1471
`
`1474
`De Novo and Inherited Deletions of the
`5q13 Region in Spinal Muscular Atrophies
`J. Melki, S. Lefebvre, L. Burglen, P. Butler,
`C). Clennont, P. Millasscau. S. Reboullet, B-
`Bénichou, M. Zeviani, D. Le Paslier, D. Cohen,
`J. Wt.-issenbach, A. Munnich
`
`Automatic Analysis, Theme
`and Sumrnarization of Machi
`Texts
`G. Salton, J. Allan. C. Buckl
`
`CY: A. Slnghal
`RESEARCH ARTICLE:::.':.'.i' j "
`Structure of the Allosteric Re
`gulatory
`esis
`Enzyme of Purine Biosynth
`_|. L. Smith, E. J. Zaluzec, ]
`R. L. Switzer. l-1. Zalkin.
`
`I‘
`
`'
`
`=
`
`REPORTS lZf."..'I'.i_‘f_‘_ii.
`
`Younger DYY“ Age Advance af
`Franz Josef Glacier in the So
`of New Zealand
`G. H. Dcnton and C. H. Hcndy
`
`11 ti] CIT1 Alps
`
`1 434
`
`Implications for Mantle Dynamics from
`the High Melting Temperature of Perovsk
`ite
`ti den
`P. E. van Kelcen. D. A. Yucn, A, P_ Va
`Berg
`
`1437
`
`Species Pool and Dynamics of
`Marine Paleocommunities
`M. A. Buzas and S. ]. Culver
`
`E 1439
`
`High-Pressure and High~Temperature
`Experiments on Core-Mantle Segregation
`in the Accreting Earth
`V. Hillgrefl, M- Drake, D. C. Ruble
`
`Phase Transitions Between
`Bandy
`(Mg,Fe);Sl04 in the Earth’s Mantle:
`Mechanisms and Rheological Implications
`D, C, Ruble and A. J. Bruarley
`
`1442
`
`1445
`
`Arabidopsis ABA R€5I30nse Gene A131}: 1448
`Features of a Calcium-Modulated Protein
`Phosphatase
`_]. Leung, M. Bouvier—Durand, P.-C. Morris,
`D, Guerrier, F. Chcfdor, ]. Gitaudat
`
`u--.......... .,.......
`
`1434
`Dating a glacier
`
`—<A‘\y—u‘ ..,.._.. .....u. -_ca.+-
`V... ..,.._ . ....,,_.........._.....J
`
`___;_-_;AAAS Board of Directors
`Nan Sc hriesheirn
`Eloisa E. Clark
`Jean'na M. Shleeve
`Retiring Presideflfi
`Chairman
`Ch ang-Lin Tien
`Francisco J. M-9'3
`Warren M. Was hinglon
`President
`Nancy S. Wexler
`Rita R. Colwe”
`President elect
`William A. Les1erJr.
`Simon A. Levin
`Anna C. Roosevelt
`
`William T. Golden
`Treasurer
`Richard S. Nicholson
`Exec;-live Oflfcer
`
`D
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`Indicates accompanying feature‘-
`account number. Postmaster: Send change cl address to Science, P.O.'E_D>I
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`,5 gg;';e.ao75.»a3 31 + _1o. Science Is indexed In the Readers Gulde lo Porr-
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`
`SCIENCE - VOL. 264 ' 3 JUNE 1994
`
`
`
`Page 3 of 6
`
`

`
`RESEARCH NEWS
`
`Drug Discovery on the Assembly Line
`
`In the Search for new drugs. dive-rsii
`y is strength. Combinatorial chemistry generates lots of molecular
`diversity,
`all at once-—and keeps track of what it creates
`
`Heiww Ford didn't invent rim
`car. But he is
`acciaimed as an indusmal
`genius jL|5[
`t}~,,_.
`same because he dev¢l..p,_.d t
`1
`l’1(:'¢1$S{.‘l‘£'Il)lyli11e
`and in so doing e11-dnged
`I it‘ W[l\_,i‘ t_‘\rg]-yrpi-ying
`is inanufactured. Li
`..
`,
`_
`of cheniists isn't tl‘:Lf\iVr:;btLi:mup
`-
`,
`\_
`-
`-‘ new
`aamemwmmaa
`.
`i [ff 1}.“ mt itatetoiiipoiinds qtiickly
`J1“ =1 01 <1’ Y. flml their work is Ch‘l1'l7i
`.
`mwowwmmmaao
`rr
`3
`: ‘
`_
`a
`.
`.aeasaaamwa
`-
`C that it takes to
`develop new drugs and save millions of [
`1
`lars in RSLD costs. but one that is ch-
`K.” '
`the whole notion of drug Liiscovi-31-y
`iiiiemcrit." says Adele M. Haley. chief (.'ll‘ll.‘i
`‘industry analyst for the Stt>ver-Haley-Ngyei
`rfe Sciences Advisory Group
`The new technology sweeping she
`industry is called eoinbinatoriaicl1ein—
`istry, a way of churning out hundi'eds
`—-or liuridreds of rnillions-—of' mm-
`pounds with known structures. “By 5i-
`multaneously creating CL')i‘l‘lp0i_|m_I5 with
`shapes, cliarges, and electrostatic char-
`acteristies covering a tremendous range
`of possibilities, combinatorial chemist
`try dramatically improves the odds of
`finding at least one new substance that
`will bind to some target [in the body]
`with extraordinary affinity," says Thomas in-
`golia, director of natural products and big.
`tecimoiogy i'eseiii'ch at Eli Lilly T1-lam he Adds
`“is really what drug discovery is all about." !
`Classical synthetic cl'ieitiisti'y was |imi[¢_-Ll
`in the array of candidates it could I]1I.15[c'r
`because Cl1L’IlliSi'S could only make the. aim
`leeular 5l‘l‘:1pc‘:i and cliaiacteristics they could
`iiiiagiiie. And while the world’s Forests,
`oceans. and compost piles are a treasu1't;_
`trove oiunexpectetl molecular entities. sort.
`ing this trove requires collecting thousands
`of natural specimens and assaying thgm for
`l1i(.)lUf__IiCdl activity. Then comes the even
`larger task of isolating and puril"ying the ar_-.
`rive ini_gredienr, determining its stiuetui-e, and
`most dii7f'iL‘iilt' of all. syntliesizing it. Combi-
`1‘ia1'orial chemistry Ci)l1.‘si)liLl‘ciiIi.‘5 these lab: )1'i-
`ous tasks into one quick succession of _~,i;i_-pg,
`The basic strategy is to assemble every
`possible combination ofa given set Ljfcllt-‘l-1‘i\
`cal building blocks While simultaneously re-
`cording which ones have been used aml in
`what order. then assay the i'L‘h'lIl[ii‘Ij__:
`inoi-
`cculcs all at once—ai‘1«;l refer to the record to
`determine the identity of any that
`look
`
`and block basic fibroblast growth factor (a
`promoter oi: cell proliferation). and move
`several of the compounds into aniinai tests as
`potential treatrnents for cancer and other
`conditions. And in what may be a speed rec-
`ord, it took only a few weeks for ciicinists at
`Chiron to develop several small organic mol-
`ecules that bind specifically to a family ofG-
`protcin-linkcd rcc<:ptors. the most coinrnon
`type of neurotransmitter receptor in the cen-
`tral nervous system. Says \li/alter Moos, vice
`president
`for chemical
`therapeutics
`at
`Chiron, "Older methods of inaking one com~
`pound at a time just can’: compete."
`Coinbinatorial chemists are quick to admit
`that the strategy is no panacea. Sofar. its ir1ain~
`stays have been peptides and oligonucleo—
`tides
`polymers consisting of repeated units.
`Such mix-and-match molecules were
`the natural choice For working out the
`basic technology, but they are fragile
`and ciiffictilt to aclininister compared to
`most existing drugs. Over the past year
`or so. however. several groups have suc-
`ceeded in applying combinatorial strat-
`egies to the simple rings and chains that
`are the building blocks of small organic
`molecules, which constitute the vast
`majority of drugs available today.
`the
`The key feature setting apart
`vai'ious combinatorial
`techniques is how
`they keep track of the vast molecular librar-
`ies they generate. Affyinax'.s Encoded Syn-
`thetic Libraries (ESL) approach. perfected
`last year. relies on easy-to-rea:.i chemical ia-
`heis, written as ‘5lIl'i11[_{>i of nucleotides. in
`ESL. each potential drug candidate is iarown
`on a 10-micron plastic head, side-by-side
`with its tag. A three-rmcleotide eodon iden-
`tifies each iiiolecular building; block.
`
`The numbers game
`The process begins when the first building
`block and its codon are added to a single large
`pool oi" heads and attach theinselves to its
`surfiice. Then the pool is split into as many
`hatches as there are building blocks-20. if
`the subunits are aniino acids
`and a differ-
`ent huildiiu_{ hlock and matching CUi.i()l'l
`is
`added to each one, creating Z0 tlifieienr two~
`unit ssonihiiiations. Now [l‘lL‘ subsets are re-
`conibincd, rcdivided into 20 new pools. and
`again reacted with one of the amino acids
`and then its eodon. resulting in 400 different
`Il'il'L‘i:—lil1ilI combinations.
`Rep!-.“«1l'i1'li1 This
`process eight times with all 20 amino acids
`‘I399
`
`\ s
`
`on
`non
`
`proinising. Since the strategy was introduced
`by researchers at Affymax Pharinaceuticais
`in 1991. it has ti‘i[.‘.}.-,'(.“.l'(-2:'.i a combinatorial ex-
`plosion of its own, hlossoining into a multi-
`tude of variants based on tlifferciit inoiecular
`building blocks and strategies For keeping
`track of the product inolecules. It lias also
`sparked a proliferation of start-up drug dis-
`covery companies cxploltin;_.; variations of
`the combinatorial chemistry theme.
`These st-.1ri:—ups and the estahlislied phar-
`maceutical companies that are htiilding their
`own in—house combinatorial teams are aim-
`ing: to streamline a process that takes an aver-
`age of i2 years and costs $359 million. ac~
`coitling to the US. Office of Technology
`Assessnlcnt. Witli combinatorial chemistry.
`says Larry Gold, co-inventor of one combi-
`natorial technology and Founder oFNeXagen
`in Boulder. Colorado, “it is now possible to
`come up with several solid drug candidates in
`a matter of months instead of years.”
`NeXapen scientists. forexample, last year
`took less than 4 montlis to generate a library
`of short, chemically staiiilizeti cliains of" mi-
`cleotides, screen them for the ability to bind
`
`1-§(2|EN(2l:‘ - voL. 264 -
`
`'3 JUNE 1994
`
`\MiX Ash DIVIDE
`/ l
`L0 ‘"1 A0 T1
`I 0 T2 I 0 T2
`* ? T3 * 0 T3
`‘T4
`‘$75
`\M|XAug oivioE‘/
`/” l
`"\
`‘OAO Tm
`Outm
`orova
`ssomso-owssrovs
`Qfio 'r,1'.
`T,T5
`T3T5
`Add and react. In one combinatorial chemistry scheme. mo-
`lecular building blocks (shapes) and their matching chemical
`lags (T) are linked one-by-one to plastic beads. Alter each
`successive addition. the beads are mixed and then divided
`into new pools. leading to a combinatorial explosion.
`
`
`
`
`
`
`
`SOURCE.CSENEWS|LLUS'l'FlATlON:C.FABEFI$Ml'iH
`
`
`
`Page 4 of 6
`
`

`
`Putting Genes on a Chip
`
`Now that co111l'1inatori-.1l clieinistry is showing
`its mettle by spinning out candidate disease
`tteattncnts (see main text), rescarcliers at Affy-
`metrix hope it will prove equally adept :1t diag-
`nosis. By 1nerp,ing silicon-patterning: techniques
`borrowed from microelectronics with combina-
`
`AFFYMETRIX
`
`Llghting a match. A fluorescent
`probe binds to sites on a matrix of
`256 different eight-nucleotide chains.
`
`torial chemistry. this small biorcch sratt—up in
`Palo Alto is producing intricate chcclvcerboar is
`of different nucleotide sequences anchored to a
`silicon chip. These chips, they say, can serve as
`detectors of aberrant genetic sequences, which
`would bind to specific sites on the Cl‘i(3Ci<(-.‘I'lJO'dI'(.l.
`"Basically, we’re writing down genetic se-
`quence information in a way that is easily acces-
`sible using standard hybridization techniqtles.”
`says Stephen Fodor, who with colleagues at par-
`ent company Affymax developed the technol-
`ogy, very-large-scale immobilized polymer synthesis (VLSlPS). in 1991. Foclor and his
`colleagues originally eiwisinned VLSlPS as 21 way to generate and screen drug candi-
`dates, but other techniques have since surpassed it for drug tievelopinent. Where
`Affyinettix hopes VLSIPS will shine, however, is in the testing of genetic and viral
`diseases. They also think that it might speed gene seqL1enci1'1g—a hope shared by the
`Human Genome Project, which has funded tl1e company to explore the technology.
`Vl.5lPS starts with a silicon chip coated with a nucleotide linlted to a light-sensitive
`chernical “hlock" group that prevents further reactions. Light shining through -.1 mask
`illuminates specific grid squares on the coated chip, triggering the removal of the bloclt
`group in those spots. The chip is then incubated with the next pliotoprotected nucleo-
`tide, which binds to the exposed spots. Another round of exposure and reaction binds a
`third nucleotide to a different set of grid sites, and so on. In 32 cycles, for example, a
`carefully planned sequence of tn‘dsl(it1g patterns and reactions can create all 65,536
`possible chains ofeight nucleotides, each one in a known location on the chip.
`The chip can then probe a solution of fluorescent—labeled DNA fragments for the
`presence of specific sequences. Complete sequence mzitclies show up as squares of bright
`fluorescence, while single-base inistnatches yield dimly lit squares. The matches could
`betray the presence of genetic defects, sucli as the cystic fibrosis gene, or pathogen
`strains. says Fodor. Together, the matches and the single-base mismatches could also
`reveal the complete nucleotide scqueiicc in :1 set of DNA frziginents, he adds.
`That's still a ways off, but in the me-.1nti1ne Fodor and his colleagues are pushing ahead
`with combinatorial diagnostics; they plan to begin shipping tliagnostic chips to research-
`ers and clinicians by the end of the year. Says Adele M. Haley, a drug industry analyst,
`“Affymettix’s technology is going to be 21 big winner. It will be fully automated and
`should be capable ofrunning upwards of 100,000 tests siinulomeously. That should offer
`sigiiificaiir s:1yint:s for big clinical laboratories.” And in totlrIy's world of medical cost-
`cutting, any savings usually translates into success.
`
`—].A.
`
`creates a library of the 25.6 billion possible
`Iitlllapeptialcs, eacli
`ider1tifieLl by ‘.1 unique
`sI'ting of 24 nucleotides.
`To assay the activity of such inolccular
`lib1".1tics,;°\ffyIn:1x cliemists mix the heads with
`:1 flL|l)|‘t“iC.Cl1t'lTi1§{L[tltl version of the receptor.
`antibody, or other molecule that is the targget
`ofthc LlL‘.‘ilI'l'.‘Ll drug, Beatl.sl1ca1‘iI1},’ niolecules
`that hind to the labeled l.'zil'§_’,eE lluorcsce, and
`:1 comiiierci-.1|ly }l\F;1ll;1l7lL‘
`l'lLltJl'(..‘\‘l:(.‘1‘ttZI.:-:ICI.'i-
`wired cell sorter can piclc them out from
`mnonu the i11i1cIiv:: licads---11 rapid ull'er11a-
`rive to the p:1inst:1kinj_7 purification and isola-
`rion I'L'(|1Ii]'L‘ll
`to extract ‘.1 promising com-
`pound from :1
`iT:i[l]l'dl spccinicn. Then it's
`1400
`
`simply :1 matter of reatlinu eacl1be:1t|’s DNA
`t-.1,:_;, using the polyincrase cl1-ain reaction
`(PCR) and stand-.1rd seqtieziciiig technology.
`to identify its molecular cargo.
`Ratllei‘ than creating labels, scientists at
`(Jhiron,
`l‘:1rl<e—D-avis. Sphinx l’|1arm11ce1iti—
`culs, and other coinpzinies rely on spati:1l lo-
`cation to tracl< their con1pounds.f\t Chiron,
`for example. compounds are grown on an
`-.1rr:1y of polyethylene pin.-1‘ |i"Iziiii[JLll2l[CLl by a
`robot -.1r111. in a carefully calculated seqttcnce,
`the pins are dipped into sets of minute test
`ttlbes r.'ot1l'a1i11inf.:, re:Icl'ivel1uildii1;.:blocks. A
`different subset of pins is exposed to each
`successive builtlin;_:l1lock, with the result that
`
`‘.-'-(Ill:‘N(IE 0 VOL. N14 0
`
`'5 JUNE I994
`
`eacli pin ends up carryi11;_::1 tlificreiit coml'-1'-
`nationofliilildingblocks.Tl1cpit1s can then
`be exposed to :1 fliioi-cscc11t—t:1r:,_t:etl version of
`thc drug I'.ll‘l_[L‘l', and the identity of :1 com-
`pound thut lias a stro11;_: affiiiity for the tzirgct
`can be determined from The pi11'_~, position.
`A third upproacli forgocs any lzlbcling
`.scheme—soInctl1ing that's possil‘!le if the
`building blocks are nucleotides, whose se-
`quence can readily be deciphcrcd. l\leXage1"1.
`for example, begins with -.1 primer sequence,
`then uses a battery of oligonucleotide synr
`thesizets to put it tlirough 25 to .30 cycles of
`nucleotide addition. After each cycle,
`the
`growing oligonticleotides from each synthe-
`sizer are mixed, then split into new hatclies.
`The result is trillions of diffe1'ent oli;gonu-
`cleotides, which can be mixed with l"di'11Et
`molecules. PCR and automated sequencing
`can then reveal the identity of the ll'1()lL‘CUlE'|1'
`needles—in—a-haystacl< that bind to the target.
`This field is so young and is breeding its
`own technical conihinations so rapidly that
`no two companies use exactly the same tech-
`nique. (Indeed, most firms hay-‘ 'a|1plicd for
`patents to cover their yariaiits of C(lI'I'ib‘111':itL1A
`rial chemistry.) But there doesn’t seein to be
`much arguing about whose approach is best.
`‘‘I’m sure each company takes pride in its
`method, but no one has a monopoly on good
`cotnbinatorial methods,” says _lE11'I10S Bristol,
`a vice president at Pa1'l<e-Davis. “What's i1n—
`portant is that this [(:Cl‘Il‘lit[LII.3 speeds up the
`early phases of the drug discovery pl'UCc3_-5 am]
`may reduce the overall cost of discoveririg a
`new chemical entity.”
`And the strategy not only betters the odtls
`of finding an active compound; becatise it
`creates such a large pool of coiirendei-_-,-, the
`candidate compounds are often more specific
`than those found in nature or syntlmsized by
`l"l".1(.lilZiL)1"ii‘ll me:1ns. Barry l-’olisl<y and his col-
`leagues at NeXai_:e11, for example, recently
`(;i‘e‘.1tt-:d ‘:1 pool of l0'i'l—tl1:ll"h'
`‘:1 l‘1u1"id1'ed tril-
`lioo—diffe1'cnt RNA molecules CU1‘1[:liI1il'1,‘.{
`a 38-ntlcleotide random ~act1t1e11c<-.-.
`The NeXaige11 chemists then screened these
`l1‘IUlCClIlES for tlic ability to discriiniliiitc be-
`tween theophylline, :1 couunon a11ti—astbI11a
`inedication. and caffeiiie, which differs from
`theophylline by only -.1 single methyl g:'i1L1p.
`One of the oligonuclcotidcs had :1n affiliity
`for theophyllinc 10.000 tiincs ;_=,rca1'ei' than
`its affinity for caficiuc—disc1'in1ination I00
`times better tl1an that of the I11o|‘1oclon'.1l anti-
`body now used to monitor blood IheopI1yI—
`li1iclevcls(Scicnct’, 1 1 March, p. l‘l2‘3).Tl1'.1t
`fear is of more than ac-.1demic interest; :1 more
`selective theophyllinc 1155111,’ would increase
`the safety of usirig the dI'u;_: to control -.1~1thm‘.1.
`
`A farewell to elegance?
`Such feats haven't won over the en tire com-
`munity ofoi'j_r11i1ic cheniists. Stalw11I'I.~i mourll
`the loss of the cle.gz1nt cl1en1isI'ry required to
`assclnlilc '.1 complex molecule pi:.‘L‘c by piece.
`
`
`
`Page 5 of 6
`
`

`
`As ii result, says Thomas N. Salzim
`nnn VICE
`president for chemistry at Merck an‘
`OE Every-
`one here is ‘cl convert” to combin ‘
`atorial chem-
`istry-—although he adds that th
`C resistance is
`a.-ions.“
`“nor for any good scientific is
`Yet even the most arden
`V advocates of
`combinatorial chemistry say
`FheY Will never
`put traditional organic ch
`eltusts out of busi-
`ness. “We still need their crearivir
`t
`d
`.2.
`velop new chemistry, new ‘l'€aCtiqnSYth0
`can use in our brute-force inei,-hogs -.at,we_
`jack Baldwin, President of Phatmaco ‘SW5
`year-old drug discovery company wfvia‘ ,a
`more, combinatorial chemistry has haryiit s
`cede some tasks to traditional
`5
`,_.1
`‘.°
`chemistry because of a practical drallvtl) llitic
`The drawback is that the kinds ofac .1
`ecules best suited to the combinatorial‘? \
`proach—peptides and nucleic acids._,-_._a
`be taken by mouth; they are either tool n t
`to be absorbed in the gastrointestinal tfiarg:
`or they get digested along the way. To me '
`with that limitation, officials at some com De
`nies. such as NeXagen and Protein Engine?‘-
`ing, are targeting diseases severe enough that
`injections will be acceptable, such as cance
`and AIDS. Or they are adopting other goals‘:
`using combinatorial libraries for diagnosgjr;
`
`pi"l‘°}“‘-'5 (599 hint) or as guides for traditiomrl
`C knmlcal synthesis.
`not rflipii Llise thelse highaffinity hinders
`ulhichslnflfiifi lpliisc ves], but as inodcls froiti
`with the
`) _rls<l~T'1'1LE1‘1'O ecules canbc crafted
`Character::1-1l0l1‘1'lflttlspatml arid lJl.UEll1Y$lC'dI
`Protein En YES.’ , exp! ::l1l‘lh‘ Edward ‘C.'z'l'l1I1t'-Jfl,
`er. B -
`l':m‘-LT11'lg 3 chief executive offic-
`'
`Vg"“ldY1“i§ the Shapes created by combi-
`}[:::(Ji3:‘1l:_lE_‘3'Tl‘ll5lYl’. for example, hiscoitipany
`the key tlulet ll-Ill’-ll€}:|slI:rLlCtui‘E‘II features that are
`that
`I
`in i ‘ltirlg ela1stase——iin enzyme
`P 3Y8 :1 role in inflarrunatory diseases—
`and several enzymes involved in clotting.
`These limits may only be temporary. As
`f10ml:_=inatorial chemists move beyond nucle-
`ic acids and peptides to small organic mol-
`ecules! ‘_heY may be able to compete head-to-
`head with traditional drug discovery tech-
`mques. Creating small molecules in combi-
`natorial fashion, says Affymax’s Gordon, "is
`definitely a challenge, but we and many oth-
`ers are finding that small molecule synthesis
`is doable.” Michael Pavia of Sphinx Pharma-
`ceuticals explains that "it’s not
`that
`it's
`harder to do with small organics; it's just that
`we need to develop the ability to do tradi-
`tional organic chemistry on solid supports.”
`
`Massachusetts Institute ofTechnology (MIT).
`Atmospheric chemists have little quarrel
`with the findings Wong's group described
`in the paper. In a cofi'in—sized chamber, the
`group monitored a simplified stratospheric
`brew including CFCs and low levels of ozone
`molecules, which were constantly created
`by ultraviolet light but were depleted by
`the CFCS. When the
`group injected elec-
`tric charges into
`
`ATMOSPHERIC CHEMISTRY
`A "“9h'F'Vi"9 Fix for Ozone Loss
`Alfred Wong knows he's in danger of over-
`reaching when he talks about extending his
`lab—scale chemical reaction to the scale of
`the globe. But the University of California
`I-05 Angelesi Plasma Physicist
`thinks the:
`chemical transformation he has seen in a
`chamber of gases has implications too impor-
`tant for the global atmosphere to keep silent
`in spite of a blast of criticism from atmg:
`spheric scientists. Wong’s bold claim: Twen.
`ry or so panels of zinc or aluminum, each at
`least the size of a football field. carried alrifr
`by balloons. could sustain 21 global version of
`the laboratory process—-and provide 3 quick
`fix for stratosplteric ozone loss.
`That implication is buried in a paper in
`the 9 May Pliysical Review Letters, when:
`Wtiiig and his colleagues describe a scheme
`for
`inactivating the chlorine atoms,
`rm-
`leaslied by inanmntle Chlorofluorocarbons
`(CFCs),
`that destroy ozone in the string.
`splrere. The paper mainly describes l‘('[l‘){)1';_l_
`Iory 1‘C=='l1If5. but Wii11g's grander claim was
`the subject of ii UCLA press release—-and
`ensuing coverage by television networks and
`print iricclia, including the Associated Press
`and Ncwsweclt. “It was very well received,“
`iioted ii spokesiiian in the UCLA press office.
`By the press perhaps, but not by atmu.
`spheric scieiitists, who cite daunting tech-
`nical probleins. ''It is a very ClC\’L‘I'li.li')i1.l1LItllI
`gets messy," says Earle Williams. who studies
`iitiimsplicric electrical phcntiiiiena at
`the
`
`Curtains to the
`ozone problem?
`Blimps would carry a reac-
`iion-triggering screen of alumi-
`num or zinc into the stratosphere.
`
`SCIENCE 0 VOL. 264 0
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`‘)jUNl:'
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`I‘-J04
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`ALFREDWONG
`
`RESEARCH NEWS
`
`for exilmplc, Sheila
`At Parke-Davis.
`Hobbs DeWitr, using the C011'1pd1‘iy's DIVER-
`SOMERS technology, has created an array
`of ringed he-terocycles (compounds contain-
`ing oxygen. nitrogen, or
`.~;ulfuI'). Among
`them are benzodiiizepines—the family that
`includes the drugs Valiuiu and Xanax—and
`hydantoins, which include Dilantin. Still,
`Cordon adds, it will probably be a few years
`before coinbiiiatorial synthesis of small mol-
`ecules rivals the power it has demonstrated
`with peptides and nucleic acids.
`When it does, the main problem combi-
`natorial chemists may face is their tech-
`riir.1ue's very efficiency. Most assay systems
`are not designed to handle billions of com-
`pounds. Then there is the glut of information
`that comes from testing such a large number
`of compounds with known structures. "In
`theory, cornbiriatorial chemistry provides
`the perfect data set for sophisticated struc-
`ture-activity relationship analysis,”
`says
`Metcl<’s Salzmann. In reality, says Chirorfs
`Moos, “we can now geric-i'ate so much data so
`fast that we're in danger of becoming over-
`whelmed." In some respects, combinatorial
`chemistry may be too much of a good thing.
`-Joseph Alper
`
`the chamber, ozone levels increased sharply.
`The researchers concluded that, by convert-
`ing reactive chlorine atoms to virtually inert
`chloride ions. the clitirges had stymied the
`ozone-destroying process.
`In their paper, Wong and his colleagues
`limited themselves to raising the possibility
`that the process could be scaled up, without
`saying how. But
`in an interview, Wong
`spelled out his scheme. Into the Arctic and
`Antarctic stratospheres, where the worst
`ozone depletion takes place, he would fly 10
`to 20 balloon—borne platforms carrying
`sheets, wires, or curtains of a metal whose
`electrons can easily be dislodged by ultravio-
`let light. As in the laboratory, Wong believes
`some of the charges would find their way to
`the reactive chlorine iirotns. converting
`them into inactive chloride ions that could
`then be collected by other, positively
`charged siirfiices. Wong says he has been
`worlcing with an engineering firm to draw up
`plans for the platfornis, which would cost $25
`million €dCl1. The total of $500 Iliillivli ft‘?
`the full fleet would be it
`liiirgiiiii-—if it re-
`stored the ozone layer.
`Some proininenr atmospheric scientists
`don't dismiss the idea of global reinediar ion.
`"IF you have it serious problem Ilike ozone
`depletion]...yoii have to think about reme-
`di-.ition," notes F. Sherwood Rowland of the
`University of Californiii, Irvine. who with
`Mario Molina, now of MIT, first described
`the oznnetlestroyiiig eliemistry of CFCs in
`1973. Ralplt Cicenine, ".1 collceigtic of Row-
`1401
`
`
`
`Page 6 of 6