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April 2004 Vol. LXXXII, No. 8

MonthlyMeetingGustavus J. Esselen Award toProfessor James Jorgenson

Richards MedalAward AddressProfessor John Ross, Stanford University

Book ReviewMaking Genes, Making Waves. by Jon Beckwith

2 The Nucleus April 2004

ACS SHORT COURSE

Designed to improve the skills and marketability of practicing B.S., M.S., and Ph.D. chemists.

The NESACS Committee on Continuing Education is pleased to sponsor this newly updated National ACS Two-Day

Short Course, at a registration fee less than half of that charged at National ACS Meetings.

Experimental Design for Productivity and Quality in R&D

This Short Course is designed for chemical scientists, engineers, R&D managers, and others who need to learn

proven methods for designing quality into products and processes. The course assumes no previous knowledge of

statistics and is aimed at both beginning and experienced R&D workers. Participants should bring a hand-held

calculator to the course.

PLACE: Dodge Hall, Northeastern University, 360 Huntington Ave., Boston, MA

DATES and TIME: Monday, May 10, 2004; 8:00 a.m. – 5:00 p.m. Room 450B

and Tuesday, May 11, 2004; 8:30 a.m. – 5:00 p.m. Room 450C

PROGRAM AGENDA - Topics will be selected from the following:

Linear Models

The importance of n, p, and f

Choice of Model

Matrix Least Squares Solutions

Regression Analysis

Estimated Responses

Residuals

Replication and Pure Error

Sums of Squares

Degrees of Freedom

The Rosetta Stone of Statistics

Basic Design Concepts

Looking for Lack of Fit

Looking for Pure Error

Calibration

Coding

Orthogonal Designs

Classical Data Analysis

Factorial-Type Designs

Yates’ Algorithm

Fractional Factorial Designs

Blocking

Various Design Possibilities

Mixture Designs

Multiple Response

Analysis of Variance (ANOVA)

Correlation Coefficient

F-Test for Regression and for Lack of Fit

Confidence Intervals and Bands

Comparing Different Designs

INSTRUCTOR:

Stanley N. Deming, Professor Emeritus of Analytical Chemistry at the University of Houston and the President of

Statistical Designs. Dr. Deming is the author or co-author of more than 90 publications in the areas of analytical

chemistry and related disciplines, including the Elsevier text Experimental Design: A Chemometric Approach,

2nd

edition (1992).

PRE-REGISTRATION REQUIRED – Registration Fees:

ACS Members if received before April 26…..…… $500.00; after April 26 ……$575.00

Non-ACS Members if received before April 26 ..…$600.00; after April 26 ……$675.00There will be a limited number of scholarships for unemployed ACS Members on a space-available basis.

Parking Fee: about $14.00/day University cafeterias will be available for lunches.

For further information contact: Prof. Alfred Viola at (617) 373 2809_________________________________________________________________________________________________________________________________________

Registration form for Short Course: Experimental Design for Productivity and Quality, May 10 – 11, 2004

Name: _____________________________ Business Affiliation: _____________________________

Mailing _________________________________ Telephone: __________________________

Address

(circle: Home or Work) ___________________________ E-mail: ____________________________

Mail with remittance to: Prof. Alfred Viola, Chair

. NESACS Committee on Continuing Education (Please make checks payable to NESACS Department of Chemistry

Sorry, we cannot accept credit cards or Northeastern University

purchase orders.) Boston, MA 02115

The Nucleus April 2004 3

The Nucleus is distributed to the members of the Northeastern Section of the American Chemical Society, to the secretaries of the Local Sections, and to editors of all local A.C.S. Section publications.Forms close for advertising on the 1st of the month of the preceding issue. Text must be received by theeditor six weeks before the date of issue.Interim Editor: Mukund S. Chorghade, 14 Carlson Circle, Natick, MA 01760:

chorghade(at)Comcast.netAssociate Editor: Myron S. Simon, 20 Somerset Rd., W. Newton, MA 02465, Tel: 617-332-5273Board of Publications: Patrick M. Gordon (Chair), Vivian K. Walworth, Marietta H. Schwartz,

E. Joseph Billo (Consultant)Business Manager: Karen Piper, 19 Mill Rd., Harvard, MA 01451, Tel: 978-456-8622Advertising Manager: Vincent J. Gale, P.O. Box 1150, Marshfield, MA 02050,

Tel: 781-837-0424; FAX: 781-837-8792Contributing Editors: Edward Atkinson, History of Chemistry; Dennis Sardella, Book Reviews;

Marietta H. Schwartz, Software Reviews.Calendar Coordinator: Donald O. Rickter, e-mail: rickter(at)rcn.comProofreaders: E. Joseph Billo, Donald O. Rickter, Myron.S. SimonWebpage: Webmaster: Samuel P. Kounaves, samuel.kounaves(at)tufts.edu

Copyright 2004, Northeastern Section of the American Chemical Society, Inc.

The Northeastern Section of the AmericanChemical Society, Inc.Office: Marilou Cashman, 23 Cottage St., Natick, MA 01760. 1-800-872-2054 (Voice or FAX) or 508-653-6329. e-mail: mcash0953(at)aol.comAny Section business may be conducted via the business office above.NESACS Homepage:http://www.NESACS.orgSamuel P. Kounaves, WebmasterACS Hotline, Washington, D.C.: 1-800-227-5558Officers 2004Chair:Jean A. Fuller-StanleyChemistry Department, Wellesley CollegeWellesley, MA 02481-8203781-283-3224; jfullers(at)wellesley.eduChair-Elect:Amy E. TapperGenzyme Drug Discovery and Development 153 Second Ave. Waltham, MA 02451781-434-3518 amy.tapper(at)genzyme.comImmediate Past Chair:John L. NeumeyerHarvard Medical School/McLean Hospital115 Mill St., Belmont, MA 02478617-855-3388 neumeyermaclean(at)Harvard.eduSecretary:Michael SingerSigma RBI3 Strathmore Rd. Natick, MA 01760-2447508-651-8151x291 msinger(at)sial.comTreasurer:James Piper19 Mill Rd., Harvard, MA 01451978-456-3155 piper28(at)attglobal.netAuditor:Anthony RosnerArchivist:Myron Simon20 Somerset Rd. Newton, MA 02465; 617-332-5273romysimon(at)mindspring.comTrustees:Joseph A. Lima, Esther A.H. Hopkins, Michael E. Strem, Councilors: Alternate Councilors:Term Ends 12/31/2004Thomas R. Gilbert Mukund S. ChorghadePatricia Hamm Timothy B. FrigoMichael J. Hearn David WarrArlene W. Light Derk A. WierdaTerm Ends 12/31/2005Mary T. Burgess Patrick M. GordonMorton Z. Hoffman Lowell H. HallDoris I. Lewis Donald O. RickterTruman S. Light LawrenceT. ScottAmy E. Tapper J. Donald SmithTerm Ends 12/31/2006Michaeline F. Chen Wallace J. GleekmanCatherine E. Costello Howard R. MaynePatricia A. Mabrouk Alfred ViolaJulia H. Miwa Barbara G. WoodDorothy J. Phillips Michael Singer

All Chairs of standingCommittees, the editor of THE NUCLEUS, and the Trustees of SectionFunds are members of theBoard of Directors. AnyCouncilor of the American Chemical Societyresiding within the section area is an ex officiomember of the Board of Directors.

ContentsACS Short Course ______________________________________2“Experimental Design for Productivity and Quality in R & D”, May 10-11, 2004

Tribute to Arno Heyn____________________________________4By Myron S. Simon

Monthly Meeting _______________________________________5Esselen Award Meeting: Professor James W. Jorgensen, W. R. Kenan, Jr.Distinguished Professor of Chemistry, University of North Carolina at ChapelHill. Award address “The Magic of Capillaries in Chemical Separations andAnalysis”

Richards Medal Address_________________________________9“Complex Chemical, Biochemical Reaction Mechanisms: Determination and Synthesis” By John Ross (reprinted, with permission, from Acc. Chem. Res.2003, 36,839-847)

February Meeting _____________________________________18Special Recognition of Arno Heyn (photos by James Phillips)

Book Review: “Making Genes, Making Waves: A Social Activist inScience”, Jon Beckwith ________________________________19By Myron S. Simon

Cover: James W. Jorgensen, W. R. Kenan, Jr. Distinguished Professor ofChemistry, University of North Carolina at Chapel Hill (Photo: UNC, Chapel Hill)

Deadlines: Summer 2004 issue: June 18, 2004 September 2004 issue: July 16, 2004


Dr. Arno Heyn, the editor of theNortheastern Section’s monthly news-magazine, the “NUCLEUS”, recentlystepped down from this post due to illhealth. He was feted at the Februarymeeting of the Section. In his distin-guished fourteen and a half -yearcareer as editor, he improved the Sec-tion’s newsletter to the point where it

is now recognized as an outstandingpublication, a standard by which oth-ers are judged and has been cited as amodel for other sections to emulate.Dr. Heyn was presented with a plaqueexpressing the gratitude of the Sectionby the Section Chair, Professor JeanFuller-Stanley, and a scroll expressingthe appreciation of the AmericanChemical Society by Dr. William Car-roll, President-Elect of the Society.Many members of the Section thenseized the microphone to second thegood wishes expressed earlier and addtheir own reminiscences. There wasunanimous praise for the yeoman serv-ices rendered by Dr. Heyn. A remark-able period has ended, and many ofthe 6000 members of the Section whorecognize the great value of theNUCLEUS as the glue which binds theSection together, are saddened by theloss of Dr. Heyn’s counsel, guidanceand wisdom. ◆◆

Summerthing2004Well, the NESACS has done it again!We have obtained those hard-to-getRed Sox tickets for the 2004 season.Our tickets are right field box seats,and will cost $44. Although we didnot get super discounts this year, youwill not overpay! We have a limitednumber of tickets available, so be sureto order early. To obtain tickets contactWally Gleekman at 617-527-1192 orvia e-mail at [email protected] orat [email protected] which game you want to see,how many tickets you want and whoand where you are. We will let youknow when to send in a check. Tick-ets are available for the followinggames:Summerthing I: Sunday, May 9, 2:05p.m Boston Red Sox vs. Kansas CityRoyalsSummerthing II: Thursday, May 27,7:05 p.m. Boston Red Sox vs. OaklandAthleticsSummerthing III: Wednesday, June23rd, 7:05 p.m. Boston Red Sox vs.Minnesota Twins ◆◆

Corporate PatronsAstraZeneca R&D BostonCorporate SponsorsAerodyne Research Inc.Cambridge Isotope LaboratoriesNew England BioLabs, Inc.Sigma-RBIStrem Chemicals Inc.DonorsConsulting Resources Corp.Houghton Chemical CompanyOrganix Inc.

The NEW NESACS website

WWW.NESACS.org

Tribute to Arno Heyn

BiographyJames Jorgenson was born in Kenosha,Wisconsin in 1952. He received hisundergraduate education at NorthernIllinois University where he received aB.S. in Chemistry in 1974. Followingthis he entered graduate school at Indi-ana University, where he worked in theresearch group of Professor MilosNovotny, and received a Ph.D. inChemistry in 1979. His Ph.D. researchconcerned two principal areas: thestudy of mammalian pheromones, andthe development of new detectionschemes for liquid chromatography.

Dr. Jorgenson joined the faculty ofthe University of North Carolina as an

Assistant Professor of Chemistry in1979. He was promoted to AssociateProfessor in 1985, Professor in 1987,appointed the Francis P. Venable Pro-fessor of Chemistry in 1994, andWilliam Rand Kenan, Jr. DistinguishedProfessor of Chemistry in 1999. Hebecame Chair of the ChemistryDepartment in 2000.

Among the honors he has receivedare the American Chemical SocietyAnalytical Division Award in Chemi-cal Instrumentation in 1992, The Mar-tin Medal of the ChromatographicSociety in 1992, elected a Fellow ofthe American Association for theAdvancement of Science in 1992, theAmerican Chemical Society Award in

Chromatography in 1993, the GolayMedal in 1994, the Eastern AnalyticalSymposium Award in Separation Sci-ence in 1995, the Torben BergmanMedal of the Swedish Chemical Soci-ety in 1996, the Anachem Award,1996, the Dal Nogare Award, 1998.

Professor Jorgenson is one of theoriginators of capillary electrophoresis.His first publications on this topicappeared in 1981. His current researchinterests include ultra-high pressureliquid chromatography, micro-columnliquid chromatography, capillary elec-trophoresis, multidimensional separa-tions, micro scale separations coupledto mass spectrometry, ultra micro andsingle cell analyses, and the design ofdetectors for chromatography and elec-trophoresis. ◆◆


AbstractNarrow bore capillary columns haveplayed an important role in chemicalseparations and analysis over the past50 years. Marcel Golay first con-ceived of capillary columns for use ingas chromatography in the mid 1950s.Capillaries were first used in a variantof electrophoresis, known as isota-chophoresis, in the mid 1960s. Andfinally, capillary columns were firstused in high-pressure liquid chro-matography (HPLC) in the mid 1970s.Despite the fact that capillaries haveprovided a highly effective format ingas chromatography, liquid chromatog-raphy, and electrophoresis, the drivingforces that led to their use in each casewere oftentimes different. One thingremains in common in all three cases,capillaries provide the most powerfulseparation format for separation andanalysis of complex mixtures.

Background on the developmentof capillaries in gas chromatography,liquid chromatography, and elec-trophoresis will be presented. Com-parisons of the development andcurrent state-of-the-art in each of thesefields will be given. Finally, specula-tion on the future of capillary-basedseparations in particular, and the futureof analytical-scale chemical separa-tions in general, will be made. ◆◆

Monthly MeetingThe 851st Meeting of the Northeastern Section of the AmericanChemical SocietyEsselen Award MeetingThursday, April 15, 2004Harvard Faculty Club, 20 Quincy St., Harvard University, Cambridge, MA5:30 pm Social Hour

Representatives from Kforce Scientific Staffing Firm Available6:30 pm Dinner8:15 pm Award Meeting, Mallinckrodt Building, 12 Oxford St., ground floor

Pfizer Lecture Hall (MB23).Dr. Jean A. Fuller-Stanley, NESACS Chair, presidingThe Esselen Award — Dr. Joseph Billo, Chair, Esselen Award

CommitteeIntroduction of the Award Recipient — Dr. Robert T. Kennedy,

University of Michigan. Presentation of the Award — Gustavus J. Esselen III“The Magic of Capillaries in Chemical Separations and Analysis”

–Award Address- James W. Jorgenson, W. R. Kenan, Jr. Distinguished Professor of Chemistry, University of North Carolina at Chapel Hill

Dinner reservations should be made no later than noon, April 8th. Please call orfax Marilou Cashman at 800-872-2054 or e-mail at [email protected] specify if vegetarian entrée desired. Reservations not cancelled at least24 hours in advance must be paid. Members, $28.00; Non-members, $30.00;Retirees, $15.00; Students, $10.00THE PUBLIC IS INVITEDAnyone who needs special services or transportation, please call Marilou Cash-man a few days in advance so that suitable arrangements can be made. Freeparking available at the Broadway garage.Next Meeting: Education Night, May 13, 2004 at Northeastern University

Gustavus John Esselen was one of themovers and shakers in the Northeast-ern Section, serving on numerous com-mittees, Chairman twice (1922, 1923)and also a Director of the nationalACS. He chaired the national meetingsof the ACS held in Boston in 1928 and1939. He was employed by the Gen-eral Electric Co. in Lynn, and ArthurD. Little, Inc. of Cambridge. In 1921he founded Gustavus J. Esselen, Inc.,which later became the Research Divi-sion of the United States Testing Co.,Inc. and addressed problems submittedby commercial clients, especially inpolymer chemistry and technology. Hewas greatly interested in furthering theprofession of chemistry, and it is in thisspirit that the funds donated by theEsselen family to the NortheasternSection were used for establishing theaward named in his honor, “…to rec-ognize and reward a chemist whosescientific and technical work has con-

tributed to the public well-being andhas thereby communicated positivevalues of the chemical profession.”

This year’s award recipient isProf. James Jorgenson.A full discussion of the criteria for theaward was published in TheNUCLEUS, Vol. 75(8), April 1997,p.10. ◆◆


NESACSNEWSBoston University Studentreceives Rhodes Scholarship

Richard Malins of Hawaii is the sev-enth Boston University student toreceive a Rhodes Scholarship, based onhis academic achievement, integrity,leadership potential, and physicalvigor. This year marks the 100thanniversary of American students earn-ing this honor and entering OxfordUniversity for two to three years ofstudy.

A recent Beckman Scholar, Malinspresented his findings on the pathologyof Alzheimer’s disease at the BeckmanCenter for the National Academy ofSciences and Engineering. His primaryfocus is on the functioning of thehuman brain, and he plans to spend histime at Oxford studying degenerativedisorders associated with aging. In arecent interview with the AssociatedPress, Malins said, “I had convincedmyself that there was no way I wasgoing to win a scholarship, so I went tothe interviews very relaxed.”

Malins is a senior double-major-ing in chemistry and neuroscience inthe College of Arts and Sciences. Theson of Captain Chester J. and ChristinaA. Malins of Pearl City, Hawaii, he is agraduate of Iolani School in Honolulu.At Boston University, he is a TrusteeScholar, a Harold Case Scholar, andalso the winner of the Mason Memor-ial Prize for Excellence in Chemistry.Malins is the second Boston UniversityTrustee Scholar to be named a RhodesScholar In addition to academics,Malins been involved in 25 produc-tions as president of the Boston Uni-versity Stage Troupe, plays the viola inthe Boston University orchestra, andhas tutored disadvantaged children.

An article with more detail aboutRick Malins appeared in the B.U.Bridge, the university’s weekly news-paper http://www.bu.edu/bridge/archive/2003/12-12/rhodes.html. ◆◆

GATEWAY CHEMICAL TECHNOLOGY

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Have you looked atthe new NESACS

website yet?Updated frequently

Consult for late-breaking news,position postings

Back issues of the Nucleus are archived in .pdf format

WWW.NESACS.org


Career FairNortheast Student Chemistry Career Fair

Friday, April 23, 2004

Brookline Holiday Inn1200 Beacon Street, Brookline, MA

REGISTRATION FREE!Schedule:8:30am-9am Continental Breakfast9am-12pm ACS Career Services workshops on

resume writing and interviewing skills12pm-1pm Buffet Luncheon1pm-5pm Job Fair – Meet with representatives

from Northeastern region chemicalcompanies about employment oppor-tunities

For details, directions, and registration, please visit theNortheastern Section Younger Chemists Committeewebsite: www.nsycc.org. ◆◆

Call For PapersThe 6th Annual Northeast Student Chemistry Research Conference

Saturday, April 24, 2004, 9am—4pmBoston University, Photonics Center

REGISTRATION $5 (payable at door)Undergraduate, graduate, and post-doctoral students in all areas of chemistry welcome!Welcoming Remarks by

Dr. Charles P. Casey, National ACS President 2004Keynote Speech 2004 by Dr. Stephen Lippard of MIT

“New Fluorescent Sensors to Study Biochemical Zinc and Nitric Oxide and to Monitor Mercury in the Environ-ment”

CASH AWARDS for best presentationsStudent oral presentations (abstract deadline April 1, 2004)Student poster presentations(abstract deadline April 8, 2004)For details, directions, registration, and abstract submission,please visit the Northeastern Section Younger Chemists Com-mittee website: www.nsycc.org. ◆◆Seminar

“Chemical Safety: A ProactiveApproach to ChemicalManagement and Security”A 2-Day Seminar entitled “ChemicalSafety: A Proactive Approach toChemical Management and Security”will be offered, on April 21-22, 2004at the University of Massachusetts,Lowell Campus.

With a special focus on GreenChemistry, this course will helpdemystify making sound economicdecisions for the environment andworker health and safety. The toxicityof solvents in the workplace and thecommunity is well established. Thiscourse will not only help to explain thereasons for this toxicity, but offer prac-tical solutions for these chemicals’replacement in light of the Precaution-ary Principle. Tuition will be $ 450.00.

For additional information pleasecontact, Carole LeBlanc, Ph.D.

Tel.: 978-934-3249 Fax: 978-934-3050 www.cleanersolutions.org,www.turi.org ◆◆


The Northeastern Section of the Amer-ican Chemical Society (NESACS)established the James Flack Norris andTheodore William Richards Under-graduate Summer Scholarships tohonor the memories of Professors Nor-ris and Richards by promoting researchinteractions between undergraduatestudents and faculty.

Research awards of $3250 will begiven for the summer of 2004. Thestudent stipend is $2750 for a mini-mum commitment of ten weeks of full-time research work. The remaining$500 of the award can be spent on sup-plies, travel, and other items relevantto the student project.

Institutions whose student/facultyteam receives a Norris/RichardsUndergraduate Summer ResearchScholarship are expected to contribute

toward the support of the faculty mem-bers and to waive any student fees forsummer research. Academic creditmay be granted to the students at thediscretion of the institutions.

Award winners are required tosubmit a report (~5-7 double-spacedpages including figures, tables, andbibliography) of their summer projectsto the NESACS Education Committeeby November 5, 2004 for publicationin The Nucleus. They are also requiredto participate in the Northeast StudentChemistry Research Conference(NSCRC) in April 2005.Eligibility: Applications will beaccepted from student/faculty teams atcolleges and universities within theNortheastern Section. The undergrad-uate student must be a chemistry, bio-chemistry, chemical engineering, or

molecular biology major in goodstanding, and have completed at leasttwo full years of college-level chem-istry by summer, 2004.Application: Application forms areavailable on the NESACS web site athttp://www.nesacs.org. Completedapplications are to be submitted nolater than April 9, 2004 to the Chair ofthe Selection Committee:

Professor Edwin JahngenUniversity of Massachusetts LowellChemistry Department, Room 520265 Riverside Street, Olney HallLowell, MA 01854-5047

Notification: Applicants will be notified of resultsby e-mail on April 23, 2004 with writ-ten confirmation to follow. ◆◆

Applications InvitedThe James Flack Norris and Theodore William RichardsUndergraduate Summer Research Scholarships

NESACS NewsCongratulations to the Department ofChemistry, University of Massachu-setts, Boston for receiving the ACSChemical Health and Safety Collegeand University Award for its efforts inproducing an exemplary chemicalhealth and safety program. ◆◆

New MembersIncludes members relocated to theNortheastern SectionInvitation to attend a SectionmeetingYou are cordially invited to attend oneof our upcoming Section meetings asguest of the Section at the social hourand dinner preceding the meeting.Please call Marilou Cashman for areservation, letting her know that youare a new member. ◆◆


Richards MedalAddressNew Approaches to the Deduction of ComplexReaction MechanismsJohn RossDepartment of Chemistry, Stanford UniversityReprinted with permission from Acc. Chem. Res. 2003,36(11), 839-847.AbstractThe formulation of a macroscopic reaction mechanism, thesequence of elementary reaction steps by which reactantsare turned into products, is dif ficult. We review several newmethods of determining the causal connectivity of chemicalspecies, the reaction pathway (the sequence of chemicalspecies), and the reaction mechanisms of complex reactionsystems from prescribed measurements and theories.I. IntroductionChemical and biochemical reaction systems may have manyspecies: reactants, products, intermediates, catalysts, andpositive and negative effectors on the catalysts. Thesespecies may be involved in many elementary reaction steps,each of which details the particular reactants and productsinvolved in a single reactive collision. The sum total ofthese elementary steps constitutes thereaction mechanism of the given systemby which the initial reactants are turnedinto final products.

The goal of establishing reactionmechanisms has long been sought inchemistry. For more than 100 years thisgoal was approached by (I) identifyingindividual chemical species, either byphysical or chemical means; (2) isolat-ing the species contributing to one ele-mentary step in the mechanism of thatsystem; (3) determining the stoichiome-try of that step; and (4) determining thekinetics of that step. This has been anarduous task, in part due to the dif ficul-ties, until recent years, of measuring theconcentrations of more than a fewspecies as a function of time. The use ofradioactive tracers has helped signifi-cantly. When these tasks were done,then began the guessing of the reactionmechanism, followed by writing thekinetic equations for the hypothesizedmechanism and deducing kinetic pre-dictions to be compared with availableexperiments. If the predictions fit theexperiments, the guessed mechanism is

possible but not necessary. There has not existed a pre-scribed method of deducing a reaction mechanism frommeasurements; there are a few clues for small systems (fewspecies)1, but no more.

This Account describes some new approaches to thededuction, not guessing, of reaction mechanisms, reactionpathways, which contain less information, and causal con-nectivities of the chemical species from specially designedexperiments and necessary theories for their interpretation.(For several such theoretical studies of genetic networks,restricted mostly to Boolean networks, see refs 2—4.) Thededuction of a mechanism from experiments still leads onlyto a sufficient mechanism, not a necessary or unique one, inthat more measurements may lead to changes in the mecha-nism. The advantage of our approaches lies in prescribingdefinite procedures for obtaining reaction mechanisms andpathways and their predictions: if they check with experi-ments they are sufficient, but not necessary or unique.

Compare the determination of the long-practiced art ofguessing reaction mechanisms as described above with thedetermination of the logic functions of an electronic device.An electronic engineer imposes electronic inputs (voltages,currents) and measures outputs of the entire system; thisleads to the construction of a truth table from which thefunctions of the device, and at least some of its components,may be deduced. A chemist would take a sledgehammer andknock the device to pieces, look for circuit elements such astransistors, capacitors. etc., and from that information try toguess the functions of the device (overstated, but indica-tive). Continued on page 10


We learned (slowly) to follow the example of the analy-sis of electronic devices and apply it to chemical kinetics. 5

First, we showed the possibility of constructing logicdevices by means of macroscopic kinetics. For example, ifand only if the concentrations of species 1 and 2 are high,then and only then, is the concentration of species 3 high;the mechanism acts as a logic AND gate. We also con-structed, on paper, various logic gates and with thesedesigned a sequential computer called a universal Turingmachine, such as a pocket computer and many much lar germachines. We then constructed a parallel computer, first onpaper, and used chemical bistable systems to carry out thecomputations of a pattern recognition experiment, the firstby implementation of a computation by macroscopic chemi-cal kinetics.6

Next we came to the question if chemical, or more per-tinently biochemical, systems can carry out computations.We answered that question in the af firmative by analyzing alarge part of the glycolytic pathway. including the tricar-boxylic acid cycle. to show that the bifurcation from fruc-tose-6-phosphate to 1,6- and 2,6-fructose biphosphates actsas a logic gate that controls the important switch from gly-colysis to gluconeogenesis. This gate is not Boolean, with asharp transition from one path to its ef fective reverse, whichwould serve poorly, but a fuzzy logic gate that changesslowly from one path to the other as it responds to multipleinputs of many effectors that control the gate.7

If computational functions are indeed built into bio-chemical reaction pathways and mechanisms, then newapproaches with suggestions from circuit theory, systemanalysis. multivariate statistics, and others may be availablefor the analysis of chemical kinetic systems as a whole. withretention of all interactions among the species. Keep thesystem together and measure the concentrations of as manyspecies as possible. With advances in several fields of ana-lytic instrumentation such as a variety of mass spectrome-ters. capillary electrophoresis, high pressure liquidchromatography, and others, the measurement of the con-centrations of many. if not all, species at a time and as afunction of time has become possible. Hence, it is timely toconsider the design of suitable experiments and appropriatetheories for the analysis of complex reaction systems in away that we may deduce from available experiments, ratherthan guess. reaction pathways and mechanisms. If speciesare not detected with the measurements available, for exam-ple, short-lived species, then in general little can be said.Sometimes, chemical knowledge may indicate a missing

species; sometimes, inferences about species not measuredmay be made.

We begin with our latest approach, pulse change of con-centrations, which is conceptually the simplest.II. Determination of Causal Connectivities of Species inReaction Networks (Mechanisms)A. Introduction and Theory.8 Consider the simple case ofa sequence of first-order reactions as shown in Figure 1. Letthis isothermal system be in a stationary state, not at equilib-rium, where the concentrations are constant but there is asteady flux, say from left to right; or at equilibrium wherethere is zero flux. The stationary state not at equilibrium ismaintained by a balance of mass flux into the system ( k0)and out of the system (k8). Now pulse (increase) the concen-tration of one of the species by an arbitrary amount. Thetheoretical analysis of the pulse methods is given in ref 8,and an experimental test of that method is presented in ref 9.(For studies of reaction mechanisms by pulse methodsrestricted to small pulses, see refs 10-12 for chemical sys-tems. A theoretical study of functional, not molecular inter-actions, in signaling and gene networks is presented in ref13.) As the concentration of one species is changed otherspecies respond with changes of concentrations. For a pulsein species X1 in Figure 1, the responses of the other speciesare shown in Figure 2. Hence the order of the responsesyields the causal (direct) connectivities of the species in thereaction mechanism.

If the system in Figure 1 is in a nonequilibrium station-ary state, then there is a net flux, say from left to right. If wepulse sonic other species, say X5, then that pulse will propa-gate downhill in Gibbs free energy, to the right strongly, butuphill to the left weakly. If the reverse rate coefficients k-1

Richards Medal AddressContinued from page 9


etc. are all set to zero, then the reaction is irreversible, andno pulse of any species propagates to the left.

We see in Figure 2 that a maximum occurs in the rela-tive concentration of any species between the curves for thepreceding and succeeding species, a result which is pre-dicted by the solutions of the kinetic equations of system 1.Several rules often hold for systems of this type: (1) Thetime of (appearance of) an extremum increases (and itsamplitude decreases) as the number of reaction steps sepa-rating that species from the initially perturbed speciesincreases, unless some species act as effectors in distantreactions. (2) Conversely, the initial curve of the relativeconcentration changes of a species with time approaches thetime axis (closer) as the number of reaction) steps separatingthat species from the initially perturbed species increases.(3) Species that are directly connected, through reactions, tothe initially perturbed species exhibit nonzero initial slopes.(4) Species that are not directly connected, through reac-tions, to the initially perturbed species exhibit zero initialslopes. (5) All responses are positive deviations from thestationary state unless there is a feedback, feedforward, orhigher order (> 1) kinetic step. (6) For short times, beforethe exit of material from the pulse to the surroundings ofsystem, the concentration change of the pulse is conserved:the sum of deviations of concentrations (weighted by stoi-chiometric coefficients) is constant and equal to the changein concentration of the initial pulse. This property is usefulin determining that all species produced from the pulsethrough reactions have been detected, and can help in deter-mining correct stoichiometric coefficients.8

If tracers (radioactive, fluorescent, etc.) are used, suchthat the concentration of the sum of the labeled and unla-beled compounds is constant, then the response to a tracerperturbation is always first order, even if the kinetics of thesystem is nonlinear.An example of mixed first- and second-order irreversiblereactions is shown in Fig. 3. These are also respectively uni-molecular and bimolecular reactions if each step is an ele-mentary step, which seems not to be the case. For example,a first-order reaction may describe an enzymatic (Michaelis-Menten) mechanism at high substrate concentration. If X i ispulsed in this system, then the responses are shown in Fig.4. The occurrence of the maxima of the response is orderedin time according to the distances from the pulsed species inthe mechanism. There are approximate relations among themaximum responses in the relative concentrations, labeledu*

i. which can be derived from the deterministic kinetic

equations for this system for small pulses. The coefficientsgive the stoichiometric coefficients of 2 in front of X 2, X5,and X6.

Complex reactions may occur in the branching or coa-lescing chains (see Fig. 5); in cycles; with feedforward andfeedback reactions; and any combinations thereof. An illus-tration of feedback is given in Fig. 6. If the species X 7 ispushed in that mechanism, and X7 increased the rate �3 asindicated, then the concentration of X3 will decrease initi-tally from its value in the stationary state and then return tothat value.

In ref. 8 we work out an example of the application ofthe pulse method to a simple model of glycolysis by solvingthe kinetic equations numerically. We thus generateresponse curves which are simple to interpret for the deduc-

Continued on page 12

�


tion of the connectivity and reaction pathway. Rather thandiscuss the exercise, we turn to an experimental test of thepulse method.B, Experimental Test of the Pulse Method. We tested9 thepulse method for determining reaction systems with theexperimental system shown in Fig. 7, which is a part of the beginning of glycolysis. This system is studied in a continuous stirred tank reactor (CSTR), a stirred vessel withan inflow and outflow. The enzymes in Fig. 7 are introducedat an initial time and kept in the vessel at a determined con-centration by a membrane which blocks their outflow, butnot that of the remainder of the system. When a stationarystate has been achieved, which takes about 30 min, one ofthe metabolites is pulsed by an injection of that species intothe outflow. The responses of six metabolites are measuredwith capillary electrophoresis until the concentrations againreturn to their values in the stationary state. The measure-ments are of modest precision: typical relative errors were4% for G6P, 11% for F6P, 15% for F1,6BP, 9% for DHAP,6% for 3PG, and 3% for G3P. However this precision is suf-ficient for obtaining substantial information about the reac-tion mechanism.

Measurements of the responses in relative concentra-tions due to a pulse in G6P are shown in Fig. 8. The tempo-ral order of propagation of the pulse is from G6P to F6P,then DHAP, G3P, and 3PG. The time of appearance of themaximum response of the first three species is in the sameorder. F1,6BP was not measured adequately in this pulse



and is not shown.Fig. 9 shows the responses due to a pulse of F1,6BP.

DHAP follows, and then G3P and 3PG. The uphill species(in Gibbs free energy), as determined from Fig. 7, respondwith low amplitude (the order of G6P and F6P is the reversefrom that expected for Fig. 7, but the precision of the meas-urements is low at low amplitude).

The response to a pulse of DHAP is interesting (Fig.10). F1,6BP has a substantially higher response thanexpected, unless there is a stoichiometric coefficient otherthan unity (see Fig. 4, the curve for u3 and the correspon-ding reaction 2X2 ?X3). G3P and 3PG follow DHAP.

The only response to a pulse of G3P is the one of thatspecies and DHAP. 3PG is therefore at the end of the line, abranch of the reaction mechanism, with no significantresponses of uphill species, but not the same branch that hasG3P in it.

Although we did not measure the concentration ofNADH, we applied a pulse of that species and found theresponses shown in Fig. 11. Note the very differentresponses of 3PG and G3P, which confirm that these twospecies are indeed in different branches. NADH is either aneffector or a reactant which increases G3P, and at the sametime either a reactant or effector that decreases 3PG. BothG3P and 3PG are connected to DHAP, which shows nochange. The effect of NADH works through DHAP to F1,6BP which shows a change in concentration. The dotted linegives the sum of the changes of F1, 6BP, G3P, and 3PG,which is essentially constant.

These experiments lead by deduction from them to thereaction pathway shown in Fig. 12. The first attempt at thatdeduction was made by assigning random integers to thechemical species so as not to be prejudiced in our deduc-tions from the measurements. We then repeated this processby using the names of the species, and obtained the sameresults. We did the analysis not using common knowledgesuch as necessary stoichiometric relations due to conserva-tion of mass. We did assume that DHAP and GAP are inequilibrium (quickly attained), which is the case and which

we tested. We were not able to measure GAP. That PEP is aninhibitor of PFK was found in separate experiment.

The main features of the reaction pathway are well pre-dicted by the pulse method, in particular bifurcation of thesequence G6P, F6P, F1,6BP into two branches of reactionsequences, one ending in G3P and the other in 3PG. The fastequilibrium of DHAP with GAP (not measured) places thatbifurcation at DHAP rather than that shown in Fig. 7. Muchof the reaction mechanism can be deduced from the reactionpathway.

We believe the pulse method to be relatively simple,effective, and generally applicable.III. Statistical Construction of Reaction Mechanisms.Correlation Functions from Measurements of TimeSeries of Concentrations.A. Introduction and Theory.14

In the last Section we discussed the issue of measure-ments of the causal connectivity of species in a reactionmechanism. We now turn to related concepts, those of thecorrelation of time series of reacting species and correlationmetric construction (CMC), and their relations to the reac-tion mechanism of the system. Causally connected speciesare generally highly correlated; however, highly correlatedspecies may, but need not be directly connected, as forinstance in branched networks or networks with feedback.The goal of CMC is the determination of reaction pathwaysand mechanism, the regulatory structure of the mechanism,and the connectivity of the species from the measuredresponses of the species to imposed fluctuations of somechosen species.

Consider a simple hypothetical reaction network suchas that shown in Fig. 13, which is common in biochemicalreactions. Let this open system be maintained in a nonequi-



librium stationary state. Perturb the concentrations of thearbitrarily chosen species I1 and I2 randomly by arbitraryamounts, and let the system relax back toward the stationarystate after each perturbation. Measure during this relaxationthe concentrations of all seven species as a function of time(the enzymes Ei are at constant concentrations).

The reciprocal of the characteristic frequency of therandom variations of the species I 1 and I2 is of the order ofthe longest relaxation time in the system. For given ratecoefficients for the system in Fig. 13, the responses of thespecies S3 to S7 to the imposed fluctuations (perturbations)in I1 and I2 are shown in Fig. 14. Note that this, as well asmost other chemical reaction mechanisms, may act as fre-quency filters of various types, and this property may haveapplications in biological systems (see ref. 15).

From these time series, correlation functions areformed, for example the correlation of species I and j,where Xi(t) is the concentration of species I at time t, xi is

the average concentration of that species over time for agiven time series, and � is a chosen time interval. Some rep-resentative correlations are shown later. We normalize thesecorrelations,

define the maximum of that correlation for any �, and definea distance, If the correlation rij is large, say the maximum of unity, then

the distance dij is zero; if the is no correlation, rij = 0, then dij= 1.41 (an arbitrary number). With these distances, we cancarry out a mathematical procedure called multidimensionalscaling analysis to build an object.14 A simple description ofthis procedure is this: take a stick and write the number ofone of the species on one end of the stick, and the number ofanother species on the other end. The stick is small for largecorrelations and larger for smaller correlations. Pick all theends of sticks with the number one and place these ends at apoint. Do the same with the number two, and so on for allthe species. You will need a multidimensional space toaccomplish the task of building this object.

Shine a light beam on the object and project this imageon a screen. Rotate the object until its image on the screengives you the maximum information about the object. If allthis, or its mathematical equivalent, is done with the reac-tion mechanism in Fig. 13, we obtain the projection in Fig.


Equation (2)

Equation (3)

Equation (4)


15. The projection of the multidimensional object con-structed from the correlation distances (CMC) gives quiteclosely the reaction pathway shown in Fig. 13.

With seven species there are (7 x 6)/2 binary correla-tions. We retain only the ones shown in Fig. 15 by a proce-dure which ensures that each species is connected to at leastone other species, and only the lar gest correlations are kept.Species 6 and 7 are in a single point: they are completelycorrelated by conservation of mass. The closer connectionof species 1 to species 4, rather than 3, depends on the ratecoefficients in the S3-to-S4 intrconversion. The closeness ofspecies 3 to species 6 and 7 indicates a point of control of 3on 6 and 7. Such information, available from correlationmetric constructions, is not available from usual listings ofelementary reaction steps in a reaction mechanism.

For further testing of CMC, we chose another examplewith two groups each having several futile cycles; to one ofthese groups we assigned faster reactions than for the othergroup (so that we have a two-time-scale reaction mecha-nism). In this case the correlation diagram analogous to Fig.15 showed a clear separation of the two groups, and hencethe existence of two time scales. It also represented the reac-tion pathway of each group.

We have presented only the simplest analysis. There aremore sophisticated methods, such as multiple regressionanalysis, which can provide information about missing (ornot measured) variables.14

B. Experimental Test of CMC. To test the correlation met-ric construction method,16 we chose a part of the much stud-ied glycolysis system shown in Fig. 16, which differs insome details from that in Fig. 7. The system is established ina nonequilibrium stationary state with a constant inflow of

glucose and buffer. Metabolites were measured by capillaryelectrophoresis; the concentrations of the enzymes werekept constant (see section II,B); and the ATP/ADP ratio washeld constant. The two effectors citrate-1 and AMP-1 werechosen for the species to be perturbed randomly by arbitraryamounts. All the metabolites listed were measured at regularintervals as, after each perturbation, the system returned toits nonequilibrium stationary state. Typical measurementsare shown in Fig. 17. A few of the correlations are given inFig. 18. The correlation of G6P with itself peaks at zero timelag �, which shows that G6P and decays symmetrically withpositive and negative �, which shows that G6P is not a sta-tionary state during this perturbation. The correlation ofG6P with AMP-1 is larger for positive than negative �,which indicates that a variation in AMP-1 precedes a varia-tion in G6P. From such information knowledge is obtainedabout the connectivity of the species.

From the measured correlations we constructed, asexplained earlier, the multidimensional diagram (also calledthe correlation metric construction) shown in Fig. 19A.Solid lines indicate negative correlations, shaded lines posi-tive correlations; arrows indicate the time sequence ofevents: for example, an increase in AMP is followed by a



decrease in G6P and an increase in F1, 6BP. In Fig. 19B, theMDS diagram of Fig. 19A is rearranged to show the usualreaction pathway determined over many years of ef fort. Theagreement with prior work is excellent and shows the viabil-ity and utility of the CMC approach. The applicability of thepulse method and the CMC approach is retained even ifthere are one or a few missing species. Many other detailsare given in ref. 16.IV. Application of Genetic Algorithm Methods to Chem-ical Kinetics

A. Introduction. Genetic algorithms are one class ofmathematical techniques for finding stated optimal goals orconditions in a given problem. The search for the chosenoptimum conditions are started randomly but then directedtoward the stated goals. The first tries, the first generation,are judged in fitness to the stated goals; the unfit areremoved, the semi-fit are altered, and the fit are retained forthe next tries, the next generation, and so on, until solutionsare found that fulfill the stated goals adequately . Alterationsare made by “mutations” in one or more parameters or vari-ables, by crossover, and by other methods reminiscent ofbiological evolution due to genetic changes, hence the namegenetic algorithms.

B. Selection of a Regulatory Structure for FluxDirection in a Simple Metabolic Model. Consider aschematic mechanism (Fig. 20) for the study of the selec-tion, by means of genetic algorithms, of a regulatory struc-ture that directs flux in a simple metabolic model.17 (Forsome references on prior studies of optimization of meta-

bolic reaction networks, see refs. 18 and 19.) F representsfood (glucose), T an energetic molecule (ATP), the k’s arerate coefficients, A and B are intermediates, � and � areenzymes, and the circles denote the ef fector action of F andT on the enzymes. We assign a task to this mechanism, thatof controlling the proper direction of the flux from F to T(glycolysis), or the reverse (glyconeogenesis), as we exter-nally vary the concentrations of F and T. If the concentrationof F happens to be high and that of T low, then we want thesystem to direct mass flux quickly from F to T, and similarlyfor the reverse situation from T to F.



Let the rate equations for the temporal variation of Aand B be

A = k1F + �� – k-1A - ��

B = k-2T + �� - kB – ��Equation (5)

For the effector control of F and T on the enzymes we takea model of noncompetitive allosteric binding20 (Fig. 21)with the rate (for enzyme �)

where the factors modifying the intrinsic Michaelis-Mentenrate expression are

The parameter K� is the dissociation constant for thecomplex of enyzme � and the effector T or F, labeled , andr� is the ratio of the catalytic rate coefficient for theenyzme with and without effector bound, respectively. If r isgreater than unity the effector is an inhibitor. We see in Fig.20 that there are four effector interactions, each with twoparameters, one K and one r, for a total of eight parameters.Hence there are eight parameters that specify the regulatoryresponse of the system for differing conditions of thereservoirs F and T. Thus it is possible for F and T to beselected a positive, or negative, or no effector on theenzymes � and �.

To specify the optimization, we define a need state foreach reservoir which is positive if the concentration of thatreservcoir falls below a given value. A functional form forthe need state is chosen such that there is an acceptablewindow of concentration around the target, within which thenumerical value of the need is close to zero, but at the edgesof which that value changes rapidly to a positive or negative

one. With the defined need states we wish to optimize thefunction

Or its time average

Where F is the need state for F and T for T. The needstates of F and T are multiplied respectively by the net fluxof concentrations into F and T. Hence if f is positive, thenthe mechanism is directing the net flux in accordance withthe need states.

We have to begin with a chosen course of variation ofthe concentration of F and T. Next we start with a set of theeight parameters and integrate eqs 5-7 to evaluate J in eq. 9.In the use of a generic algorithm we wish to vary the eightparameters in a systematic way. Further details are given inthe Appendix of ref. 17.

Five different courses of variation of the concentrationsof F and T were chosen to train 100 individuals (systems)for proper flux control. The results are interesting. In all buta few cases, the effect of F on the enzyzme � is one ofactivation, and that of T one the same enzyme one ofinhibition. For the enzyme � the reverse is true: T is anactivator and F an inhibitor. There are exceptions, but thenthe networks perform not as well. This reciprocal effect onthe opposing branches of the cycle is the regulatory patternto be expected for efficient homeostasis: the mechanismseeks to control the fluxes so as to keep the concentrationsof the reservoirs at the desired levels. This result arisessolely from the optimization procedure of flux directioncarried out by the genetic algorithm.

No single network was found that performs best on allthe courses of changing environments. There is no singlewinner; the winners are survivors that perform adequately,but not necessarily outstandingly, from course to course.The absence of a single winner prevents global dominanceand presents the opportinity for biological deiversity.

C. Systematic Determination of a ReactionMechanism and Rate Coefficients. For an application ofgenetic algorithms to this subject, see ref. 20.I thank all my co-workers cited in this review for theircontributions and friendship.References(1) Berry, R.S..; Rice, S.A.; Ross, J. Physical Chemistry, 2nd ed.;

Oxford University Press; Oxford, 2000 p. 1064.(2) Liang, S.; Fuhrmann, S.; Simogyi, R. Reveal, A General

Reverse Engineering Algorithm For Inference of Genetic-Network Architectures. Pac. Symp. Biocomput. `98 1998, 3,18-29.

(3) Akutsu, T.; Miyano, S.; Kuhara, S. Algorthms For InferringQualitative Models of Biological Networks. Pac. Symp.Biocomput. `00 2000, 5, 293-304.

(4) D`Haesseleer, P.; Liang, S.; Simogyi, R. Genetic NetworkContinued on page 18


Inference: From Co-Expression Clustering to ReverseEngineering. Bioinformatics 2000, 16, 707-726.

(5) Hjelmfelt, A.; Ross, J. Implementation of Logic Functionsand Computations by Chemical Kinetics. Phys. D 1995, 84,180-193 and references therein.

(6) Laplante, J.; Pemberton, M.; Hjelmfelt, A.; Ross, J.Experiments on Pattern Recognition by Chemical Kinetics. J.Phys. Chem. 1995, 99, 10063-10065.

(7) Arkin, A.; Ross, J. Computational Functions in BiochemicalReaction Networks. Biophys. J. 1994, 67, 560-578. Forrelated experiments, see: Hauri, D.C.; Shen, P.; Arkin, A.P.;Ross, J. Steady State Measurements on the Fructose 6-Phosphate/Fructose 1,6-Bisphosphate Interconversion Cycle.J.Phys. Chem. B 1997, 101, 3872-3876.

(8) Vance, W.; Arkin, A.; Ross, J. Determination of CausalConnectivities of Species in Reaction Networks. Proc. Natl.Acad. Sci. 2002, 99, 5816-5821.

(9) Torralba, A.S.; Yu, K.; Shen, P.; Oefner, P.J.; Ross, J.Experimental Test of a Method For Determining CausalConnectivities of Species in Reactions. Proc. Natl. Acad. Sci.2003 100, 1494-1498.

(10) Tyson, J. Classification of Instabilities in Chemical ReactionSystems. J. Chem. Phys. 1975, 62, 1010-1015.

(11) Chevalier, T.; Schreiber, I.; Ross, J. Toward a SystematicDetermination of Complex Reaction Mechanisms. J. Phys.Chem. 1993, 97, 6776-6787.

(12) Mihalik, E.; Skodt, H.; Hinne, F.; Sorenson, P.G.; Showalter,K. Normal Modes for Chemical Reactions From Time SeriesAnalysis. J. Phys. Chem A 1999, 103, 8246-8251.

(13) Kholodenko, B.N.; Klyatkin, A.; Bruggeman, F.J.; Sontag,E..;Westerhoff, H.V.; Hoek, J.B. Untangling The Wires: AStrategy to Trace Functional Interactions in Signaling andGene Networks. Proc. Natl. Acad. Sci. 2002, 99, 12841-12846.

(14) Arkin, A.; Ross, J. Statistical Construction of ChemicalReaction Mechanisms From Measured Time –Series. J. Phys.Chem. 1995, 99, 970-979.

(15) Samoilov, M.; Arkin, A.; Ross, J. Signal Processing by SimpleChemical Systems. J. Phys. Chem. 2002, 106, 10205-10221.

(16) Arkin, A.; Shen, P.; Ross, J. A Test Case of Correlation MetricConstruction of a Reaction Pathway from Measurements.Science 1997, 277, 1275-1279.

(17) Gilman, A.; Ross, J. Genetic-Algorithm Selection of aRegulatory Structure That Directs Flux in a Simple MetabolicModel. Biophys. J. 1995, 69, 1321-1333.

(18) Bray, D.; Lay, S. Computer Simulated Evolution of a Networkof Cell-Signalling Molecules. Biophys J. 1994, 66, 972-977.

(19) Heinrich, R.; Hotzhutter, H.G. Efficiency and Design ofSimple Metabolic Systems. Biochim. Biophys. Acta 1985, 44,959-969.

(20) Fersht, A. Enzyme Structure and Mechanism, 2nd. Ed.; W.H.Freeman and Co.: New York, 1984; p. 475.

(21) Tsuchiya, M.; Ross, J. Determination of Reaction Mechanismand Rate Coefficients for a Complex Reaction Network. J.Phys. Chem. A 2001, 105, 4052-4058. ◆◆


Arno receives a special plaque from Jean-Fullers Stanley, Section Chair

Arno with William Carroll, ACS President Elect All photographs by James Phillips

Arno with Myron Simon, Associate Editor, TheNucleus

February MeetingSpecial Recognition

of Arno Heyn


242 Pages, $27.95 (Hardcover)Review by Myron S. Simon, Ph.D.What does a scientist owe to society?At what point does the science that onedoes raise questions which require abreak with the “etiquette” of the scien-tific establishment to which onebelongs? And, should a scientistbecome a “whistle blower” wheneverhe or she believes that science is beingused improperly to influence socialissues?

These questions form the basis ofthis fascinating short autobiography byProfessor Beckwith, the AmericanCancer Society Research Professor ofMicrobiology and Molecular Geneticsat Harvard Medical School. In it hedescribes and defends his career of twostrands. Making Genes refers to hisbrilliant work in devising the firstmethod for cloning genes, the firstmethod for isolating and purifying agene, as well as the fundamental stud-ies in understanding the mechanismsfor activating or repressing genes, andthe understanding of how proteins aretransferred through bacterial mem-branes. Making Waves refers to thesecond strand, the life he led as anactivist, leaping into public promi-nence throughout his life in callingattention to real and potential misusesof science which affect society. Theperiod of the 1960’s was a time oftremendous unrest in academia , culmi-nating in 1970, in the murders of stu-dents at Kent State College and theresulting strikes and sit-ins on manycollege campuses. While Beckwithdoesn’t refer directly to this, it is easyto see what an influence this climatehad on his development.

Beckwith took his undergraduateand graduate degrees at Harvard, thelatter in the Chemistry Department.His graduate work was in biochemistryand his thesis was on how fungi incor-porate chloride into the organic com-

pounds they manufacture. A course inmolecular biology with James Watsonled him to the work of François Jacoband his group in Paris which was usingbacterial (Escherichia coli) genetics tostudy fundamental problems in biology.The style of research the Paris groupused, “daring leaps of logic, simpleexperiments that seemed to yield pro-found insights”, and the lively literarystyle in which the papers were writtencaught Beckwith’s imagination. Afterreceiving the Ph.D. degree in 1960,pursuit of a postdoctoral appointmentin Jacob’s laboratory in the PasteurInstitute became an obsession.

Postdoctoral fellowships withArthur Pardee at Berkeley and Prince-ton and with William Hayes at Ham-mersmith Hospital, Microbial GeneticsResearch Unit, in London gave Beck-with the opportunity to learn the tech-niques of bacterial genetics. As had theFrench scientists, Beckwith has madethe cells of the bacterium E.coli hisresearch quarry. Work begun withPardee, and later work in Englanddemonstrated his abilities and by 1964,when an opening allowed him to jointhe Paris group, it came after he hadpublished a paper correcting the site ofthe operator in the Jacob study, hadachieved recognition, and had receivedan appointment at Harvard MedicalSchool..

During a productive year in Parishe pioneered a method to move genesfrom large (chromosomal) to smaller(viral) DNA fragments to study themmore easily. This was the first methodfor cloning. In 1965 he returned toHarvard Medical School and continuedhis E.coli experiments, devisingmutant genes which allowed him tostudy how the promoter site of thegene works. But the most excitingresults came a few years later as abyproduct of cloning experiments.Edwin Land used to say that break-throughs in understanding were not

flashes of genius but rather cessationsof stupidity. Either way, Beckwith hadone or the other and came up with thefirst ever method to isolate and purifygenes.

The Harvard College of the ‘50s,Beckwith felt, was not particularlyinterested in political change, althoughhe was aware that there were fellowundergraduates questioning the valuesof society. I find this strange, becauseten years earlier, when I was there, Ican recall the battles among theRepublican Club, the Liberal Union,and a group that my room mates werewont to call the Communists, whichwere nothing if not political. Perhapspressures from the greater stage, theMcCarthy attacks in the Eisenhowerera, had their damping effect on that“Little Red Schoolhouse on theCharles.” At any rate, Beckwith did notbecame aware of the progressive cur-rents until his first postgraduate post atBerkeley. Politicization of his thinkingwent rapidly, and by the time he was atPrinceton he was walking in a protestdemonstration against the threat of warwith Cuba during the missile crisis. InParis at the Institut Pasteur he foundcongenial the left-wing attitudes pre-vailing among his fellow scientists,and his interest in jazz and friendshipswith black expatriates led to an under-standing of racism as an evil, and thewar in Viet Nam as a disgrace. Return-ing to the med school in 1965, he wasa confirmed liberal political activist.

In 1969, with the ability to isolateindividual genes, the Beckwith teamrealized that their forthcoming publica-tion would also be highly visible to thenonscientific world . They recognizedthat their work had opened the possi-bility of human experimentation, ofgenetic engineering with unknown, butpotentially damaging consequences tothe human race. Put badly, the genewas out of the bottle. Beckwith calleda press conference. At this juncture thetwo strands in his life, science andsocial activism joined.

In the press conference the firstisolation of a gene from a chromosomewas announced, and statements weremade that the work might lead to


Book ReviewMaking Genes, Making Waves: A Social Activist in ScienceJon BeckwithHarvard University Press, 2002


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future dangers for mankind. Wide-spread reports stressed the latter, andBeckwith was castigated by many inthe scientific community who felt thathe was suggesting potential problemsfifty years away, and had exaggeratedthe dangers and even the importance ofthe work. But while the work directlyinvolved only bacterial systems, withinfive years development of recombinantDNA techniques permitted the isola-tion of genes from any organism. (By1973 a moratorium on recombinantDNA existed.)

Beckwith’s action had put him inthe role of spokesman for the young,concerned scientists who had becomepoliticized and cynical largely by theactions of their government in VietNam. Another incident sealed his repu-tation as a far left agitator. In 1970 theEli Lilly Award in Microbiology andImmunology was offered him by theAmerican Society of Microbiology. After consideration he accepted thehonor, but when the ceremony tookplace he announced that he would turnover the $1000 prize money to theBlack Panther clinic and defense fund.Further, he excoriated the practices ofbig pharma in his acceptance speech.

While Beckwith was attempting toteach the social responsibilities of sci-ence and scientists, he continued tostudy major problems in biology usingmutant genes in E.coli. Using this bac-terium, he probed what causes a geneto turn on and generate its protein andlearned what stops this activity. Hewondered how proteins are capable ofpassing through cellular membranesand showed the necessary groups theprotein must contain. He found thatformation of the disulfide bridges inproteins require an enzyme catalyst.The clarity with which Beckwithwrites about his research makes hisbook a primer for understanding muchabout molecular biology, and can berecommended on that score alone.

The main value of the book, how-ever, is his preaching the need for sci-entists to be aware of how their sciencecan be misused, promoting disastrous

consequences for society. As a geneti-cist he became aware fairly late ofwhat he calls genetic’s “atomic bomb.”Little known these days is the eugenicmovement’s push to improve the genepool of this country. He describes howgeneticists supported eugenics in theUnited States, in the early part of thelast century. The movement claimedthat “bad” genes were responsible forcriminal behavior, low intelligence,and other “abnormalities.” The effectson society were huge. Laws in manystates were passed, under which tens ofthousands were sterilized, and the fed-eral government passed the Immigra-tion Restriction Act of 1924 to keepout the undesirable genes of the so-called “inferior” cultures of eastern andsouthern Europe. Although eugenicsbegan to fade after 1924, Hitler and theNazi government in later years usedthe work of German geneticists, whohad fallen back on earlier research byAmerican geneticists, to justify theirracial policy of sterilizations and mur-dering of millions.

Later chapters describe Beck-with’s exposing the “Myth of theCriminal Chromosome”, the battleagainst E.O.Wilson’s Sociobiology,and other cases where genetic studieswere misused. In 1989 at the inceptionof the Human Genome Project, JamesWatson, the original director, set aside3-5% of the budget to study the ethical,legal, and social implications (ELSI) ofthe project. The study would examineany “potential adverse social conse-quences of the project and to suggestmeans of preventing these conse-quences.” Beckwith became a memberof the ELSI Working Group. Themixed success and disappointments of this group of scientists and nonsci-entists working to solve potential problems (with pressures from consid-erations of insurance dollars, massscreening of populations, genetic test-ing running wild) is reflected in Beck-with’s flight to C.P .Snow’s TwoCultures. Still, all was not in vain.

“An environment now exists inwhich concern for the social and ethi-cal consequences of science is at leastnot a taboo subject.”— Jon Beckwith◆◆

Book ReviewContinued from page 19


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Index of AdvertisersAdvanced Synthesis.............................20Am. Instrument Exchange ...................22Chemic Laboratories ...........................21Chemir Analytical Services .................21Chemo Dynamics ..................................9Dana Lipp Imaging..............................21Desert Analytics Laboratory................22DuPont Analytical Solutions ...............23Eastern Scientific Co. ............................4Front Run Organx................................22Gateway Chemical Technology.............6GL Synthesis, Inc. ...............................21HT Laboratories, Inc............................22Huffman Laboratories, Inc. .................21J. S. T. ..................................................21Jacquline M. Arendt, Esq.....................22Mass-Vac, Inc.........................................7Micron Inc. ..........................................22NuMega Resonance Labs ....................21Organix, Inc. ........................................22Organomed Corporation ......................20PolyOrg Inc..........................................20Prime Organics ....................................22Quantitative Technologies, Inc. ...........23Robertson Microlit Labs........................8SBH Sciences, Inc. ..............................22Schwarzkopf Microanalytical..............22Scientific Bindery................................23Spectral Data Services, Inc...................20SPEX CertiPrep ....................................21Tyger Scientific, Inc .............................20Waters Corporation...............................21Yasui Seiki Co. .....................................22


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CONTACTPATRICK GORDON

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ASSISTANT EDITOR

THE NUCLEUS

Duties include receiving articles, arranging the layout of each issue, in-teracting with editors and officers of the Section.

Good writing style, an eye for details and facilities for word processing are required.

Training providedCome join our team

Check the NESACS Homepagefor late additions:http://www.NESACS.orgNote also the Chemistry Department web pagesfor travel directions and updates. For example:http://web.mit.edu/chemistry/http://www-chem.harvard.edu/events/http://www.umassd.edu/cas/chemistry/ [new url]http://www.dartmouth.edu/~chem/

Apr 5Prof. Dirk Trauner (Univ. of Calif., Berkeley)“Chemistry Mimicking Nature - and Taking It aStep Further”Boston Univ., Metcalf Center, 590 Commonwealth, 4 pmProf. Young-Tae Chang (New York Univ.)“Tagged Small Molecule Approach to FacilitatedChemical Genetics”MIT, Room 6-120, 4 pm

Apr 6Prof. Minhaeng Cho (Korea University)“Coherent Multidimensional Spectroscopy andPolypeptides”MIT, Room 4-270, 4 pm - 5 pmProf. Ian Harrison (Univ. of Virginia)“C-H Bond Activation of Methane at MetalSurfaces: Several Ways...”Tufts Univ., Pearson Chemistry Building, 62 Talbot Ave., Medford, Room P-106, 4:30 pmProf. James B. Hendrickson (Brandeis Univ.)“Organization of Organic Chemical Knowledgefor Automatic Generation of Synthesis Routes:The ‘SynGen’ Program”U Mass-Boston, Chemistry Conference Room,Science Building, 1st floor, room 89, 4:30 pm

Apr 7Prof. Jimmie Doll (Brown Univ,)Joint Theoretical Chemistry LectureMIT, Room 36-156, 3 pm - 5:30 pmProf. Malcolm Green (Oxford Univ.)“The Chemistry of Single-walled CarbonNanotubes”Inorganic Seminar MIT, Room 6-120, 4 pm

Apr 8Prof. Ben L. Feringa (Univ. of Groningen)Organic Seminar SeriesMIT, Room 6-120, 4 pm

Apr 13Dr. Edward J.J. Grabowski (VP, ChemistryProcess Research, Merck Research Labs),Chemistry in Industry,“Reflections on Process Research: An Insider'sView of Chemical Development in thePharmaceutical Industry”MIT, Room 6-120, 9:30 am

Apr 14Prof. Ben Shen (Univ. of Wisconsin)Chemical Biology Series“Natural Product Biosynthesis and SecondaryMetabolic Pathway Manipulation”Boston College, Merkert 130, 4 pmProf. Barbara A. Seaton (BU School ofMedicine)“Structural Basis of Peripheral MembraneProtein Action”Brandeis Univ., Edison Lecks Building,Gerstenzang 122, 3:45 pmYoung Mi Kim (MIT, Swager Group), InorganicSeminar,“Synthesis and Applications of ElectronDeficient Conjugated Polymers”MIT, Room: 6-120, 4 pm

Apr 15Prof. Craig Townsend (Johns Hopkins Univ.)Organic SeminarMIT, Room 6-120, 4 pmProf. Lucio Frydman (Weizmann Institute,Israel)“Multidimensional NMR Goes Ultrafast:Principles and Applications of a New Sub-second Spectroscopy”, Woodward LectureSeries in the Chemical Sciences,Harvard-MIT Phys. Chem. SeminarMIT, Room 4-370, 5 pm - 6 pmProf. Nadrian Seeman (New York Univ.)“Structural DNA Nanotechnology”Tufts Univ., Pearson Chemistry Building, 62Talbot Ave., Medford, Room P-106, 4:30 pm

Apr 16Prof. G.Tayhas R. Palmore (Brown Univ.)“Studies on the Growth Morphology of CrystalsTemplated on Crystals”Brandeis Univ., Edison Lecks Building,Gerstenzang 122, 3:45 pm

Apr 19Prof. Joseph Francisco (Purdue Univ.)“Halogen-Catalyzed Oxidation Reactions in theEnvironment”Brandeis Univ., Edison Lecks Building,Gerstenzang 122, 3:45 pmProf. Natalie Ahn (Univ. of Colorado)“Functional Proteomics: Methods andApplications to Signal Transduction”,

Woodward Lecture Series in the ChemicalSciences, Organic Chemistry SeminarHarvard Univ., MB-23 Pfizer Hall, 12 Oxford Street, 4:15 pm

Apr 20Prof. Stephen Kent (Univ. of Chicago)“The Chemistry of Chemical Protein Synthesis:Methods & Targets”Tufts Univ., Pearson Chemistry Building, 62 Talbot Ave., Medford, Room P-106, 4:30 pm

Apr 21Prof. Jonas Peter (Calif. Inst. of Technology)Special Inorganic SeminarMIT, Room 6-120, 4 pm

Apr 22Prof. Thomas Mallouk (Penn State Univ.)“A Building Block Approach to MesoscopicMaterials”, Woodward LectureSeries in the Chemical Sciences, Phys. Chem.Seminar Harvard Univ., MB-23 Pfizer Hall, 12 Oxford Street, 4 pm

Apr 26Prof. Samuel Danishefsky (Columbia Univ.)Lambert Lecture, “On the Power of ChemicalSynthesis”Boston Univ., Metcalf Center, 590Commonwealth, 4 pmProf. Robert H. Crabtree (Yale Univ.)“Carbenes Catalysis and the Outer Sphere”Brandeis Univ., Edison Lecks Building,Gerstenzang 122, 3:45 pmProf. Timothy Mitchison (Harvard MedicalSchool Cell Biology Dept.)“Probing Cell Division with Imaging andChemistry”MIT, Room 6-120, 4 pm

Apr 27Prof. Brian Gibney (Columbia Univ.)“On the Role of Nonnatural Amino Acid Ligandsin De Novo Heme Protein Design”Tufts Univ., Pearson Chemistry Building, 62 Talbot Ave., Medford, Room P-106, 4:30 pmDr. C. Eric Schwartz (UCB Research)“Discovery of Novel Chemokine ReceptorAntagonists”U Mass-Boston, Chemistry Conference Room,Science Building, 1st floor, room 89, 4:30 pm

Apr 28Prof. Bruce Berne (Columbia Univ.)Joint Theoretical Chemistry LectureMIT, Room 36-156, 3 pm - 5:30 pm

Apr 29Dr. Phaedon Avouris (IBM)“Carbon Nanotube Electronics and Electro-Optics.” (Woodward Lecture in the ChemicalSciences, Harvard-MIT Phys. Chem. Seminar)Harvard Univ., MB-23 Pfizer Hall, 12 Oxford Street, 5 pm - 6 pmDr. S.R. Holmes-Farley (Genzyme Corp.)“Advances in Polymeric Pharmaceuticals”UMass Lowell, Olney Hall 218, 3:30 pm

Notices for the NucleusCalendar should be sent to:Dr. Donald O. Rickter, 88 Hemlock St.,Arlington, MA 02474-2157e-mail: [email protected]

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April 04 Nucleus ROSS+ - NESACS · The Nucleus April 2004 3 The Nucleus is distributed to the...

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