p . 2 2 T h e s h i m m e r o f b i o l o g yp . 1 0 P i c t u r i n g t h e m i n d a t w o r kp . 4 P i e r c i n g t h e b o d y w i t h p r e c i s i o n p . 1 6 T w o p a t h s t o t h e f u t u r e06W I N T E R

Powerful techniques shed new light

Out of the shadowA PUBLICATION OF VANDERBILT UNIVERSITY MEDICAL CENTER

A N e w W a y o f L o o k i n g

a t S c i e n c e

Lens

Releasing the power of lightHow imaging science istransforming medicine

Lens – A N e w Wa y o f L o o k i n g a t S c i e n c e

WINTER 2006

VOLUME 4, NUMBER 1

EDITOR

Bill Snyder

CONTRIBUTING WRITERS

Leigh MacMillanMelissa MarinoBill Snyder

PHOTOGRAPHY/ILLUSTRATION

Rhoda BaerDavid CutlerDean DixonDominic DoyleSteve FischDavid JohnsonAnne Rayner

DESIGN

Diana Duren/Corporate Design, Nashville

DIRECTOR OF PUBLICATIONS

MEDICAL CENTER NEWS AND PUBLIC AFFAIRS

Wayne Wood

EDITORIAL OFFICE

Office of News and Public AffairsCCC-3312 Medical Center NorthVanderbilt University Nashville, Tennessee 37232-2390615-322-4747E-mail address: william.snyder@vanderbilt.edu

El hambre es el primer ojo del cuerpo(Hunger is the original eye of the body)

– V E R Ó N I C A V O L K O W

Cover: Scientists ply the glow of the firefly to plumb the mysteries of the body.

Illustration by David Cutler.

Lens is published three times a year by Vanderbilt University Medical Center in cooperation with

the VUMC Office of News and Public Affairs and the Office of Research. Lens® is a registered

mark of Vanderbilt University.

Our goal: to explore the frontiers of biomedical research, and the social and ethical dimensions

of the revolution that is occurring in our understanding of health and disease. Through our Lens,

we hope to provide for our readers – scientists and those who watch science alike – different

perspectives on the course of discovery, and a greater appreciation of the technological, eco-

nomic, political and social forces that guide it.

© 2006 by Vanderbilt University

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contentsT A B L E O F

2 THE REACH OF IMAGING SCIENCE

4 PIERCING THE BODY WITH PRECISION

The scalpel is giving way to the scan, at least in some cases of cancer. New imagingtechnologies are raising hopes that doctors soon will be able to locate tumorswith pinpoint accuracy – and without the need for surgery. Imaging also isspeeding the discovery and evaluation of new drugs that potentially can stoptumors in their tracks.

8 AUTOPSY OF THE LIVING

10 PICTURING THE MIND AT WORK

Since the X-ray was discovered, scientists have tried to capture images of thefunctioning brain. Today’s techniques can that and much more: they can illus-trate the symphony of activity underlying memory, addiction and love. Soon itmay be possible – with the help of imaging – to individualize therapy for schizophrenia and to preserve and even augment brain function.

16 TWO PATHS TO THE FUTURE

Emboldened by her groundbreaking imaging studies, Nora Volkow, M.D., directorof the National Institute on Drug Abuse, is determined to transform the wayaddicts are treated by the medical profession and the criminal justice system.While she sees this as part of her duty as a physician, Volkow also acknowledgesthe world-changing legacy of her great-grandfather, Leon Trotsky.

22 SEEING THE SHIMMER OF BIOLOGY

Fireflies are a source of wonder to children and adults alike. Scientists have discoveredhow to harness their biological glow, called bioluminescence, to reveal secrets frominside living animals. The chemical reaction that produces light can be used to followcancer cell metastasis, stem cell migration, gene expression, and protein activity, allas they are happening in vivo.

28 BRAVE NEW VISIONS

Richard Hargreaves, Ph.D., vice president of Imaging at Merck ResearchLaboratories, and Judy Illes, Ph.D., director of the Program in Neuroethics atStanford University, describe recent progress in the use of imaging technologies,their potential and challenges to further development of the field. Can imaginglower the cost of developing new drugs? Are there places we shouldn’t go?

32 PEEKING INTO THE WOMBOne of the most powerful applications of imaging science is the diagnosis of fetalabnormalities. Remarkably detailed pictures can be obtained using ultrasoundand magnetic resonance imaging (MRI). The goal is well planned and orchestratedcare once the baby is born and – in some instances – even before birth.

06W I N T E R

page 4 Watching drugs hit their tumor targets

page 10 Islands of brain activity, woven together

page 16 Drive of an athlete; eyes of an artist

Lens

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A fter X-rays were first dis-covered in 1895, theirstrange and wonderful

properties were almost immediatelyexploited for medical uses. They gavephysicians for the first time the ability to“see” inside the human body non-invasively,and a whole new medical specialty, diag-nostic radiology, was created. A little overa century later, a similar revolution isoccurring with the development of a mul-titude of advanced technologies capable ofproviding a broad array of information tobiomedical scientists and clinicians.

Imaging science is the new disciplinethat connects discoveries in the basic sciences and engineering to applications in biology and medicine. The new tech-nologies build on advances in other fieldssuch as molecular biology and proteomics,and have enormous potential to improveclinical care and to make important con-tributions to medical research.

Over the last few years, a compendiumof powerful imaging techniques has beendeveloped, not only for clinical medicinebut also for basic research. Imaging todayplays a central role in patient managementand care. Radiological imaging methodssuch as X-rays and nuclear imaging, computed tomography (CT), magneticresonance imaging and spectroscopy (MRI,MRS), positron emission tomography (PET)and ultrasound imaging are essential forthe diagnosis of numerous disorders, forproviding crucial insights into the patho-physiology of many types of disease, and

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The extraordinary reach of imaging science

By John C. Gore, Ph.D.

Director, Vanderbilt University Institute of Imaging ScienceChancellor’s University Professor of Radiology & Radiological Sciences and Biomedical EngineeringProfessor of Molecular Biology & Biophysics, and of Physics

Biology, biomarkers and the workingsof the human brain

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for obtaining measures of the response ofpatients to treatments.

In vivo imaging methods also havewidespread applications in research, forthe elucidation of biological structure andin the study of fundamental biochemical,molecular and physiological processes.Imaging can be used in many differentways: to assess tissue structure and forquantitative morphometry, such as meas-uring the growth or regression of tumors;to measure intrinsic tissue characteristicsand composition, such as tumor cell densityor neural myelination; to map variousmetabolic and physiological properties,such as blood flow or oxygen use; and todetect and quantify fundamental processesat the molecular and cellular levels, suchas the expression of specific genes.

Much of imaging research today isaimed at the development of biomarkersin order to derive information on specificbiological processes or responses to treat-ment. For example, in patients with cancer,imaging-based biomarkers of tumor vascularproperties may be used to predict early inthe course of the disease whether a partic-ular treatment regimen will be successful.

The development of functional brainimaging by MRI and the study of neuro-chemistry with MRS and PET are twoother recent advances that have had amajor impact on our understanding ofbrain architecture and function, allowingus to understand the neural basis for bothnormal and abnormal behaviors.

New technological developments andadvances in molecular sciences, such as thedevelopment of novel agents that can tar-get specific receptors, have expanded theapplications of imaging to the molecularlevel, especially through the use of opticalor nuclear detection methods. The result isthat imaging applications permeate almostall current areas of medical research.

The greatest successes for applica-tions of imaging science in the futurewill come from environments where thecomplementary natures of different imaging

approaches is realized, and where expertsin basic sciences and technical aspects ofimage formation and analysis work closelywith biomedical scientists who ask appro-priate questions. Vanderbilt UniversityMedical Center has taken a lead in estab-lishing a new, multidisciplinary Institute ofImaging Science (VUIIS), in recognition ofthe pervasive importance and intellectualvitality of imaging.

VUIIS provides Vanderbilt researcherswith state-of-the-art research imaging ofanimals and human subjects across a broadrange of modalities. It comprises an expertfaculty that includes physicists, engineers,computer scientists, chemists, physiologistsand clinical scientists, working together toaddress important problems within imag-ing science and applications of imaging.The Institute manages an impressive arrayof imaging resources, including systemsdedicated to the study of preclinical mod-els of disease such as microPET, microCT,optical, ultrasound and MR imaging ofsmall animals. It also will shortly house a7 Tesla human scanner for MRI and MRS,

one of fewer than 10 such systems in theworld, and the flagship for exciting newresearch directions.

These facilities will be integrated,along with chemistry labs dedicated to thedevelopment of new probes for molecularimaging and computing labs for advancedimage analysis, in a new 42,000-square-foot building that will be completed inthe fall of 2006. The new Institute willprovide Vanderbilt a world-class researchfacility in all aspects of biomedical imag-ing, and provide an exemplary trainingenvironment for specialists as well as otherresearch scientists in the use of imaging.The faculty and trainees within VUIIS arealready engaged in numerous projectsapplying imaging methods in cancer biol-ogy, basic and clinical neurosciences,metabolic disorders and clinical trials.

This issue of Lens highlights some ofthe current areas of emphasis in imagingscience at Vanderbilt and elsewhere. LENS

Pictured at left: John C. Gore, Ph.D., with three-dimensional rendering of a functional magneticresonance image (fMRI) of the brain projectedonto his forehead.

Pictured below: Brain image obtained byVanderbilt scientists on a 7 Tesla MRI scanner atPhilips Medical Systems reveals small structuressuch as tiny blood vessels (white dots in the darkgray regions of the image and magnified inset)that are beyond the resolving power of convention-al scanners. An identical scanner will be installedat Vanderbilt in the spring of 2006. One Tesla isroughly 20,000 times the strength of the magnet-ic field of the earth. The 7 Tesla scanner allowsscientists and clinicians to study brain structure,function, and neurochemistry at an unprecedentedlevel of detail.

Courtesy of Vanderbilt University Institute ofImaging Science

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Pictured left: Dennis E. Hallahan, M.D.,chairman of Radiation Oncology atVanderbilt University Medical Center,adjusts a plastic frame that holds thehead still during treatment using an image-guided radiation therapy system, calledTrilogy, made by Varian Medical Systems.

Photo illustration by Dean Dixon

he scalpel is giving way to the scan – at least in somecases of cancer.

New imaging technologies are raising hopes thatdoctors soon will be able to locate tumors with pinpointaccuracy, and track their hour-by-hour response to treat-ment – without the need for surgery.

Coupled with recent advances in genetics and molecular biology, imaging is speedingthe discovery and evaluation of safer, more effective treatments that can stop tumors intheir tracks.

“In the past 10 years we’ve made tremendous strides in improving imaging of can-cer,” says Dennis E. Hallahan, M.D., chairman of Radiation Oncology at VanderbiltUniversity Medical Center. “In the near future we will be using functional imaging toimage pre-cancer.”

At Vanderbilt, for example, a sophisticated technique called dynamic contrast-enhancedmagnetic resonance imaging (DCE-MRI) is being tested in women with breast cancer.

The goal: to see whether new “targeted” therapies are shrinking tumors by disruptingtheir blood supplies. If successful, the technique could avoid the need for repeat biopsies,says Tom Yankeelov, Ph.D., director of Cancer Imaging in the Vanderbilt UniversityInstitute of Imaging Science.

“Particularly in breast cancer there’s currently no adequate . . . some would saythere’s no non-invasive method at all, to determine whether or not a tumor is respondingto treatment,” Yankeelov says.

“It’s really a sad state of affairs,” he says. “Repeat biopsies are not really an optionbecause you have to go under the knife each time – who wants to do that?”

In addition, “biopsies by definition only sample a portion of the tumor. It is entirelypossible that you could sample a section of tissue that is free of active disease and miss thesections that are actively proliferating.

“That is why imaging is so powerful,” Yankeelov says. “You can get a more completedescription of the tumor status, and you can do it non-invasively.”

That’s the aim of DCE-MRI, a modified MRI technique in which a contrast agent isinjected into the patient to outline the profusion of fragile, leaky blood vessels that springup to feed growing tumors. (See next page).

Nearly 40 anti-angiogenic drugs, which inhibit the growth of these vessels, are nowin clinical trials. Advanced imaging technologies like DCE-MRI, by detecting changes inblood flow and vessel permeability or “leakiness,” for example, may help doctors deter-mine whether the tumor is responding – even after the first course of chemotherapy.

More work needs to be done, however, before DCE-MRI will be ready for the clinic.“I personally think (it) is really just another tool in the toolbox,” Yankeelov adds.

Newer imaging techniques can measure glucose metabolism, hypoxia (lack of oxygen)and the diffusion of water molecules in and out of cells – indicators of how big the tumor is,how “healthy” it is, and whether it is surviving attempts to kill it.

By tracking various markers that have been tagged with a radioisotope, PET also can tellwhether a tumor is dying – or proliferating. Similarly, mass spectrometry techniques candetect changes in the expression of various proteins by tumors in response to treatment.

Piercing thebody with

precision

THow imaging is aidingthe fight against cancer

By Bill Snyder

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Whether these techniques can predict theoutcome of therapy and its impact on patientsurvival remains to be proven clinically.

Another technical challenge: “regis-tering” the different images – mappingcoordinates representing the same anatom-ical point so that the same “voxel,” orthree-dimensional piece of data, lines upin each of them.

Guiding the scalpelRegistration already is an integral

part of stereotactic surgery and radio-surgery, the precise guidance of scalpels andradiation beams to remove abnormalities,including tumors, with minimal damageto surrounding tissue.

New techniques developed byVanderbilt engineers and computer scientistsare extending the reach of the neurosurgeonand radiation oncologist even further. Theircontributions are proving to be invaluable,especially for treatment of aggressive,infiltrating glioblastomas of the brain.

“The visual cues we have at surgery arereally poor,” explains Reid C. Thompson,M.D., director of Neurosurgical Oncologyat Vanderbilt. “There isn’t often a discreteedge … maybe there’s a slight discol-oration … maybe the tumor just feels alittle different.”

As a result, he says, “you either don’ttake out enough tumor in the brain, andwe know that’s probably not good interms of prognosis, or you take out toomuch, which is an obvious problem.”

To further define the margins of thetumor during surgery, Anita Mahadevan-Jansen, Ph.D., and her colleagues in the

Department of Biomedical Engineeringhave developed an optical probe thatwithin 30 seconds can differentiatebetween normal and abnormal brain tis-sue based on the spectra of light bouncedoff of them.

A recent clinical study concluded thatthe instrument can achieve what amounts toan “optical biopsy” with “near-instantaneousfeedback,” improving the percentage oftumor that is removed during surgery andreducing operating time and expense.

Michael I. Miga, Ph.D., assistant professor of Biomedical Engineering anddirector of the Biomedical ModelingLaboratory, has harnessed a widely usedcommercial technique, laser range scan-ning, to adjust for changes in the surfaceof the brain as the surgeon cuts into it.

By repeatedly sweeping a laser beamacross the brain surface, the scanner produces“point clouds” or sets of three-dimensionalpoints that – in clinical studies – haveaccurately predicted the changing locationsof the tumor as well as nearby blood ves-sels and other delicate structures duringthe operation.

The development of these techniquesowes much to the rich, longtime collabo-ration between Vanderbilt engineers, computer scientists and neurosurgeons.

Leaders in this effort include J. MichaelFitzpatrick, Ph.D., and Benoit M. Dawant,Ph.D., professors in the Department ofElectrical Engineering & ComputerScience; Robert L. Galloway, Ph.D., pro-fessor of Biomedical Engineering; andNeurosurgery Department chair George S.Allen, M.D., Ph.D.

During the past 15 years, Vanderbiltresearchers have improved the registrationof preoperative images with anatomicalinformation collected by an optical probeduring surgery. The combined image, projected onto a computer screen in theoperating room, helps the surgeon hold atrue course through tissue topography thatchanges with each touch of the scalpel.

Dawant, who with Fitzpatrick co-directs the Medical Image ProcessingLaboratory, has developed computational“atlases” of the brain and liver – markedby recognizable anatomical guideposts suchas blood vessels – that can be “warped” tofit individual patient cases.

Similarly, Galloway and his colleagueshave teamed up with surgeons to createintraoperative guidance systems that useoptical tracking or articulated “arms” totrack the surgical position in three dimen-sions. (See page 7)

The primary software platform, called ORION, for Operating RoomImage-Oriented Navigation, can be modi-fied to support neurosurgical and surgicalapplications, including ones such as liversurgery, where the target moves withpatient breathing.

All this would not have been possiblewere it not for the astronomical increase incomputing power, Miga adds.

“We solve about 80,000 coupledequations in a model, and we do that inabout 15 to 18 seconds,” he says. “Andwhen I say 80,000 equations, I’m talkingabout essentially a spatial understandingof how the organ we’re looking at isdeforming or moving.”

Starving a tumorFragile, leaky blood vessels nourishing a breast tumor are revealed with the help of dynamic contrast-enhanced MRI. The red voxels (three-dimensional data points) produce a 3-D volume rendering of blood flow (perfusion) and leakiness (permeability) before treatment (A).

In the same patient after chemotherapy (B), a drastic reduction in perfusion/permeability indicates treatment is successfully "starving" the tumor by disrupting its blood supply.

(C) and (D) are single-slice images taken from the center of the 3-D volume renderings before and after treatment. The hope is that this kind of analysis will enable doctorsto determine early on whether the tumor is responding to therapy.

Courtesy of Tom Yankeelov, Ph.D.

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Hitting the targetThompson says the next logical step in

cancer imaging is to develop a molecularimaging agent, “some unique marker in thetumor that you could target … that wouldallow the tumor to fluoresce” as the surgeonpeers through the operating microscope.

With Vanderbilt chemistry professorDarryl J. Bornhop, Ph.D., Thompson isinvestigating another class of fluorescentmolecules, the rare-earth lanthanidechelates, which potentially could be usedto delineate tumors both in MRI scansand under the operating microscope.

Many cancer cells express a high den-sity of peripheral benzodiazepine receptors(PBRs), named for their ability to bindanti-anxiety drugs like Valium and Xanax.To PK-11195, a compound that bindstightly to PBR, Bornhop attaches fluo-rescing complexes of lanthanide chelates.

In animal studies, the injected markershows unique, dual capabilities: Bornhop’shybrid shows up in MRI scans, and itsfluorescent tag can be observed throughthe microscope. If it works in humans, thesurgeon could match the fluorescence seenduring surgery to the pre-operative MRI.

While PBR targeting also may beuseful in the treatment of other tumors,including those of the breast and colon, italone may not be enough, Bornhop cau-tions. A “cocktail” of chemicals will probably be needed – especially to monitorhow a tumor is responding to therapy.

One possible avenue: cell adhesionmolecules, which play important roles ininflammation, cell migration, cell signal-ing – and cancer.

About a decade ago, Hallahan and hiscolleagues at the University of Chicagoobserved that the inner linings of tumorblood vessels sprouted these distinctiveglycoproteins (carbohydrate-protein com-plexes) when zapped by a dose of radiation.He wondered how he could capitalize onthis phenomenon.

After moving to Vanderbilt to chairthe Department of Radiation Oncology in1998, Hallahan assembled a diverse teamthat included Todd D. Giorgio, Ph.D.,associate professor of BiomedicalEngineering and Chemical Engineering.

The researchers began searching forfragments of proteins – short sequences ofamino acids called peptides – that wouldhone in on tumor blood vessels.

Hallahan hoped the peptides wouldbind specifically to these radiation-inducedmarkers inside tumor blood vessels. Whentagged with radioisotopes, these tinyguided missiles could be used to monitorthe effectiveness of drugs designed to shut

down the tumor’s blood supply. They alsocould deliver their own toxic payloads.

The researchers found an amino-acidsequence, arginine–glycine–aspartic acid orRGD, that bound specifically to the markers.

In a preliminary feasibility study,they labeled the peptide with a gammaray-emitting radioisotope, injected it intopatients receiving high-dose radiation totreat metastatic brain tumors, andwatched the tumors light up in imagestaken by a gamma camera. “This studyshows that it is feasible to guide drugs tohuman neoplasms by use of radiation-guided peptides,” they reported in 2001.

Next, the researchers coated “nanopar-ticles” (about the size of a virus) with fibrinogen, a blood-clotting protein thatcontains the RGD sequence, tagged theparticles with a radioisotope, injected theminto tumor-bearing mice, and blasted thetumors with radiation. Not only did theblood vessels light up, but the fibrinogencoating apparently triggered clots to forminside the vessels, blocking blood flow andcausing the tumors to shrink.

Currently the researchers are searchingfor peptides and antibodies that zero in ontumor blood vessels following low-doseirradiation in combination with Sutent(SU11248).

“That’s why it takes so long to get adrug or an antibody to market,” explainsRaymond L. Mernaugh, Ph.D., director ofthe Molecular Recognition and ScreeningFacility in the Vanderbilt Institute ofChemical Biology who is participating inthe research. “You go through all thesesteps to prove that you have somethingthat’s very specific, doing exactly whatyou want.”

Sutent is a “targeted” cancer therapy,now in clinical trials, which blocks an

enzyme key to the development of tumorblood vessels. Not all tumors or patientsrespond to targeted therapy, however.Hallahan’s goal is to develop a way ofdetermining within hours, rather thanweeks, whether the drug is working.

Meanwhile, Giorgio and his col-leagues have identified peptides capable ofpenetrating the nuclei of cells in thebreast, and which potentially can differen-tiate normal cells from tumors. By attachinggold nanoparticles to the peptides, thismethod could generate an early andextremely precise view of breast cancer.

Similarly, the recent discovery of neu-ral stem cells could lead to improvementsin the early detection and treatment ofgliomas. Scientists believe these stemcells, the source of normal brain tissue,under some circumstances can be trans-formed into tumors.

“Let’s say you could image the stemcells,” Thompson imagines. “Then youcould see that your therapy made (theabnormal cells) go away … I hope wewould get to a point where if somebodycame in with a tumor we’d be able to simply flip the switch and shut it off andkeep it from progressing … without havingto do surgery.

“It is absolutely changing the way wethink about these kinds of cancers.” LENS

Image-guided brain surgeryA tracked surgical probe collects data from abrain tumor during surgery (left). The informa-tion is used to index pre-operative images tothe correct slice of the tumor (right) and to dis-play the surgical position on that slice on amonitor in the OR. The CT image (upper left),PET image (lower right) and two MR images(upper right and lower left) update in real timeas the probe is moved.

Courtesy of Robert L. Galloway, Ph.D.

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Nov. 8, 1895, an accidental dis-

covery ushered in a scientific and medicalrevolution that would allow us to seeinside the living human body for the first time.

While conducting an experimentwith cathode rays, Wilhelm Roentgen,Ph.D., noticed a strange glow on a distantcardboard screen. Knowing that cathoderays could not pass through the obstaclesbetween his cathode ray tube and theglow, he proposed the existence of a noveltype of penetrating ray, which he called the“X-ray.” After spending several solitaryweeks analyzing the rays, Roentgen pub-lished his findings in late December,along with an eerie X-ray photograph(radiograph) of his wife’s hand.

Roentgen’s discovery opened up thehuman body without a single incision. Soon,the medical profession was using X-rays tolocate lodged bullets and bone fractures.With the further refinement of the technol-ogy and the development of contrastagents, even soft tissues came into focus.

Rock ‘n’ rollDespite the improved resolution of

contrast-enhanced X-ray images, overlyingbones obscured some parts of the body fromview. By moving the X-ray tube and film intandem, bones that stood in the way wereblurred out and a single cross-sectional slicethrough the body was highlighted.

This new technique, called tomography,was first described by the Dutch radiologist

Bernard Ziedses des Plantes in 1931.Tomography could produce a series ofimages that could be stacked to give thephysician information about volume. Thefirst commercial tomograph, called thelaminagraph, was built at the MallinckrodtInstitute of Radiology at WashingtonUniversity in St. Louis in 1937.

Although laminagraphs are relatedto modern computed tomography (CT),such technology had to await the dawn ofthe computer age. A major player was aLondon-based electronics firm, Electricand Musical Industries Limited (EMI),perhaps best known as the Beatles’ record label.

Supported in part by the sales ofBeatles records, the EMI group, led byGodfrey Newbold Hounsfield, developedand brought the first CT scanner to mar-ket in 1971. As image resolutionimproved and scanning speed increased,the CT scan soon became the “standard ofcare” for suspected brain disorders. It hassince become a powerful method for imag-ing the body as well.

Over the seven decades that passedbetween the first X-ray devices and themodern version of CT, the basis for thenext wave of medical imaging – one thatdidn’t involve harmful radiation – wasslowly taking shape.

ResonanceIn the late 1930s, physicists discovered

that atomic nuclei containing odd numbersof protons (such as hydrogen) would alignthemselves with a strong magnetic fieldand revert to their original state, or “relax,”when the field was turned off. This changecould be detected by the radiofrequencywaves given off in the process.

Since bodily tissues differ in theirwater content (and consequently, hydrogencontent), scientists realized that this“nuclear magnetic resonance,” or NMR,could be used to distinguish between softtissues – and possibly to detect disease.

In 1971, Raymond Damadian, M.D.,a physician at Downstate Medical Schoolin Brooklyn, N.Y., used NMR to distin-guish excised cancerous tissue from normal,healthy tissue.

Autopsy of the livingA brief history of imaging scienceBy Melissa Marino

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Two years later, Paul Lauterbur, Ph.D.,a chemist at the State University of NewYork at Stony Brook, introduced rotatingmagnetic field gradients and computeralgorithms to assemble a two-dimensionalimage from NMR data. Using this tech-nique, he produced the first NMR imageof a living subject, a clam.

Damadian and colleagues followed in 1977 with the first NMR image of ahuman subject.

Peter Mansfield, Ph.D., a physicist atthe University of Nottingham in England,developed mathematical calculations thatallowed faster acquisition of the NMRimage. His work led to the “fast” or“functional” MRI (fMRI), which couldacquire images at the rate of 30 to 100frames per second.

In 1989, Seiji Ogawa, Ph.D., a physi-cist at AT&T Bell Laboratory in NewJersey, described the phenomenon – calledBlood Oxygenation Level Dependent(BOLD) effects – that forms the basis forfunctional MRI (fMRI). The changes inoxygenation of blood hemoglobin in “activated” brain regions perturb the localmagnetic environment, serving as a naturalcontrast agent.

Since changes in the BOLD signaldepend on the changes in blood flow andoxygenation, fMRI provided a measure ofbrain activity and the unparalleled abilityto safely and non-invasively probe thephysiological basis of neurological andpsychological disorders as well as normalcognitive function.

Medical ‘Geiger counters’Despite the attractiveness of MR as a

radiation-free, and presumably safe, imag-ing technique, nuclear technology hasspawned some of the most sensitive andpowerful imaging methods to date – singlephoton emission computed tomography(SPECT) and positron emission tomogra-phy (PET).

The discovery of naturally-occurringradioactive elements, like uranium, polo-nium and radium, in the late 19th Centurysparked the “atomic age.” However, thesenaturally radioactive elements are not nor-mally found in the body, so their medicaluse was limited.

In 1934, the creation of artificialradioisotopes of normally non-radioactiveelements common in the body (includingcarbon, oxygen, nitrogen and fluorine)gave physicians the tools they needed toadapt radioactive compounds for medicalpurposes. As these radioisotopes decayed,

they produced gamma rays, which couldbe detected with a Geiger counter.

Deriving an image was not the priorityat first; the goal was to detect “hot spots”in the body where the radioactive com-pounds accumulated. But, in 1951,Benedict Cassen, Ph.D., at UCLA built thescintiscanner, a device that scanned thebody using pen-sized gamma ray detectorsand created a crude print-out of those hotspots. Acquiring a usable image fromthese radioactive compounds suddenlyseemed possible.

In 1968, the first nuclear imagingmachine, single photon emission computedtomography (SPECT) was built. However,the seminal advance in nuclear imagingcame in 1975, when Michael Phelps,Ph.D., and Edward Hoffman, Ph.D., atWashington University in St. Louisreported their development of PETT(positron emission transaxial tomography),later shortened to “PET.”

When a positron emitted by a decay-ing radioisotope collides with a nearbyelectron, two gamma rays traveling inopposite directions are produced. Using ahexagonal array of gamma detectors andcomputational methods similar to thosethat generated CT images, the WashingtonUniversity scientists built a device thatcould construct three-dimensional “maps”of positron emission deep within the body.

PET was primarily used for researchpurposes until 1979, when another mile-stone – the development of radioactiveFDG (fluorodeoxyglucose), a glucose analog – further propelled the technologyinto the medical field. With FDG, physi-cians can track the metabolic activity ofcells, aiding in the diagnosis of cancer andother diseases.

Smiling in the wombIn 1877, the discovery of piezoelec-

tricity laid the foundation for one of thesafest and most economical methods ofseeing into the body – ultrasound.

Piezoelectric crystals generate a voltagein response to applied mechanical stress,including sound waves. During WorldWar I, they were used in the first sonardevices to detect sound waves bounced offenemy submarines.

In 1937, sound waves were firsttransmitted through a patient’s head toderive a crude image of the brain.Ultrasound ultimately found its niche inobstetrics and gynecology in the 1950sfollowing reports of the damaging effectsof X-rays on the fetus.

Since then, ultrasound has morphedfrom flat black-and-white, two-dimensionalimages intelligible only to trained profes-sionals to the sharp and startling 4-D“movies” of the fetus kicking, yawningand smiling in the womb.

Because ultrasound also can capturethe movements of heart muscle and valves,an application called echocardiography isnow used to examine the heart – beforeand after birth. LENS

Pictured at left: Whole body scans, like thismagnetic resonance image, can help physi-cians determine the extent of cancer spreadthroughout the body. They also could be usedroutinely to screen healthy people for a gamutof diseases, although this use is controversial.Courtesy of the Vanderbilt University Instituteof Imaging Science.

Pictured below: (Top) 3D reconstruction of anMRI of the heart and mediastinal vessels in achild with a congenital narrowing of the aorta.(Bottom) 3D ultrasound image of the fetal face.

Courtesy of Marta Hernanz-Schulman, M.D.,and David A. Parra, M.D. (top), and Arthur C.Fleischer, M.D. (bottom).

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By Melissa Marino

Picturing the

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“Traditionally, imaging meant radiology – you went tothe X-ray department. Imaging is now much more broadlybased,” says John C. Gore, Ph.D., director of the VanderbiltUniversity Institute of Imaging Science.

Now, techniques like functional magnetic resonanceimaging (fMRI) and positron emission tomography (PET)provide much more than a static snapshot of the brain’sform. They can illustrate the symphony of activity thatunderlies memory, addiction and love. They can also resolvedysfunction related to psychiatric and neurological diseaseand watch how drugs and educational interventions “nor-malize” brain activity.

“Can we measure the effect of a behavioral therapy?Can you tell whether someone is going to recover fromaphasia? Those are questions that radiologists have not pre-viously thought much about,” Gore says. “They now havethe tools to do it.”

The explosion of fMRI studies in psychiatry and psychol-ogy has revealed volumes of information about individualbrain regions and their principal functions.

While this may convey the rather simplistic notion thatthe brain is highly compartmentalized, another imagingtechnique based on MRI, diffusion tensor imaging (DTI),may help weave these isolated islands of brain activity backtogether again into a functional network.

“With fMRI, you can look at brain function – where inthe brain certain information is processed,” says Adam W.Anderson, Ph.D., associate professor of Biomedical Engineeringand of Radiology and Radiological Sciences at Vanderbilt.

“With DTI, you can look at the connection between areasof the brain that are processing that information.”

From the energy emitted by the nuclei of hydrogenatoms in the presence of a magnetic field, MRI can generateexquisitely detailed images of soft tissues, including thegrayish parts of the brain that contain the neurons (called“gray matter”).

DTI, on the other hand, illuminates “white matter,”bundles of long fibers (axons) that transmit signals betweendifferent parts of the brain. In particular, the techniquemeasures “anisotropy,” the degree to which water movementis greater along fibers than in other directions.

Anisotropy may help explain why some patients withschizophrenia experience auditory hallucinations. Last year,Swiss researchers reported finding increased anisotropy inthe brains of patients who frequently heard voices, particu-larly in the white-matter tracts that connect hearing andlanguage centers.

Increased anisotropy is a measure of greater connectivityin the axon bundles. Neurons that are too strongly coupledto each other may fire off signals too readily, resulting inover-activation of parts of the brain that process externalsounds and language, the researchers reported last year.

For patients with schizophrenia, this may explain theinability to distinguish their own, self-generated thoughtsfrom external speech.

The Swiss report, entitled “Pathways That Make Voices,”reinforces the value of DTI in exploring other neurologicaland psychiatric diseases, says Anderson.

In collaboration with other Vanderbilt researchers,Anderson is using the technique to investigate knownwhite-matter diseases such as multiple sclerosis, and todetermine the effects of prenatal cocaine exposure on brain connectivity.

DTI and other MRI techniques also are proving usefulto understanding how the developing brain is wired, andhow conditions such as premature birth can affect cognitivedevelopment. The goal is to find ways to prevent “anatomicdisturbances” from impairing “functional capacities,”Anderson, Gore and their colleagues at Yale pointed out ina recent paper.

Since the discovery of the X-ray, scientists have tried to take picturesof the mind at work. One hundred ten years later, they have never beencloser. Soon it may be possible to predict – and avert – the develop-ment of drug addiction, to individualize therapy for schizophrenia andother disorders, and to preserve and even augment brain function.

Pictured at left: Diffusion ten-sor image illuminates “whitematter,” bundles of long fibers(axons) that transmit signalsbetween different parts of thebrain. Colors indicate the direc-tion in which the bundles arerunning (green = back to front,red = side to side, blue = top tobottom). The gray “base” – anMRI slice through the brainshowing the eyes – and the out-line of the head are included to

help orient the image in space.The bundles dangling beneaththe base are going to the brain-stem and temporal lobe. Suchimages could be used to helpsurgeons excise brain tumorswithout damaging fiber bundles.

Image courtesy of theVanderbilt University Institute ofImaging Science; illustration by Dominic Doyle

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“Neuropsychologists have spent a lotof time looking at the brain as it fallsapart from injury,” adds imaging pioneerMarcus E. Raichle, M.D., professor ofRadiology, Neurology and Anatomy &Neurobiology at Washington UniversitySchool of Medicine in St. Louis. “But itwould be equally important to watch itbeing put together during development.”

Right drug, right doseSchizophrenia remains one of the most

challenging brain disorders. Characterizedby delusions and hallucinations, the illnessdisrupts cognition and emotion, profoundlyaffecting a person’s ability to think clearlyand interact with others.

Imaging techniques, including PETand fMRI, are aiding understanding of thedisease and the development of drugs totreat it.

The classic antipsychotic drugs, suchas Thorazine, block receptors for the neu-rotransmitter dopamine, which also is centrally involved in Parkinson’s disease,addiction and other brain conditions. Butwhile these drugs squelch the delusionsand hallucinations, in high doses they alsocause Parkinson’s-like symptoms, includingrigidity and loss of muscle control, andthey don’t improve cognitive function.

In the early 1990s, Herbert Y.Meltzer, M.D., and colleagues at CaseWestern Reserve University helped establishthat clozapine and other second-generation“atypical” antipsychotics could effectivelytreat psychosis and improve cognitionwithout causing Parkinsonism. This wasgreat news, but how did the two classes ofdrugs produce such different effects?

That’s where imaging came in.Robert M. Kessler, M.D., and his

colleagues at Vanderbilt had developed anumber of radiolabeled compounds visibleon PET scans that bound to a particulardopamine receptor, called D2, if it was notalready occupied by an antipsychotic drug.In this way, the researchers could generatepictures of where in the brains the drugswere working.

Working with Meltzer, who currentlydirects the Division of Psychopharmacologyat Vanderbilt, the researchers found that while the older drugs block D2receptors throughout the brain, the atypical class selectively binds to recep-tors in the cortex, the center of higherbrain function, but not in areas involvedin motor function.

“It’s a surprise nobody expected,”says Kessler, Roentgen Professor ofRadiology and Radiological Sciences anddirector of the Center for Molecular

Ronald Baldwin, Ph.D., is on the front lines of a major effort at Vanderbilt to developnew radiotracers, not only to improve understanding of brain diseases but to speeddrug development.

It’s an ambitious task.At the heart of radiopharmaceutical preparation is the cyclotron – a hulking

machine entombed by thick concrete shielding with a control panel resembling thecockpit of a jet airliner.

The cyclotron accelerates charged particles, usually protons, in dizzying circles tonear the speed of light, until they are sent smashing into a sample of nonradioactivematerial (carbon, fluorine, oxygen or nitrogen). This collision forces an extra protoninto the target atom’s nucleus, resulting in a radioisotope that can then be insertedinto the pharmaceutical compound – again, not always an easy feat.

To improve safety, ever decreasing amounts of radiation are incorporated into radio-pharmaceuticals, making simple chemical reactions tricky.

“There’s a lot of art in radiochemistry … a lot of reactions that are ‘bread and butter’ bench reactions just don’t work,” Baldwin says, because of the low concentra-tions of radioisotope used.

With the initiative to develop several new radiopharmaceuticals for both brain andcancer imaging, he has his work cut out for him.

Baldwin doesn’t seem to mind, though. He just wants folks to remember where thebrilliant images on the screen originated.

“Chemists are often in the background,” he says with a smile. “People sometimesforget where (the images) came from.”

– MELISSA MARINO

How to Make an Atomic Drug

Ronald Baldwin, Ph.D., pre-pares radiopharmaceuticalsin a shielded cabinet withthe help of robotic arms.A

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“We took a class of drugs which we knew hadspecial clinical effects, but the mechanism wasunclear. We found specific patterns of receptorblockade … that we think are responsible, atleast in part, for their superior therapeuticproperties.”

R O B E R T M . K E S S L E R , M . D . , D I R E C T O R ,C E N T E R F O R M O L E C U L A R I M A G I N G AT VA N D E R B I LT

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Mysteries of music and mathLyric soprano Gloria Lenhoff has sung

in opera houses and performance halls allover the country. Her repertoire spansmore than 2,000 pieces in 30 languages,yet she can’t read music.

Lenhoff has Williams syndrome, a rareneurodevelopmental condition characterizedby mild-to-moderate mental retardation,blood vessel disease and – among other surprising traits – an affinity for music.

The genetics of the disorder are wellknown, but an aberration that slices out aspecific a region of chromosome 7 cannotexplain Lenhoff’s unique gifts.

Brain imaging may help.Researchers at Stanford University,

for example, have used fMRI to study thebrains of people with Williams syndromewhile they listened to snippets of Bach,Beethoven and Mozart. In 2003, theyreported finding “strikingly different” patterns in the way the brains of peoplewith Williams syndrome processed music,compared to normal controls.

When the control group listened tomusic, the hearing center in the brain’stemporal lobe lit up. Among people withWilliams syndrome, however, brain activa-tion was more widespread, and includedthe amygdala, an almond-shaped structurenear the base of the brain that plays a keyrole in emotions.

Imaging. “It is the same receptor, thesame protein” in both places.

The Vanderbilt researchers also haveused fMRI to study the effect of drugtreatment on specific cognitive functions,such as short-term working memory. Byilluminating changes in blood flow andoxygenation, fMRI can create “pictures” ofhow the brain works under various treat-ment conditions.

Because individual patients responddifferently to different medications, molec-ular imaging may one day help identifythe best drug for a particular patient.

“We may find that schizophrenia isnot one disease, but several differenttypes,” Kessler says. “ … We may be ableto determine what factors predispose oneto being treated by one class of drugs asopposed to another.

“We may be able to individualizetherapy, provide better dosing so that theside effects are spared and the therapeuticbenefits are enhanced.”

Finding the right dose of the rightdrug is critical, says Ronald Baldwin,Ph.D., research associate professor ofRadiology at Vanderbilt.

“A lot of people are actually over-dosed,” says Baldwin, who develops novelradiotracers to probe the actions of drugsin the brain. “They are getting more drugthan they need to get an effect. Withradiotracer imaging, you can look at thereceptor that’s binding the drug to seehow much drug is occupying it.”

The finding may provide clues to thecomforting power of music, says ElisabethM. Dykens, Ph.D., associate director ofthe Vanderbilt Kennedy Center forResearch on Human Development.

Dykens, a professor of Psychology, hasstudied the personality characteristics ofpeople with Williams syndrome and otherdevelopmental disorders for several years.

People with Williams syndrome areprone to heightened anxiety and fear of loudnoises. At the same time, they can be exceed-ingly social, highly verbal and friendly.

A recent study led by Dykens foundthat those who were more musicallyinvolved tended to be less anxious andfearful. The goal now is to try to link thisobservation to specific areas of the brain.“We hope to see how this connection playsout in the imaging studies,” she says.

Functional MRI also is proving to bea powerful educational tool.

Gore was among the first to applyfMRI to evaluate reading disabilitieswhile at Yale University, where he direct-ed the Nuclear Magnetic ResonanceResearch Center.

Children with dyslexia have difficultyrecognizing and comprehending writtenwords. Rhyming games and other drillsthat break down and rearrange sounds toproduce different words can help themimprove their reading skills.

The human brain is an energy glutton. Comprising only about 2 percent of bodyweight, it consumes nearly 20 percent of the body’s oxygen intake. Why does thebrain need so much energy, even when it is at rest?

Marcus E. Raichle, M.D., a member of the Washington University team that devel-oped PET in the 1970s, believes he may have an answer.

During experimental tasks, some areas of the brain become more active while otherareas become less active as measured by changes in metabolism and blood flow.When subjects are studied at rest with their eyes closed, however, activity in these“task-negative” areas goes up, Raichle and his colleagues reported in 2001.

These areas, he says, are nodes of a “default” brain network that functions intrinsical-ly and in a correlated manner during the resting or baseline state. Its activity decreaseswhen an attention-demanding task raises the oxygen requirement in other areas.

Raichle sees purpose and evolutionary significance in this phenomenon. The defaultsystem serves as a “sentinel,” constantly monitoring the horizons of the external envi-ronment (as well as the world within). It also is “forecasting” and preparing for futureevents based on prior experience.

“The brain is basically in the prediction business,” he explains. “We use both ourgenetically endowed experience plus what we learn in our own experience, and usethat to predict what’s going to happen next. And we spend most of our brain’s (ener-gy) budget on doing that.”

Is this activity some aspect of the thing we call “consciousness?” Perhaps, says Raichle. If so, could fMRI determine whether a person in a persistent vegetative state really

has some flicker of consciousness left? Time, and further research, may tell. “Whatever (the default system) is doing is a reflection of what the brain is mainly

doing,” Raichle says. “We have to back away from the notion that the brain is mainlyreacting to the world in which we live, and take the perspective that it is … creating, inthe context of ourselves, a model of the world in which we live and expect to live.”

– MELISSA MARINO

The brain at rest

Doug Fuchs, Ph.D., and Lynn S. Fuchs, Ph.D.,are using fMRI to assess treatment of math dis-abilities at the Vanderbilt Kennedy Center forResearch on Human Development.

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magnetic resonance technique called MRspectroscopy to measure several brainchemicals including N-acetylaspartate(NAA), which is found primarily insideneurons (nerve cells). The researchersdetected lower levels of NAA in the cere-bellum in alcoholics, compared to normalcontrols, suggesting the presence of dam-aged or dying neurons.

The cerebellum, located at the base ofthe skull, controls muscle tone, balanceand fine movement coordination. It alsotransmits signals to the prefrontal cortexbehind the eyes, which plays key roles inworking memory and judgment, as well asemotion, arousal and attention.

Levels of NAA were lowest – indicatingthe greatest amount of neuron damage –in the cerebella of patients who had start-ed drinking heavily at an earlier age andwho had a family history of alcoholism.These patients also relapsed earlier after aperiod of abstinence than did alcoholicswith higher NAA levels, the researchersreported in 2002.

“It’s almost as if their brains weremore sensitive to developing brain injury,”concludes Martin. “In the future, we maybe able to do spectroscopy and predictwhich patients will do well and whichones will not.”

Imaging technologies such as fMRInot only can record damage done by drugs;they are shedding light on the processes in

the brain – including reward, motivation,memory and craving – that can lead to andmaintain addictive behavior.

Functional MRI measures the magneticproperties of hemoglobin, the iron-bearingoxygen transporter in red blood cells.Activation of part of the brain increases thedemand for oxygen, and thus the intensityof the magnetic signal.

Ronald L. Cowan, M.D., Ph.D., anassistant professor of Psychiatry, and ofRadiology and Radiological Sciences atVanderbilt, is using fMRI to study how brainactivation changes over time in response toamphetamine, a powerful stimulant.

By taking a series of images, he hopesto “picture” different stages of drug-takingbehavior – from the anticipation of gettingthe drug, through the experience of eupho-ria, or the “high,” and as the effect of thedrug wears off.

“We have little idea what … causes aperson to decide to engage in a rewardingactivity, be it eating, sex, gambling ordrugs,” Cowan explains. “We don’t knowwhat parts of the brain are involved in theinitiation of that activity.

“We’re hoping to find a part of thebrain early on that gets activated beforethe experience of euphoria, that actuallypredicts that it is going to happen,” hesays. “That might give us a target fortherapy, or at least for further study.” LENS

With fMRI, “you can actually see thatin the brain, in the circuits involved inreading,” Gore says. Sequential brain scansindicate that brain activity in these childrenactually “normalizes,” or begins to resembleactivity seen in children without dyslexia.

Gore, who came to Vanderbilt in2002, is now working with investigators atthe Kennedy Center to extend that work tochildren with math learning disabilities.

Researchers believe math disability –difficulty in solving math problems – maybe a different syndrome or have a differentcause than reading disabilities like dyslexia,says Lynn S. Fuchs, Ph.D., who, with herhusband, Doug Fuchs, Ph.D., has helpedpioneer the diagnosis and treatment oflearning disorders.

The Fuchses, who share the NicholasHobbs Chair in Special Education atVanderbilt, and Donald L. Compton, Ph.D.,assistant professor of Special Education, areusing fMRI to assess how brain functionchanges in response to an interventionaimed at improving math skills.

“The reason to do the scanning is …to understand how the brain is changingas math improves,” Gore explains. “Is itchanging in a way that makes it lookmore like a normal brain, or is it changingin a way that compensates for some kindof structural problem that really can’t bechanged with intervention?

“If you can actually train parts of thebrain to do the job the most efficient way,”he adds, “then that is the best thing to do.Imaging can identify optimal strategies.”

Predicting relapse and recoveryAddiction is another challenging

medical problem that is slowly revealingits secrets to brain imaging.

Through the use of PET and, morerecently, fMRI, scientists are beginning todefine – anatomically and biochemically –what drugs of abuse do to the brain.

“We’ve known for probably 30 years ormore that using drugs like alcohol for longperiods of time causes injury to the brain,”says Peter Martin, M.D., professor ofPsychiatry and Pharmacology and directorof the Division of Addiction Medicine inthe Department of Psychiatry at Vanderbilt.

In computed tomography (CT) scans,for example, “the brains of alcoholics seemto have shrunk compared to normal,” hesays. Yet images of the brain’s structuredon’t correlate well with impairmentsdetected in neuropsychological tests. So,in the early 1990s, “we started looking atwhat was happening chemically in thoseregions of the brain that shrink.”

Martin and his colleagues used a

Picturing the brain in a good moodFunctional magnetic resonance images show the brain of a study participant respondingto an oral dose of amphetamine. The drug can produce the experience of a “high” oreuphoria when taken in large doses. The images, of three different “sections” or views ofthe brain, detected changes in two different areas (top and bottom rows) over the courseof about 90 minutes when the participant reported “positive” emotions on a mood scale.The blue color indicates deactivation of one brain region, while the orange spot indicatesactivation of another. While more detailed analysis is required to determine which specificregions respond to amphetamine, imaging studies like this are providing clues to the rolesthat different areas of the brain play in drug-taking behavior.

Courtesy of Ronald L. Cowan, M.D., Ph.D., and his colleagues at Vanderbilt and theMcLean Hospital Brain Imaging Center in Belmont, Mass.

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Two pathsto thefutureNora Volkow’s revolutionaryapproach to addiction

By Bill Snyder

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Volkow, Ph.D. “It’s such a horrible enemy and sodifficult to beat. And that’s why I think she chosethis subject of study. Nora has never taken theeasy way in life, never.”

Volkow, 49, displays an intriguing amalgamof traits: athletic drive and stamina (the formercompetitive swimmer runs six miles every morningbefore work); an exuberant sense of wonder aboutthe world; and a knack for looking at sciencethrough the eyes of an artist (she paints, and herolder sister is Mexican poet Verónica Volkow).

Most importantly, she says, “I’m a scientist.I’ve always loved science. That’s how I see myself.”

So far in her career, Volkow has authored orcontributed to more than 300 scientific articles.Through groundbreaking imaging studies of thebrain’s frontal cortex and its dopamine-driven cir-cuitry, she has helped reveal the neurobiologicalunderpinnings of addiction, and how drug-inducedchanges in brain chemistry contribute to its hall-mark craving, compulsion and loss of control.

Two pathsAddiction is not the only area that has come

under Volkow’s sharp-eyed scrutiny.She and her Brookhaven colleagues also have

linked long-term use of anti-psychotic drugs tothe withdrawal and blunting of emotions seen inindividuals with schizophrenia; showed how ther-apeutic doses of Ritalin and other stimulants canimprove attention; and found evidence thatdopamine, a chemical messenger important indrug addiction, may also play a role in overeatingand obesity.

“She really is one of those people who thinkvery much into the future,” says former NIDAdirector Alan I. Leshner, Ph.D., CEO of theAmerican Association for the Advancement ofScience. “She’s always, in her own research, beenleading the cutting edge … She has brought that toNIDA as well. That’s exactly where it ought to be.”

While she firmly believes in the diseasemodel, Volkow is quick to point out that addictionis not simply the result of particular genes andbrain chemicals. “Predisposition is not predetermi-nation,” she told a congressional subcommittee lastApril. “Environment and other biological factors,including family, culture and community, are of

Using an imaging technique called PET, NoraVolkow, M.D., and her colleagues at the Universityof Texas in Houston documented areas of “deranged”cerebral blood flow resembling tiny strokes inpeople who took copious amounts of the drug.

Cocaine was known to constrict blood vessels.Heavy use of the drug had been linked to fatalheart attacks and strokes. Yet their findings atfirst were greeted with skepticism.

Then in 1986, University of Maryland bas-ketball star Len Bias collapsed and died of acocaine overdose, and the tide began to turn.“When you go against the current, it takes timeto change its course,” says Volkow, now director ofthe National Institute on Drug Abuse (NIDA).

Just as she once helped dislodge widely heldnotions about cocaine, today this strong-mindedscientist is determined to transform the way addictsare treated – or, more often, not treated – by themedical profession and the criminal justice system.

While she sees this a part of her duty as aphysician, to serve the most vulnerable membersof society, Volkow also acknowledges the world-changing legacy of her great-grandfather, exiledRussian revolutionary Leon Trotsky.

“It’s not religious; it’s just a sense of humanity,a sense of being part of humankind,” she says, herwords wrapped in the melodic tones of her nativeMexico. “You are alive, you have a certain talent,and you have a responsibility to use it to help others.”

“This is the smartest person I know,” saysJoanna Fowler, Ph.D., senior chemist at BrookhavenNational Laboratory in Upton, N.Y., who hasworked with Volkow since the mid-1980s. “Peoplejust glom onto her. She’s like pouring out ideas allday … She can take a problem and very easily seethrough it; see relationships, simplify things.”

At the same time, says Fowler, “she’s a verycompassionate person ... very much involved inthe social impacts of drug abuse.

“Drug addiction impacts enormously even onthings that you wouldn’t normally think of, likecancer in cigarette smoking, like heart disease,like violence with alcoholics, and accidents andAIDS,” she says. “I think we’re very fortunate tohave a person like Nora.”

“I see her as a warrior fighting against a uni-versal enemy,” adds her younger sister, Natalia

Cocaine was considered to be a “safe”party drug in the high-flying ’80s when ayoung psychiatrist decided to see what itdid to the brain.

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great importance to the development ofaddiction and are essential to its prevention.”

Drugs aren’t the only way to treataddiction. Imaging studies can validatethe effectiveness of cognitive and behav-ioral therapies, as well. Potentially theymay help identify social interventions thatprotect young people from abusing drugsin the first place.

“I always take two paths,” Volkowexplains, “one path that is going to leadus to the science and the knowledge thatwill really revolutionize the way that wetreat drug addiction, so that five or 10years from now we will be treating drugaddiction completely differently.

“But at the same time, developingstrategies that can benefit those that areafflicted by addiction, or interventionsthat can prevent the use of drugs. Weneed to get science that looks into thefuture … but we also need to address theneeds right now.”

Volkow’s path started in the housewhere her great-grandfather was murdered.

Born Lev Davidovich Bronstein,Trotsky was a brilliant political theoristand proponent of permanent worldwiderevolution by the working class. Founderof the Red Army, he was second only toVladimir Lenin during the early years ofBolshevik rule. After Lenin’s death in1924, Trotsky was expelled from theSoviet Union when Joseph Stalin tookcontrol of the government and launched apurge of his rivals.

Trotsky lived for a few years inTurkey, then in France and Norway beforeeventually finding refuge in Mexico City,where he continued to write books criticalof the Stalin regime. Family members whoremained in the Soviet Union wereimprisoned or shot. In 1940 – shortlyafter his grandson Esteban moved fromTurkey to join him – Trotsky was assassi-nated by one of Stalin’s agents.

Esteban Volkov Bronstein became achemist and married Palmira Fernández, afashion designer from Madrid who hadfled the Spanish Civil War. They had fourdaughters, and continued to live inTrotsky’s carefully preserved house (it isnow a museum).

Volkov’s daughters, who end theirlast name with a “W” instead of theRussian “V,” gradually heard details oftheir great-grandfather’s story – but notfrom their father. “It was a very, verypainful period, so he couldn’t really speakabout it,” Nora explains.

They learned from the constantstream of visitors who knocked onTrotsky’s door.

Pictured here, from top: Nora as ateenager; with her mother in 1980;standing (right) with her sister Nataliaon the peak of Popocatépetl (the high-est active volcano in the NorthernHemisphere), southeast of Mexico City;and with her father. Esteban Volkovsays he and his wife, who died in1997, tried to nurture in their daugh-ters an appreciation of the artisticand intellectual life - and freedom ofexpression. "I established an absolutetrue democracy in the family," he says."There was no imposition. Each onecould choose the career that shewould like." Natalia earned a doctoratein information systems from the LondonSchool of Economics, and is a deputydirector general of Mexico's NationalInstitute of Statistics, Geography andInformatics. Her identical twin, Patricia,is a doctor and expert on AIDS.

Photos courtesy of Nora and NataliaVolkow

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images revealed decreased brain activity inthe frontal cortex of patients who had beentaking anti-psychotic drugs like Thorazinefor long periods of time. “The greater thedecrease in brain activity, the greater the‘poverty of thinking,’” Volkow says.

Anti-psychotic drugs like Thorazinewere known to block the receptors fordopamine, a neurotransmitter that conveyssignals between the frontal cortex and otherparts of the brain. The frontal cortex, inturn, is involved in a host of cognitive and“executive” functions, from language andmemory to impulse control and the abilityto solve problems.

While the researchers were unable todetermine how much of the withdrawaland blunting of emotions observed in thepatients was due to the drugs, and howmuch to their disease, the study was oneof the first to open up the frontal cortexthrough the window of PET.

After completing her residency in1984, Volkow moved to the University ofTexas in Houston to continue her researchat a PET research center founded by cardi-

“As little girls, whenever somebodyrang the bell and asked us to guide themthrough the house, we did so, and that wasa privilege,” recalls Natalia. “We usuallytook a long time talking to them – listen-ing to them.”

On one occasion, a group of visitorsfrom South America took the tour, andafterwards Nora got into a lengthy conver-sation about One Hundred Years of Solitude,which she was reading. Later she learnedthat one of the men with whom she hadbeen talking all afternoon was the book’sauthor, Gabriel García Márquez.

The living brain“She was a great reader of all kinds of

books,” recalls her father, now 79. At thesame time, “Nora always was a very warmand sweet person. She always showed agreat love and passion for animals.”

Volkov is not in the least surprised atthe meteoric rise of his middle daughter’scareer. “Nora has a very basic principle,”he says. “She always had a very, very greatrespect for the truth.”

Fluent in four languages (includingFrench and German), Volkow received herundergraduate and medical school trainingat the National Autonomous University of Mexico in Mexico City, where she was recognized as the best student of herundergraduate and medical school classes.

In 1981, after receiving her medicaldegree, she read an article in ScientificAmerican about a new imaging technologycalled positron emission tomography (PET).She was mesmerized by the splotchy, bril-liantly colored images of the living brain. Inan instant, the direction of her life changed.

Instead of applying for postgraduatestudy at the Massachusetts Institute ofTechnology, Volkow opted for residencytraining in psychiatry at New YorkUniversity and the chance to work – in acollaborative research program –with thePET pioneers at Brookhaven, a Departmentof Energy-operated laboratory near the farend of Long Island.

Five years earlier, a Brookhaven teamled by Fowler and Alfred P. Wolf, Ph.D.,had produced a radiotracer for glucose, the brain’s primary fuel. Colleagues at theUniversity of Pennsylvania used it to createthe first images of the living human brain.The intensity of the color on the PET scanreflected the concentration of 18F-fluo-rodeoxyglucose (FDG), and thus where thebrain was active.

By the early 1980s, the Brookhaventeam – bolstered by an energetic psychiatryresident – was using PET to study thebrains of people with schizophrenia. Their

ologist K. Lance Gould, M.D. Here herpath turned again.

The university hospital had no patientswith schizophrenia to study, Volkowrecalls, but there were plenty of cocaineaddicts. So, with the help of addictionspecialist Kenneth Krajewski, M.D., andphysicists Nizar Mullani, Ph.D., andStephen Adler, Ph.D., Volkow conductedthe first PET studies of the brains ofcocaine addicts.

At first, she says, no one believed theimages of deranged blood flow, suggestiveof stroke. It would be 1988 – three yearslater – before their findings were pub-lished by the British Journal of Psychiatry.

By then, Volkow and Adler had marriedand had accepted positions at Brookhaven.

Volkow, who also joined the facultyin psychiatry at the State University ofNew York at Stony Brook, says she wastempted back by Wolf’s offer to labelcocaine for her. “That was extraordinary,”she says, “because it actually opened upthe first study to be able to look at thedynamics of these drugs in the brain.”

Pictured here: Volkow administers a contrastagent prior to a PET study in 1990. In thebackground are research nurse Noel Netusil,R.N., (left) and technician Renee Modell, now a nuclear medicine physician.

Courtesy of Brookhaven National Laboratory

“We’re doing a disfavor to the well-being … of patients … by not addressingthe problem of addiction.”

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director of the Office of Science &Technology Policy.

“I asked her to be the AssociateDirector for Life Sciences at Brookhavenbecause I thought her dynamic style andclear vision for the work that could bedone there would bring focus and energyto the division,” he says. “I think it pre-pared her well for her current position.”

Wolf died in 1998, but Volkow’sextraordinary partnership with Fowler andthe other Brookhaven scientists continuedto churn new scientific ground.

“It’s a very unusual relationship,”Fowler says. “We’re personally very closeand also scientifically close, and we talkall the time … Every time I read some-thing interesting, and the same with her,we call and we talk about it.”

As Volkow’s perspective on addictionwas broadening, so too were her opportuni-ties. In the fall of 2002, Elias A. Zerhouni,M.D., director of the National Institutes ofHealth, asked her to lead NIDA, whichfunds the bulk of research conductednationally (and internationally) on thehealth aspects of drug abuse and addiction.

Volkow, the scientist, wanted to con-tinue her research. Volkow, the visionary,saw an opportunity to apply that researchto improve the lives of people. Armedwith Zerhouni’s promise that she couldcontinue her research (she spends a longweekend every month at Brookhaven), inApril 2003 she became the fifth personand first woman to direct the 30-year-oldinstitute, which now has an annual budgetof more than $1 billion.

Championing scienceAs a leader, Volkow is more revolu-

tionary than bureaucrat. Her agenda isdiverse and far-ranging, but its central themeis making connections – uniting physiciansand pharmaceutical companies, drug

Making connectionsSoon Volkow and her colleagues, who

frequently included Wolf and Fowler,were labeling all sorts of things: D2, areceptor through which dopamine sendsits signals; monoamine oxidase, an enzymethat breaks down dopamine; andmethylphenidate (Ritalin), which waslabeled by Yu-Shin Ding, Ph.D.

In 1993, the Brookhaven groupreported that cocaine abusers had lowerlevels of the dopamine D2 receptor com-pared to normal controls. Reductions inreceptor levels were associated withdecreased metabolism, as measured byglucose consumption, particularly in theorbitofrontal cortex and cingulate gyrus.

The cingulate gyrus, a ridge of tissuedeep in the brain, is part of the limbic sys-tem, associated with mood and emotions.What was surprising was the connection tothe orbitofrontal cortex, located just abovethe eyes, the same area that functionsabnormally in patients with obsessive-compulsive disorder and that is believed tounderlie their compulsive behaviors.

“We always thought of drug addictionas a disease of the primitive parts of ourbrain, the limbic parts … the pleasurecenters,” Volkow said in a 2002 lecture.“And here, the frontal cortex, which epito-mizes the higher levels of our ‘reasoning’human brain, appears to be involved.”

During the next few years, theBrookhaven scientists documentedreduced levels of dopamine D2 receptorsin the brains of alcoholics, heroin abusersand methamphetamine addicts. In addition,they found methamphetamine causedinflammatory changes in the brain thatwere associated with loss of memory,attention and motor skills.

In 2001, the Brookhaven group, led byGene-Jack Wang, M.D., reported thatobese people – like those addicted to

alcohol, cocaine or methamphetamine –have lower-than-normal levels ofdopamine D2 receptors.

“Individuals with low numbers of D2receptors may be more vulnerable toaddictive behaviors including compulsivefood intake,” the researchers concluded.“We speculate that … decrements in D2receptors perpetuate pathological eating asa means to compensate for the decreasedactivation of reward circuits, which aremodulated by dopamine.”

Just because a person is vulnerable,however, doesn’t necessarily mean he or shewill become addicted. Exercise, for example,has been shown to increase the level of D2receptors and dopamine release in rats.

Volkow believes it may be possible toidentify protective factors in humans, par-ticularly in the age group most vulnerableto drug addiction – the adolescent.

“Very much the initiation of experi-menting with drugs occurs in social settings,in group settings, in adolescents that wantto actually be part of groups,” she says.“It’s a very important area of research todevelop, so we can better understand theneeds of kids and come up with strategiesto overcome situations where this responseis going to be elicited.”

Volkow became a U.S. citizen in 1993.While her group published their findingsprolifically, she rose through Brookhaven’sadministrative ranks: director of theNuclear Medicine Program (1994); chairof the Medical Department (1996); firstdirector of the NIDA RegionalNeuroimaging Center (1997); and thefirst woman to serve as AssociateLaboratory Director for Life Sciences (1999).

“Nora is a dynamic, creative personwith a broad vision of her field and a pas-sion for science,” says former Brookhavendirector John H. Marburger III, Ph.D.,Science Advisor to the President and

Obesity and the brainPET scans taken at Brookhaven National Laboratory suggest that the brains ofobese individuals have fewer dopamine D2 receptors than do brains of normal con-trols. A radiolabeled compound (raclopride) that binds to the receptors was used todetermine receptor concentration. Red spots in an averaged image of the controlbrains (top left) indicate a greater concentration of raclopride, and thus more D2receptors, than are present in an averaged image of the obese group (top right).Overall brain metabolism, measured by the concentration of FDG, a radiotracer forglucose, did not differ significantly between the two groups (bottom panel). Sincedopamine modulates motivation and reward circuits, the researchers concludedthat dopamine deficiency in obese individuals may perpetuate pathological eatingas a means to compensate for decreased activation of these circuits.

Reprinted from The Lancet, Vol. 357, Wang GJ, et. al., “Brain dopamine and obesity,”pages 354-357, © 2001, with permission from Elsevier.

ComparisonSubjects

ObeseSubjects

raclopride

FDG

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drugs that may interrupt the conditionedresponses reinforcing compulsive drug-tak-ing behavior as well as compulsive eating.

Brain imaging also could be used tomeasure the effectiveness of non-drugtreatments. Since chronic drug abuseweakens the reward and motivation cir-cuitry of the brain so that it only respondsto more drug, it may be possible to “exer-cise” the brain in a way that increases theresponse to normal reinforcing stimuli andreduces the likelihood of relapse.

Yet Volkow agrees with Schroeder:“We have information we’re not using.”

“Drugs permeate the medical system,”she says. “We’re doing a disfavor to thewell-being of a wide variety of patients –whether they have lung disease, whetherthey have cancer, whether they have men-tal illness, whether they have an infectiousdisease – by not addressing the problem ofaddiction.” LENS

courts and community groups to improvethe treatment and prevention of addiction.

Among her top priorities: under-standing the interactions between drugabuse, mental illness and AIDS.

Experimenting with drugs oftenbegins during the novelty-seeking, peerpressured years of adolescence, and is amajor contributor to the continued rise inHIV/AIDS in the United States. Drug usecan lower resistance to risky behaviors likeunprotected sex or sharing needles.

Drug abuse complicates treatment ofother diseases, such as diabetes and cancer,yet addiction among patients with “co-morbid” conditions often is ignored,Volkow asserts. Limited access to drugtreatment also contributes to the dispro-portional impact of AIDS and incarcerationon minority groups.

African-Americans make up only 13percent of the U.S. population, yetaccount for half of all HIV infections andmore than 40 percent of jail and prisoninmates. “These numbers,” she says, “areunacceptably high, embarrassingly high.”

Volkow’s blunt approach has been a“breath of fresh air” to retired Judge KarenFreeman-Wilson, CEO of the NationalAssociation of Drug Court Professionals.According to association statistics, treatmentof drug-addicted criminal offenders canreduce by at least half the rate of recidi-vism – the relapse to criminal behavior.

“She has been a tremendous help tous to really educate people on the scienceof addiction … but more importantly, thescience of treatment,” explains Freeman-Wilson, a former Indiana attorney generalwho established that state’s first drugcourt in 1996.

During Volkow’s presentations, “I can see the lightbulbs going on in theheads of judges who obviously operate onevidence,” she continues. “With thatinformation, people have been able to say,‘Well, maybe this isn’t just a bad person.Maybe this is a bad disease. And maybewe have to look at it and address it in atotally different way.’”

While many find Volkow’s frank

speech refreshing, former Robert WoodJohnson Foundation President and CEOSteven A. Schroeder, M.D., wishes she andothers in government would advocatemore forcefully for treatment programsand policies – such as methadone andsmoking cessation programs – that arealready known to work.

“Unless I’m missing it … there is nofederal champion for that. And that’s ashame. It’s a missed opportunity to makeour country healthier,” says Schroeder,who directs the Smoking CessationLeadership Center at the University ofCalifornia at San Francisco.

Schroeder’s point is well taken,Leshner responds, but Volkow’s responsi-bility is much broader than advocacy. “Sheactually does advocate,” he says, “but ...her job is to make sure that the science isas good as it can be and then to bring thescience to the attention of policy makers.”

Volkow believes that continuedresearch is the way to overcome many ofthe challenges to improving treatment ofaddiction. PET studies, for example, areaiding the development of anti-obesity

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Seeing the shimmer of biology in actionCREATURES THAT GLOW LEND THEIR PROTEINS TO BIOMEDICAL RESEARCH

By Leigh MacMillan

F I E L D O F F I R E F L I E S N E A R N E W L O N D O N , C O N N .C O U R T E S Y O F J A M E S E . L L O Y D , P H . D . , U N I V E R S I T Y O F F L O R I D A

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by Leigh MacMillan

It’s a scene that says sum-mertime – sparks of light in the gloaming andchildren darting after them, Mason jars at theready. The captured fireflies might be releasedor they might be tortured. They are sure to beadmired.

The glow of fireflies – called lightning bugs in some regions of the country – isa source of wonder to children and adults alike. Over the past decade, scientists havediscovered how to harness this biological glow, called bioluminescence, to revealsecrets from inside living animals. The chemical reaction that produces light can beused to follow cancer cell metastasis, stem cell migration, gene expression, and pro-tein activity, all as they are happening in vivo.

Bioluminescence imaging is part of the burgeoning field of molecular imaging,which aims to “see” not just anatomy, but specific molecular or cellular processes,says Sanjiv Sam Gambhir, M.D., Ph.D., director of the Molecular Imaging Programat Stanford University.

“The goal is to do this as non-invasively as possible so that one can interrogate aliving subject repeatedly over time,” Gambhir says. “Ultimately, we want to funda-mentally change the way in which we diagnose and manage disease by really lookingat molecular information.”

Let there be lightFireflies are not alone in their ability to generate light – marine organisms

including jellyfish, sea pansies and squid, along with various worms, fungi and bac-teria all possess the biochemistry to shine. They glow to signal interest in courtshipand mating, lure prey, defend, camouflage, and respond to stress.

Light production depends on the presence of a protein enzyme called aluciferase, from the Latin “lucem ferre” – bringer, or bearer of light. The luciferaseperforms a biochemical reaction on its substrate – luciferin for the firefly protein –usually requiring energy, oxygen and other co-factors, with the end products includingthe release of a single photon of light.

Of the wide variety of luciferases, the protein from the firefly has been mostcommonly used in biological research. It was first purified and characterized 30 yearsago, and it gained widespread exposure as an “optical reporter gene” for cells in cul-ture beginning in the late 1980s.

Such luciferase assays to study gene regulation in cultured cells were in full swingwhen Christopher H. Contag, Ph.D., got frustrated with the methods for studyinginfectious diseases. Contag, a virologist by training, was following mother-to-infant

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transmission of HIV by comparing viralgenetic sequences.

“It turned out to be a very complicatedanalysis, and I said at the time, ‘wouldn’tthis be so much easier if we could justwatch the whole process?’” recalls Contag,now co-director of the Molecular ImagingProgram at Stanford. “It occurred to usthat we should be developing tools forwatching complex biological processes inthe context of living animals, and at somepoint in time, living humans.”

A search of the available imagingmodalities and a fortuitously timed lectureby an environmental microbiologist aboutluminescent bacterial enzymes pointedContag and his wife Pamela R. Contag,Ph.D., in the direction of bioluminescence.

“We figured that since animals andpeople don’t glow in the dark, if you putsomething in the body that does glow inthe dark, you should get great signal-to-noise ratios since there should be relative-ly no background noise,” Contag says. Wenow know there are background signals –

from biological processes in animals that produce small amounts of light –but for bioluminescence imaging, henotes, “the signal-to-noise ratio is reallyextraordinary.”

For their first studies, the Contagsand their colleagues followed biolumines-cent bacteria in a mouse.

“When we saw the first images ofglowing bacteria in the intestines of amouse, I said, ‘Every biology lab in theworld will want to use this; this will be fan-tastic,’” Contag recalls. The team publishedits findings in 1995, and Contag anticipat-ed that use of the technology “wouldexplode.” It took a little longer than heexpected, with adoption by many laborato-ries occurring only in the last five years.

To propel what they saw as a power-ful technology, the Contags and David A.Baneron, M.D., founded a company calledXenogen to market the technology, alongwith unique instrumentation and biologi-cal reagents that utilize luminescent signalsfor studying biology in animals. Pamela

Contag has served as president of Xenogensince the company’s inception in 1995.

Christopher Contag remained atStanford. “I decided to take a very broadapproach and demonstrate the breadth ofthis technology,” he says. “So we’ve beentracking viruses and tumor cells and stemcells, and in the early days attempted toshow how versatile this technology is.Now we’re focusing on stem cells and cancer biology.”

Lightbulbs inside cellsInvestigators at Vanderbilt embraced

bioluminescence imaging early on to fol-low cells and gene expression in livinganimals. Watching cells as they migratethrough a living animal, take up residence,multiply, and in the case of tumor cells,metastasize to new sites, has been themost popular application of biolumines-cence to date.

“What bioluminescence gives you is a level of sensitivity of detection that is not attainable by any other currentmethod,” says E. Duco Jansen, Ph.D.,associate professor of BiomedicalEngineering at Vanderbilt.

The way it works is conceptuallyquite simple, Jansen explains. Cells of anysort can be infected with viruses or engi-neered to incorporate a luciferase gene.After being injected into small animals,usually mice, the cells begin to produce theluciferase protein. Investigators then injectthe substrate molecule – such as luciferin –into the animals, and the luciferase acts onit, releasing photons of light.

“So we have effectively a lightbulbinside the cell,” Jansen says.

That lightbulb is really quite weak –the mice do not actually glow like fireflies.But some of the photons of light do maketheir way out of the animal, and sophisti-cated charge couple device (CCD) cameras,cooled with liquid nitrogen to minimizenoise, can capture them. Imaging systemssuch as those produced by Xenogen, whichare available to Vanderbilt scientists via thenew Institute of Imaging Science, makethe process relatively straightforward. The

“The greatest contribution to human medi-cine that probably all molecular imagingapproaches, including bioluminescence, willhave is in refining and accelerating our ani-mal models of disease, such that we cantest and develop drugs more efficiently.”

Christopher H. Contag, Ph.D., co-director of the Molecular Imaging Programat Stanford University

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systems manage everything from adminis-tration of the inhaled anesthetic to quanti-tation of the detected light.

Tumor cells were the early front-run-ners in the “cells-to-watch” category.

“It’s a pretty well-established paradigmnow to incorporate a luciferase into atumor cell line, implant those modifiedcells into animals, and then monitor theluciferase activity to find where the tumorcells become established and to follow thegrowth of the tumor,” says J. OliverMcIntyre, Ph.D., research professor ofCancer Biology at Vanderbilt.

And because of the high sensitivity ofbioluminescence, the very early stages oftumorigenesis and of metastasis are openfor study.

“Bioluminescence imaging lets usdetect very small numbers of cells – in thehundreds – from the internal organs of asmall animal,” says P. Charles Lin, Ph.D.,associate professor of Radiation Oncologyat Vanderbilt. “There is no other wayright now to detect those cells.”

Watching tumor growth and metasta-sis in real time gives investigators a windowto a tumor’s molecular environment and toits susceptibility to therapeutic interven-tions. McIntyre, who works with Lynn M.Matrisian, Ph.D., professor and chair ofCancer Biology at Vanderbilt, describeshow the group has used bioluminescence tostudy the effect of an enzyme called MMP-

9, which “chews up” the matrix materialbetween cells, on tumor growth.

Heath Acuff, Ph.D., at the time agraduate student in the group, comparedthe establishment of lung tumors in micewith and without MMP-9. Luciferase-expressing tumor cells were injected intothe tail vein of mice; they then homed tothe lung and grew, and the investigatorsfollowed their growth by looking at thelight being produced.

Mice lacking MMP-9 had fewertumors at the end of the study, and by following the mice over time, the investi-gators knew this difference occurred veryearly, within the first 24 hours.

“The imaging really provides this tem-poral information from individual animalsor groups of animals that is not so easy toobtain by other methods,” McIntyre says.

Shining light on diabetes The high sensitivity of biolumines-

cence imaging was just what Alvin C.Powers, M.D., professor of Medicine atVanderbilt, needed to track his favoritecells – those that populate pancreatic islets.Islets – so-named because they appear tobe small cellular “islands” within the pan-creas – are home to the insulin-producingbeta cells and several other hormone-releasing cell types.

Islet transplantation is an emergingexperimental therapy for type 1 diabetes

and has shown promise in multiple smallclinical trials. One difficulty in movingthe field forward, Powers explains, is thatinvestigators have no way to follow theislets after transplantation.

“We really need a way to assess wherethe islets go after transplantation, howmany survive, (and) what kinds of thera-pies promote islet survival,” Powers says.

In collaboration with Jansen, Powersand colleagues have “tagged” islets withluciferase. They have used primarily astrategy of infection: first the investigatorsharvest islets, both from mice and humans,then they infect the islets with a virus carrying the luciferase gene. A certain per-centage of the islet cells incorporate theluciferase, and after transplantation into amouse the surviving cells can be followedwith bioluminescence imaging.

The team is also beginning to useislets from genetically modified mice thathave luciferase in all of the beta cells ofthe islet. These light-emitting islets offerthe advantage that all cells permanentlyexpress the luciferase.

In both models, the investigators areattempting to optimize transplantationparameters, Powers says. What is the bestsite for survival? Which growth factorsbest promote survival? Is it best to treatthe islets with growth factors before trans-plantation, to treat the animals after trans-plantation, or both?

“Bioluminescence is really the onlyway to non-invasively assess these isletsover time,” Jansen says. He notes that itwould be possible to sacrifice animals toget single time-point snapshots, but thatmethodology would require a very largenumber of animals and retain the problemof biological variation between individuals.Non-invasive imaging of any sort, in the

New software is improving the spatial resolution of bioluminescence imaging. Inthese test images, a luminescent bead has been implanted inside a siliconmouse model. On the left, a “standard” planar bioluminescence image showslight scattered as it moves through the model mouse. The image on the rightshows the result of bioluminescence tomography using Xenogen’s Living ImageSoftware 3D Analysis Package. The red pixel indicates the reconstructed lightsource location.

Courtesy of Jack Virostko, graduate student in the lab of E. Duco Jansen, Ph.D.

Human pancreatic islets glow after infection with a virus carrying thefirefly’s light-producing luciferase gene. Number of islets in each well:(top row, from left) 0, 1,000, 50; (bottom row) 100, 500, 1,000. The1,000 islets in the middle well of the top row were not infected, do notproduce the luciferase enzyme, and therefore do not emit light.

Image courtesy of Alvin C. Powers, M.D.

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same animal over time, gives the best sta-tistical results by avoiding interindividualvariability, he says.

And as with the luminescent tumorcells, the glowing islets offer a model sys-tem for evaluating new pharmaceuticalinterventions. Suppose, Jansen says, that adrug company has a new immunosuppres-sant drug candidate. That company canuse the transplanted islet model and bio-luminescence imaging to quickly assessthe drug candidate’s efficacy.

“Being able to screen compounds inlive animals, with a relatively highthroughput readout, is critical for pharma-ceutical companies,” Jansen says. “If adrug candidate can be eliminated from the pipeline earlier because of in vivomolecular imaging, that translates intohuge cost savings. And likewise, if a candidate can make it to the market sooner, that means millions of dollars ofadded revenue. Drug companies are veryinterested in these small animal in vivomolecular imaging approaches.”

Blaze of inflammationBioluminescence imaging changed the

way Timothy S. Blackwell, M.D., associateprofessor of Medicine at Vanderbilt, thinksabout lung inflammation and injury. Inaddition to tracking cells and bacterialpathogens, Blackwell’s group has been following gene expression in the contextof inflammation.

To do this, the team engineered a“transgenic” mouse that contains the fireflyluciferase gene, linked to a stretch of DNAthat responds to a transcription factor – aprotein that controls the expression of othergenes – called NF-kappa-B. When NF-kappa-B is active in cells, it turns on theproduction of luciferase and the cells light

up. NF-kappa-B is an important mediatorof inflammatory processes.

In some of their first studies with thesetransgenic reporter mice, the investigatorsstudied short-term versus long-term infu-sions of endotoxin, “with the idea of tryingto figure out the parameters of inflammatorysignaling that lead to lung injury – was itdose, timing, duration, cellular distribu-tion – those sorts of things,” Blackwell says.

The bioluminescence imaging revealedthat the duration of the inflammatorystimulus affected the final outcome, he says.A single bolus injection of endotoxin causeda peak of NF-kappa-B activation, as meas-ured by light output, but no lung injury.The same dose of endotoxin given as aninfusion over 24 hours caused a progressiveand sustained activation of NF-kappa-B inthe lung, and resulted in lung injury.

“That was something that would havebeen very time consuming to try to figureout without the use of bioluminescence,”Blackwell says, “and it has led us to otherstudies now trying to understand whichcells are activated over this period of timeand identify specific injury-provokinggene products.

“The ability to look non-invasively at NF-kappa-B activity over time in a rel-atively quantitative way is helping us todefine the balance of factors that causeeither lung injury or effective hostdefense against infection,” Blackwell says.“Ultimately we might be able to come upwith ways to prevent injury and stillmaintain adequate defenses.”

These inflammation-reporting micehave been useful for Vanderbilt’s Lin aswell. Lin is interested in blood vessel for-mation – angiogenesis – in the context ofdiseases including cancer, arthritis andcardiovascular disease.

In the case of arthritis, inflammationappears to trigger excessive angiogenesis,which facilitates tissue growth and even-tually causes bone damage, Lin explains.Anti-angiogenic therapies may be effectivein preventing the tissue growth. Lin’sgroup is using multiple imaging technolo-gies – an increasingly common approachknown as multi-modality imaging – toprobe the arthritic joint: bioluminescenceto see the inflammation, X-ray to look atbone damage, and fluorescence techniquesto visualize the blood vessels.

“We think this is a very powerful wayto study how the blood vessel affects diseaseprogression as well as what kind of therapywe can use to stop this process,” Lin says.“Imaging has really moved from traditionalmodes of looking at structure into func-tional imaging, from static into kinetic.We’re no longer satisfied looking at singlepoint snapshots of dynamic processes.”

A cornerstone technologyWhile bioluminescence imaging offers

excellent sensitivity for tracking cells andseeing gene expression in living animals,it suffers from poor spatial resolution.Because light is absorbed and scattered bytissues as it makes its way out of the ani-mal, images become “fuzzy.” Jansen likensit to having a pencil in a glass of waterand adding a few drops of milk – you canstill make out an image, but it’s no longerclear that it’s a pencil.

“All of the imaging modalities havestrengths, and they all have weaknesses,”Jansen says. “Bioluminescence is great atsensitivity, but it’s lousy at resolution. So inmany cases we combine it with somethinglike CT or MR, or even fluorescence.”

There are current attempts to improvethe spatial resolution of bioluminescenceimaging by collecting data at differentwavelengths of light, taking a surface mapof the animal and then computing thethree-dimensional source distribution,Jansen says. Other attempts include usinga rotating stage to image the animal fromdifferent planes.

“Being able to image the biologicalevent is critical in studies of drugdevelopment. The advantage hereis that bioluminescence imagingcan be done in vivo and repeatedlyin the same animal, which getsyou better data.”

E. Duco Jansen, Ph.D., associateprofessor of Biomedical Engineeringat Vanderbilt

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Absorption of light by tissues posesanother problem for bioluminescence.Although it is a very useful imaging technique for small animals, where it hasto travel only a short distance to reach the surface, it’s not likely to translate tohumans except in niche areas. One of thoseareas could be encapsulated cell therapies –therapeutic cells, like glucose-sensing,insulin-producing beta cells that are “con-tained” within a membrane of some sortand implanted just under the skin.

“Developing encapsulated cell thera-pies will be greatly enhanced by buildinginto those cells markers that tell us if thecells are alive and doing what they’re sup-posed to be doing,” says Stanford’s Contag.“Since the cells would be under the skin,bioluminescence imaging should work. Ithink that’s a perfect scenario for its firstclinical application.”

Another place bioluminescence imag-ing might find clinical use is in breastcancer detection, Contag says. Proteinstagged with luminescent markers wouldhave the advantage of great signal to noisefor detecting very small numbers of cells.

“The question is, is it going to bebetter than anything else out there, andwe won’t really know until someone triesit,” Contag says.

Whether or not bioluminescenceimaging makes it to the clinic, “my guessis that optical imaging in small animalswill become the mainstay for many labora-tories using animal models,” Contag says,“and bioluminescence will be one of thecornerstone technologies for developingnew ways to treat disease and to visualizebiology as it occurs in the living body.”

That’s bright stuff for those flashingsummertime lights. LENS

A bone fracture appears tobe a relatively simple medicalproblem to solve: cast it, wait,and everything will be fine. Forabout 10 percent of fracturepatients though, healing doesn’tcome easily. These patients,600,000 people every year inthe United States, requirebone grafts or synthetic pros-theses to mend their breaks.

Anna Spagnoli, M.D., assis-tant professor of Pediatricsand Cancer Biology, has anoth-er idea. She wants to usestem cells, harvested from apatient’s bone marrow, to aidfracture healing.

“As a pediatrician, I amespecially interested in usingstem cells to treat childrenwith severe bone diseases likeosteogenesis imperfecta,” agenetic disorder characterizedby bones that break easily,Spagnoli says.

Investigators have known for30 years that bone marrowcontains two types of stemcells – the better known varietythat repopulates the blood andanother sort called mesenchy-mal stem cells that canbecome bones, cartilage, mus-cle, and even neurons, sheexplains. The potential ofthese cells to form cartilage isof particular importance forfracture healing, since carti-lage grows as a “template” fornew bone growth.

Spagnoli and colleaguesturned to bioluminescenceimaging to track mesenchymalstem cells in a mouse fracturemodel. They watched as thecells migrated through the ani-mal and homed to the injuredsite after three days.

“This was an extremelyimportant observation becausehoming of mesenchymal stem

cells had never before beenclearly demonstrated,” Spagnolisays. Bioluminescence imaginghas also allowed the investiga-tors to quantitate the numberof cells that migrate to thefracture site, she says.

“What we want to do in thelong term is to engineer thesecells with growth factors thatpromote cartilage formationand fracture healing – to com-bine stem cell therapy withgene therapy,” Spagnoli says.

For mesenchymal and otherstem cells, the only way theresearch will eventually gener-ate therapies “is if we haveways to follow cells after they’reput into humans,” says SanjivSam Gambhir, M.D., Ph.D.,director of the MolecularImaging Program at StanfordUniversity. “If you label thesecells with a reporter gene,they’re permanently tagged –

bar-coded – for life. And wecan keep finding the status ofthese cells over time.”

Bioluminescence imaginglikely won’t be the strategy tofollow stem cells in humans,Gambhir says, but it is extreme-ly valuable as a starting pointfor small animal studies.

“The technologies that arehaving the most impact in bio-logical models right now arethe optical technologies –because of their relative easeof use and suitability for smallanimals,” Gambhir says.“Bioluminescence and fluores-cence are the main workhorsesfor solving certain problemsbefore moving to the morecomplex technologies.”

– LE IGH MACMILLAN

Firefly’s glow reveals stem cell role in mending fractures

Fighting infection – the glow from within

Bioluminescence imaging reveals inflammation-related gene expression in mice infected withthe pathogen Pseudomonas aeruginosa. Theimages show increasing intensities of biolumi-nescence, from deep blue to bright white, inmice before injection of the pathogen (A), and24 hours after injection of increasing doses ofP. aeruginosa: (B), (C) and (D). Studies like thiscould lead to new treatments aimed at aug-menting the host defense, particularly in critical-ly ill patients.

From Sadikot RT, et. al., The Journal ofImmunology, 2004, 172:1801-1808. © 2004, American Association ofImmunologists, Inc.

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BRAVE NEW VISIONSThe promises and perils ofimaging the brain

Q & A

In separate interviews with Lens editor Bill Snyder,Richard Hargreaves, Ph.D., Vice President,Imaging at Merck Research Laboratories in WestPoint, Penn., and Judy Illes, Ph.D., Director ofthe Program in Neuroethics at the StanfordCenter for Biomedical Ethics in Palo Alto, Calif.,describe recent progress in the use of imagingtechnologies, their potential and challenges tofurther development of the field.

Hargreaves has a Ph.D. in physiology from King’sCollege London. At Merck since 1988, he led thebiology core for the discovery of Maxalt, an anti-migraine medication, and Emend, which helpsprevent chemotherapy-induced nausea and vomit-ing. Illes earned a doctorate in Hearing andSpeech Sciences from Stanford, specializing inexperimental neuropsychology. She has conductedresearch on human neuroimaging, language andcognition, and co-founded the Stanford BrainResearch Center in 1998

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Interview 1: Richard Hargreaves, Ph.D.

Imaging technologies are playing anincreasingly important role in drug discovery.

Radiotracer imaging such as positronemission tomography (PET) allows scientists tosee whether a molecule “engages” its target suf-ficiently to test for therapeutic efficacy. If themolecule doesn’t bind to its target, or saturatesthe target and yet fails the efficacy test, “thenwe can move on to a new therapeutic concept,”Hargreaves says.

In the early stages of drug discovery anddevelopment, imaging “actually increases theattrition in the number of molecules you test,”he says. “You actually throw more moleculesaway to get the best one.”

Can imaging reduce the cost ofdeveloping drugs?

Built into the cost of any drug are allthe failures of the molecules you test alongthe way. If earlier on you can select thebest development candidates, you improveyour chances of moving through thedevelopment process in a more informedand efficient way.

Remember, too, that making early“go/no-go” decisions also has ethical impli-cations for the human subjects who takepart in clinical trials, since fewer will beexposed to potentially ineffective therapies.

If you get it right, you’ll bring goodmedicines to the market faster.

Is imaging improving treatment?

In oncology, PET radiotracers can beused to assess different aspects of tumorphysiology, such as glucose metabolism,cell proliferation, angiogenesis (growth ofnew blood vessels), apoptosis (cell death)and oxygenation.

PET tracers exist for some of theseand are well embedded in clinical care. Anexample is 18F-fluorodeoxyglucose (FDG),which provides a measure of glucose metab-olism. Others, such as 18F-fluorodeoxy-L-thymidine (FLT), which may reflect cellproliferation, are still being validated.

The beauty of being able to trackaspects of tumor growth and viabilitymeans that you can see very early on afteradministering an experimental therapywhether it is impacting tumor physiologyin any way at all. If it is, then you have avery good reason to carry on and look fortumor regression.

In our oncology projects, we’re alsolooking for molecular imaging agents thatcan tell you whether people are likely to

respond to targeted therapies and howwell our drugs engage them.

I think that imaging truly has theopportunity to revolutionize and personal-ize care in oncology. We’re going to seethe fruits of that ripen in the near future.

How has imaging improved ourunderstanding of the brain?

Functional imaging has fundamentallychanged the way we can question brainsystems because we can see them in action.It has given whole new dimensions tomany areas of neuroscience such as pain,basic sensory systems, psychiatric disordersand their co-morbidity with other disordersof the central nervous system, cognition,language and neural mechanisms thatunderlie developmental plasticity andrecovery of function.

Imaging studies that help us under-stand neurodegenerative brain disease canalso help pave the way to better healthcare in the future.

At Merck, we have participated in theAlzheimer’s Disease NeuroimagingInitiative (ADNI), a collaborative consor-tium between industry, academia and theNational Institute on Aging. The goal isto validate imaging tools such as PET andmagnetic resonance imaging (MRI) andfluid biomarkers – alongside neuropsychi-atric scores – for tracking the progressionof Alzheimer’s disease in people currentlyon the best therapies available for thiscondition.

This is an important study because it will tell us what an aging Alzheimer’sdisease population looks like in NorthAmerica today. Once we have an under-standing of that, then we have a referencelibrary or baseline that we can use to eval-uate whether our new medicines producetrue improvements in clinical care bymodifying disease progression.

It would be brilliant if you couldprevent Alzheimer’s disease totally, butjust think of a therapy that delays itsonset by 10 years. That too would be aphenomenal achievement.

Can these collaborations overcomeconcerns about disclosure and conflicts of interest?

It’s in the interest of the patient, theNational Institutes of Health, the FDA,health care providers, and all of us in thepharmaceutical industry to move safe andeffective new medicines forward efficiently.

We will attempt internally to makeimaging agents that validate target engage-ment for our new therapies and have thedesired mechanistic effects. That’s propri-etary to drug discovery programs. Eventually,when appropriate, we will try to makethese agents available to all for research.

When we move into evaluating dis-ease and finding imaging endpoints thatchart progression, the story is somewhatdifferent. Here the imaging endpoints arevaluable to everybody trying to treat thatdisease – independent of the mechanismthey are using to do so.

In this case there is a very good casefor a consortia approach, which combinesthe efforts of interested pharmaceuticalcompanies with academia and perhaps alsodiagnostic companies. The goal: definingnew surrogates that speed drug assessmentand approval, particularly in areas wheremedical need is poorly met.

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I think the ADNI has the potential tobe a wonderful example of this approach.We’re going to set the “goal posts” forimaging biomarkers and the evaluation oftherapies in Alzheimer’s disease.

Will imaging increase the emphasison using drugs to treat disease, orwill it help validate behavioral/cognitive approaches as well?

I think the two go together. The industry spends its time making

highly selective pharmacological agents.But if you combine those together withthe amazing imaging of brain function,then you can understand the functional/chemical neuroanatomy of health and disease as well.

Functional brain imaging should helpyou design better therapies – be theypharmacological or non-pharmacological.Indeed, it’s already begun to help usunderstand what the placebo componentof responses really is, and to segregateresponders from non-responders in thefield of pain research.

If brain scans become a practical,reproducible method of predictingrisk for disease, what kind of ethicalissues will it raise?

Clinically, brain structural imaging isused to assess disease and to make treat-ment decisions based on prediction oflong-term sequelae. I think functionalbrain imaging has a way to go before itreaches this point.

One concern that has been raised aboutfunctional brain imaging in the past is thatwe may find things that are unexpected,or image things that may be predictive ofevents or behaviors for which we have nosolution or control. This is clearly an ethicalissue, and we need to think how to respondin advance.

Do you want to bury your head in thesand and not know, or do you want todevelop a strategy or set of rules that canhelp you deal ethically with the issues thatcould be raised as you strive, through imag-ing, to understand brain disease and providea platform for discovery of better therapies?

The bottom line for me is that manynew prognostic and diagnostic medicaltechnologies raise these types of issues.You need to think about them and plan

how to respond in advance, or reconsiderwhat you are doing. It’s not just sciencefor science’s sake.

Is there concern that the field isover-hyped?

It’s very visual and so it’s very power-ful. It tends to get jazzed up. Scientistsneed to be central in communicating whatthe functional MRI technique is.

What are its limitations? What arewe actually measuring, and how certaincan we be about what we see? How has itbeen validated? If we do the same thingtwice, do we get the same answer?

Does the field need standards? Yes,undoubtedly. Let’s be sure to use this toolto ask the unique questions that can actu-ally be answered with it, rather than as amore complicated and expensive route toanswers that could be obtained more sim-ply and reliably another way. Otherwise, itcan be neo-phrenology, can’t it?

At the end of the day, we need to usefunctional brain imaging carefully, andmanage our excitement to make sure thatwe give clear context and boundaries towhat we do and what we see.

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Interview 2: Judy Illes, Ph.D.

Imaging is at the intersection of neuro-science and bioethics, says Illes. Technology likefunctional MRI can provide measurements ofcognitive phenomena ranging from fear andaddiction to learning and memory. Imagingallows scientists to probe the deep recesses of thehuman mind, she says, “romance and hatredand prejudice, existential thinking.” Even thefetal brain is being imaged.

What are some of the ethical con-cerns about imaging?

What if we could use those data topredict behavior in the future? What if wecould in an adolescent predict propensityto aggression or sociopathy or suicide?How are we going to handle people inwhom we are able to predict potentiallydevastating behaviors?

What will it mean to be able to pre-dict the onset of a disease may occur 30years down the line, especially when there’sno treatment? Alzheimer’s a perfect case ofthat. The issues of prediction are immense.

Some hardcore MR (magnetic reso-nance) physicists who developed this tech-nology would say, ‘Nah! Nah! Never!’ But

Just as imaging tech-nologies are guiding and,in some cases, replacingthe scalpel, they are revo-lutionizing the evaluationof new cancer drugs.

Traditionally, a drug’seffectiveness has beendetermined by its impacton patient survival, or bymeasuring the diameterof a tumor on a series ofX-rays or CT scans takenover the course of sever-al weeks.

That’s too slow foroncologists like CraigLockhart, M.D., M.H.S.,assistant professor ofMedicine in the Vanderbilt-Ingram Cancer Center. Ifthere was a way of telling,within 48 hours, that apatient’s tumor was notshrinking or otherwiseresponding to the drug,“we’d be able to save thatpatient a lot of time andpotential toxicity,” he says.

John Gore, Ph.D., direc-tor of the VanderbiltUniversity Institute of

Imaging Science, is equallyimpatient. “We want tohave more quantitative,more sensitive and morespecific measures” ofdrug response, he says.“Imaging is the only wayto do that.”

Gore envisions radiolo-gists and imaging scien-tists from the Institute sitting down with oncolo-gists at the CancerCenter to plan “whatimaging should be donefor every clinical trial.”

That’s also the goal of the National CancerInstitute (NCI), which isfunding the establishmentof Image ResponseAssessment Teams, com-posed of radiologists andimaging scientists, whowould contribute to thedesign of clinical studiesat cancer centers acrossthe country.

“We’re trying to getoncologists and imagersto work on the sameteam … to prove the

value of therapeuticmaneuvers,” explains C.Carl Jaffe, M.D., chief ofthe NCI’s DiagnosticImaging Branch.

“We don’t mean toimply the imaging commu-nity doesn’t care aboutoncologic trials,” Jaffeadds. “They’re leadingthe development of newmethods … (But) cancertrials are a special situa-tion. You have to havegreater uniformity, greatercommunication andgreater discipline in orderto produce quality datathat can be trusted.”

Advances in imagingtechnology will continue torefine – and challenge –the testing of new drugs.“For now, we have prettydarn good technology, butit’s relatively undisci-plined,” Jaffe says. “ …It just needs to be stabi-lized. That’s where we’reheaded.”

– BILL SNYDER

A Closer Look at Drugs: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : :

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I don’t know. I think that the evidence isthat we haven’t been stopped yet in ourinnovations. It’s just a matter of time.

Are there places we shouldn’t go?

Is everything allowable as long as it’sdone ethically? Should there be boundariesimposed on our science because of theirnew potential real-world applications?

I will argue that limitations on ethi-cally conducted science are not appropri-ate. It’s just part of the human conditionto be curious and innovate and push theenvelope. But now we have every goodreason to couple our ethical thinking withour neuroscience.

I think part of the ethical constructionof research is not only good protocols andprotection of human subjects, but actuallythinking about the downstream implica-tions of the research.

What if you’re doing a study of peoplewith schizophrenia and you find a mass?How do you handle that with that kind ofpopulation? What about children? What ifsomething comes out and they end up witha result that may be stigmatizing? Thatcould have a lifelong implication.

What if somebody develops a drugthat can check addictive behaviors? Whatkind of interventions are developed andbecome available? All the more reason tostart thinking about the ethics of it. If infact we can use an imaging technology topredict addiction, then we definitely wantto have a response ready.

And to the extent that we continue todo these studies that probe personhood,it’s not enough just to say, ‘I’m not goingto hurt somebody in my experiments.’ Butit is becoming, I believe, a requirement tothink, ‘If I find out that there is a locus orloci or network for making race judg-ments in the human brain, this is how I’mgoing to handle the information in termsof its dissemination.’

Without being too alarmist and certainly without being negative, I do feelthat unless we start to introduce a reason-able – not a heavy, but a reasonable – ethical component to the kind of workthat we’re doing, there are risks of adverseeffects on people that then have the adverseeffect of potentially slowing down theprogress of research.

And so by being proactive, and bytrying to address these issues jointly fromwithin the neuroscience and bioethicscommunity, we can get a very good handleon what the issues are and what are theways that we can empower our scienceethically so that we can either prevent the

adverse events down the road or at least beable to manage them very efficiently.

What are the limitations of thesetechnologies?

They start at the beginning with thedesign of an experiment. Any experiment,especially one that probes complex phe-nomena such as existential decisions, takessome pretty clever design and invariablywill reflect – and I don’t see how it couldnot – the cultural orientation and biases ofthe experimenters developing it.

The way I value something might bevery different from the way you valuesomething at Vanderbilt. When we startto probe personhood, we’re unequivocallyinvoking issues of values and culture, eth-nicity, so there’s a limitation right there.

Another limitation is, as we know, inthe statistical processing of the data. Thedifferent kind of statistics you do may affectthe results, and along with that we don’thave a very good handle yet on individualneuro-functionality in terms of blood flow, forexample. We’re still using group averages,although people are really making somefantastic strides in that domain.

Some investigators are concerned thatwe’re only able to study subsets of certaindisease populations. I think of autism, forexample, where we have quite a few stud-ies on high functioning autistic childrenbut considerably fewer on those who arelow functioning and more difficult tomanage, certainly in the context of anMRI environment.

One that I’d add is in the day-to-day variability of physiology that goesinto brain measurements. We know that brain physiology changes are different by gender, by stress level,

by food level. Again, understanding individual variability is really crucial.

There are definitely limitations tousing the knowledge we gain in the labo-ratory, especially about these incrediblycomplex phenomena in the real-world setting. But nonetheless, we are measuringthem in the laboratory. These laboratorystudies are being covered by the press andthe word is out in the public domain.

And so we as neuroethicists reallyhave to work closely with our neurosciencecolleagues in the trenches to be proactiveabout aligning the ethical considerationsof some of these studies up front in theresearch design and really trying to antici-pate what kind of social impact or legalimpact or ethical impact it might havedown the road.

We’re accustomed to, in many ways,living in a very privileged environmentwhere we publish in science journals andwe speak with our colleagues at meetings,and a little bit filters out to the public.But I really believe and our data suggestthat we’re in a different place now and wehave to consider these ethical, legal, socialissues to a far greater extent than we everdid before. LENS

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Peeking intothe wombBy Bill Snyder

One of the most powerful applications of imaging scienceis the diagnosis of fetal abnormalities.

“Imaging provides an ability to depict things that previ-ously were only able to be diagnosed by surgery,” saysMarta Hernanz-Schulman, M.D., director of PediatricDiagnostic Imaging at Vanderbilt University Medical Center.

Some conditions can be treated before birth. For example, when the male urethra – the tube that car-

ries urine from the bladder to the outside – is obstructed,the bladder can become massively dilated. Urine may backup the ureters, causing severe kidney damage. By insertinga needle through the uterine wall into the fetal bladder,under the guidance of ultrasound, the obstetrician can drainthe bladder into the amniotic fluid surrounding the baby,thereby relieving pressure on the kidneys.

Usually pregnant women are referred for further imagingstudies when a routine ultrasound indicates there may be aproblem, says Sharon M. Stein, M.B., Ch.B., associate pro-fessor of Radiology and Radiological Sciences, and Pediatrics.

Computed tomography (CT) is not used because of theneed to protect the fetus from exposure to X-rays. Instead,remarkably detailed pictures can be obtained using ultra-sound and magnetic resonance imaging (MRI), which haveno known harmful effects.

During a weekly fetal therapy conference, Vanderbiltspecialists in radiology, neonatology, surgery, urology, geneticsand medical ethics review the images, and use them toguide decisions about the management of the pregnancy,including the timing of delivery.

The aim, says Stein, is to ensure “that everything iswell orchestrated and planned for optimum care” once thebaby is born.

Pictured here: Fetal magnetic resonance imageswith structures noted with arrows. A) Normal brain and bladder.B) Hydrocephalus – abnormal accumulation offluid in the brain.C) Congenital diaphragmatic hernia – hole in thediaphragm that allows the liver and bowel(marked) to enter the chest cavity.D) Myelomeningocele – open neural tube defect(spina bifida).

Courtesy of Sharon M. Stein, M.B., Ch.B.

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Jeffrey R. Balser, M.D., Ph.D.Anesthesiology, PharmacologyAssociate Vice Chancellor for Research

Andrea Baruchin, Ph.D.Medical Education and AdministrationDirector of Strategic Planning Office of Research

Gordon R. Bernard, M.D.MedicineAssistant Vice Chancellor for Research

Randy D. Blakely, Ph.D.PharmacologyDirector, Center for Molecular Neuroscience

Peter Buerhaus, Ph.D., R.N.Senior Associate Dean for Research, School of Nursing

Richard Caprioli, Ph.D.Biochemistry, Chemistry, PharmacologyDirector, Mass Spectrometry Research Center

Ellen Wright Clayton, M.D., J.D.Pediatrics, LawCo-DirectorCenter for Genetics and Health Policy

Raymond N. DuBois, M.D., Ph.D.Medicine, Cancer Biology, Cell & Developmental BiologyDirector, Vanderbilt-Ingram Cancer Center

John H. Exton, M.D., Ph.D.Molecular Physiology and Biophysics,Pharmacology

Steven G. Gabbe, M.D.Obstetrics and GynecologyDean, School of Medicine

William N. Hance, B.A., J.D.Director, Office of News and Public Affairs

George C. Hill, Ph.D.Microbiology & ImmunologyAssociate Dean for Diversityin Medical Education

Michael C. Kessen, B.A.Director, Corporate & Foundation RelationsMedical Center Development

Joel G. Lee, B.A.Associate Vice Chancellor, Medical Center Communications

Lee E. Limbird, Ph.D.PharmacologyVice President for ResearchMeharry Medical College

Mark A. Magnuson, M.D.Molecular Physiology & Biophysics,MedicineDirector, Center for Stem Cell Biology

Lawrence J. Marnett, Ph.D.Biochemistry, Cancer ResearchDirector, Vanderbilt Institute of Chemical Biology

John A. Oates, M.D.Medicine, Pharmacology

Alastair J.J. Wood, M.B., Ch.B.Pharmacology, MedicineAssociate Dean for External Affairs

The empty medicine chestRegarding the Summer 2005 issue,

the medicine chest is about to be emptied.My guess is that more than one pharma-ceutical company will collapse as theresult of their failure to abide by the samerules that guide good medical practice.The requirement to “do no harm” hasbeen ignored due in part to what appearsto be a real lack of understanding of theconnection between prescribed drugs andinsulin resistance.

Approximately 85 percent of us aregenetically predisposed to developing oneor more of the components of metabolicsyndrome (related to insulin resistance):obesity, coronary artery disease, gallblad-der disease, type 2 diabetes, hypertension,colon cancer, breast cancer or other relatedproblems. Providing medications for those disorders that alter one or more biochemi-cal pathways related to insulin resistancewithout taking into consideration whatimpact it might have on other metabolicpathways is not only irresponsible but also reprehensible.

Both the pharmaceutical industry andthe university also need to take into con-sideration Peter Drucker’s Theory of S-Curve Discontinuity. Drucker states that allproducts and processes have a defined lifecycle that can be graphed as an “S” curve.

At the outset of the development of aproduct or process, the effort and/or fundsexpended are high, while the results arequite low (the lower horizontal part of thecurve).Then things begin to click, withproductivity and profitability increasing atan exponential rate (the vertical portion).At some point, however, no amount ofnew effort or funds produces the kind ofresults previously experienced (the upperhorizontal part of the S).

What happens when we reach the topof the S-Curve? We establish a totally newproduct or process that is based on a completely different concept, a new S-Curve, what Drucker calls a “discontinuity.”Individuals who don’t understand or get

on the new S-Curve find themselves ingreat turmoil, chaos and confusion.

In health care, S-curve discontinuitybegan approximately 20 years ago, whenwe began to experience the transition fromthe “illness” curve to the “wellness” curve.

Prescription drugs used to modifyinsulin resistance-related diseases aredoomed to failure, as they are on the illnessS-Curve. These diseases are preventableusing the following formula: routine exer-cise + adequate sleep – stress – nicotine –high glycemic index calories + omega 3essential fatty acids – unnecessary prescribedmedications – excessive alcohol intake =reduced insulin resistance + improved health.

Although Vanderbilt is renowned forits research on the old illness S-Curve, it istime for it to spend more time, energy andmoney on promotion of health and preven-tion of disease. And it is time for publica-tions like yours to begin to disseminateinformation on this “non-glitzy” subject.

RICHARD C. ADLER, M.D.

Clinical Assistant Professor of Preventive Medicine

University of Tennessee Health Science Center, Memphis

Consulting editor, Metabolic Syndrome and Related Disorders

Vanderbilt University – BA ‘55, MD ‘59

Letters to the editor may be mailed to:Bill SnyderVanderbilt University Medical CenterCCC-3312 Medical Center NorthNashville, TN 37232-2390Or faxed to (615) 343-3890

Lens Editorial Board

LensL E T T E R S T O T H E E D I T O R

T h r o u g h o u r

Lens Vanderbilt University Medical Center CCC-3312 Medical Center Nor thNashville, TN 37232

Colorized image of the head of an adult femaleAnopheles gambiae mosquito, the insect that trans-mits malaria. Because malaria kills more than 1 million people a year, most of whom are children inAfrica, An. gambiae is considered to be “the mostdangerous animal on the planet.”

Scanning electron microscope image courtesy ofLarry Zwiebel, Ph.D.; colorization by Dominic Doyle

I N T H E N E X T I S S U E :The world is flat, but bumpy International research collaborations are trans-forming global health care. But they are easiersaid than done.

Tricking the mosquito’s “nose” Basic biological research suggests a new, envi-ronmentally friendly approach to thwarting anancient scourge: malaria.

Skipping the 20th Century How export of the latest information technolo-gy is aiding the fight against AIDS in Africa.

PRSRT STDU.S. POSTAGE

PAIDNASHVILLE TNPERMIT NO.

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