Hamilton Smith, MD

Distinguished Professor Emeritus

Hamilton Smith, M.D. is a professor emeritus at the J. Craig Venter Institute and former director of the Synthetic Biology and Bioenergy Group that created the first synthetic cell in 2010 and designed and synthesized the first minimal bacterial genome in 2016. He received an A.B. degree in Mathematics from the University of California, Berkeley in 1952 and the M.D. degree from the Johns Hopkins School of Medicine in 1956. He completed a residency in Internal Medicine in 1962. From 1962-67, he did research on lysogeny in phage P22 at the University of Michigan. In 1967, he was appointed Assistant Professor of Microbiology at Johns Hopkins. In 1970, he discovered the first Type II restriction enzyme, HindII. He received the Nobel Prize in Medicine in 1978 for that work. From 1975 to 1998, he studied the DNA transformation mechanism in Haemophilus Inflluenzae Rd. In 1993, Dr. Smith began his long association with Craig Venter. In 1995, they collaborated to sequence the genome of H. Inflluenzae Rd, and from 1998 to 2002, at Celera Genomics they sequenced Drosophila and the human genome. After leaving Celera, Smith and Venter began their work in synthetic biology.

Research Priorities

Deciphering the genetic requirements for minimal bacterial life
  • Assignment of genetic functions to unknown genes in the minimal cell by computational, biochemical and genetic methods.
Designing a minimal yeast cell
  • Determining non-essential genes by global DNA cassette insertional mutagenesis.
Understanding the mechanism of DNA cassette insertional mutagenesis in yeast
  • Genetic and biochemical analysis of the DNA insertion mechanism.

Publications

Gross Chromosomal Rearrangements in Kluyveromyces marxianus Revealed by Illumina and Oxford Nanopore Sequencing.
International journal of molecular sciences. 2020-09-26; 21.19:
PMID: 32993167
Kinetic Modeling of the Genetic Information Processes in a Minimal Cell.
Frontiers in molecular biosciences. 2019-11-28; 6.130.
PMID: 31850364
Polar Effects of Transposon Insertion into a Minimal Bacterial Genome.
Journal of bacteriology. 2019-10-01; 201.19:
PMID: 31262838
Direct transfer of a Mycoplasma mycoides genome to yeast is enhanced by removal of the mycoides glycerol uptake factor gene glpF.
ACS synthetic biology. 2019-01-15;
PMID: 30645947
Tuning Gene Activity by Inducible and Targeted Regulation of Gene Expression in Minimal Bacterial Cells.
ACS synthetic biology. 2018-06-15; 7.6: 1538-1552.
PMID: 29786424
Minimal Cells-Real and Imagined.
Cold Spring Harbor perspectives in biology. 2017-12-01; 9.12:
PMID: 28348033
One step engineering of the small-subunit ribosomal RNA using CRISPR/Cas9.
Scientific reports. 2016-08-04; 6.30714.
PMID: 27489041
The Sequence of the Human Genome.
Clinical chemistry. 2015-09-01; 61.9: 1207-8.
PMID: 26185218
Bacterial genome reduction using the progressive clustering of deletions via yeast sexual cycling.
Genome research. 2015-03-01; 25.3: 435-44.
PMID: 25654978
Where next for microbiome research?
PLoS biology. 2015-01-20; 13.1: e1002050.
PMID: 25602283
Designed surface residue substitutions in [NiFe] hydrogenase that improve electron transfer characteristics.
International journal of molecular sciences. 2015-01-16; 16.1: 2020-33.
PMID: 25603181
A broad survey reveals substitution tolerance of residues ligating FeS clusters in [NiFe] hydrogenase.
BMC biochemistry. 2014-06-17; 15.10.
PMID: 24934472
Transferring whole genomes from bacteria to yeast spheroplasts using entire bacterial cells to reduce DNA shearing.
Nature protocols. 2014-04-01; 9.4: 743-50.
PMID: 24603933
Rescue of mutant fitness defects using in vitro reconstituted designer transposons in Mycoplasma mycoides.
Frontiers in microbiology. 2014-01-01; 5.369.
PMID: 25101070
Assembly of eukaryotic algal chromosomes in yeast.
Journal of biological engineering. 2013-12-10; 7.1: 30.
PMID: 24325901
Dual organism design cycle reveals small subunit substitutions that improve [NiFe] hydrogenase hydrogen evolution.
Journal of biological engineering. 2013-07-02; 7.1: 17.
PMID: 23819621
Direct transfer of whole genomes from bacteria to yeast.
Nature methods. 2013-05-01; 10.5: 410-2.
PMID: 23542886
Sequence analysis of a complete 1.66 Mb Prochlorococcus marinus MED4 genome cloned in yeast.
Nucleic acids research. 2012-11-01; 40.20: 10375-83.
PMID: 22941652
Assembly of large, high G+C bacterial DNA fragments in yeast.
ACS synthetic biology. 2012-07-20; 1.7: 267-73.
PMID: 23651249
Genetic analysis of the Alteromonas macleodii [NiFe]-hydrogenase.
FEMS microbiology letters. 2011-09-01; 322.2: 180-7.
PMID: 21718346
Heterologous expression of Alteromonas macleodii and Thiocapsa roseopersicina [NiFe] hydrogenases in Escherichia coli.
Microbiology (Reading, England). 2011-05-01; 157.Pt 5: 1363-74.
PMID: 21349975
Single-step linker-based combinatorial assembly of promoter and gene cassettes for pathway engineering.
Biotechnology letters. 2011-03-01; 33.3: 549-55.
PMID: 21107654
[NiFe] hydrogenase from Alteromonas macleodii with unusual stability in the presence of oxygen and high temperature.
Applied and environmental microbiology. 2011-03-01; 77.6: 1990-8.
PMID: 21257809
Chemical synthesis of the mouse mitochondrial genome.
Nature methods. 2010-11-01; 7.11: 901-3.
PMID: 20935651
The evolution of RecD outside of the RecBCD complex.
Journal of molecular evolution. 2009-10-01; 69.4: 360-71.
PMID: 19841849
Creating bacterial strains from genomes that have been cloned and engineered in yeast.
Science (New York, N.Y.). 2009-09-25; 325.5948: 1693-6.
PMID: 19696314
Discovery of [NiFe] hydrogenase genes in metagenomic DNA: cloning and heterologous expression in Thiocapsa roseopersicina.
Applied and environmental microbiology. 2009-09-01; 75.18: 5821-30.
PMID: 19633107
Enzymatic assembly of DNA molecules up to several hundred kilobases.
Nature methods. 2009-05-01; 6.5: 343-5.
PMID: 19363495
A systems biology tour de force for a near-minimal bacterium.
Molecular systems biology. 2009-01-01; 5.330.
PMID: 19953084
One-step assembly in yeast of 25 overlapping DNA fragments to form a complete synthetic Mycoplasma genitalium genome.
Proceedings of the National Academy of Sciences of the United States of America. 2008-12-23; 105.51: 20404-9.
PMID: 19073939
Complete chemical synthesis, assembly, and cloning of a Mycoplasma genitalium genome.
Science (New York, N.Y.). 2008-02-29; 319.5867: 1215-20.
PMID: 18218864
Genome transplantation in bacteria: changing one species to another.
Science (New York, N.Y.). 2007-08-03; 317.5838: 632-8.
PMID: 17600181
Essential genes of a minimal bacterium.
Proceedings of the National Academy of Sciences of the United States of America. 2006-01-10; 103.2: 425-30.
PMID: 16407165
Cell-free cloning using phi29 DNA polymerase.
Proceedings of the National Academy of Sciences of the United States of America. 2005-11-29; 102.48: 17332-6.
PMID: 16286637
Generating a synthetic genome by whole genome assembly: phiX174 bacteriophage from synthetic oligonucleotides.
Proceedings of the National Academy of Sciences of the United States of America. 2003-12-23; 100.26: 15440-5.
PMID: 14657399
Mural RJ, Adams MD, Myers EW, Smith HO, Miklos GL, Wides R, Halpern A, Li PW, Sutton GG, Nadeau J, Salzberg SL, Holt RA, Kodira CD, Lu F, Chen L, Deng Z, Evangelista CC, Gan W, Heiman TJ, Li J, Li Z, Merkulov GV, Milshina NV, Naik AK, Qi R, Shue BC, Wang A, Wang J, Wang X, Yan X, Ye J, Yooseph S, Zhao Q, Zheng L, Zhu SC, Biddick K, Bolanos R, Delcher AL, Dew IM, Fasulo D, Flanigan MJ, Huson DH, Kravitz SA, Miller JR, Mobarry CM, Reinert K, Remington KA, Zhang Q, Zheng XH, Nusskern DR, Lai Z, Lei Y, Zhong W, Yao A, Guan P, Ji RR, Gu Z, Wang ZY, Zhong F, Xiao C, Chiang CC, Yandell M, Wortman JR, Amanatides PG, Hladun SL, Pratts EC, Johnson JE, Dodson KL, Woodford KJ, Evans CA, Gropman B, Rusch DB, Venter E, Wang M, Smith TJ, Houck JT, Tompkins DE, Haynes C, Jacob D, Chin SH, Allen DR, Dahlke CE, Sanders R, Li K, Liu X, Levitsky AA, Majoros WH, Chen Q, Xia AC, Lopez JR, Donnelly MT, Newman MH, Glodek A, Kraft CL, Nodell M, Ali F, An HJ, Baldwin-Pitts D, Beeson KY, Cai S, Carnes M, Carver A, Caulk PM, Center A, Chen YH, Cheng ML, Coyne MD, Crowder M, Danaher S, Davenport LB, Desilets R, Dietz SM, Doup L, Dullaghan P, Ferriera S, Fosler CR, Gire HC, Gluecksmann A, Gocayne JD, Gray J, Hart B, Haynes J, Hoover J, Howland T, Ibegwam C, Jalali M, Johns D, Kline L, Ma DS, MacCawley S, Magoon A, Mann F, May D, McIntosh TC, Mehta S, Moy L, Moy MC, Murphy BJ, Murphy SD, Nelson KA, Nuri Z, Parker KA, Prudhomme AC, Puri VN, Qureshi H, Raley JC, Reardon MS, Regier MA, Rogers YH, Romblad DL, Schutz J, Scott JL, Scott R, Sitter CD, Smallwood M, Sprague AC, Stewart E, Strong RV, Suh E, Sylvester K, Thomas R, Tint NN, Tsonis C, Wang G, Wang G, Williams MS, Williams SM, Windsor SM, Wolfe K, Wu MM, Zaveri J, Chaturvedi K, Gabrielian AE, Ke Z, Sun J, Subramanian G, Venter JC, Pfannkoch CM, Barnstead M, Stephenson LD
A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome.
Science (New York, N.Y.). 2002-05-31; 296.5573: 1661-71.
PMID: 12040188
On the sequencing and assembly of the human genome.
Proceedings of the National Academy of Sciences of the United States of America. 2002-04-02; 99.7: 4145-6.
PMID: 11904395
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigó R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A, Zhu X
The sequence of the human genome.
Science (New York, N.Y.). 2001-02-16; 291.5507: 1304-51.
PMID: 11181995
Prediction of transcription terminators in bacterial genomes.
Journal of molecular biology. 2000-08-04; 301.1: 27-33.
PMID: 10926490
Adams MD, Celniker SE, Holt RA, Evans CA, Gocayne JD, Amanatides PG, Scherer SE, Li PW, Hoskins RA, Galle RF, George RA, Lewis SE, Richards S, Ashburner M, Henderson SN, Sutton GG, Wortman JR, Yandell MD, Zhang Q, Chen LX, Brandon RC, Rogers YH, Blazej RG, Champe M, Pfeiffer BD, Wan KH, Doyle C, Baxter EG, Helt G, Nelson CR, Gabor GL, Abril JF, Agbayani A, An HJ, Andrews-Pfannkoch C, Baldwin D, Ballew RM, Basu A, Baxendale J, Bayraktaroglu L, Beasley EM, Beeson KY, Benos PV, Berman BP, Bhandari D, Bolshakov S, Borkova D, Botchan MR, Bouck J, Brokstein P, Brottier P, Burtis KC, Busam DA, Butler H, Cadieu E, Center A, Chandra I, Cherry JM, Cawley S, Dahlke C, Davenport LB, Davies P, de Pablos B, Delcher A, Deng Z, Mays AD, Dew I, Dietz SM, Dodson K, Doup LE, Downes M, Dugan-Rocha S, Dunkov BC, Dunn P, Durbin KJ, Evangelista CC, Ferraz C, Ferriera S, Fleischmann W, Fosler C, Gabrielian AE, Garg NS, Gelbart WM, Glasser K, Glodek A, Gong F, Gorrell JH, Gu Z, Guan P, Harris M, Harris NL, Harvey D, Heiman TJ, Hernandez JR, Houck J, Hostin D, Houston KA, Howland TJ, Wei MH, Ibegwam C, Jalali M, Kalush F, Karpen GH, Ke Z, Kennison JA, Ketchum KA, Kimmel BE, Kodira CD, Kraft C, Kravitz S, Kulp D, Lai Z, Lasko P, Lei Y, Levitsky AA, Li J, Li Z, Liang Y, Lin X, Liu X, Mattei B, McIntosh TC, McLeod MP, McPherson D, Merkulov G, Milshina NV, Mobarry C, Morris J, Moshrefi A, Mount SM, Moy M, Murphy B, Murphy L, Muzny DM, Nelson DL, Nelson DR, Nelson KA, Nixon K, Nusskern DR, Pacleb JM, Palazzolo M, Pittman GS, Pan S, Pollard J, Puri V, Reese MG, Reinert K, Remington K, Saunders RD, Scheeler F, Shen H, Shue BC, Sidén-Kiamos I, Simpson M, Skupski MP, Smith T, Spier E, Spradling AC, Stapleton M, Strong R, Sun E, Svirskas R, Tector C, Turner R, Venter E, Wang AH, Wang X, Wang ZY, Wassarman DA, Weinstock GM, Weissenbach J, Williams SM, WoodageT, Worley KC, Wu D, Yang S, Yao QA, Ye J, Yeh RF, Zaveri JS, Zhan M, Zhang G, Zhao Q, Zheng L, Zheng XH, Zhong FN, Zhong W, Zhou X, Zhu S, Zhu X, Smith HO, Gibbs RA, Myers EW, Rubin GM, Venter JC
The genome sequence of Drosophila melanogaster.
Science (New York, N.Y.). 2000-03-24; 287.5461: 2185-95.
PMID: 10731132
Global transposon mutagenesis and a minimal Mycoplasma genome.
Science (New York, N.Y.). 1999-12-10; 286.5447: 2165-9.
PMID: 10591650
DNA uptake signal sequences in naturally transformable bacteria.
Research in microbiology. 1999-11-01; 150.9-10: 603-16.
PMID: 10673000
The malaria genome sequencing project: complete sequence of Plasmodium falciparum chromosome 2.
Parassitologia. 1999-09-01; 41.1-3: 69-75.
PMID: 10697835
Shotgun sequencing of the human genome.
Science (New York, N.Y.). 1998-06-05; 280.5369: 1540-2.
PMID: 9644018
A new transformation-deficient mutant of Haemophilus influenzae Rd with normal DNA uptake.
Journal of bacteriology. 1998-02-01; 180.3: 746-8.
PMID: 9457884
In vitro Tn7 mutagenesis of Haemophilus influenzae Rd and characterization of the role of atpA in transformation.
Journal of bacteriology. 1997-12-01; 179.23: 7315-20.
PMID: 9393695
A new strategy for genome sequencing.
Nature. 1996-05-30; 381.6581: 364-6.
PMID: 8632789
Frequency and distribution of DNA uptake signal sequences in the Haemophilus influenzae Rd genome.
Science (New York, N.Y.). 1995-07-28; 269.5223: 538-40.
PMID: 7542802
Whole-genome random sequencing and assembly of Haemophilus influenzae Rd.
Science (New York, N.Y.). 1995-07-28; 269.5223: 496-512.
PMID: 7542800
A restriction enzyme from Hemophilus influenzae. I. Purification and general properties. 1970.
Biotechnology (Reading, Mass.). 1992-01-01; 24.38-50.
PMID: 1330118
Finding sequence motifs in groups of functionally related proteins.
Proceedings of the National Academy of Sciences of the United States of America. 1990-01-01; 87.2: 826-30.
PMID: 1689055
A restriction enzyme from Hemophilus influenzae. II.
Journal of molecular biology. 1970-07-28; 51.2: 393-409.
PMID: 5312501
Salk Intitute Lecture — 2016 DOE JGI Genomics of Energy & Environment Meeting
Johns Hopkins Medicine — The Hamilton Smith Award for Innovative Research
UW-Madison Lecture
Salk Intitute Lecture — Making miniature machines - with Hamilton Smith
The Nobel Prize — Interview with Hamilton Smith and Richard Roberts
22-Dec-2020
Press Release

Hamilton O. Smith, M.D., Synthetic Biology Pioneer and Nobel Laureate, to Step Down from Daily Duties at J. Craig Venter Institute

Dr. Smith will maintain advisory role as professor emeritus

19-Dec-2020
The San Diego Union-Tribune

After saving countless lives, Nobel laureate Hamilton Smith retires as his own health falters

He has been a fixture in San Diego science for decades

13-Jun-2012
Press Release

JCVI Researchers, as Part of NIH Human Microbiome Project Consortium, Publish Papers Detailing the Variety and Abundance of Microbes Living on and in the Human Body

Study Represents Largest Group of Healthy Individuals Studied to Date

JCVI also Details its Metagenomics Reports (METAREP) Open Source Bioinformatics Tool

20-Aug-2009
Press Release

J. Craig Venter Institute Researchers Clone and Engineer Bacterial Genomes in Yeast and Transplant Genomes Back into Bacterial Cells

New methods allow for the rapid engineering of bacterial chromosomes and the creation of extensively modified bacterial species; should also play key role in boot up of synthetic cell

24-Jan-2008
Press Release

Venter Institute Scientists Create First Synthetic Bacterial Genome

Publication Represents Largest Chemically Defined Structure Synthesized in the Lab

Team Completes Second Step in Three Step Process to Create Synthetic Organism

28-Jun-2007
Press Release

JCVI Scientists Publish First Bacterial Genome Transplantation Changing One Species to Another

Research is important step in further advancing field of synthetic genomics

29-Sep-2004
Press Release

J. Craig Venter Announces Consolidation of Three Research Organizations Into One New Not-For-Profit Organization — The J. Craig Venter Institute

The Center for Advancement of Genomics (TCAG), Institute for Biological Energy Alternatives (IBEA), and J. Craig Venter Science Foundation Joint Technology Center (JTC) consolidated to form J. Craig Venter Institute

13-Nov-2003
Press Release

IBEA Researchers Make Significant Advance in Methodology Toward Goal of a Synthetic Genome

Group Synthesizes Biologically Active Genome of Bacteriophage φX174

IBEA research, funded by Dept. of Energy, is an important advance toward the goal of a completely synthetic genome that could aid in carbon sequestration and energy production

21-Nov-2002
Press Release

IBEA Receives $3 Million Dept. of Energy Grant for Synthetic Genome Development

Hamilton Smith, M.D., Nobel Laureate, Named Scientific Director of IBEA