N O V E M B E R I S S U E 1 9 9 5

1

MOLECULAR MEDICINEFOR THE 21ST CENTURY

ADVANCED DATA ANALYSIS

AND THEORETICAL MODELS SPEED

DEVELOPMENT OF NEW DRUGS AND VACCINES

I n the next century, “biological warfare” against new viruses such as HIV, the AIDS-causing virus, and

new deadly strains of old menaces such astuberculosis may supersede allother forms of combat. Theability to fight off these majorhealth threats will depend largely onscientists’ ability to design effective andinexpensive vaccines and drug therapies.

Los Alamos researchers are using their expertisein theory and computation to manage and ana-lyze the flood of information currently beinggenerated in laboratory experiments and clinicaltrials. Their efforts will aid both theoreticians andexperimentalists working to combat the spread ofcontagious diseases.

A MONTHLY PUBLICATION OF THEPUBLIC AFFAIRS OFFICE OF

LOS ALAMOS NATIONAL LABORATORY

LOS ALAMOS NATIONAL LABORATORY, AN AFFIRMATIVE ACTION / EQUAL OPPORTUNITY EMPLOYER, IS OPERATED BY THE UNIVERSITY OF CALIFORNIA FOR THE U.S. DEPARTMENT

OF ENERGY UNDER CONTRACT NO. W-7405-ENG-36

LOS ALAMOS NATIONAL LABORATORY PUBLIC AFFAIRS OFFICE, MS-A118

LOS ALAMOS, NM 87545

N O V E M B E R I S S U E 1 9 9 5

2

EDITORDiane Banegas

MANAGING EDITORMeredith Coonley

(505) 665-3982 • suki@lanl.gov

STAFF WRITERTheresa Salazar

STAFF PHOTOGRAPHERLeRoy N. Sanchez

CONTRIBUTING WRITERGary Kliewer

CONTRIBUTING ILLUSTRATOREdwin Vigil

CONTRIBUTING PHOTOGRAPHERFred Rick

PRINTING COORDINATOR

G.D. Archuleta

LOS ALAMOS NATIONAL LABORATORY

PUBLIC AFFAIRS OFFICE, MS P355

LOS ALAMOS, NM 87545

The extraordinarilyrapid spread of HIVand the emergence ofpersistent drug-resistantstrains of tuberculosis,cholera, and otherinfectious diseases hasresulted in a wealth ofinformation fromexperimental and clini-cal studies; so muchinformation, in fact,

that new approaches to treating infectious diseases are lag-ging behind the successful acquisition, processing, andpublishing of scientific data.

By combining the Laboratory’s supercomputing power withadvanced techniques in data analysis, Los Alamos researcherscan help the medical community select the most promisingvaccines and drug treatments, rapidly evaluate changes inpathogens that begin to display drug resistance, and identify

ÓA teacherinstructspat ients at the HazelwoodTuberculos isHospita l inLouisv i l le , Ky.Surgica l masksprevent thespread ofgerms. TBgerms aretransmittedthroughcoughing,sneezing, oreven ta lk ing.In the United States,15 mi l l ionpeople areinfected withtuberculos isand more than26,000 newact ive cases ofTB are reportedeach year .Mult i -drug-res istant TB,which countsfor one-third ofa l l cases insome areas ofth is country,wi l l cost theUnited States$2 b i l l ion th isdecade. TB isa lso a leadingsecondaryinfect ion ofAIDS pat ients . Photo courtesy of

AP/Wide Wor ld

Photos

N O V E M B E R I S S U E 1 9 9 5

new ways of overcoming an emerging resistance. The intendedresult: scientists run up fewer blind alleys looking for cures.

To close the gap, Los Alamos researchers are collaboratingwith pharmaceutical companies and other laboratories tocollect, interpret, and integrate the vast collections of avail-able data into a coherent structure.

Los Alamos has a long tradition of investigating health-relatedtopics. This tradition stems from the Laboratory’s earliestdays when the effects ofradiation on workers’health were first studied.As a consequence of theseconcerns, Los Alamoslaunched a research pro-gram to understand thehealth effects of exposureto different types of radia-tion and chemicals. Thesesubstances can adverselyaffect health by damagingcell DNA, which can leadto tumors and cancers.

A number of individualresearch projects haveevolved from theLaboratory’s efforts tounderstand the mecha-nisms that alter DNA,including the GenBank, a database of human DNAsequences; the flow cytometer, a laboratory tool capable ofsorting individual DNA molecules; and the Centerfor Human Genome Studies, which was established tohelp decode the DNA of all 22 pairs of human chromo-somes plus the X and Y sex chromosomes. The field ofmolecular medicine builds on Los Alamos’ extensive experi-ence in gene research.

3

ÈThis 1954 photo

depicts twopol io patents

in i ronlungs beingtransported

to a treat-ment center .

An attenuatedpol io vacc ine

was f i rstproduced byJonas Sa lk in

1955, fo l lowedby a l ive ora l

vacc ine in 1961by A lbert Sabin.

Vacc ines toprotect aga instpol io outbreakswere produced

after severa ldecades of

sc ient i f icresearch.

Los A lamosresearchers

are developingmathemat ica l

and computa-t iona l tools

that wi l l he lpspeed the

development ofeffect ive and

inexpens ivevacc ines and

drug therapiesfor infect ious

diseases. Photo courtesy of

AP/Wide Wor ld

Photos

MOLECULAR DIVERSITY

In the past, drugs were developed primarily by exploiting the innatedisease-fighting properties of plant and animal tissue. This method pro-duced many effective drug therapies, but researchers fighting on thefront lines of the AIDS pandemic know that traditional drug treatmentsare too sluggish to hobble HIV’s swift ability to replicate and mutateinside the body.

Scientists still look to nature for cures, but the development of new vac-cines and drug therapies relies increasingly on a relatively new disciplineknown as molecular medicine.

At Los Alamos, the computational aspects of molecular medicine are underdevelopment. This kind of medical research uses computers to designdrugs and vaccines and measure their effectiveness, or “fitness,” whenpitted against pathogens in a virtual world known as a “rugged landscape.”

Los Alamos researchers are involved in a consortium that includesacademic institutions and commercial drug and biotechcompanies to develop computer models capable of ana-lyzing molecular sequence data. Modeling drugs and theirinteractions with pathogens in this fashion will suggestto experimentalists what drugs to develop by predictingtheir ability to combat pathogens.

The experimentalists, in turn, share their research results withtheoreticians and computer scientists, who are in the process of incor-porating the information into a central database. Such a database canprovide a forum where theoreticists and experimental-ists can exchange results and information.

Some of the computer modeling tools being used atLos Alamos were developed initially to analyze rapidlymutating viruses such as HIV. The modeling technique has since beenexpanded to the new and highly promising field of “molecular diversity.”Rather than relying on nature to generate and select new geneticvariations, this field — sometimes called applied molecularevolution — lets scientists control evolution in a test tube bycreating an environment in which molecules evolve throughartificial selection.

The idea behind molecular diversity is to generate billions of diversepieces of DNA, RNA, proteins, or other organic molecules at

N O V E M B E R I S S U E 1 9 9 5

4

Molecularevolut ion letssc ient istscontrolevolut ion in atest tube bycreat ing anenvironment in whichmolecules evolvethrough art if ic ia lse lect ion. Forexample, adiverse pool ofmolecules (1)is mixedwith poss ib leant ibodies (2) ,which then makecopies of themolecules thatf it (3) .

Ô(1 )

(2 )

(3 )

5

random, then see whichdo best at, for instance,fitting into a receptor onthe protein envelopethat encapsulates thevirus’ genetic material.(The HIV protein enve-lope continues to offerthe principal target for asuccessful vaccine.) Topcandidates identified inthis manner are repro-duced with mutations,and the screening pro-cess is repeated. This isan accelerated lab-oratory version of evo-lution through naturalselection that allowsresearchers to developand test huge numbersof variants in a matter ofhours. The data outputof molecular diversity experiments is tremendous. Los Alamos is currentlydeveloping databases and analysis algorithms to handle this flood of data.

PATTERNS IN PATHOGENS

Over the last decade, new and advanced laboratory techniques such aspolymerase chain reaction and automated sequencing of molecules haveprovided detailed information about genetic variation in pathogens suchas HIV and HPV, the latter being the human papilloma virus responsiblefor diseases ranging from harmless skin warts to lethal cancers.

A database initiated in 1986 at Los Alamos includes genetic sequenceinformation on HIV as the sequences are identified by researchersaround the globe. Information contained in the HIV Sequence Databaseis used each year by more than a thousand researchers worldwide.

Computational analysis of the molecular sequence data has resulted inspecific suggestions for improved vaccines for a dominant strain of HIV.

N O V E M B E R I S S U E 1 9 9 5

5

ÈDan K inder of

GlaxoWel lcomeuses a robot to

synthes izechemica ll ibrar ies .

Los A lamosresearchersare work ing

withcommercia l

pharmaceut ica land b iotech

companies andacademic

inst i tut ions todevelop

theoret ica lmodels of

drugs and theirinteract ions

withpathogens.

Such modelssave va luable

t ime andresources by

predict ing howa drug wi l l

combat apart icu lar

pathogen.Photo courtesy of

GlaxoWel lcome

6

The suggestions have been incorporat-ed into new vaccines presentlyundergoing development and testingby collaborating pharmaceutical com-panies. The researchers have identifiedeight different families, or subtypes, ofthe dominant form of the HIV virus,providing valuable insight into howrapidly the virus changes as it spreadsthrough the population.

The World Health Organization’s globalprogram on AIDS selected the LosAlamos researchers to advise them onthe molecular characterization of AIDSviruses in Uganda, Rwanda, Thailand,and Brazil, the four countries in whichWHO is undertaking preliminary vac-cine trials.

The Centers for Disease Controlrequested information from LosAlamos on HIV molecular sequenceswhile investigating a Florida dentist

with AIDS who allegedly infected five of his patients. The CDC alsoturned to Los Alamos for help tracking transmission of immunodefi-ciency viruses of apes and monkeys to lab workers handling animal viruses.

Los Alamos recently initiated a similar database for the human papillomavirus. HPV is the leading sexually transmitted disease in the world.Cervical cancer, caused by a few of the 75 or more known types of HPV,is a leading cause of cancer-related deaths in women in the world.

IMMUNE SYSTEM-PATHOGENINTERACTION

Models of the interaction of the immune system with pathogens havebeen developed at Los Alamos and used in collaborative projects to eval-uate potential treatments for HIV. The goal of these models is to helpscientists devise novel ways of manipulating the immune system forcommercial applications.

N O V E M B E R I S S U E 1 9 9 5

6

ÓA chi ldsuffer ing fromcholera waitswith h is motherin a L ima, Peru,hospita l fortreatment. Bythe t ime th isphoto wastaken in Apr i l1991, thecholeraepidemic inPeru hadcla imed morethan 1,000l ives . Newoutbreaks ofcholera appearwhen hygienepract ices areinadequate andfood and watersuppl iesbecomecontaminated. Photo courtesy of

AP/Wide Wor ld

Photos

N O V E M B E R I S S U E 1 9 9 5

Los Alamos researchers are collaborating with scientists at LawrenceLivermore National Laboratory and the University of California at SanFrancisco to examine the effectiveness of localized heat treatments onpatients’ lymph nodes as a means of inactivating HIV. The researchersare refining their models to take into consideration the special condi-tions of lymph nodes and other reservoirs of HIV.

Another study builds on scientists’ recent discovery that some kinds ofribonucleic acid, or RNA, can act as enzymes and break up other RNAmolecules into short segments incapable of replicating. Los Alamosresearchers have used mathematicalmodels to examine a treatment thatpackages these RNA “scissors” in a viruscapable of infecting HIV-infected cells.Their models evaluated a blueprint forthe virus, which the National Institutesof Health is developing.

In the course of modeling and assess-ing treatments for HIV and otherpathogens, the researchers gained anew understanding of how the bodybattles HIV. A report of this studyappeared in the January 1995 issue of

Nature. Using clinical data obtainedfrom New York University’s AaronDiamond AIDS Research Center, theresearchers for the first time quantita-tively documented HIV’s tremendousreplication rate in the body.

The study also demonstrated that theimmune systems of AIDS patients arecontinuously churning out armies ofT-cells, but HIV’s burgeoning population ultimately overwhelms thecapacity of the body’s immune system. (See related article in the March1995 issue of Dateline: Los Alamos.)

C O N T A C T S : A L A N L A P E D E S ,

G E R A L D M Y E R S , A N D A L A N P E R E L S O N

T H E O R E T I C A L D I V I S I O N

( 5 0 5 ) 6 6 7 - 7 6 0 8 • E - M A I L : a s l @ l a n l . g o v

7

ÈBy combining

the Laboratory’ssupercomput ing

power withadvanced

techniquesin data ana lys is ,

Los A lamosresearchers

Alan Pere lson( left ) ,

A lan Lapedes(center ) , andGera ld Myers

are help ing the medica lcommunity

se lect the mostpromis ing

vacc ines anddrug treatments

for new deadlyv i ruses and

tougher stra insof o ld infect ious

diseases.

8

NEW COMPUTER DATASTORAGE MEDIA

IS VIRTUALLYINDESTRUCTIBLE

LOS ALAMOS-DEVELOPED TECHNOLOGY

CAN STORE DATA

FOR THOUSANDS OF YEARS

S tep on it, it won’t break. Try to set it on fire, it won’t burn. Place a magnet next to it, it won’t erase. What is it?

It’s HD-ROM, or High-Density Read-Only Memory,developed at Los Alamos. This new information-storagetechnology is more durable and more reliable than CD-ROM,or Compact Disc Read-Only Memory, and has the capacity tostore two complete sets of Encyclopædia Britannica on a steelpin less than 3 inches long.HD-ROM’s main purpose is to store archival data, but it also can storehigh-density data in binary (digital), alphanumeric (human-readable),and graphic formats. Not only can various types of data be stored onHD-ROM, but data can be stored at different densities.

This feature makes it possible to storetextual and graphical information together— a feature no other media can perform.Conventional media require that graphicalinformation and text be stored on separatedisks. And, unlike existing materials, inHD-ROM, the data is written directly onthe media. Because of its durability, theHD-ROM will outlast the computer systemthe data was processed on. This eliminatesthe need to transfer data to new physicalmedia when the original wears out.

HD-ROM is a component of a system that includes an ion-beammicromill, or data writer, and a force-tunneling microscope, which is acommercial system for reading data. Etching information directly on themedia speeds the rate at which the data can be read. The writingprocess involves an ultrahigh vacuum environment that allows for highdensity and clean etching of information. The vacuum eliminates the

N O V E M B E R I S S U E 1 9 9 5

8

ÓResearchersBruce Lamart ine( left ) and RogerStutz makeadjustments tothe ion-beammicromi l l . Th ismachine wr itesdata on HD-ROM media .

9

smearing that sometimes occurs when data is written onmedia at high pressures.

Today’s information storage media are highly perishable. Mostof their components come from magnetic materials that aresensitive to solvents and other magnetic materials.

Researchers would prefer to use materials like steel, iridium,and silicon because of their ability to withstand mishandlingand natural degradation. Media constructed with these materi-als are so durable that exposure to solvents or other magnetic materialshas no effect on the encoded data. Solvents will only clean steel andbecause the HD-ROM is non-magnetic, materials with magnetic proper-ties won’t damage or erase data. Records will last for hundreds, eventhousands, of years.

Existing information-storage media have another drawback. Interpretingcomputer data visually from media such as magnetic tape and opticaldisks is as difficult as interpreting ancient Egyptian hieroglyphs withoutthe Rosetta Stone.

CD-ROM and floppy disks are encoded with a bit-stream of “ones” and“zeroes” that represent information. This is known as binary data. Theaverage person can’t tell what those ones and zeroes mean. So, computersneed a bit-stream interpreter to translate whether a stream of ones andzeroes is a number, a portion of a picture, or the sound of music.

HD-ROM does not require a bit-stream interpreter for alphanumeric andgraphical formats because visually apparent characters are recovereddirectly. For binary data, HD-ROM describes in human-readable formatthe instructions needed for the interpreter to read the data.

HD-ROM has potential applications in areas such as bank transactionrecords, surveillance mapping, seismic records, and even audio and videocassette masters. The researchers estimate the manufacturing costs forHD-ROMs will be comparable to the manufacturing costs of CD-ROMs.

Los Alamos is actively seeking an industrial partner to turn HD-ROMinto a marketable product. Patents on HD-ROM and the ion-beammicromill are pending.

C O N T A C T S : B R U C E L A M A R T I N E A N D R O G E R S T U T Z

M A T E R I A L S T E C H N O L O G Y : P O L Y M E R S A N D C O A T I N G S

A N D S P E C I A L T E C H N O L O G I E S

( 5 0 5 ) 6 6 5 - 2 3 6 6

N O V E M B E R I S S U E 1 9 9 5

ÕBigger doesn’tnecessar i lymean better . I ttakes 12,000computerf loppy d isks tostore theinformat ionthat f i ts on thet iny stee l p in,seen at thecenter of thedisk . The p incan store twocomplete setsof theEncy lopædiaBr i tannica.

10

LOS ALAMOS DEVELOPSNEW METALLIC MEMBRANEFOR FILTERING HYDROGEN

THIN FOIL MEMBRANE OUTPERFORMS

OTHER FILTERS AVAILABLE TO INDUSTRY

Pure hydrogen — and nothing else — passes through a new metallic membrane invented by Los Alamos researchers.

The new filter may find applications in a broad range of industriesbecause it can remove or supply pure hydrogen faster and less expen-sively than current systems. For example, it could advance thedevelopment of hydrogen fuel cells, a technology intended to replacegasoline-burning engines. One drawback to the fuel-cell technology isthat impurities quickly poison the cells if pure hydrogen is not used. Thethin metallic membrane developed at Los Alamos allows only hydrogento pass through it and is economical enough to be practical for a fuel cell.

In another application, the metallic membrane could be used to speed thedehydrogenation process used in creating numerous plastics and poly-mers, while capturing a supply of pure hydrogen to power the factory.

The Los Alamos membrane, whichoperates even better at high tempera-tures (above 300 degrees Celsius) andincreased pressure than at room tem-perature and atmospheric pressure,attractive economically because unlikeexisting filters it can be produced inlarge sheets, or rolls.

The membrane resembles commonaluminum foil. The Los Alamosresearchers produced the membranewith the readily available metals tanta-lum and palladium. Tantalum is arelatively strong and inexpensive metalwith the special property that hydrogenatoms can pass easily through it, so thismetal is used as the structural supportof the membrane.

N O V E M B E R I S S U E 1 9 9 5

Los A lamosresearcherNathanie lPeachey makesadjustments toan apparatusused fortest ing a newmeta l l icmembrane.

Ô

11

Tantalum foil about 13 micrometers thick is cleaned in a vacuum cham-ber by bombarding it with argon ions, a conventional technology. Next,without breaking the vacuum, both sides of the cleaned foil are coatedwith a 1-micrometer-thick layer of pure palladium. The resulting fusedmetallic sandwich eliminates much of the cracking and oxidation prob-lems common to other membranes.

The key to the filter’s success is the way hydrogen molecules respond tothe metal sandwich. A hydrogen molecule binds to the palladium sur-face and breaks into two individual atoms. The atoms then pass throughthe tantalum much faster than they would through just a palladiummembrane. When the atoms reach the outer surface, another thin palla-dium layer recombines the atoms back into a hydrogen molecule. Thefiltered product is pure hydrogen in high volume. To encourage hydro-gen’s passage through the filter, the researchers nudge the gas onto thefilter and apply suction on the other side to pull purified hydrogen offthe filter.

The researchers have filed a patent on this new technology.

C O N T A C T : R O B E R T D Y E

M A T E R I A L S T E C H N O L O G Y : P O L Y M E R S A N D C O A T I N G S

( 5 0 5 ) 6 6 7 - 3 4 0 4 • E - M A I L : r c d y e @ l a n l . g o v

11

N O V E M B E R I S S U E 1 9 9 5

ÓThe th in fo i lmembraneal lows purehydrogen, andnothing e lse, tof i l ter through.Researchersappl ied LosAlamos’expert ise inth in f i lmfabr icat ion toproduce afused sandwichof the readi lyava i lab le meta lstanta lum andpal lad ium.

A MONTHLY PUBLICATION OF THEPUBLIC AFFAIRS OFFICE OF

LOS ALAMOS NATIONAL LABORATORY

Nonprofit Organization U.S. Postage Paid

Los Alamos, NM Permit No.107

A MONTHLY PUBLICATION OF THEPUBLIC AFFAIRS OFFICE OF

LOS ALAMOS NATIONAL LABORATORY

Nonprofit Organization U.S. Postage Paid

Los Alamos, NM Permit No.107

N O V E M B E R I S S U E 1 9 9 5

BRIEFLY …

NEW MEXICO COMMUNITY COLLEGES SEND FACULTY AND STUDENTS TO SUMMER SCHOOL ATLOS ALAMOS. Seven faculty members and students from community colleges in Carlsbad, Española,Farmington, and Las Vegas recently completed eight weeks of research in advanced manufacturing at Los Alamos.Their research projects were tailored to give them knowledge that will help their respective communities developnew science facilities and programs. A student from New Mexico State University in Carlsbad conducted surveysand interviews with Carlsbad-area businesses on the development of a planned Advanced Manufacturing andInnovative Training Center that will identify new markets and projects as well as provide training programs. Tworepresentatives from Northern New Mexico Community College in Española gained knowledge to advance thedevelopment of a new microelectronics academic program. Two representatives from San Juan College inFarmington have returned to their campus with hands-on experience in precise machining that will enhanceinstruction in the field. And two representatives from Luna Vocational Technical Institute in Las Vegas designed acomputer-integrated manufacturing laboratory that will be housed in a refurbished building near the Institute’smain campus. CONTACT : ABAD SANDOVAL , (505 ) 667-1230 , E -MA IL : abad@lan l .gov

LALP-95-2-11

12

IN THIS ISSUE:

MOLECULAR MEDICINE

FOR THE 21ST CENTURYP A G E 1

NEW COMPUTER DATA

STORAGE MEDIA IS

VIRTUALLY

INDESTRUCTIBLEP A G E 8

LOS ALAMOS DEVELOPS

NEW METALLIC

MEMBRANE FOR

FILTERING HYDROGENP A G E 1 0