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296 AmericanScientist,Volume93

Macroscope

An Engineering Approach toTranslational Medicine

Michael N. Liebman

n the years

since the completionof the Human Genome Project,physician-scientists have applied newenergy to translating findings from thelaboratory into better treatments forpatients. Yet this accelerated, unidi-rectional transfer of knowledge fromthe bench to the bedside, a practicethat goes by the name of translationalmedicine, is hitting an obstacle: Thegeneration of data is far outstrippingscientists’ ability to convert it into us-able knowledge. I believe that, para-doxically, this problem stems from thetightly focused approach that givesscience much of its power. Genomics,proteomics and other high-throughputtechnologies are seductively powerful, but that seduction may limit our viewof the complex problems of physiologyand disease.For example, scientists can now cor-relate a disease with a specific pattern ofgene expression. Such experiments arestraightforward and fairly quick whenthe tools are available, and they pro-vide a massive quantity of data. How-ever, by diverting limited resources oftime, money and personnel, miningthis wealth of data may actually leadinvestigators away from grasping thegoverning laws from which they could build predictive models of the disease.I am not suggesting that investiga-tors should give up high-throughput, brute-force methods. Today’s technol-ogy is a boon to science and a power-ful component of my own research.However, as clinical investigators, westand to reap significant benefits on behalf of society by expanding our fo-cus and viewing translational medi-cine not through the eyes of a scientist, but as an engineer might.Why an engineer? Because an engi-neer uses the fruits of science to feed theappetite of technology. Unlike scientists,who tend to approach problems from a“bottom-up” perspective by collectingdata and seeking patterns, engineerstake a “top-down” approach, probing aspecific system for clues, taking it apartand considering how each componentcan be handled in a tailored solution.An engineer is a problem solver ratherthan a hypothesis generator.The two perspectives are neatlysymbiotic in physics and chemistry, forwhich fundamental laws yield predic-tive models. But in the life sciences, biologists, including physicians, must be more aware of the gap between sci-ence and technology—we still knowtoo little about the complexity of livingsystems to make many generalizationsfrom first principles.I propose that an engineering ap-proach, what might be called “real sys-tems analysis,” may be a better wayfor scientists to identify and developsolutions for biomedical problems.This kind of problem solving requiresthat translational-medicine researchplace more emphasis on going fromthe bedside to the bench, rather thanthe other way around. The ClinicalBreast Care Program (CBCP) is a col-laboration between Windber ResearchInstitute and Walter Reed Army Medi-cal Center, and it is the prototype foran integrated approach to the studyof breast cancer. Here, I present someexamples of how top-down problemsolving in the CBCP has providedunique insights.

Disease Is a Process, Not a State

For the purposes of diagnosis, analysisand experimentation, academic physi-cians tend to focus on disease at a singlepoint in time. But disease needs to betreated as a process that evolves overtime through the interaction of genetic,environmental and lifestyle factors. Thisview puts a premium on understandingthe complex history of a patient, and itacknowledges that most disease cannot be tied to a single cause.When physicians make a diagnosis,it’s natural to focus on the patient andsymptoms at the time of presentation.The doctor’s knowledge of a patient’spast is typically limited to major ill-nesses, allergies and family history. Yetclinical assessments could be muchmore meaningful if we understood theway that genes and environment inter-act to produce disease. For example,we know that certain biomarkers, suchas mutations in the genes BRCA1 orBRCA2, indicate higher risks of breastcancer. But the fact that a woman has amutation in BRCA1 doesn’t mean thatshe will develop breast cancer—it only

Michael N. Liebman is chief scientific officer of theWindber Research Institute in southern Pennsylva-nia. He has directed computational biology, bioin- formatics and genomics programs at the Universityof Pennsylvania Cancer Center, Roche Pharmaceu-ticals, Wyeth Pharmaceuticals, Vysis Incorporatedand the Amoco Technology Company. Liebmanserves on a number of commercial, governmentaland nonprofit advisory boards, including the Hu-man Health and Medicinal Chemistry Commissionof the IUPAC. Address: Windber Research Insti-tute, 600 Somerset Avenue, Windber, PA 15963.Internet: m.liebman@wriwindber.org

Physician-scientistsmay benefit froman approach thatemphasizes solving problems over generatinghypotheses

indicates that she needs to be moni-tored more closely.Likewise, smoking, high alcohol con-sumption and obesity are correlatedwith an increased risk of breast can-cer, but we know little about how eachfactor raises the risk—much less abouthow two or more might work in concertto increase risk. This situation leaves uswith a circular argument: To justify thecost of collecting a comprehensive pa-tient history, we need proof that suchdata are relevant, but we can’t evalu-ate which data are relevant because wedon’t have a database of comprehensivepatient histories.We in the CBCP think that detailedinformation will prove useful, althoughwe don’t know exactly what connec-tions will emerge from the mass ofvariables. We are collecting from eachpatient a lengthy history that includesher exposures to tobacco and alcohol,details about pregnancy, childbirth and breastfeeding, and a record of changesin her body mass. We also try to includeinformation about the timing of theseevents in a person’s life. The chronol-ogy is particularly relevant for breastcancer because the breast develops con-tinuously from birth through old age.This lifetime of changes also presentsan additional challenge: Not only dothese factors influence risk differentlyover time, but their interactions withone another also vary with age.An engineering perspective treats thepatient as a system, or a set of subsys-tems, that has been acted on, differen-tially, by many elements that influenceits state at critical points over time. Our job is to identify these critical points sothat they might be controlled. Whereasmany current studies identify correla-tions between isolated variables, wehope that the wider scope of the CBCP’ssystems-based approach will help usdetermine causality, thereby improvingdiagnosis and treatment.

Aging as a Background to Disease

The breast changes between a woman’stime

in utero

and her post-menopausalyears. This maturation process is differ-ent for women who have had childrenthan for those who have not, and it alsovaries under the influence of severalvariables: age of menarche, use of hor-monal birth control, number and timingof children, the practice of breastfeeding,age of menopause and use of hormone-replacement therapy. Thus, our defini-tion of “normal” varies with age andexperience, and an optimal diagnosismust use a systems-based approach tocompare an individual cancer patient’s baseline (which we must guess at) toher disease state (which we can measureduring diagnosis and treatment). Theimmediate aim of our project is to de-termine background levels of gene andprotein expression in breast tissue andto find out how these numbers vary ina healthy population. This informationwill be a significant step in the develop-ment of molecular diagnostics.Note that a woman’s life stages arenot separated by fixed boundaries. Rath-er, each represents a unique intersectionof a woman’s age and an event. Giventhis complexity, it was crucial to sievethe scientific literature for data that wecould integrate into a systems approach.This was more difficult than one mightthink. Scientists have studied these stag-es for decades, producing a tremendous body of work in physiology and pathol-ogy—more than any one scientist canmaster. Furthermore, we recognized thateven the most encyclopedic and fair-minded review article cannot escapethe inherent bias of its author. Thus, wehave harnessed some computing power,employing text data-mining to cull theliterature. This effort has two aims: torefine the definitions of these stages andto extract information about the under-lying physiological and developmentalchanges. This information becomes thefoundation for our molecular analysesand helps integrate clinical and molecu-lar data. We plan to augment this com-putational approach with a community- based longitudinal study that includesmolecular and behavioral components.

Breast-cancer diagnosis and treatment might improve if physician-scientists knew more about a pa-tient’s life experiences prior to her diagnosis. For the ancient Greeks, the Fates who governed eachperson’s life were incarnate as a girl, a woman and a crone, as shown in this 16th-century tapestry.