Philipp Holliger

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).{{cite journal|last=|first=|date=|title=Phil Holliger - Biography|url=https://www2.mrc-lmb.cam.ac.uk/groups/ph1/holliger_bio.html|journal=Holliger Lab Website|volume=|pages=|via=}}{{cite thesis|last1=Holliger|first1=Philipp|date=1994|title=Multivalent and bispecific antibody fragments from E.coli: new strategies for antibody-based diagnostics and therapeutics from bacteria|url=|journal=ETH Zurich|volume=|pages=|doi=10.3929/ethz-a-001469985|hdl=20.500.11850/142158}}

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.{{cite journal|last1=Holliger|first1=P.|last2=Prospero|first2=T.|last3=Winter|first3=G.|date=15 July 1993|title="Diabodies": small bivalent and bispecific antibody fragments|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=90|issue=14|pages=6444–6448|doi=10.1073/pnas.90.14.6444|pmid=8341653|pmc=46948|bibcode=1993PNAS...90.6444H|issn=0027-8424|doi-access=free}}{{cite journal|last1=Holliger|first1=P.|last2=Riechmann|first2=L.|date=15 February 1997|title=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|url=https://www.ncbi.nlm.nih.gov/pubmed/9032075|journal=Structure|volume=5|issue=2|pages=265–275|doi=10.1016/s0969-2126(97)00184-6|pmid=9032075|issn=0969-2126|doi-access=free}}

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.{{Cite journal|last1=Ghadessy|first1=F. J.|last2=Ong|first2=J. L.|last3=Holliger|first3=P.|date=2001-03-27|title=Directed evolution of polymerase function by compartmentalized self-replication|journal=Proceedings of the National Academy of Sciences|language=en|volume=98|issue=8|pages=4552–4557|doi=10.1073/pnas.071052198|pmid=11274352|pmc=31872|bibcode=2001PNAS...98.4552G|issn=0027-8424|doi-access=free}} Holliger was elected a member of EMBO in 2015.{{Cite web|title=Find people in the EMBO Communities|url=https://people.embo.org/profile/philipp-holliger|access-date=2020-09-15|website=people.embo.org}}

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.{{Cite web|title=Synthetic XNA molecules can evolve and store genetic information, just like DNA|url=https://www.discovermagazine.com/planet-earth/synthetic-xna-molecules-can-evolve-and-store-genetic-information-just-like-dna|access-date=2021-05-16|website=Discover Magazine|language=en}}

Further work by the Holliger lab enabled the in vitro evolution of XNA ligands (aptamers) and XNA catalysts similar to RNA enzymes (known as ribozymes), termed XNAzymes{{cite journal|last1=Coghlan|first1=Andy|title=Synthetic enzymes hint at life without DNA or RNA|url=https://www.newscientist.com/article/dn26641-synthetic-enzymes-hint-at-life-without-dna-or-rna/?ignored=irrelevant%23.VH2ynIftnx5|journal=New Scientist}} as well as the elaboration of simple XNA nanostructures.{{cite journal|last1=Barras|first1=Colin|title=Artificial DNA folds into parcels that can survive inside us|url=https://www.newscientist.com/article/2081477-artificial-dna-folds-into-parcels-that-can-survive-inside-us/|journal=New Scientist}} 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.{{Cite journal|last1=Arangundy-Franklin|first1=Sebastian|last2=Taylor|first2=Alexander I.|last3=Porebski|first3=Benjamin T.|last4=Genna|first4=Vito|last5=Peak-Chew|first5=Sew|last6=Vaisman|first6=Alexandra|last7=Woodgate|first7=Roger|last8=Orozco|first8=Modesto|last9=Holliger|first9=Philipp|date=June 2019|title=A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids|journal=Nature Chemistry|volume=11|issue=6|pages=533–542|doi=10.1038/s41557-019-0255-4|issn=1755-4349|pmc=6542681|pmid=31011171|bibcode=2019NatCh..11..533A}}

Origin of life

Holliger has also made contributions towards a better understanding of early steps in the origin of life. 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{{cite journal|last1=Wochner|first1=Aniela|last2=Attwater|first2=James|last3=Coulson|first3=Alan|last4=Holliger|first4=Philipp|date=8 April 2011|title=Ribozyme-Catalyzed Transcription of an Active Ribozyme|url=https://www.science.org/doi/10.1126/science.1200752|journal=Science|language=en|volume=332|issue=6026|pages=209–212|bibcode=2011Sci...332..209W|doi=10.1126/science.1200752|issn=0036-8075|pmid=21474753|s2cid=39990861}} and subsequently RNA sequences longer than itself.{{cite journal|last1=Attwater|first1=James|last2=Wochner|first2=Aniela|last3=Holliger|first3=Philipp|date=December 2013|title=In-ice evolution of RNA polymerase ribozyme activity|journal=Nature Chemistry|language=en|volume=5|issue=12|pages=1011–1018|bibcode=2013NatCh...5.1011A|doi=10.1038/nchem.1781|issn=1755-4349|pmc=3920166|pmid=24256864}} More recently, he described the first polymerase ribozyme that can use nucleotide triplets to copy highly structured RNA templates{{cite journal|last1=Attwater|first1=James|last2=Raguram|first2=Aditya|last3=Morgunov|first3=Alexey S|last4=Gianni|first4=Edoardo|last5=Holliger|first5=Philipp|date=15 May 2018|title=Ribozyme-catalysed RNA synthesis using triplet building blocks|journal=eLife|volume=7|pages=e35255|doi=10.7554/eLife.35255|issn=2050-084X|pmc=6003772|pmid=29759114|s2cid=46889517 |doi-access=free }} 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 and the ability of diverse pools of RNA sequences to recombine enhancing pool complexity.{{Cite journal|last1=Mutschler|first1=Hannes|last2=Taylor|first2=Alexander I|last3=Porebski|first3=Benjamin T|last4=Lightowlers|first4=Alice|last5=Houlihan|first5=Gillian|last6=Abramov|first6=Mikhail|last7=Herdewijn|first7=Piet|last8=Holliger|first8=Philipp|date=2018-11-21|editor-last=Weigel|editor-first=Detlef|editor2-last=Muller|editor2-first=Ulrich|title=Random-sequence genetic oligomer pools display an innate potential for ligation and recombination|journal=eLife|volume=7|pages=e43022|doi=10.7554/eLife.43022|pmid=30461419|pmc=6289569|issn=2050-084X |doi-access=free }} 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.{{Cite journal|last1=Mutschler|first1=Hannes|last2=Wochner|first2=Aniela|last3=Holliger|first3=Philipp|date=June 2015|title=Freeze–thaw cycles as drivers of complex ribozyme assembly|journal=Nature Chemistry|language=en|volume=7|issue=6|pages=502–508|bibcode=2015NatCh...7..502M|doi=10.1038/nchem.2251|issn=1755-4349|pmc=4495579|pmid=25991529}}

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Category:Swiss biologists

Category:Swiss biochemists

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Category:21st-century Swiss scientists

Category:ETH Zurich alumni