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Science 309 (5731): 75-

Copyright © 2005 by the American Association for the Advancement of Science

What Don't We Know?

Donald Kennedy and Colin Norman

At Science, we tend to get excited about new discoveries that lift the veil a little on how things work, from cells to the universe. That puts our focus firmly on what has been added to our stock of knowledge. For this anniversary issue, we decided to shift our frame of reference, to look instead at what we don't know: the scientific puzzles that are driving basic scientific research.

We began by asking Science's Senior Editorial Board, our Board of Reviewing Editors, and our own editors and writers to suggest questions that point to critical knowledge gaps. The ground rules: Scientists should have a good shot at answering the questions over the next 25 years, or they should at least know how to go about answering them. We intended simply to choose 25 of these suggestions and turn them into a survey of the big questions facing science. But when a group of editors and writers sat down to select those big questions, we quickly realized that 25 simply wouldn't convey the grand sweep of cutting-edge research that lies behind the responses we received. So we have ended up with 125 questions, a fitting number for Science's 125th anniversary.

First, a note on what this special issue is not: It is not a survey of the big societal challenges that science can help solve, nor is it a forecast of what science might achieve. Think of it instead as a survey of our scientific ignorance, a broad swath of questions that scientists themselves are asking. As Tom Siegfried puts it in his introductory essay, they are "opportunities to be exploited."

We selected 25 of the 125 questions to highlight based on several criteria: how fundamental they are, how broad-ranging, and whether their solutions will impact other scientific disciplines. Some have few immediate practical implications--the composition of the universe, for example. Others we chose because the answers will have enormous societal impact--whether an effective HIV vaccine is feasible, or how much the carbon dioxide we are pumping into the atmosphere will warm our planet, for example. Some, such as the nature of dark energy, have come to prominence only recently; others, such as the mechanism behind limb regeneration in amphibians, have intrigued scientists for more than a century. We listed the 25 highlighted questions in no special order, but we did group the 100 additional questions roughly by discipline.

Our sister online publications are also devoting special issues to Science's 125th anniversary. The Science of Aging Knowledge Environment, SAGE KE (, is surveying several big questions confronting researchers on aging. The Signal Transduction Knowledge Environment, STKE (, has selected classic Science articles that have had a high impact in the field of cell signaling and is highlighting them in an editorial guide. And Science's Next Wave ( is looking at the careers of scientists grappling with some of the questions Science has identified.

We are acutely aware that even 125 unknowns encompass only a partial answer to the question that heads this special section: What Don't We Know? So we invite you to participate in a special forum on Science's Web site (, in which you can comment on our 125 questions or nominate topics we missed--and we apologize if they are the very questions you are working on.

Species diversity patterns in insular land snail communities of Borneo.
M. Schilthuizen, T.-S. Liew, T.-H. Liew, P. Berlin, J. P. King, and M. Lakim (2013)
Journal of the Geological Society 170, 539-545
   Abstract »    Full Text »    PDF »
Electroencephalogram signatures of loss and recovery of consciousness from propofol.
P. L. Purdon, E. T. Pierce, E. A. Mukamel, M. J. Prerau, J. L. Walsh, K. F. K. Wong, A. F. Salazar-Gomez, P. G. Harrell, A. L. Sampson, A. Cimenser, et al. (2013)
PNAS 110, E1142-E1151
   Abstract »    Full Text »    PDF »
Atmospheric propagation modeling indicates homing pigeons use loft-specific infrasonic 'map' cues.
J. T. Hagstrum (2013)
J. Exp. Biol. 216, 687-699
   Abstract »    Full Text »    PDF »
Strategies to Address Low Drug Solubility in Discovery and Development.
H. D. Williams, N. L. Trevaskis, S. A. Charman, R. M. Shanker, W. N. Charman, C. W. Pouton, and C. J. H. Porter (2013)
Pharmacol. Rev. 65, 315-499
   Abstract »    Full Text »    PDF »
The Pleasure of Not Knowing.
C. Matuk (2013)
Science 339, 523-524
   Abstract »    Full Text »    PDF »
An epigenetic view of plant cells cultured in vitro: somaclonal variation and beyond.
C. Miguel and L. Marum (2011)
J. Exp. Bot. 62, 3713-3725
   Abstract »    Full Text »    PDF »
Coordinated postnatal down-regulation of multiple growth-promoting genes: evidence for a genetic program limiting organ growth.
J. C. Lui, P. Forcinito, M. Chang, W. Chen, K. M. Barnes, and J. Baron (2010)
FASEB J 24, 3083-3092
   Abstract »    Full Text »    PDF »
Alanine-shaving Mutagenesis to Determine Key Interfacial Residues Governing the Assembly of a Nano-cage Maxi-ferritin.
Y. Zhang, S. Raudah, H. Teo, G. W. S. Teo, R. Fan, X. Sun, and B. P. Orner (2010)
J. Biol. Chem. 285, 12078-12086
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Commentaries on Viewpoint: Emergent phenomena and the secrets of life.
P. A. Robbins, B. Suki, J. J. Fredberg, F. E. Yates, J. H. T. Bates, T. Similowski, L. Glass, and A. J. E. Seely (2008)
J Appl Physiol 104, 1848-1850
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Water properties from first principles: Simulations by a general-purpose quantum mechanical polarizable force field.
A. G. Donchev, N. G. Galkin, A. A. Illarionov, O. V. Khoruzhii, M. A. Olevanov, V. D. Ozrin, M. V. Subbotin, and V. I. Tarasov (2006)
PNAS 103, 8613-8617
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Neutron Scattering and Diffraction Studies of Fluids and Fluid-Solid Interactions.
D. R. Cole, K. W. Herwig, E. Mamontov, and J. Z. Larese (2006)
Reviews in Mineralogy and Geochemistry 63, 313-362
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Rat airway smooth muscle cell during actin modulation: rheology and glassy dynamics.
R. E. Laudadio, E. J. Millet, B. Fabry, S. S. An, J. P. Butler, and J. J. Fredberg (2005)
Am J Physiol Cell Physiol 289, C1388-C1395
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