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Revolutionizing medicine in the 21st century through systems approaches

  1. 1. Biotechnol. J. 2012, 7 DOI 10.1002/biot.201100306 www.biotechnology-journal.comPerspectiveRevolutionizing medicine in the 21st century through systemsapproachesLeroy Hood1, Rudi Balling2 and Charles Auffray31 Institute for Systems Biology, Seattle, WA, USA2 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg3 European Institute for Systems Biology and Medicine, CNRS–UCBL–ENS, Université de Lyon, Lyon, FrancePersonalized medicine is a term for a revolution in medicine that envisions the individual patient Received 22 MAR 2012as the central focus of healthcare in the future. The term “personalized medicine”, however, fails Revised 09 MAY 2012to reflect the enormous dimensionality of this new medicine that will be predictive, preventive, per- Accepted 16 MAY 2012sonalized, and participatory – a vision of medicine we have termed P4 medicine. This reflects aparadigm change in how medicine will be practiced that is revolutionary rather than evolutionary.P4 medicine arises from the confluence of a systems approach to medicine and from the digitali-zation of medicine that creates the large data sets necessary to deal with the complexities of dis-ease. We predict that systems approaches will empower the transition from conventional reactivemedical practice to a more proactive P4 medicine focused on wellness, and will reverse the esca-lating costs of drug development and will have enormous social and economic benefits. Our vi-sion for P4 medicine in 10 years is that each patient will be associated with a virtual data cloud ofbillions of data points and that we will have the information technology for healthcare to reducethis enormous data dimensionality to simple hypotheses about health and/or disease for each in-dividual. These data will be multi-scale across all levels of biological organization and extremelyheterogeneous in type – this enormous amount of data represents a striking signal-to-noise (S/N)challenge. The key to dealing with this S/N challenge is to take a “holistic systems approach” todisease as we will discuss in this article.Keywords: Functional genomics · Network biology · Personalized medicine · Systems medicine1 Why does P4 medicine require so much plex solutions, in response to adapting to the ever- data? changing environment. Biological complexity re- minds one of the famous Rube Goldberg cartoon inBiology and disease are incredibly complex [1]. which Rube had assembled 14 gadgets connectedThis is a consequence of the processes taking place together to cool his soup. In order to understandduring Darwinian evolution, which are not direct- how Rube’s apparatus works – one would have toed, but rather random and chaotic – they build have a parts list of all the components, know howchanges on top of present successful, but also com- the parts are connected together and understand the dynamics of how the parts move with respect to one another to cool the soup (the dynamics of the soup-cooling machine). These are three of the ma- jor requirements for a systems approach to under-Correspondence: Dr. Leroy Hood, Institute for Systems Biology, standing biological systems – the parts list, their401 Terry Avenue North, Seattle, WA 98109-5234, USAE-mail: interconnections, and the dynamics of the parts interactions – to determine how the system func-Abbreviations: COPD, chronic obstructive pulmonary disease; DEG, differ- tions or exhibits dysfunction.entially expressed genes; iPS, induced pluripotent stem cell© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1
  2. 2. Biotechnology Biotechnol. J. 2012, 7 Journal2 Viewing biology as an information science 3.1 Systems biology of prion diseaseThe informational view of biology allows data to be To illustrate these principles, let us consider thenicely organized around three central ideas. First, studies we have carried out on neurodegenerationthere are two types of biological information, the in mice initiated by the injection of infectious pri-digital information of the genome and the environ- on proteins into the brain [3]. These studies weremental signals that come from outside the genome. important because we could look at the initiationThese two types of information are integrated to- and dynamics of the progression of the diseasegether to specify the central mechanisms of life – from inception (e.g. the infection) to death, focus-evolution, development, physiological responses, ing initially on the mRNAs expressed in the brainaging, and the initiation and progression of disease. and how they changed across the 22-week pro-Second, an interesting question is what joins the gression of the disease. To identify the differential-integrated information to phenotype? Two infor- ly expressed genes (DEGs), the diseased brainmation handling structure do – biological networks transcriptomes were subtracted from the controlthat capture, transmit, integrate, and pass informa- transcriptomes at 10 time points across the pro-tion on to molecular machines to execute the func- gression of the disease. These temporal dynamicaltions of life. Hence the dynamics of networks and studies revealed several striking points. First, 7400molecular machines constitutes one of the central RNA transcripts appeared to be changed in thefoci of systems approaches to biology and disease. course of the disease – encoded by nearly 1/3rd ofFinally, biological information is hierarchical and the mouse genes. These data obviously represent amulti-scale across all levels of biological organiza- significant S/N problem. This noise arises from twotion – from DNA, RNA, proteins, metabolites, inter- sources: technical noise and biological noise. Bio-actions, and cells, to organs, individuals, popula- logical noise arises from measuring a particulartions, and ecologies – all representing an inter- phenotype (e.g. the brain transcriptome) that is thetwined ascending and descending hierarchy of in- sum of several different aspects of biology that lieformation. The environment impinges upon outside the phenotype of interest (in this case neu-information at each of these levels to modulate re- rodegeneration). Approaches were developed in-peatedly the original digital genome signal. Hence volving eight different inbred strain/prion strainit is essential to integrate information from the dif- combinations for subtracting away the other typesferent levels to explicate the environmental contri- of biological variations – to focus on the biology ofbutions if one is ever to understand how the system neurodegeneration. These subtractions suggestedworks – for this requires understanding how the in- that about 300 DEGs are associated with neurode-formation of the genome and environment interact. generation (these subtractions thus provided moreThese informational views of biology are also key than a 20-fold enrichment in S/N). Second, fourto dealing with the S/N issues arising from the gen- major biological networks appeared to participateeration of large data sets with high-throughput in prion disease as revealed by histopathologicalmethods. The biological information has to be inte- studies. The core 300 DEGs were mapped into thegrated with clinical information and translated into four interaction networks encoding these histo-efficient and reliable decision support systems for pathologies at ten different time points across thehealth care. 22 weeks of disease progression. Two hundred of these genes mapped into the four major networks and the remaining 100 defined six smaller net-3 A systems approach to disease works – not previously known to be involved with prion disease. Third, the dynamics of how theseDisease arises as a consequence of disease-per- transcripts changed across disease progress ex-turbed networks in the diseased organ that propa- plained virtually every aspect of the pathophysiol-gate from one or a few disease-perturbed networks ogy of the disease – a remarkable advance in un-to many as the disease progresses. These initial dis- derstanding disease dynamics. Fourth, the four ma-ease perturbations may be genetic (e.g. mutations) jor networks were sequentially disease-perturbed.and/or environmental (e.g. infectious organisms). The importance of this observation is that it pro-These perturbations alter the information ex- vides new strategies for diagnosis and therapy thatpressed in these networks dynamically – and these may focus on the most proximal of the disease-per-altered dynamics of information flow explain the turbed networks. Finally, this dynamical networkpathophysiology of the disease and suggest new analysis did suggest several new approaches toapproaches to diagnosis and therapy [2]. blood diagnostics using, for example, comparative organ transcriptome analyses to identify organ-2 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
  3. 3. Biotechnol. J. 2012, 7 www.biotechnology-journal.comspecific transcripts. In this manner, more than thus compared and combined the results obtained100 brain-specific mouse transcripts could be iden- in human patients with those collected in animaltified – and many of these encoded proteins that models or previously reported in the literature, andwere secreted into the blood – there to constitute a the evidence obtained did not support the workingbrain-specific blood fingerprint that could distin- hypothesis. Rather, they pointed to an alternate hy-guish for the brain, health from disease, and in the pothesis that specific epigenetic changes linked tocase of disease, the type of disease. Fifteen of these histone modifiers are associated with muscle dys-brain-specific proteins permitted early preclinical function and possibly driven by hypoxia, suggest-diagnosis of prion disease, the stratification of dif- ing that they could be investigated as novel targetsferent types of neurodegenerative diseases, and the for therapeutic intervention to restore muscleability to follow the progression of prion disease – function in COPD patients.all from the blood. The use of such organ-specificblood fingerprints will thus be a powerful tool fordiagnostics in the future [4]. 4 Emerging technologies3.2 Systems biology of respiratory and muscle The study of leading-edge problems in biology or disease disease quickly pushes studies to the point that new technologies are needed to open up new di-Another landmark study illustrates the power of mensions of patient data space. Let us discuss six ofsystems biology and network modeling approaches these emerging technologies in the context of P4to decipher the interplay of molecular networks in medicine.multiple organs and their perturbations in a com-plex chronic respiratory disease such as chronic 4.1 Family genome sequencingobstructive pulmonary disease (COPD), which, inaddition to progressive airway obstruction, is char- The genome is the digital source code of life, en-acterized by muscle wasting [5]. COPD is a chronic coding many of our most fundamental features –life-threatening inflammatory disease of the lungs such as development and physiological mecha-characterized by progressive airway limitation nisms for responding to the environment. Bothleading to severe impairment in the quality of life processes may be modified by epigenetic marks.of the patients. It is largely irreversible and associ- With the rapid progress in sequencing technolo-ated with muscle wasting. It is increasing in preva- gies, family genome sequencing, that is determin-lence and represents the fourth most important ing the complete genome sequences of all of thecause of death worldwide. Current treatments aim members of a family, is enabling the integration ofat reversing the disease process through a combi- genomics and genetics with fascinating results. Fornation of exercise training, anti-inflammatory example, the sequencing of the genomes of a fam-drugs and dietary supplements. In this study, tran- ily of four where the parents were normal and thescriptomic expression profiles were collected in two kids each had two genetic diseases revealed theskeletal muscle biopsies of the COPD patients and multi-dimensional power of this approach [7].controls at rest, before and after exercise training. First, about 70% of the sequencing errors could beThrough integration of the differentially expressed identified by using plausibility checks on the basisgenes detected with serum cytokine levels and a of the principles of simple Mendelian genetics.range of recorded physiological responses, the au- Second, rare variants could be immediately identi-thors were able to identify interaction networks fied by asking whether two or more members of theperturbed in the disease state. This provided sup- family had them (hence they could not be sequenc-porting evidence that a distinctive feature of COPD ing errors). Third, the haplotypes of the members ofis the uncoupling between tissue remodeling and the family could be determined through being ablethe control of energy metabolism, and that this is to map precisely the recombination sites in thethe result of a perturbation of transcriptional regu- children’s chromosomes and hence the linkages oflation leading to the modulation of inflammatory their constellations of genetic variants across eachcytokines such as interleukin (IL)-1β. Previous of the diploid autosomes and the sex had pointed to a possible role of NF-κB tar- This is important because then one can ask forgets in these transcriptional regulation abnormali- those family members with the disease – what frac-ties [6]. In order to test the validity of this working tion of their chromosomal haplotypes are shared,hypothesis through a second iteration of the sys- for it is in these shared chromosome regions thattems biology process, the authors designed and the disease-related genes must reside. This greatlyperformed a set of validation experiments. They reduces the area of chromosomal space that needs© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3
  4. 4. Biotechnology Biotechnol. J. 2012, 7 Journalto be searched for disease-related genes. Finally, biological processes occurring after the genome isthe number of disease gene candidates for the two transcribed, including RNA editing, RNA splicing,children could be reduced to just four genes – and protein processing, and chemical modification.the proper assignments were relatively straightfor- Proteins are also dynamic – often changing their 3Dward. Thus family genome sequencing, through the structures in the context of carrying out their bio-integration of genetics and genomics, increases logical functions, thus responding to environmen-enormously the S/N in most whole genome analy- tal changes. Proteins, together with other complexses while searching for disease-related genes. biomolecules and metabolites, execute the func- We believe that in 10 years the individual com- tions of life and hence are closer to the phenotypeplete genome sequence will be a routine part of a than DNA or RNA.personal medical record – and it will provide fun- One powerful approach to the quantificationdamental insights into optimizing health. This is in and identification of proteins from complex mix-keeping with the fact that within 5 years we predict tures (tissues, blood, cells, etc.) is the use of MS.that the cost of a complete genome sequence will be Proteins are purified from other compounds, di-a few hundred dollars. We believe that what will be gested by an enzyme such as trypsin to create pep-a fundamental driver of societal acceptance of tides and the peptides can then be analyzed (e.g.complete genome sequences are “actionable gene sequenced) and quantified in the mass spectrome-variants.” An actionable variant is one that allows a ter. Initially, MS was used in a shotgun manner tophysician to specify how a patient may improve his identify and quantify proteins in complex mixturesor her health. For example, there are variants of a – but it was quickly determined that often most ofvitamin D transporter that lead to significant os- the peptides analyzed are those from the predom-teoporosis in the early 40’s (a young age). This con- inant proteins in the mixture. Accordingly, a newdition can be reversed merely by having the patient approach termed targeted proteomics was pio-take 20 times the normal dose of vitamin D. More neered [8] where one could identify peptides thatthan 250 of these “actionable gene variants” have uniquely define each protein, then determinealready been identified. It is the continually in- which of these peptides behave well in the masscreasing number of actionable gene variants that spectrometer – and then synthesize isotopically la-will be the major driver in having society accept beled peptides that when added to the peptide mix-whole genome sequences as an important part of ture would enable precise quantification. Robeach person’s medical record. Indeed, in the future Moritz at the Institute for Systems Biology, in col-our genome sequence will be checked every year to laboration with Ruedi Aebersold at the ETH, hasidentify new actionable variants. Hence our recently identified 3–6 peptide assays for each ofgenome sequence will be an investment in our 20 000 human proteins. These assays have beenhealth for the rest of our lives. placed in a database that is openly accessible to all scientists. Hence, targeted proteomics has “democ-4.2 Proteomics ratized” the human proteins in the same sense that the HGP “democratized” all human genes – name-The proteome is the entire complement of proteins ly they are now accessible to all scientists (Moritz,in a given biological compartment (an individual, in preparation). These targeted proteomics assaysan organ, a cell, the blood, etc). Proteins have sev- will be powerful tools in analyzing biological anderal features that distinguish them from DNA and disease mechanisms and they will provide power-make their analyses more complex. First, DNA is ful approaches to the identification of disease bio-digital in nature (e.g. the chromosomes are digital markers.strings of Gs, Cs, As, and Ts with a diploid repre- In the future we will want to create protein as-sentation in the nucleus – only two copies of most says that can analyze thousands of proteins from agenes), while proteins, in addition to the digital in- fraction of a droplet of blood on hundreds of mil-formation translated from the genome sequence lions of patients each year. MS will not be extend-into strings of the 20 amino acids, are associated able to analyses of this dimension. For example, wewith analog information (e.g. they fold into complex envision being able to analyze perhaps 50 organ-3D structures and they may be present in one com- specific blood proteins from each of 50 human or-partment, such as the blood, as one or a few copies gans on a biannual basis. Jim Heath at Caltech hasor 1010 copies – manifesting an enormous dynamic pioneered a microfluidic protein ELIZA chip thatrange of concentrations). While there are about can make 50 measurements in 5 min from 300 nL20 000 protein-coding genes in the human genome, of blood [9]. To be able to expand 50 measurementsthere may be millions of proteins because proteins to 2500 measurements (50 times 50) will require(translated from mRNAs) can be modified by many developing new types of protein-capture agents for4 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
  5. 5. Biotechnol. J. 2012, 7 www.biotechnology-journal.comthe ELIZA assays – both peptide capture agents One can also use single-cell analyses to character-[10] and aptamer capture agents [11] appear prom- ize disease states (e.g. how many quantized popu-ising. lations are there in tumors), or to separate the 10 or so classes of white blood cells to determine4.3 Metabolomics whether and how they can be useful in the diagno- sis of disease. Our prediction is that single-cellMS is the method of choice to determine the analyses will transform profoundly our under-metabolome of individual patients. Currently MS or standing of health and disease.LC coupled to GC are able to resolve 300–500metabolites, such as amino acids, fatty acids, nu- 4.5 Imagingcleotides, and many other small molecules [12].Whereas the targeted or untargeted quantification Spatial and temporal information will be key forof metabolites provides the most “proximal” phe- the development of reliable disease models that al-notype, this information is still static in nature. Cur- low the identification of actionable network com-rently in vivo, whole organism methods are under ponents. For this reason advanced high-resolutiondevelopment using stable isotopes that allow to fol- and high-content imaging technology is being de-low the fate and rate of individual metabolites, the veloped [15, 16], to enable the reliable interpreta-measurement of metabolite fluxes and enzyme tion of molecular and cellular disease processesrates, thereby tremendously increasing the infor- and eventually the integration into molecular diag-mation about disease progression and potential nostics and medical decision support systems.adaptive, compensatory physiological and patho-physiological mechanisms. The MS-based methods 4.6 Induced pluripotent stem cellsare now being complemented by pattern-recogni-tion array-sensors that capture volatile organic Induced pluripotent stem (iPS) cells from individ-compounds in exhaled breath, providing disease- ual patients will be useful in exploring mechanismsspecific molecular signatures. These so-called of disease initiation and progression, in revealing“electronic noses” are non-invasive diagnostic de- fundamental aspects of development and in creat-vices, which have shown promising results, e.g. in ing the differentiated cell types of patients in a testthe early detection of diseases such as lung cancer tube which can be analyzed with environmental[13], and the distinction between asthma and probes (ligands, drugs, etc.) eventually to stratifyCOPD [14]. disease by virtual of different responses for each subtype of a disease that has its own unique com-4.4 Single-cell analyses bination of disease-perturbed networks [17, 18]. iPS cells derived from blood white cells and skin orVirtually all studies until very recently have been cheek fibroblasts will be complemented by iPScarried out on complex mixtures of cells (either cells derived from cells of the immune system thatfrom tissues or from the blood). It is clear that much have undergone Tcr or Bcr recombination, openingbiology is executed by virtue of cells of different the possibility for treating antigen-specific autoim-types interacting with one another – or by interac- munity and allergies.tions with environmental signals from tissue scaf- The combination of an informational view offolds or other cells. Hence in order to understand medicine, the systems approaches to disease, thefundamental biological or disease mechanisms – emergence of new technologies and strategies thatsingle cell analyses will be critical. Microfluidic open up new dimensions of patient data space andtechniques have been developed that allow single pioneering analytical tools (mathematical andcells to be analyzed at the genomics and proteomics computational) enable the development and im-levels. One of the fundamental questions that can plementation of P4 medicine in healthcare and so-be answered with single-cell analyses is the num- ciety.ber of discrete (quantized) populations of cells thatexist within a tissue or organ. Once the single-cellanalyses have been carried out, the uniquely defin- 5 P4 medicineing cell-surface molecules can be identified thatwill permit the separation of the quantized popula- Systems medicine provides the strategies, tools,tions by cell sorting. Then the cells of these quan- and computational and analytical abilities to ana-tized populations can be investigated to see how lyze enormous amounts of information [19]. P4they respond to environmental signals or the inter- medicine uses these strategies and tools to attackaction with cells from other quantized populations. disease (and wellness) for the benefit of the indi-© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5
  6. 6. Biotechnology Biotechnol. J. 2012, 7 Journalvidual [20]. P4 medicine also must deal with the so- role in optimizing wellness. Already now 60 or morecietal challenges of systems medicine. Let us con- digital parameters can be measured for each pa-sider at a high level where we will be with the 4Ps tient – providing unique opportunities for drivingin 10 or so years. the optimization of individual wellness [21].5.1 Predictive 5.3 PersonalizedWe suggest in 10 years that genomes will be a rou- On average, humans differ from one another by 6tine part of each patient’s medical record. From the million nucleotides in their genome sequence, andactionable gene variants we will be able to provide an uncharacterized number of subsequent changeseach patient with critical information for optimiz- in other biomolecules. Hence each of us is unique –ing his or her wellness as well as dealing with the and will have to serve as our own control for fol-future potential for disease development. We pre- lowing transitions from health to disease or vicedict the availability of a small handheld device that versa. This is the essence of personalized medicinecan prick your thumb, measure 2500 organ-specif- – medicine must focus on each individual uniquely.ic proteins, send this information to a server for In 10- or 15-years, with the fast decline in theanalysis and feedback the information on the state cost of next-generation sequencing, we will poten-of your 50 organ systems. These measurements will tially have access to the complete genomes and at-be longitudinal in nature throughout our lives, im- tendant medical, molecular, cellular, and environ-mediately identifying any transitions from health mental data for a growing fraction of the humanto disease, sending alerts early on and suggesting population in both developed and developingpreventive measures such as changes in dietary or countries. This will afford us an unparalleled op-exercising habits. These measurements will thus portunity to mine these data for the predictivealso be used to optimize wellness. medicine of the future – but only if these data are made readily available for qualified researchers5.2 Preventive and health practitioners. Our view is that it is criti- cal that society should have access to the data ofSystems approaches to studying disease-perturbed each person and patient and that these data, afternetworks will provide a completely new approach anonymization, should be available to qualified in-to the identification of drug targets, through vestigators to mine for the predictive medicine ofreengineering of disease-perturbed networks to the future that will transform healthcare for ourmake them behave in a more normal or manage- children and grandchildren (as well as us). Afterable fashion through the use of multiple drugs to all, society has created the resources that led to theperturb the networks. We will have to learn how to emergence of P4 medicine – and these resourcesanalyze and interpret reconstructed disease net- should be leveraged through extensive data miningworks from individual patients and identify opti- to pioneer the development of the future of medi-mal interference strategies. In a first phase we will cine. It will be important to provide legal safe-need to re-engineer networks with drugs in mi- guards against discriminatory use of these data –croorganisms in order to elucidate the general en- e.g. by employers and insurance companies.gineering principles that will then be applied to hu-mans. From a disease prevention point of view the 5.4 Participatorymost proximal disease-perturbed networks will bethe most promising ones to address first with this The patient will participate in many of the differentstrategy. dimensions of P4 medicine. First, patients or Systems approaches will enable us to under- healthcare customers will increasing participate instand, for the first time, how to effectively induce patient-driven social networks that will sustain thecellular immunity. Hence we will be able to gener- process of the acceptance of P4 medicine by de-ate vaccines that can deal with infectious chal- manding better healthcare for each person individ-lenges such as AIDS, malaria, and tuberculosis. But ually. Second, patients will need to be informed andmost important for prevention, we will increasing- educated as to the opportunities and challenges ofly focus on optimizing wellness for the individual. P4 medicine. This holds true for physicians and in-This will be done through identification of metrics deed the entire healthcare community, which willthat will let us assess wellness and its dynamics for have to be educated as to the revolution that P4each individual. The digital revolution of medicine medicine is bringing through a profound revisionthat will make enormous amounts of the individ- of the medical training curriculum. We believeual’s data available to him or her will play a critical there will be a critical role for information technol-6 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
  7. 7. Biotechnol. J. 2012, 7 www.biotechnology-journal.comogy in this education process. Third, patients will derstand how the digital genome information andhave to actively participate in the process of mak- environmental information combine to generateing available their billions of bytes of digitized data the normal and disease phenotypes. The assess-for the healthcare database of the future. The chal- ment of each of these networks is fundamental tolenges involved in IT for healthcare in acquiring, capturing the environmental signals that impingevalidating, storing, mining, integrating, and finally at each of these levels upon the core digital signal.modeling these highly heterogeneous data are Hence a true understanding of biology and diseasedaunting – and not being effectively approached mechanisms requires capturing the information ofyet by any of the current players in the information each of these networks and a better understandingtechnology for healthcare landscape. We need to of the systems properties that emerge from theirdevelop user-friendly software solutions for combinations.crowd-sourcing enabling an efficient highly inter- P4 medicine stands in striking comparison toactive patient–healthcare interface. Finally, it will more conventional evidence-based medicine. Inbe important to create a “gold standard” for health- contrast to evidence-based medicine, P4 medicinecare information on the internet – so that patients is proactive rather than reactive; is focused on well-(and physicians) can obtain reliable healthcare in- ness-maintenance rather than disease; employsformation. many measurements on the individual patient rather than few; is individual-centric rather than population based; integrates and mines large ag-6 General features of P4 medicine gregated patient data sets to pioneer the P4 medi- cine of the future; employs patient-driven societalP4 medicine is concerned with understanding for networks as a catalyst for change; and stratifies dis-the individual patient of his or her “network of net- eases into their distinct subtypes for impedanceworks” – a hierarchy of networks operating across matches against proper drugs. The quantized self –multiple, complex, dynamic, and intertwined levels that is, the collection of many digital measurementsof biological organization encompassing both the on each individual will give us real time and read-individual and his or her environment. A genetic ily digestible insights into optimizing our wellnessnetwork can be defined by analyzing how defects in – and minimizing our disease. The article by Larrypairs of genes affect the phenotype of the organ- Smarr [21] in this issue illustrates beautifully thisism. Gene regulatory networks result from the in- principle.teraction of transcription factors with their cognate P4 medicine has two central goals – the quan-cis-regulatory elements on chromosomes. The pro- tification of wellness and the demystification ofteins produced through transcription and transla- disease – and the two become intimately related fortion in turn interact with one another and with each individual.other small molecules within functional protein in-teraction networks: e.g. metabolites and enzymesinteract in metabolic networks. These diverse bio- 7 Impact of P4 medicine on societychemical activities are integrated at the level ofcells interacting with one another within cellular, P4 medicine will mandate that every sector of thetissular, and organ networks, all of which are as- public and private healthcare systems rewrite theirsembled together within an individual organism in business plans over the next 10 years in accordancethe context of its extended environment (e.g. hu- with the imperatives of each of the 4Ps. In our ex-mans interacting in social networks). Each of these perience, the bureaucracies and conservative lead-networks is interfacing with the other types of net- erships of healthcare providers will constitute ma-works to form the “network of networks.” Obvious- jor barriers to adapting to P4 medicine. The inter-ly disease-perturbations in one network will reflect esting point is that many new companies willthroughout the other networks as a consequence of emerge during the next 10 years that will be fo-their integrated interfaces. Thus one challenge of cused on the needs of P4 medicine. Hence there aredisease is to ultimately understand how to con- enormous economic opportunities ahead of us.struct these individual networks from individual P4 medicine will in time turn around the everpatient data, to determine how these networks are escalating costs of healthcare – and indeed bringintegrated and finally to ascertain how disease- them down to the point that P4 medicine will be ex-perturbations reflect throughout the “network of portable to the developing world (just as the digiti-networks” to modify its information content. Hence zation of communications made the cell phoneP4 medicine is about integrating the information available and affordable both to individuals in thefrom each of these networks so as to be able to un- developed nations as well as the developing na-© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 7
  8. 8. Biotechnology Biotechnol. J. 2012, 7 Journaltions). Hence we can contemplate the previously integrative, and milestone-driven effort with vi-unthinkable – the possibility of a worldwide “de- sionary leadership. At our institutions we becamemocratization” of healthcare. The cost reductions convinced of the power of national and interna-will come from the revolutions that are being initi- tional strategic partnerships some years ago. Theseated by systems medicine (making blood a window partnerships allow one to select the best scientistsfor health and disease; the stratification of disease, and engineers to help solve discrete sub-problemstherapy by reengineering disease-perturbed net- within the P4 context; to choose partners with com-works with drugs, and the metrics for wellness, plementary skills and technologies; to enable com-etc.), the digitization of medicine (hence making pletely new approaches to fundraising that is es-data incredibly cheap – and thus bringing costs sential for attacking big scientific and medicaldown) and the advance of exciting areas in con- problems; and to bring together complementary re-temporary medicine (cancer, stem cells, aging, neu- sources (hospital infrastructure), materials (pa-rodegeneration, etc.). tient samples), and data (patient records). As noted above, P4 medicine will lead to a digi- ISB has fashioned key strategic partnerships fortalization of medicine – with very broad implica- P4 medicine. We have developed a strategic part-tions (the creation of patient/consumer-driven so- nership with the Grand Duchy of Luxembourg thatcial networks, the quantification of self, the infor- fostered the creation of the LCSB at the Universitymation technology for healthcare which will cap- of Luxembourg, a partnership focusing on neu-ture the digitalized data of individuals to create a rodegenerative diseases and Parkinson disease ini-database for the predictive medicine of the future). tially, that is being expanded to sustain the devel-The quantification of wellness and the demystifica- opment of the EISBM in Lyon in relation with thetion of disease will create wealth for the institutions local hospitals and authorities, academic and in-and organizations that are at the leading edge of dustrial partners of the Lyonbiopole competitivethis paradigm change. For example, we predict that cluster.a wellness industry will emerge over the next 10–15 We have also created the non-profit P4 Medi-years that will far exceed the healthcare industry – cine Institute (P4MI) with Ohio State Medicalleading to a unique series of potential economic School. The objective of P4MI is to help create aoportunities. network of 5–6 clinical centers and ISB to employ conventional and ISB clinical assays in pilot proj- ects to demonstrate the power of P4 medicine. We8 How do we bring P4 medicine to patients? are now embarking on pilot projects that include wellness and premature pre-term births. P4MI willThere are general challenges to bringing P4 medi- also help recruit selected industrial partners to thiscine to patients. First, we must invent the systems network. P4MI has a fellows program that will be-strategies, technologies, and analytical tools neces- gin writing white papers on some of the key socie-sary to implement the P4 medicine vision in prac- tal challenges to P4 medicine. Similarly, plans aretice. Second, P4 medicine poses a host of challenges materializing for the formation of a School of Med-to society – ethics, privacy, confidentiality, legal, icine at the University of Luxembourg that will im-economic, regulatory, national policy, etc. These so- plement systems principles in the training curricu-cial challenges represent the greatest barrier to im- lum, and is forming a Personalized Medicine Con-plementation of P4 medicine. Hence there must be sortium with regional and international clinicalintegrated efforts for bringing P4 medicine to pa- partners.tients – for each is essential to the vision of P4 med- Ultimately, after successful pilot projects per-icine. formed by ISB and its partners in a growing world- P4 medicine represents a fundamental para- wide network of systems P4 medicine centers anddigm change in healthcare. Paradigm changes are institutes, we would like to persuade a small nation,always met with enormous skepticism [22]. We be- state or region to consider adopting a global P4lieve the key to convincing skeptical physicians, healthcare system. It would be a unique opportuni-payers, providers, and indeed the many players in ty to pioneer medicine of the future and play athe healthcare systems is the successful comple- leadership role in transforming medicine from itstion of pilot projects that demonstrate the revolu- current reactive mode to the proactive P4 mode. Ittionary power of P4 medicine. goes without saying that any nation that is a leader P4 medicine is a comprehensive and challeng- in the P4 revolution will potentially encountering problem for medicine, the healthcare system striking economic opportunities.and society. It requires a systems-driven, cross-dis-ciplinary, large data-generating and data-analysis,8 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
  9. 9. Biotechnol. J. 2012, 7 Dr. Leroy Hood received an MD from Dr. Rudi Balling studied nutrition at the John Hopkins and a PhD from Caltech Universities of Bonn, Germany, and where he was a faculty member for Washington State University, USA. 22 years. In 1992 he founded the cross- After receiving his PhD in Human disciplinary University of Washington Nutrition from the University of Bonn Department of Molecular Biotechnolo- in 1985 he held research positions at gy in Seattle where in 2000 he co- the Mount Sinai Research Institute in founded the Institute for Systems Biol- Toronto, Canada and the Max Planck ogy. Dr. Hood is pioneering the transi- Institutes of Biophysical Chemistry and tion from current reactive medicine to a proactive (P4) medicine. Immunobiology in Göttingen and Freiburg. In 1993 he became Direc- He has published >700 peer-reviewed papers and textbooks, holds tor of the Institute of Mammalian Genetics at the Helmholtz Centre 32 patents and founded 13 biotechnology companies, including for Environment and Health in Munich. From 2001 to 2009 he was Amgen, Applied Biosystems, Systemix, Darwin, Rosetta, Integrated Scientific Director of the Helmholtz Centre for Infection Research in Diagnostics and the Accelerator. Dr. Hood is a member of the Nation- Braunschweig. He has published >150 papers in leading international al Academy of Sciences, the American Philosophical Society, the Amer- journals. In September 2009 he became the founding director of the ican Association of Arts and Sciences, the Institute of Medicine and Luxembourg Centre for Systems Biomedicine (LCSB) at the University the National Academy of Engineering. He has received the 1987 Lasker of Luxembourg in partnership with Leroy Hood and the ISB in Seattle, Award, the 2002 Kyoto Prize and the 2011 Russ Prize and was awarded dedicated to the development of P4 medicine with an initial focus on 17 honorary degrees from various academic institutions worldwide. Parkinson’s disease.We would like to acknowledge the support of the Lux-embourg Centre for Systems Biomedicine and the Dr. Charles Auffray graduated in Physi-University of Luxembourg (LH and RB), the NIH ology and Biochemistry (Ecole NormaleGeneral Medical Sciences Center for Systems Biolo- Supérieure), obtained a PhD in Molec-gy GM076547 (LH) and a Department of Defense ular Immunology (Pierre & Marie Curiecontract on Liver Toxicity W911SR-09-C-0062 (LH). Paris University and Pasteur Institute).The formation of the European Institute for Systems He was Post-doctoral Fellow and JuniorBiology & Medicine hosted at Claude Bernard Uni- Faculty (Harvard University); Groupversity is supported by the Lyonbiopole competitive Leader (Institute of Embryology,cluster and its academic, industrial, and local au- Nogent s/Marne); Scientific Directorthority partners, including Grand Lyon, Région (Généthon, Evry); Head of CNRS Research Unit (Functional GenomicsRhône-Alpes, Direction de la Recherche et de la Tech- and Systems Biology for Health, Villejuif). In 2010, he founded the Eu-nologie, and the Finovi Foundation (CA). ropean Institute for Systems Biology & Medicine in Lyon. Dr. Charles Auffray develops a systems approach to cancer and the physio-pathol-The authors declare no conflict of interest. ogy of the immune, neuro-muscular and respiratory systems by inte- grating functional genomics, mathematical, physical and computa- tional approaches through public-private partnerships and EU-funded9 References projects. He has published >250 original papers and 11 books. He co- founded the Systemoscope International Consortium with Profs Leroy [1] Hood, L., Deciphering complexity: A personal view of sys- tems biology and the coming of “Big” science. Genet. Eng. Hood (Seattle Institute for Systems Biology) and Zhu Chen (Shanghai Biotechnol. News 2011, 31, 131. Center for Systems Biomedicine) to support the development of sys- [2] Del Sol, A., Balling, R., Hood, L., Galas, D., Diseases as net- tems (P4) medicine. work perturbations. Curr. Opin. Biotechnol. 2010, 21, 566–571. [3] Hwang, D., Lee, I. Y., Yoo, H., Gehlenborg, N. et al., A systems approach to prion disease. Mol. Syst. Biol. 2009, 5, 252. [4] Shizhen, Q., Zhou, Y., Lok, A., Tsodikov, A. et al., SRM target- [6] Langen, R. C., Schols, A. M., Kelders, M. C., Wouters, E. F., ed proteomics in search for biomarkers of HCV-induced Janssen-Heininger, Y. M., Inflammatory cytokines inhibit progression of fibrosis to cirrhosis in HALT-C patients. Pro- myogenic differentiation through activation of nuclear fac- teomics 2012, 12, 1244–1252. tor-kappab. FASEB J. 2001, 15, 1169–1180. [5] Turan, N., Kalko, S., Stincone, A., Clarke, K. et al., A systems [7] Roach, J. C., Glusman, G., Smit, A. R., Huff, C. D. et al., Analy- approach identifies molecular networks defining skeletal sis of genetic inheritance in a family quartet by whole muscle abnormalities in chronic obstructive pulmonary dis- genome sequencing. Science 2010, 328, 636–639. ease. PLoS Comput. Biol. 2011, 7, e1002129.© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 9
  10. 10. Biotechnology Biotechnol. J. 2012, 7 Journal [8] Picotti, P Bodenmiller, B., Mueller, N., Domon, B., Aeber- ., [15] Supatto, W., Truong, T. V Débarre, D., Beaurepaire, E., Curr. ., sold, R., Full dynamic range proteome analysis of S. cere- Opin. Genet. Dev. 2011, 21, 538–548. visiae by targeted proteomics. Cell 2009, 138, 795–806. [16] Sigrist, S. J., Sabatini, B. L., Optical super-resolution mi- [9] Wang, J., Ahmad, H., Ma, C., Shi, Q. et al., A self-powered, croscopy in neurobiology. Curr. Opin. Neurobiol. 2012, 22, one-step chip for quantitative and multiplexed detection of 86–93. proteins from pin-pricks of whole blood. Lab Chip 2010, 10, [17] Park, I. H., Arora, N., Huo, H., Maherali, N. et al., Disease- 3157–3162. specific induced pluripotent stem cells. Cell 2008, 134,[10] Millward, S. W., Henning, R. K., Kwong, G. A., Pitram, S. et al., 877–886. Iterative in situ click chemistry assembles a branched cap- [18] Zhu, H., Lensch, M. W., Cahan, P Daley, G. Q., Investigating ., ture agent and allosteric inhibitor for Akt1. J. Am. Chem. Soc. monogenic and complex diseases with pluripotent stem 2011, 133, 1820–1828. cells. Nat. Rev. Genet. 2011, 12, 266–275.[11] Ostroff, R. M., Bigbee, W. L., Franklin, W., Gold, L. et al., Un- [19] Auffray, C., Chen, Z., Hood, L., Systems medicine: The future locking biomarker discovery: Large-scale application of ap- of medical genomics and healthcare. Genome Med. 2009, 1, tamer proteomic technology for early detection of lung can- 2. cer. PLoS ONE 2010, 7, e15003. [20] Hood, L., Friend, S. H., Predictive, personalized, preventive,[12] Hiller, K., Metallo, C. M., Kelleher, J. K., Stephanopoulos, G., participatory (P4) cancer medicine. Nat. Rev. Clin. Oncol. Nontargeted elucidation of metabolic pathways using sta- 2011, 8, 184–187. ble-isotope tracers and mass spectrometry. Anal. Chem. [21] Smarr, L., Quantifying your body: A how-to guide from a 2010, 82, 6621–6628. systems biology perspective. Biotechnol. J. 2012, 7. DOI:[13] Peng, G., Tisch, U., Adams, O., Hakim, M. et al., Diagnosing 10.1002/biot.201100495. lung cancer in exhaled breath using gold nanoparticles. Nat. [22] Kuhn T., The Structure of Scientific Revolutions, University of Nanotechnol. 2009, 4, 669–673. Chicago Press, USA, 1962.[14] Fens, N., Roldaan, A. C., van der Schee, M. P Boksem, R. J., ., et al., External validation of exhaled breath profiling using an electronic nose in the discrimination of asthma with fixed airways obstruction and chronic obstructive pul- monary disease. Clin. Exp. Allergy 2011, 41, 1371–1378.10 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim