Marc W. Kirschner, Ph.D. is founding chair of the Department of Systems Biology. He and John Gerhart are co-authors of Cells, Embryos, and Evolution (Blackwell, 1997) and their newly published book, The Plausibility of Life: Resolving Darwin¹s Dilemma (Yale University Press, 2005). Dr. Kirschner was elected Foreign Member of the Royal Society of London and as a Foreign Member of the Academia Europaea in 1999. He was the 2001 recipient of the William C. Rose Award, presented by the American Society for Biochemistry and Molecular Biology. Later that year, he received a 2001 International Award by the Gairdner Foundation of Toronto. He was awarded the Rabbi Shai Shacknai Lectureship Prize for 2003 at the Lautenberg Center for General and Tumor Immunology at The Hebrew University in Jerusalem. In December 2003, Kirschner received the E.B. Wilson Medal, the American Society of Cell Biology¹s highest scientific honor named for an early 20th century pioneer of American biology who advocated the chromosomal theory of inheritance, is awarded by scientific peers to those who have made significant and far-reaching contributions to cell biology over the course of a career. He received the Dickson Prize for Science from Carnegie Mellon University for his outstanding contributions to science in 2004. He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and has served on the Advisory Committee to the Director of the National Institutes of Health and as President of the American Society for Cell Biology. Dr. Kirschner¹s laboratory investigates three broad, diverse areas: regulation of the cell cycle, the role of cytoskeleton in cell morphogenesis, and mechanisms of establishing the basic vertebrate body plan.

In 1993, Dr. Kirschner arrived at Harvard Medical School from the University of California, San Francisco, where he had served on the faculty as Professor for fifteen years. Dr. Kirschner graduated from Northwestern University in 1966 and received his Ph.D. from the University of California, Berkeley in 1971. Following postdoctoral research at Berkeley and at the University of Oxford, he was appointed an Assistant Professor at Princeton University in 1972.

Research Interests

Organizing Space and Time. In the development of an organism, as in the theater, timing is everything. Imagine if, one night, the actors in a play were to miss every single cue, delivering each line perfectly, but always too early or too late. The evening would be a disaster. The same is true in embryonic development. Starting at the moment when sperm and egg meet, cells in the embryo send signals to each other to coordinate the growth of organs, limbs, and tissues. Not only do the signals have to be correct, they also must be perfectly timed. Otherwise, disasters like cancer can result.

The Kirschner lab studies, among many other things, the way a developing frog embryo orchestrates numerous signals to yield the final, complex organism. Just as multiple cues would destroy an actor's ability to deliver his lines at the right time, it would seem like the existence of multiple signals ought to result in cellular cacophony. But, somehow, the cells in the embryo can sort out the meaning of the different signals that are bombarding them. In particular, the lab is investigating the signals that tell cells when to divide.

Research Projects

Some of the most fascinating problems of biology concern spatial organization and temporal control. The embryo developing from a single egg generates a pattern of differentiation and growth that is closely controlled and, especially in vertebrate embryos, capable of remarkable regulation and recovery from injury. Many pathological conditions are the failure to regulate growth, control differentiation, or establish the proper morphological connections. In my laboratory we are concerned with three major problems of spatial and temporal control: control of the cell cycle, patterning of embryonic tissues, and control of cell morphology.

We started simple assays for the regulation of cell division in frog oocytes and embryos. But these assays, combined with an explosion of new genetic and biochemical information on the cell cycle, have quickly evolved into very specific biochemical investigations, applicable to all higher organisms. The two central players in cell division control are a set of unstable regulatory subunits called cyclins and a set of inactive catalytic subunits called cyclin-dependent kinases. Together, they govern the important cell cycle transitions that control DNA replication and mitosis. To study the activation and the inactivation of these kinases, we have developed in vitro systems using extracts from frog eggs. Activation and inactivation are under both external control by signals that regulate call proliferation and internal control by processes that maintain the fidelity of DNA replication and mitosis. Entry into mitosis is regulated not only by the accumulation of the appropriate cyclin but by kinases and phosphatases that we have studied.

The activation of DNA replication is poorly understood, but we have shown that it, too, is dependent on cyclins. Although more than one cyclin-dependent step may be required, we have begun to describe the downstream pathways by fractionating extracts that spontaneously synthesize DNA directly after mitosis. Exit from mitosis is regulated by cyclin degradation, which is initiated by the activation of a cyclin-dependent kinase. Cyclin degradation is of considerable interest, since the stability of the protein is under such exquisite control. Our data show that the regulated step is the covalent attachment of a protein called ubiquitin to the N-terminus of cyclin. The attachment is mediated by a 9 amino acid motif in the N-terminus of all mitotic cyclins. We have also shown that ubiquitination of another set of cyclins may be important in the activation of DNA replication. We would like to know whether regulated degradation is used elsewhere in developing embryos and to identify the mechanism of recognition.

As embryos develop the regulation of cell division and cell differentiation becomes increasingly reliant on intercellular communication, rather than on cell-autonomous mechanisms. In vertebrate embryos intercellular signals organize the body axis of the embryo on the dorsal side, including the neural tube, somites, and notochord. We have delineated the role of one of the signaling molecules, fibroblast growth factor (FGF), in frog embryonic development by expressing dominant inhibitors comprising the extracellular domain of the FGF receptor. FGF interacts with other signaling pathways, and we are attempting to understand how these signals lead to a well proportioned elaboration of embryonic tissues. In addition, we are looking for other ligand-receptor pairs in the embryo. The establishment of the body plan in the trunk of the embryo is recapitulated in the tadpole tail. But, in the tail, the pattern of cell division and cell movements is very different from that in the trunk. We hope, by studying cell specification in the tail, to determine the signals and responses most critical for pattern formation.

One of the most refractory and important problems in cell biology is spatial organization of cells, which is manifest embryonically in the organization of the egg and somatically in the differentiation and mitotic division of all cell types. We have focused our attention on the organization of the cytoskeleton, principally microtubules. Microtubules are particularly important in the mitotic spindle and in elongating cellular processes, especially those of neurons. We have been interested in the control of microtubule dynamics, the nucleation of microtubules from centrosomes in mammalian cells, and the role of microtubules in morphogenetic processes, such as axon growth and cell movement. Using low-light video microscopy of a fluorescently tagged subunit of microtubules in neurons, we have shown that the placement of microtubules is a critical early step in the choice of direction in nerve cell growth. We are determining the signals outside the cell to which microtubules respond as well as the intervening biochemical steps that result in microtubule polymerization or stabilization, and ultimately, polarized cell growth. A combination of real-time visual observation of cell biological mechanisms with reconstruction of functions by biochemical assays in cell-free systems, I believe, offers the best opportunity for understanding these difficult problems of cell biology.

Selected References

Stukenberg, P.T., Lustig, K.D., McGarry, T.J., King, R.W., Kuang, J. and Kirschner, M.W. (1997). Systematic identification of mitotic phosphoproteins. Current Biology 7: 338-348.

Philpott, A., Porro, E.B., Kirschner, M.W. and Tsai, L.H. (1997). The role of cyclin-dependent kinase 5 and a novel regulatory subunit in regulating muscle differentiation and patterning. Genes Development 11: 1409-1421.

Rankin, S. and Kirschner, M.W. (1997). The Surface contraction waves of Xenopus eggs reflect the metachronous cell-cycle state of the cytoplasm. Current Biology 7: 451-454.

Lustig, K.D., Stukenberg, P.T., McGarry, T.J., King, R.W., Cryns, V.L., Mead, P.E., Zon, L.I., Yuan, J and Kirschner, M.W. (1997). Small Pool Expression Screening: A Novel Strategy for the Identification of Genes Involved in Cell Cycle Control, Apoptosis and Early Development. Methods in Enzymology, 283: 83-99.

King, R.W., Lustig, K.D., Stukenberg, P.T., McGarry, T.J., and Kirschner, M.W. (1997). Expression cloning in the test tube. Science 277:973-974.

Yew, P.R., and Kirschner, M.W. (1997). Proteolysis and DNA Replication: the CDC34 Requirement in the Xenopus Egg Cell Cycle. Science 277: 1672-1676.

Salic, A.N., Kroll, K.L., Evans, L.M., and Kirschner, M.W. (1997). Sizzled: A secreted Xwnt8 antagonist expressed in the ventral marginal zone of Xenopus embryos. Development 124: 4739-4748.

Kirschner, M. and Gerhart, J. (1998). Comment on "Epigenetic inheritance in evolution". [Commentary] Journal of Evolutionary Biology 11: 213-217.

Yu, H., Peters, J-M., King, R.W., Page, A., Hieter, P., and Kirschner, M.W. (1998). Identification of a Cullin Homology Region in a Subunit of the Anaphase-Promoting Complex [AU1]. Science 279: 1219-1222.

Ma, L., Cantley, L.C., Janmey, P.A., and Kirschner, M.W. (1998). Co-requirement of specific phosphoinositides and small GTP-binding protein Cdc42 in inducing actin assembly in Xenopus egg extracts. Journal of Cell Biology 140: 1125-1136.

Kroll, K.L., Salic, A., Evans, L., and Kirschner, M.W. (1998). Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation. Development 125: 3247-3258.

Fang, G., Yu, H., and Kirschner, M.W. (1998). The Checkpoint Protein MAD2 and the Mitotic Regulator CDC20 Form a Tenary Complex with the Anaphase-Promoting Complex to Control Anaphase Initiation. Genes & Development 12: 1871-1883.

McGarry, T.J. and Kirschner, M.W. (1998). Geminin: An Inhibitor of DNA Replication is Degraded during Mitosis. Cell 93: 1043-1053.

Kirschner, M. and Gerhart, J. (1998). Evolvability (Perspective). Proc. Natl. Acad. Sci. USA 95: 8420-8427.

Fang, G., Yu, H., and Kirschner, M.W. (1998). Direct Binding of CDC20 Protein Family Members Activates the Anaphase-Promoting Complex in Mitosis and G1. Mol. Cell 2: 163-171.

Ma, L., Rohatgi, R. and Kirschner, M.W. (1998). The Arp2/3 complex mediates actin polymerization induced by the small GTP-binding protein Cdc42. Proc. Natl. Acad. Sci. USA 95: 15362-15367.

Zhou, B. and Kirschner, M.W. (1999) Quantitative Measurement of the Catastrophe Rate of Dynamic Microtubules. Cell Motility and the Cytoskeleton, 43: 43-51.

Rohatgi, R., Ma, L., Miki, H., Lopez, M., Kirchhausen, T., Takenawa, T., and Kirschner, M.W. (1999) The Interaction between N-WASP and the Arp2/3 Complex Links Cdc42-Dependent Signals to Actin Assembly. Cell 97: 221-231.

Zou, H., McGarry, T.J., Bernal, T., and Kirschner, M.W. (1999) Identification of a Vertebrate Sister-Chromatid Separation Inhibitor Involved in Transformation and Tumorigenesis. Science 285: 418-422.

Haushalter, K.A., Stukenberg, P.T., Kirschner, M.W. and Verdine, G.L. (1999).  Identification of a new uracil-DNA glycosylase family by expression cloning using synthetic inhibitors.  Current Biology 9: 174-185.

Philpott, A., Tsai, L., and Kirschner, M.W. (1999)  Neuronal Differentiation and Patterning in Xenopus: The Role of cdk5 and a Novel Activator Xp35.2.  Developmental Biology 207: 119-132.

Zhou, B. and Kirschner, M.W. (1999)  Quantitative Measurement of the Catastrophe Rate of Dynamic Microtubules.  Cell Motility and the Cytoskeleton, 43: 43-51.

Rohatgi, R., Ma, L., Miki, H., Lopez, M., Kirchhausen, T., Takenawa, T., and Kirschner, M.W.  (1999)  The Interaction between N-WASP and the Arp2/3 Complex Links Cdc42-Dependent Signals to Actin Assembly.  Cell 97: 221-231.

Zou, H., McGarry, T.J., Bernal, T., and Kirschner, M.W.  (1999)  Identification of a Vertebrate Sister-Chromatid Separation Inhibitor Involved in Transformation and Tumorigenesis.  Science 285: 418-422.

Odde, D.J., Ma, L., Briggs, A.H., DeMarco, A., and Kirschner, M.W. (1999)  Microtubule Bending and Breaking in Living Fibroblasts.  Journal of Cell Science 112: 3283-3288.

Fang, G., Yu, H., and Kirschner, M.W. (1999)  Control of mitotic transitions by the anaphase-promoting complex.  Phil. Trans. R. Soc. Lond. 354: 1583-1590.

Kroll, K.L. and Kirschner, M.W. (1999)  Easy passage: Germline transgenesis in frogs (Commentary). Proc. Natl. Acad. Sci. USA 96: 14189-14190.

Davis, R.L. and Kirschner, M.W. (2000)  The fate of cells in the tailbud of Xenopus laevis.  Development 127: 255-267.

Salic, A., Lee, E., Mayer, L., and Kirschner, M.W. (2000)  Control of b-Catenin Stability: Reconstitution of the Cytoplasmic Steps of the Wnt Pathway in Xenopus Egg Extracts.  Molecular Cell 5: 523-532.

Pfleger, C.M. and Kirschner, M. W. (2000)  The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1.  Genes & Development 14: 655-665.

Luo, X., Fang, G., Coldiron, M., Lin, Y., Yu, H., Kirschner, M.W., and Wagner, G.  (2000)  Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20.  Nature Structural Biology 7: 224-229.

Chen, F., Ma, L., Parrini, M.C., Mao, X., Lopez, M., Wu, C., Marks, P.W., Davidson, L., Kwiatkowski, D.J., Kirchhausen, T., Orkin, S.H., Rosen, F.S., Mayer, B.J., Kirschner, M.W., and Alt, F.W.  (2000)  Cdc42 is required for PIP (2)-induced actin polymerization and early development but not for cell viability.  Current Biology 10 (13): 758-765.

Rohatgi, R., Ho, H., and Kirschner, M.W. (2000)  Mechanism of N-WASP Activation by CDC42 and Phosphatidylinositol 4,5-bisphosphate.  Journal of Cell Biology 150 (6): 1299-1309.

Yamaguchi, H., Miki, H., Suetsugu, S., Ma, L., Kirschner, M.W., and Takenawa, T. (2000)  Two tandem verprolin homology domains are necessary for a strong activation of Arp2/3 complex-induced actin polymerization and induction of microspike formation by N-WASP. Proc. Natl. Acad. Sci. USA 97: 12631-12636.

Stukenberg, P.T. and Kirschner, M.W. (2001)  Pin1 Acts Catalytically to Promote a Conformational Change in Cdc25.  Molecular Cell 7: 1071-1083.

Pfleger, C.M., Salic, A., Lee, E., and Kirschner, M.W. (2001)  Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1.  Genes & Development 15:1759-1764.

Rohatgi, R., Nollau, P.; Ho, H., Kirschner, M.W., and Mayer, B.J. (2001)  Nck and Phosphatidylinositol 4,5-Bisphosphate Synergistically Activate Actin Polymerization through the N-WASP-Arp2/3 Pathway. Journal of Biological Chemistry 276: 26448-26452.

Pfleger, C.M., Lee, E., and Kirschner, M.W. (2001). Substrate recognition by the Cdc20 and Cdh1 components of the Anaphase Promoting Complex. Genes & Development, 15:2396-407.

Lee, E., Salic, A., and Kirschner, M.W. (2001). Physiological regulation of β-catenin stability by Tcf3 and CK1ε. Journal of Cell Biology 154: 983-993.

Peterson, J.R., Lokey, R.S., Mitchison, T.J., and Kirschner, M.W. (2001). A chemical inhibitor of N-WASP reveals a new mechanism for targeting protein interactions. Proc. Natl. Acad. Sci. USA 98: 10624-10629.

Ho, H.-Y., Rohatgi, R., Ma, L., and Kirschner, M.W. (2001). CR16 forms a complex with N-WASP in brain and is a novel member of a conserved proline-rich actin-binding protein family. Proc. Natl. Acad. Sci. USA 98: 11306-11311.

Davis, R.L., Turner, D.L., Evans, L.M., and Kirschner, M.W. (2001). Molecular Targets of Vertebrate Segmentation: Two Mechanisms Control Segmental Expression of Xenopus hairy2 during Somite Formation. Developmental Cell 1: 553-565.

Wan, Y. and Kirschner, M.W. (2001). Identification of multiple CDH1 homologues in vertebrates conferring different substrate specificities. Proc. Natl. Acad. Sci. USA 98: 13066-13071.

Wan, Y., Liu, X., and Kirschner, M.W. (2001). The Anaphase-Promoting Complex Mediates TGF-β Signaling by Targeting SnoN for Destruction. Molecular Cell 8: 1027-1039.

Stemmann, O., Zou, H., Gerber, S.A., Gygi, S.P., and Kirschner, M.W. (2001). Dual Inhibition of Sister Chromatid Separation at Metaphase. Cell 107: 715-726.

Georgi, A.B., Stukenberg, P. T., and Kirschner, M.W. (2002). Timing of Events in Mitosis. Current Biology 12: 105-114.

Eden, S., Rohatgi, R., Podtelejnikov, A.V., Mann, M., and Kirschner, M.W. (2002). Mechanism of regulation of WAVE1-inducedactin nucleation by Rac1 and Nck.  Nature418: 790-793.

Kwan, K.M. and Kirschner, M.W.  (2003).  Xbra functions as a switch between cell migration and convergent extension in the Xenopus gastrula.  Development 130: 1961-1972.

Ayad, N.G., Rankin, S., Murakami, M., Jebanathirajah, J., Gygi, S., and Kirschner, M.W.   (2003)  Tome-1, a Trigger of Mitotic Entry, is Degraded During G1 via the APC. Cell 113: 101-113 .

Lowe, C.J., Wu, M., Salic, A., Evans, L., Lander, E., Stange-Thomann, N., Gruber, C.E., Gerhart, J., and Kirschner, M.  (2003)  Anteroposterior Patterning in Hemichordates and the Origins of the Chordate Nervous System.  Cell 113: 853-865.

Lee, E., Salic, A., Krger, Heinrich, R., Kirschner, M.W.  (2003)  The Roles of APC and Axin Derived from Experimental and Theoretical Analysis of the Wnt Pathway. Public Library of Science 1: 116-132.

Song, M., Song, S., Ayad, N., Lee, J., Hong, H., Chang, J., Kim, J., Choi, E., Kirschner, M., Lim, D. (2004) The tumor suppressor RASSF1A regulates mitotic progression through interaction with Cdc20 and inhibition of the anaphase promotingcomplex.   Nature Cell Biol. 6(2):129-137.

Campellone, K.G., Rankin, S., Pawson, T., Kirschner, M.W., Tipper, D.J., and  Leong, J.M.  (2004)  Clustering of Nck by a 12- residue Tir phosphopeptide is sufficient to trigger localized actin assembly.  Journal ofCell Biology 164 (3): 407416.

Wei ,W., Ayad, N.G., Wan, Y., Zhang, G.J., Kirschner, M.W., Kaelin, W.G., Jr. (2004) Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428 (6979): 194-8.

Gautreau, A., Ho, H.Y., Li , J., Steen, H., Gygi , S.P., Kirschner, M.W. (2004) Purification and architecture of the ubiquitous Wave complex. Proc Natl Acad Sci U S A. 101(13): 4379-83.

Martinez-Quiles, N., Ho, H.Y., Kirschner, M.W., Ramesh, N., Geha, R.S. (2004) Erk/Src Phosphorylation of Cortactin Acts as a Switch On-Switch Off Mechanism That Controls Its Ability To Activate N-WASP. Mol Cell Biol. 24(12): 5269-5280.

Ho, H.Y., Rohatgi, R., Lebensohn, A.M., Ma, L., Li, J., Gygi, S.P., Kirschner, M.W. (2004) Toca-1 Mediates Cdc42-Dependent Actin Nucleation by Activating the N-WASP-WIP Complex. Cell 118 (2): 203-216.

Peterson, J.R., Bickford, L.C., Morgan, D., Kim, A.S., Ouerfelli, O., Kirschner, M.W., Rosen, M.K. (2004) Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Nat Struct Mol Biol. Aug; 11(8):747-755. Epub 2004 Jul 04.

Margalit, D.N., Romberg, L., Mets, R.B., Hebert, A.M., Mitchison, T.J., Kirschner, M.W., RayChaudhuri, D. (2004) Targeting cell division: Small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethality. Proc. Natl. Acad. Sci. USA. 101(32): 11821-11826. Epub 2004 Aug 02.

Rape, M., and Kirschner, M. W. (2004) Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. Nature. Dec 2; 432 (7017): 588-595. Epub 2004 Dec 2.

Lowe, C. J., Tagawa, K., Humphreys, T., Kirschner, M., Gerhart, J. (2004) Hemichordate embryos: procurement, culture, and basic methods. Methods Cell Biol. 74: 171-194.

Lee LA, Lee E, Anderson MA, Vardy L, Tahinci E, Ali SM, Kashevsky H, Benasutti M, Kirschner MW, Orr-Weaver TL. (2005) Drosophila genome-scale screen for PAN GU kinase substrates identifies Mat89Bb as a cell cycle regulator. Dev Cell. 8(3):435-42.

Steen H, Jebanathirajah JA, Springer M, Kirschner MW. (2005) Stable isotope-free relative and absolute quantitation of protein phosphorylation stoichiometry by MS. Proc Natl Acad Sci U S A. 102(11):3948-53.

Rankin S, Ayad NG, Kirschner MW. (2005) Sororin, a substrate of the anaphase- promoting complex, is required for sister chromatid cohesion in vertebrates. Mol Cell. 18(2):185-200.

Kirschner, M.W.  (2005) The Meaning of Systems Biology (commentary).  Cell 121: 503-504.

Gerhart, J., Lowe, C., Kirschner, M. (2005) Hemichordates and the origin of chordates. Current Opinion in Genetics and Development 15 (4): 461-467.

Viadiu, H., Stemmann, O., Kirschner, M.W., Walz, T. (2005) Domain structure of separase and its binding to securin as determined by EM. Nat Struct Mol Biol. 12 (6):552-3.

Kwan, KM and Kirschner, MW (2005)  A microtubule-binding Rho-GEF controls cell morphology during convergent extension of Xenopus laevis. Development 132(20):4599-610.

Jebanathirajah JA, Pittman JL, Thomson BA, Budnik BA, Kaur P, Rape M, Kirschner M, Costello CE, and O'Connor PB. (2005) Characterization of a New qQq-FTICR Mass Spectrometer for Post-Translational Modification Analysis and Top-Down Tandem Mass Spectrometry of Whole Proteins. J Am Soc Mass Spectrom. 16(12):1985-99.

Ayad NG, Rankin S, Ooi D, Rape M, Kirschner MW. (2005) Identification of ubiquitin ligase substrates by in vitro expression cloning. Methods Enzymol. 399:404-14.

Rape M, Reddy SK, Kirschner MW. (2006) The processivity of multiubiquitination by the APC determines the order of substrate degradation. Cell 124(1):89-103.

Lebensohn AM, Ma L, Ho HYH, and Kirschner MW (2006) Cdc42 and PI(4,5)P2-Induced Actin Assembly in Xenopus Egg Extracts. Method Enzymol.
406: 156-173.

Ho HYH, Rohatgi R, Lebensohn AM, and Kirschner MW (2006) In Vitro Reconstitution of Cdc42-Mediated Actin Assembly Using Purified Components. Methods Enzymol. 406: 174-190.

Weiner OD, Rentel MC, Ott A, Brown GE, Jedrychowski M, Yaffe MB, Gygi SP, Cantley LC, Bourne HR, Kirschner MW. (2006) Hem-1 Complexes Are Essential for Rac Activation, Actin Polymerization, and Myosin Regulation during Neutrophil Chemotaxis. PLoS Biol. 4(2):e38 [Epub ahead of print] PMID: 16417406 [PubMed - as supplied by publisher]

Peterson JR, Lebensohn AM, Pelish HE and Kirschner MW (2006) Biochemical Suppression of Small-Molecule Inhibitors: A Strategy to Identify Inhibitor Targets and Signaling Pathway Components. Chemistry & Biology 13: 443-452.

Books

Gerhart, J.C. and Kirschner, M.W. Cells, Embryos and Evolution. Boston: Blackwell Science, 1997.

Kirschner, M.W. and Gerhart, J.C. The Plausibility of Life: Resolving Darwin’s Dilemma. New Haven: Yale University Press, 2005.