Philipp Holliger

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Philipp Holliger
Born
Philipp Holliger
NationalitySwiss
Alma mater
  • ETH Zurich
  • MRC Centre for Protein Engineering (PhD)
Scientific career
Fields
  • Molecular biology
  • synthetic biology
  • Xenobiology
Institutions
  • MRC 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
Add a Photo
CitizenshipSwitzerland
WebsiteOfficial website

Philipp Holliger, Ph.D. is a Swiss molecular biologist best known for his work on Xeno nucleic acid|xeno nucleic acids (XNAs) [1][2][3][4][5][6][7][8]and RNA engineering [9][10][11][12][13][14][15]. Holliger is a program leader at the MRC Laboratory of Molecular Biology (MRC LMB)[16].

Background

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 Centre for Protein Engineering|MRC Centre for Protein Engineering (CPE) in Cambridge under the mentorship of Sir Gregory Winter (CPE and MRC LMB) and Prof. Tim Richmond (ETH)[17][18][19][20].

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 bacteriophage|filamentous bacteriophages[20][21][22][23][24][25].

After he became an independent group leader at the MRC LMB, Holliger shifted his research focus towards synthetic biology, where he developed methods for DNA sequencing#Large-scale sequencing and de novo sequencing|emulsion-PCR and in vitro evolution[26][27][28][29]. Holliger was elected a member of EMBO in 2015[30].

Research

XNAs

Combining nucleic acid chemistry with novel methods for History of RNA biology#Combinatorial selection of RNA molecules enables in vitro evolution|in vitro evolution he developed, Holliger and colleagues were able to reprogram replicative DNA polymerase|DNA polymerases for the synthesis and Reverse transcriptase#Process of reverse transcription|reverse transcription of synthetic genetic polymers with entirely unnatural backbones (XNAs). This work showed for the first time that synthetic alternatives to DNA could store genetic information just like DNA[1][2][3] and was profiled in a piece by Scientific American as one of ten world changing ideas[2].

Further work by the Holliger lab enabled the in vitro evolution of XNA ligands (Aptamer)[1][2][3] and XNA catalysts similar to RNA enzymes (known as ribozymes), termed XNAzymes[4][5][6] as well as the elaboration of simple XNA nanostructures[7][8]. 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[31][32].

Origin of life

Holliger has also made contributions towards a better understanding of early steps in the Abiogenesis|origin of life[9][10][11][12][13][14][15][33][34][35][36]. 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[37], Holliger and colleagues initially engineered an RNA polymerase ribozyme capable of synthesising another ribozyme[9][10][11] and subsequently RNA sequences longer than itself[12][13]. More recently, he described the first polymerase ribozyme that can use nucleotide triplets to copy highly structured RNA templates[14][15][38] 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[12][13][33][34] and the ability of diverse pools of RNA sequences to recombine enhancing pool complexity[39]. 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 Chaperone (protein)|chaperones in modern biology[35].

Applications

Many of the methodologies developed by the Holliger laboratory at the LMB have been patented and found wide commercial application.

Holliger’s work on XNAs and the origin of life on earth may also have implications for the search for life elsewhere in the universe, showing the range of chemistries on which genetics might be based and the icy worlds in which life might first arise[5][34][40].

References

  1. ↑ 1.0 1.1 1.2 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. ↑ 2.0 2.1 2.2 2.3 "10 innovations that are radical enough to alter our lives". Scientific American.
  3. ↑ 3.0 3.1 3.2 "Synthetic XNA molecules can evolve and store genetic information, just like DNA". Discover Magazine.
  4. ↑ 4.0 4.1 Taylor, A. I.; Pinheiro, V. B.; Smola, M. J.; Morgunov, A. S.; Peak-Chew, S.; Cozens, C.; Weeks, K. M.; Herdewijn, P.; Holliger, P. (2015). "Catalysts from synthetic genetic polymers". Nature. 518 (7539): 427–430. Bibcode:2015Natur.518..427T. doi:10.1038/nature13982. PMC 4336857. PMID 25470036.
  5. ↑ 5.0 5.1 5.2 "Scientists make enzymes from scratch". BBC News Website.
  6. ↑ 6.0 6.1 Coghlan, Andy. "Synthetic enzymes hint at life without DNA or RNA". New Scientist.
  7. ↑ 7.0 7.1 Taylor, Alexander I.; Beuron, Fabienne; Peak-Chew, Sew-Yeu; Morris, Edward P.; Herdewijn, Piet; Holliger, Philipp (16 June 2016). "Nanostructures from Synthetic Genetic Polymers". ChemBioChem. 17 (12): 1107–1110. doi:10.1002/cbic.201600136. ISSN 1439-4227. PMC 4973672. PMID 26992063.
  8. ↑ 8.0 8.1 Barras, Colin. "Artificial DNA folds into parcels that can survive inside us". New Scientist.
  9. ↑ 9.0 9.1 9.2 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.
  10. ↑ 10.0 10.1 10.2 "No DNA needed, RNA goes solo". Nature. 472 (7342): 139. April 2011. doi:10.1038/472139e. ISSN 1476-4687.
  11. ↑ 11.0 11.1 11.2 Marshall, Michael. "First life: The search for the first replicator". New Scientist.
  12. ↑ 12.0 12.1 12.2 12.3 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.
  13. ↑ 13.0 13.1 13.2 13.3 Geddes, Linda. "Earth's first life may have sprung up in ice". New Scientist.
  14. ↑ 14.0 14.1 14.2 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.
  15. ↑ 15.0 15.1 15.2 Page, Michael Le. "A new synthetic molecule may solve a paradox about life's origin". New Scientist.
  16. ↑ "MRC Laboratory of Molecular Biology group leader profiles". LMB Website.
  17. ↑ "Philipp Holliger | Faculty Member | Faculty Opinions". facultyopinions.com.
  18. ↑ "Phil Holliger - Biography". Holliger Lab Website.
  19. ↑ "Dr Philipp Holliger - Networks of evidence and expertise for public policy". www.csap.cam.ac.uk.
  20. ↑ 20.0 20.1 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.
  21. ↑ 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.
  22. ↑ 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 (London, England: 1993). 5 (2): 265–275. doi:10.1016/s0969-2126(97)00184-6. ISSN 0969-2126. PMID 9032075.
  23. ↑ Holliger, P.; Winter, G. (November 1997). "Diabodies: small bispecific antibody fragments". Cancer Immunology, Immunotherapy: CII. 45 (3–4): 128–130. doi:10.1007/s002620050414. ISSN 0340-7004. PMID 9435855.
  24. ↑ Riechmann, L.; Holliger, P. (1997-07-25). "The C-terminal domain of TolA is the coreceptor for filamentous phage infection of E. coli". Cell. 90 (2): 351–360. doi:10.1016/s0092-8674(00)80342-6. ISSN 0092-8674. PMID 9244308.
  25. ↑ Holliger, Philipp; Wing, Mark; Pound, John D.; Bohlen, Heribert; Winter, Greg (1 July 1997). "Retargeting serum immunoglobulin with bispecific diabodies". Nature Biotechnology. 15 (7): 632–636. doi:10.1038/nbt0797-632. ISSN 1546-1696. PMID 9219264.
  26. ↑ 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.
  27. ↑ Ghadessy, Farid J.; Holliger, Philipp (2007). "Compartmentalized self-replication: a novel method for the directed evolution of polymerases and other enzymes". Protein Engineering Protocols. Methods in Molecular Biology (Clifton, N.J.). Vol. 352. pp. 237–248. doi:10.1385/1-59745-187-8:237. ISBN 978-1-59745-187-1. ISSN 1064-3745. PMID 17041269.
  28. ↑ Loakes, David; Holliger, Philipp (2009-08-21). "Polymerase engineering: towards the encoded synthesis of unnatural biopolymers". Chemical Communications (Cambridge, England) (31): 4619–4631. doi:10.1039/b903307f. ISSN 1364-548X. PMID 19641798.
  29. ↑ McKie, Robin; editor, science (2008-04-19). "Biologists join the race to create synthetic life". The Observer. ISSN 0029-7712. Retrieved 2020-09-15. {{cite news}}: |last2= has generic name (help)
  30. ↑ "Find people in the EMBO Communities". people.embo.org. Retrieved 2020-09-15.
  31. ↑ 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.
  32. ↑ Community, Nature Research Chemistry (2019-04-23). "Genetic function without charge". Nature Research Chemistry Community. Retrieved 2020-09-15.
  33. ↑ 33.0 33.1 Attwater, James; Wochner, Aniela; Pinheiro, Vitor B.; Coulson, Alan; Holliger, Philipp (2010-09-21). "Ice as a protocellular medium for RNA replication". Nature Communications. 1 (1): 76. Bibcode:2010NatCo...1...76A. doi:10.1038/ncomms1076. ISSN 2041-1723. PMID 20865803.
  34. ↑ 34.0 34.1 34.2 McNally, Jess (2010-09-21). "Life on Earth May Have Had an Icy Start". Wired. ISSN 1059-1028. Retrieved 2020-09-15.
  35. ↑ 35.0 35.1 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.
  36. ↑ Sarchet, Penny. "The epic hunt for the place on Earth where life started". New Scientist. Retrieved 2020-09-15.
  37. ↑ Johnston, W. K.; Unrau, P. J.; Lawrence, M. S.; Glasner, M. E.; Bartel, D. P. (2001-05-18). "RNA-catalyzed RNA polymerization: accurate and general RNA-templated primer extension". Science. 292 (5520): 1319–1325. Bibcode:2001Sci...292.1319J. doi:10.1126/science.1060786. ISSN 0036-8075. PMID 11358999.
  38. ↑ "Episode 49: August 2018". eLife. 2018-08-24. Retrieved 2020-09-25.
  39. ↑ 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.
  40. ↑ "NASA Astrobiology Institute". astrobiology.nasa.gov. Retrieved 2020-09-15.

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