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Philipp Holliger

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Philipp Holliger
Alma materETH Zurich, MRC Centre for Protein Engineering (PhD)
Scientific career
FieldsMolecular biology, Synthetic biology, Xenobiology
InstitutionsMRC Centre for Protein Engineering, MRC Laboratory of Molecular Biology
ThesisMultivalent and bispecific antibody fragments from E. coli (1994)
Doctoral advisorSir Gregory Winter, Professor Tim Richmond
Websitehttps://www2.mrc-lmb.cam.ac.uk/group-leaders/h-to-m/philipp-holliger/

Philipp Holliger is a Swiss molecular biologist best known for his work on xeno nucleic acids (XNAs)[1] and RNA engineering.[2][3] Holliger is a program leader at the MRC Laboratory of Molecular Biology (MRC LMB).[4]

Background

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He earned his degree in Natural Sciences (Dipl. Natwiss. ETH) from ETH Zürich, Switzerland, where he worked with Steven Benner, and his Ph.D. in Molecular Biology at the MRC Centre for Protein Engineering (CPE) in Cambridge under the mentorship of Sir Gregory Winter (CPE and MRC LMB) and Tim Richmond (ETH).[5][6]

While in the Winter laboratory, Holliger developed a new type of bispecific antibody fragment, called a diabody and worked on elucidating the infection pathway of filamentous bacteriophages.[7][8]

After he became an independent group leader at the MRC LMB, Holliger shifted his research focus towards synthetic biology, where he developed methods for emulsion-PCR and in vitro evolution.[9] Holliger was elected a member of EMBO in 2015.[10]

Research

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XNAs

Combining nucleic acid chemistry with methods for in vitro evolution he developed, Holliger and colleagues were able to reprogram replicative DNA polymerases for the synthesis and reverse transcription of synthetic genetic polymers with entirely unnatural backbones (XNAs). This showed for the first time that synthetic alternatives to DNA could store genetic information just like DNA.[1][11]

Further work by the Holliger lab enabled the in vitro evolution of XNA ligands (aptamers)[1] and XNA catalysts similar to RNA enzymes (known as ribozymes), termed XNAzymes[12] as well as the elaboration of simple XNA nanostructures.[13] The unnatural backbone chemistries of XNA molecules exhibit novel and useful properties. For example, unlike the natural nucleic acids, some XNAs cannot be broken down easily by the human body or are chemically much more stable. Recently, Holliger also described the synthesis and evolution of XNAs with an uncharged backbone, showing that genetic function (i.e. heredity and evolution) is possible – in contrast to previous proposals – even in the absence of a charged backbone.[14]

Origin of life

Holliger has also made contributions towards a better understanding of early steps in the origin of life.[2][3] One scenario, termed the RNA world hypothesis, suggests that a key event in the origin of life was the emergence of an RNA molecule capable of self-replication and evolution, founding a primordial biology (lacking DNA and proteins) that relied on RNA for its main building blocks. Starting from a previously discovered ribozyme with RNA polymerase activity, Holliger and colleagues initially engineered an RNA polymerase ribozyme capable of synthesising another ribozyme[15] and subsequently RNA sequences longer than itself.[16] More recently, he described the first polymerase ribozyme that can use nucleotide triplets to copy highly structured RNA templates[17] including segments of itself.

In the course of this work, Holliger explored the properties of water ice, a simple medium likely to have been widespread on the early Earth, and found that it promotes the activity, stability and evolution of RNA polymerase ribozymes[16] and the ability of diverse pools of RNA sequences to recombine enhancing pool complexity.[18] He also discovered that the steep concentration and temperature gradients resulting from freeze-thaw cycles could be harnessed to drive ribozyme assembly and folding, acting akin to chaperones in modern biology.[19]

References

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  1. ^ a b c Pinheiro, Vitor B.; Taylor, Alexander I.; Cozens, Christopher; Abramov, Mikhail; Renders, Marleen; Zhang, Su; Chaput, John C.; Wengel, Jesper; Peak-Chew, Sew-Yeu; McLaughlin, Stephen H.; Herdewijn, Piet; Holliger, Philipp (20 April 2012). "Synthetic Genetic Polymers Capable of Heredity and Evolution". Science. 336 (6079): 341–344. Bibcode:2012Sci...336..341P. doi:10.1126/science.1217622. ISSN 0036-8075. PMC 3362463. PMID 22517858.
  2. ^ a b Wochner, Aniela; Attwater, James; Coulson, Alan; Holliger, Philipp (2011-04-08). "Ribozyme-Catalyzed Transcription of an Active Ribozyme". Science. 332 (6026): 209–212. Bibcode:2011Sci...332..209W. doi:10.1126/science.1200752. ISSN 0036-8075. PMID 21474753. S2CID 39990861.
  3. ^ a b Geddes, Linda. "Earth's first life may have sprung up in ice". New Scientist. Retrieved 2021-05-16.
  4. ^ "MRC Laboratory of Molecular Biology group leader profiles". LMB Website.
  5. ^ "Phil Holliger - Biography". Holliger Lab Website.
  6. ^ Holliger, Philipp (1994). Multivalent and bispecific antibody fragments from E.coli: new strategies for antibody-based diagnostics and therapeutics from bacteria. ETH Zurich (Thesis). doi:10.3929/ethz-a-001469985. hdl:20.500.11850/142158.
  7. ^ Holliger, P.; Prospero, T.; Winter, G. (15 July 1993). ""Diabodies": small bivalent and bispecific antibody fragments". Proceedings of the National Academy of Sciences of the United States of America. 90 (14): 6444–6448. Bibcode:1993PNAS...90.6444H. doi:10.1073/pnas.90.14.6444. ISSN 0027-8424. PMC 46948. PMID 8341653.
  8. ^ Holliger, P.; Riechmann, L. (15 February 1997). "A conserved infection pathway for filamentous bacteriophages is suggested by the structure of the membrane penetration domain of the minor coat protein g3p from phage fd". Structure. 5 (2): 265–275. doi:10.1016/s0969-2126(97)00184-6. ISSN 0969-2126. PMID 9032075.
  9. ^ Ghadessy, F. J.; Ong, J. L.; Holliger, P. (2001-03-27). "Directed evolution of polymerase function by compartmentalized self-replication". Proceedings of the National Academy of Sciences. 98 (8): 4552–4557. Bibcode:2001PNAS...98.4552G. doi:10.1073/pnas.071052198. ISSN 0027-8424. PMC 31872. PMID 11274352.
  10. ^ "Find people in the EMBO Communities". people.embo.org. Retrieved 2020-09-15.
  11. ^ "Synthetic XNA molecules can evolve and store genetic information, just like DNA". Discover Magazine. Retrieved 2021-05-16.
  12. ^ Coghlan, Andy. "Synthetic enzymes hint at life without DNA or RNA". New Scientist.
  13. ^ Barras, Colin. "Artificial DNA folds into parcels that can survive inside us". New Scientist.
  14. ^ Arangundy-Franklin, Sebastian; Taylor, Alexander I.; Porebski, Benjamin T.; Genna, Vito; Peak-Chew, Sew; Vaisman, Alexandra; Woodgate, Roger; Orozco, Modesto; Holliger, Philipp (June 2019). "A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids". Nature Chemistry. 11 (6): 533–542. Bibcode:2019NatCh..11..533A. doi:10.1038/s41557-019-0255-4. ISSN 1755-4349. PMC 6542681. PMID 31011171.
  15. ^ Wochner, Aniela; Attwater, James; Coulson, Alan; Holliger, Philipp (8 April 2011). "Ribozyme-Catalyzed Transcription of an Active Ribozyme". Science. 332 (6026): 209–212. Bibcode:2011Sci...332..209W. doi:10.1126/science.1200752. ISSN 0036-8075. PMID 21474753. S2CID 39990861.
  16. ^ a b Attwater, James; Wochner, Aniela; Holliger, Philipp (December 2013). "In-ice evolution of RNA polymerase ribozyme activity". Nature Chemistry. 5 (12): 1011–1018. Bibcode:2013NatCh...5.1011A. doi:10.1038/nchem.1781. ISSN 1755-4349. PMC 3920166. PMID 24256864.
  17. ^ Attwater, James; Raguram, Aditya; Morgunov, Alexey S; Gianni, Edoardo; Holliger, Philipp (15 May 2018). "Ribozyme-catalysed RNA synthesis using triplet building blocks". eLife. 7: e35255. doi:10.7554/eLife.35255. ISSN 2050-084X. PMC 6003772. PMID 29759114. S2CID 46889517.
  18. ^ Mutschler, Hannes; Taylor, Alexander I; Porebski, Benjamin T; Lightowlers, Alice; Houlihan, Gillian; Abramov, Mikhail; Herdewijn, Piet; Holliger, Philipp (2018-11-21). Weigel, Detlef; Muller, Ulrich (eds.). "Random-sequence genetic oligomer pools display an innate potential for ligation and recombination". eLife. 7: e43022. doi:10.7554/eLife.43022. ISSN 2050-084X. PMC 6289569. PMID 30461419.
  19. ^ Mutschler, Hannes; Wochner, Aniela; Holliger, Philipp (June 2015). "Freeze–thaw cycles as drivers of complex ribozyme assembly". Nature Chemistry. 7 (6): 502–508. Bibcode:2015NatCh...7..502M. doi:10.1038/nchem.2251. ISSN 1755-4349. PMC 4495579. PMID 25991529.
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