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C O M M E N TA R Y “ ”

Th e fi rst scientifi c journals in the late 17th century transformed the practice of science, which until then had oft en been a secre-tive occupation shrouded in mystery, and ushered in a culture of sharing that made it easier for scientists to build on each other’s contributions (Fig. 1). By speeding the com-pounding of knowledge, this, in turn, has-tened the pace of scientifi c discovery and spearheaded the technological progress that spawned our advanced industrial society. Yet in recent times, the reward and recog-nition lavished on successful individual sci-entists have somehow become an apparent deterrent to sharing. Th is occurs at a time when, paradoxically, the available tools, with the Internet being most notable, make such sharing more productive and sensible than ever. In the pharmaceutical industry, which has struggled to keep up the pace of its innovation, sharing could be the key that allows companies to access the vast creative, intellectual, and technological resources re-quired to tackle the formidable challenge of turning the riches of the genome into a trea-sure trove of new treatments.

A SMARTER WAY TO DO DRUG R&D

Sir Isaac Newton credited his accomplish-ments to standing “on the shoulders of giants.” Modern-day scientists do the same with each other. Th us, the movement that was born in the 1660s with publication of the Philosophi-cal Transactions of the Royal Society has blos-somed into thousands of journals that vie for scientists’ manuscripts. Sharing is a concept that resonates with researchers because it has

been an engine of scientifi c progress through much of the modern age.

Sharing also fosters cross-pollination, an essential driver of creativity. Over a thou-sand new scientifi c papers enrich the life science literature every day. Turning that

knowledge into novel insights, hypotheses, or ideas for treatments is an endeavor that is broader than any single drug company or research laboratory. Pharmaceutical fi rms

seldom have all the resources needed to ap-proach a disease by the many avenues that can yield viable therapies. Take type 1 juve-nile diabetes, for instance. It can potentially be treated with insulin, immunosuppres-sive drugs, vaccines, monoclonal antibod-ies, stem cells, tissue implants, gene therapy, allo- or xenotransplants, or a combination thereof. Th is combinatorial approach re-quires vast competencies across many fi elds that are unlikely to be found under one roof. Sharing addresses this challenge by bring-ing together people with complementary skills. Hollingsworth (1), who has studied breakthrough innovation across hundreds of biomedical research organizations, has observed that the most productive ones have numerous linkages to networks of sci-entists in diverse fi elds where the exchange of ideas takes place. When marshaled to-ward a common goal, these interacting innovation networks have been especially good at generating breakthrough solutions. Th ey are also more effi cient. Investing in a single or narrow set of options can lead to

overfunding projects that are not yet ready for translation. Scherer (2) has shown that in-creasing the number of compet-ing projects undertaken in par-allel is more likely to optimize the tradeoff between the speed and cost of R&D than pouring all resources into a single or small set of projects.

Sharing can happen on at least two levels. One is shar-ing knowledge and resources to make the discovery process more effi cient. If a company has developed biochemical and in vitro assays and an animal model for a particular disease, for instance, why screen only the compounds that its chem-ists can make? Why not lever-age that investment by invit-ing the chemists of the world, many of whom do not have the resources to develop their own assays, to submit their compounds for testing? Th is is the rationale behind Eli Lilly’s recently launched Phenotypic Drug Discovery or PD2 ini-

tiative (3). If an interesting compound is identifi ed, Lilly has the opportunity to ne-gotiate a collaboration with the compound’s owner. Innocentive is another venture that

D R U G D I S C O V E R Y

A Call for Sharing: Adapting Pharmaceutical Research to New Realities

Bernard H. Munos* and William W. Chin

*Corresponding author. E-mail: b.munos@lilly.com

Published 2 December 2009; Volume 1 Issue 9 9cm8

Eli Lilly and Company, Lilly Corporate Center,

Indianapolis, IN 46285, USA.

From the dawn of time, the sharing of knowledge has been one of the main forces driv-

ing science and innovation. Yet in recent decades, a proprietary culture, which wrongly

posits that all intellectual property must be restricted, has spread across the pharma-

ceutical industry and threatens to stall the engine that has given us so many valuable

treatments. This paper argues that pharmaceutical companies, together with universities

and government agencies, stand to gain much from reversing that trend and engaging

in widespread collaboration early in the research process to expand foundational knowl-

edge and create a shared infrastructure to tap it.

Fig. 1. Egypt’s “Fourth Great Pyramid.” The ancient Library of Alexandria was humanity’s fi rst attempt at sharing knowledge on a massive scale. Founded in the third cen-tury B.C.E., it grew to house nearly 700,000 scrolls, attracting scholars from all over the Mediterranean. For seven centuries, it proudly stood as a symbol of knowledge towering over humanity’s secular pursuits. Sadly, it succumbed to civil war and neglect at about 400 C.E.

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C O M M E N TA R Y “ ”seeks to harness the benefi ts of sharing by connecting problem owners (or “seekers”) to a worldwide online community of about 170,000 registered “solvers” (4). Results show that, in about 40% of the cases, some solvers have just the expertise needed to crack the challenges and are rewarded by cash prizes off ered by the seekers.

A second level of sharing revolves around goals that are diffi cult to achieve but whose rewards are potentially quite valuable. Pio-neering science has always been about dis-secting and fusing existing and new knowl-edge, a process that oft en reveals new vistas. And sharing can take that process to a level that begets genuine collective creation. De-Monaco (5) has shown that many thera-peutic innovations come from physicians who try to help patients for whom standard treatments have failed, and in doing so iden-tify new uses for existing drugs. Why not facilitate this process by opening the com-panies’ massive databases to the scrutiny of the world’s scientists? Some companies are already doing it. Lilly has long champi-oned transparency in clinical trials and was among the fi rst to endorse their mandatory registration in a public database and to pub-lish audited results. More recently, Glaxo-SmithKline shared genomic profi ling data on more than 300 cancer cell lines, and No-vartis released the results of a large genomic analysis of type II diabetes. Ultimately, shar-ing should bring about an effi cient division of labor in which companies collaborate and share the cost of advancing foundational knowledge, such as identifying single-nu-cleotide polymorphisms (SNPs) and other biomarkers; developing disease-state mod-els; elucidating pathways in complex dis-eases; and bringing to maturity sciences and technologies such as translational medicine, epigenomics, and stem cell biology. Compa-nies can then focus the bulk of their resourc-es on areas that are likely to yield new treat-ments, such as designing small molecules that eff ectively modulate specifi c targets and pathways, with distinctive clinical benefi ts over the current standard of care.

Sharing can also foster innovation in de-veloping countries. If scientists in geograph-ically isolated locations can access online tools and data that until recently were avail-able only to researchers from wealthy coun-tries, they might no longer need to emigrate in order to innovate. Instead, these scientists can leverage the online resources to conduct research that matters to them. Hohman et al. (6) recently used this paradigm to iden-

tify several promising compounds, some of which are existing drugs that can restore ef-fi cacy to chloroquine, an inexpensive and oft en ineff ective malaria treatment. If sci-entists in developing countries can create valuable intellectual property that then gen-erates the resources to fund future discovery cycles, they might be more inclined to sup-port intellectual property protection.

THE DAWN OF SCIENCE 2.0?

Th ere are many ways in which scientists in industry and academia can share informa-tion. We have mentioned a few. Another form of collaboration is to help strengthen the research infrastructure. For instance, the Critical Path Institute, an independent orga-nization founded at the behest of the U.S. Food and Drug Administration (FDA), has formed several industry consortia to devel-op new tools that can accelerate the develop-ment of medicines. One of them is creating disease progression models for Alzheimer’s and Parkinson’s diseases. Others work on validating biomarkers for cancer and car-diovascular diseases. A similar eff ort under-pins the Innovative Medicines Initiative in Europe. And there are still more consortia searching for new SNPs or elucidating cell-signaling pathways, as well as cooperatives to create superior animal models of disease and groups who share toxicology data. Drug companies are learning to collaborate on a range of issues, both large and small. Th ere are industry consortia to address privacy and data security issues, or the questions that arise between trial sponsors and inde-pendent review boards, or to advance the science of inhaled drugs by conducting joint R&D projects. Th ese consortia are extreme-ly cost-eff ective. Yet keeping them going has not always been easy because of industry’s strong proprietary culture, which tends to value internal work over collaboration. Th is total-ownership mindset, however, is becoming unaff ordable, making sharing an imperative. Entrepreneurs are stepping in to help. Edwards (7), for instance, has banded with the U.S. National Institutes of Health (NIH), GlaxoSmithKline, and several uni-versities to make a large number of chemi-cal and clinical probes freely available to the world’s scientists, who must in turn share their fi ndings. Other ideas, once unthink-able, may no longer be far off . For example, a consortium whose mission would be to administer a compound collection com-prising most or all of big pharma’s chemical collections would off er obvious benefi ts. If

a company has undiscovered treatments in its vaults, why not allow others to identify them? How long can mistrust stand in the way of the common good?

Th ese examples target low-hanging fruit and tend to involve institutions rather than individual scientists. Yet it is possible to imagine other sharing schemes [for in-stance, based on the open-source concept (8)] that can empower true collaborative creation of novel therapies. In 2008, India’s Council of Scientifi c and Industrial Re-search launched such an Open-Source Drug Discovery platform aimed at tuberculosis (9). Th is platform breaks down the steps of drug discovery into 10 work packets such as target identifi cation, target expression, drug screen development, in silico docking of molecules, etc. Any scientist interested in contributing his or her expertise can log on, join the appropriate work packet, and pitch in. More than 1250 scientists from 25 coun-tries have signed up to do so.

In a similar vein, Scott (10) at Indiana University–Purdue University Indianapolis (IUPUI) has created a Distributed Drug Dis-covery system, or D3, which breaks down drug discovery into three stages that rely on the expertise of volunteers in low-cost centers around the world. Th e fi rst step uses computational chemists and the idle power of numerous personal computers to scan the molecular space and identify a small number of promising drug candidates. Th e second step uses students at universities in the United States, Spain, Poland, and Russia to synthesize the molecules as part of their training. Th e last step, currently performed with the help of scientists at NIH, will even-tually use students and inexpensive tests to perform primary biological screening.

Some pioneers from academia have gone further and are pushing to use the interactive tools of Web 2.0, which include blogs, wikis, YouTube, social Web sites, and RSS feeds, to create a robust framework for open science that would make drug R&D a broad-based participatory exercise. Web 2.0 is based on the idea of user-generated content: Someone sets up a Web site, and users create the content. Th e idea seems to be getting some traction. Scienceblogs.com hosts 75 blogs, some of them attract-ing 1.5 million visitors a month. Others such as Neurodudes (11), Brain Waves (12), and In the Pipeline (13) appeal to audi-ences of neuroscientists and pharmaceuti-cal researchers. Social bookmarking Web sites such as Connotea or CiteULike help

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C O M M E N TA R Y “ ”scientists locate material that their peers have found useful. Since 2007, the Journal of Visualized Experiments, a peer-reviewed, PubMed-indexed platform, has published biological research in video format (14). Some scientists, however, choose to use the more informal YouTube (15) to disclose material, such as negative or inconclusive results, which are diffi cult to publish in a peer-reviewed medium. Jean-Claude Brad-ley at Drexel University has pioneered the use of open notebooks to share his chem-istry experiments in real time with the rest of the world (16). Th e OpenWetWare Web site (17) uses wikis to share experimental protocols and lab books that display every-thing, successful or not. Nature’s Network (18) and biomedexperts (19) are social Web sites designed to help scientists locate and connect with relevant expertise.

Some researchers have voiced concerns about the lack of quality standards that pervades this rising tide of user-created content. Th ey fear that, because it is free, easy to fi nd, and frequently off ered in a col-loquial, more engaging format than peer-reviewed literature, it may acquire a promi-nence unjustifi ed by its scientifi c value. In fact, one should not pit Science 1.0—peer-reviewed literature—against Science 2.0. Far from competing with each other, these channels meet diff erent but complemen-tary needs. Shared user-generated content rules the forum where novel ideas and in-sights take shape. It meets the demand for informal and rapid-fi re communications of participating scientists. Most of the work of researchers never makes it into a peer-reviewed journal and remains, therefore, inaccessible to most people. Yet there is much to be learned from the setbacks and meanderings that accompany the making of a scholarly paper. Open science helps lift the veil of secrecy so that researchers can learn from each other’s stumbling.

IF YOU BUILD IT, WILL THEY COME?

Despite the benefi ts that come with it and the availability of tools that allow it, many scientists remain ambivalent about sharing. In 2006, Nature launched an experiment that gave scientists the opportunity to com-ment on papers undergoing peer review. It was not a success. Th ere were few com-ments, and most of them were not substan-tive. Despite vocal advocates, few scientists have adopted the tools of open science, and industry oft en restricts the ability of its re-searchers to do so. Part of the problem is

that the system used to assess and reward scientifi c output favors “closed” science. By and large, scientists are still judged by their number of experiments, publications, pat-ents, and citations. Th ere is no credit, and thus no reward, for writing a blog or post-ing comments.

Employers are also wary. Hanging out on the Web takes precious time away from building molecules and other “real work.” Pouring your mind into a blog could result in inadvertent disclosures that might com-promise intellectual property. It can also tip off a competitor, who could take your half-baked idea, improve it, and scoop you.

Th e infrastructure for sharing may be in place, but the cultural barriers are prov-ing more daunting than the technical ones. Many of these fears are rooted in the pro-prietary mindset that has long dominated the industry. Yet sharing is helping to overcome them. For instance, many drug companies have developed robust methods to test the safety of their drugs. However, mutual distrust has kept these companies from working toward a common approach, leaving FDA scientists confused about which methods are better and should be the preferred ones. In 2006, the Predictive Safety Testing Consortium, organized by the Critical Path Institute, invited pharma-ceutical companies to meet with scientists from the FDA and the European Medicines Agency to test and compare their respec-tive methods, so that regulators could is-sue better guidance. Th ey now convene monthly and involve over 200 scientists in the discussions.

REKINDLING THE CULTURE

OF SHARING

Th e fear of jeopardizing intellectual property or giving away valuable ideas that might be appropriated by colleagues or competitors without due credit looms large in the endur-ing resistance to sharing. Th is concern, al-though legitimate, fails to appreciate that the process of innovation has been profoundly transformed by the growing complexity of science. Innovation once resulted mostly from large quantum advances. Today, how-ever, innovation increasingly stems from the aggregation of numerous small contri-butions. Th is trend, which became notice-able a couple of decades ago, has reached problematic proportions. Th ere is hardly an invention today that cannot be traced to nu-merous prior patented discoveries. Secur-ing the rights to this intellectual property

has signifi cantly slowed innovation and in-creased its cost. It is not uncommon for such negotiations to take years and for the sum of the royalties on the prior art to threaten the viability of the innovation being pursued, a problem known to patent lawyers as “royalty stacking.” Any holdout can freeze the pro-cess, causing further delays and costs. Th e Internet has the potential to signifi cantly increase the fl ow of microcontributions and leverage downstream innovation according-ly. Yet the fear of having one’s ideas stolen is hindering sharing and spoiling this oppor-tunity (Fig. 2). It would help if the existing legal framework were to be supplemented in a way that would protect microcontribu-tions as they arise, in a process somewhat akin to what already happens with copy-rights. Th is could perhaps be achieved with an online registry that allows scientists to record and time-stamp their contributions as an optional but cheaper and faster alter-native to patenting them. If such a contribu-tion should subsequently fi nd its way into a commercial product, its inventor(s) would be entitled to part of a statutory share of the product’s revenues that would be split among such claimants.

Th e drug industry today produces about 20 new drugs annually, roughly the same number as it did 50 years ago. Each compa-ny produces new drugs at a constant rate, and all attempts to speed drug innovation

have failed to increase this mean drug out-put (20). However, evidence suggests that enhanced sharing of knowledge can change these dynamics by making everyone better informed and increasing success, a process economists call spillover. Th e Internet, as an example, off ers unprecedented oppor-

Fig. 2. Seize the day. In 1959, John F. Kennedy made a speech in the authors’ hometown of Indianapolis, Indiana, and remarked that the Chinese word for crisis was made up of two characters, one that represents danger and an-other that represents opportunity. Fifty years later, his message still resonates.

Danger Opportunity

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C O M M E N TA R Y “ ”tunities for sharing, which hold the hope of energizing therapeutic innovation and ushering in a new golden age of drug dis-covery. However, secretive behaviors in-herited from the past and reinforcement by an intellectual property–protection frame-work that predates the Internet threaten to derail these opportunities. Changing this situation will take bold initiatives from se-nior industry and academic leaders as well as policy-makers to build in the incentives that are now lacking. One expected result should be greater collaboration upstream in the drug R&D process to expand foun-dational knowledge and create a shared infrastructure as well as tools to mine it. Such collaboration will eliminate much duplicative work, allowing pharmaceutical companies to refocus the resulting savings on downstream research through which new drugs and competitive advantage are created. Stated diff erently, companies should compete in areas that off er a viable return on investment, and share where

pre-competitive collaboration helps all of us discover new therapies more effi ciently and eff ectively, as patients and society de-mand. In sum, we issue a call to action to the pharmaceutical industry, universities, and government agencies to join hands and intensify sharing in order to help repower pharmaceutical innovation.

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tional Change, J. Hage, M. T. H. Meeus, Eds. (Oxford Univ. Press, New York, 2006), pp. 423–442.

2. F. M. Scherer, Pharmaceutical Innovation (Working Paper No. 07-19, AEI-Brookings Joint Center, 2007).

3. Eli Lilly’s PD2 Initiative, https://www.pd2.lilly.com/pd2Web. 4. Innocentive, http://www.innocentive.com. 5. H. J. DeMonaco, A. Ali, E. Hippel, The major role of clini-

cians in the discovery of off -label drug therapies. Phar-macotherapy 26, 323–332 (2006).

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7. A. M. Edwards, C. Bountra, D. J. Kerr, T. M. Willson, Open access chemical and clinical probes to support drug dis-covery. Nat. Chem. Biol. 5, 436–440 (2009).

8. B. Munos, Can open-source R&D reinvigorate drug re-search? Nat. Rev. Drug Discov. 5, 723–729 (2006).

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10. W. L. Scott, M. J. O’Donnell, Distributed Drug Discovery, Part 1: Linking academia and combinatorial chemistry to fi nd drug leads for developing world diseases. J. Comb. Chem. 11, 3–13 (2009).

11. Neurodudes, http://www.neurodudes.com. 12. Brain Waves, http://www.corante.com/brainwaves. 13. In the Pipeline, http://www.pipeline.corante.com. 14. Journal of Visualized Experiments, http://www.jove.com. 15. YouTube, http://www.youtube.com. 16. Open Notebook Science, http://www.usefulchem.

wikispaces.com. 17. OpenWetWare, http://www.OpenWetWare.org. 18. Nature Network, http://www.network.nature.com. 19. BiomedExperts, http://www.biomedexperts.com. 20. B. Munos, Lessons from 60 years of pharmaceutical in-

novation. Nat. Rev. Drug Discov. 8, 959–968 (2009).

Citation: B. H. Munos and W. W. Chin, A call for sharing: Adapting pharmaceutical research to new realities. Sci. Transl. Med. 1, 9cm8 (2009).

10.1126/scitranslmed.3000155

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A Call for Sharing: Adapting Pharmaceutical Research to New RealitiesBernard H. Munos and William W. Chin

DOI: 10.1126/scitranslmed.3000155, 9cm89cm8.1Sci Transl Med

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