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I have found the extension "et al" with biologists from different nationalities like : Avery et al ; Taylor et al etc.

My question : 1. What does it mean? 2. Why only biologists?


The Latin phrase et alia (abbreviated et al.) means and others.

It is not limited to biologists, nor those of different nationalities. If I refer to this computer graphics article, I can refer to it as "the paper written by Henrik Jensen, et al., regarding physically based modeling of fire… "

Note that the expansion of et al. can also be et alii and et aliae, which are the masculine and feminine forms, respectively; et alia is the neuter form.


'Great Books' List

Compiled from messages to the AP Biology Electronic Discussion Group, this is a collection of "biological" books for pleasure reading, for background knowledge, and for student assignments. Please contact AP Central to add titless or to help briefly annotate selections.

Copyright dates courtesy of Amazon.com. Fiction is marked with an (F) and nonfiction with an (NF).

Agosta, William C. | Chemical Communication: The Language of Pheromones (1992) (NF)
Pheromones are used in a variety of animals in reproduction, territory marking, signaling, and other forms of communication.

Agosta, William C. | Bombardier Beetles and Fever Trees: A Close-Up Look at Chemical Warfare and Signals in Animals and Plants (1997) (NF)
A book with excellent explanations of the use of chemicals in living organisms.

Agosta, William C. | Thieves, Deceivers, and Killers: Tales of Chemistry in Nature (2002) (NF)
A collection of stories woven together with the thread of chemistry—antibiotics, enzymes in extremophiles, intricate chemical communication in insects, etc.

Alvarez, Walter | T-Rex and the Crater of Doom (1998) (NF) (1999) (NF)
A description of the evidence that links the production of the Chicxulub Crater in Mexico by an asteroid and the extinction of the dinosaurs.

Andrews, Lori B. | The Clone Age: Adventures in the New World of Reproductive Technology (1999) (NF)
Reproductive technology and the law associated with it for the layperson.

Angier, Natalie | The Beauty of the Beastly (1996) (NF)
A book of essays about organisms on which we don't normally dwell—divided into seven chapters entitled "Loving," "Slithering," "Dancing," "Dying," "Adapting," "Healing," and "Creating."

Agosta, William C. | Thieves, Deceivers, and Killers: Tales of Chemistry in Nature (2002) (NF)
A collection of stories woven together with the thread of chemistry—antibiotics, enzymes in extremophiles, intricate chemical communication in insects, etc.

Angier, Natalie | Natural Obsessions: Striving to Unlock the Deepest Secrets of the Cancer Cell (1999) (NF)
The work of young scientists in the areas of molecular genetics and the genetics of cancer.

Anthony, Piers | Tatham Mound (1991) (F)
A native American story woven around skeletons unearthed in a mound discovered on a Boy Scout camp in Florida.

Asimov, Isaac | Wellsprings of Life (1960) (F)
The middle book of a set of three biochemistry books, this one deals with origin of life, molecules (including DNA), spontaneous generation, and evolution.

Asimov, Isaac | Fantastic Voyage (1966) (F)
A medical team is miniaturized and injected into a VIP's bloodstream to destroy a clot that threatens his life.

Auel, Jean | The Clan of the Cave Bear (1983), The Valley of the Horses (1983), The Mammoth Hunters (1986), The Plains of Passage (1993), Shelters of Stone (2003) (F)
A story of a Cro-Magnon woman raised by Neanderthals who must learn the ways of others like her when she is expelled from the Neanderthal community.

Bakker, Robert T. | The Dinosaur Heresies: New Theories Unlocking the Mystery of the Dinosaurs and Their Extinction (1986) (NF)
Support for Bakker's controversial view of dinosaurs as active, warm-blooded, intelligent beings.

Bear, Greg | Darwin's Radio (1999) (F)
Something that has slept in our genes for millions of years is waking up and accelerating human evolution.

Benchley, Peter | Beast (1993) (F)
A giant squid terrorizes Bermuda.

Benchley, Peter | White Shark (1996) (F)
Nazis fashion a creature from a man.

Benson, Ann | Plague Tales (1997) (F)
The story of two plagues that are linked despite the plagues being separated by hundreds of years.

Benson, Ann | The Burning Road (1999) (F)
The sequel to Plague Tales.

Bernstein, Leonard, Alan Winkler, and Linda Zierdt-Warsha | Multicultural Women of Science (paperback 1996) (NF)
A compilation of 37 hands-on activities and experiments that accompany descriptions of the work of female scientists from around the world.

Bodanis, David | The Secret House: 24 Hours in the Strange and Unexpected World in Which We Spend Our Nights and Days (1986) (NF)
Everything we always wanted to know (or did not want to know) about the microscopic organisms that live on and around us.

Braver, Gary | Elixir (paperback 2001) (F)
A scientist stumbles onto a "fountain-of-youth" drug.

Browne, Janet | The Power of Place (2002) (NF)
Second part of the Darwin biography begins with the arrival of letters from Wallace and follows through to his death.

Browne, Janet | Charles Darwin: Voyaging (1995) (NF)
Traces the interesting life of Darwin from birth to 1858 just before his publishing of Origin of Species.

Bronowski, Jacob | Science and Human Values (1999) (NF)
Thought-provoking essays on science as an integral part of our culture.

Bybee, Rodger W. editor | NSTA:Evolution in Perspective: The Science Teacher's Compendium (2004) (NF)
Twelve different articles concerning a teacher's role in presenting and nurturing an understanding of the theory of evolution as an ongoing scientific endeavor. (see full review at NSTA Publications site)

Bryson, Bill | A Short History of Nearly Everything (2003) (NF)
Reports how humans figured out major concepts in science, from the age of the universe to continental drift to how cells work, complete with interesting dialogue from the world's famous truth seekers.

Cannell, Stephen J. | The Devil's Workshop (1999) (F)
Prions are used as a bioweapons agent in this story by the man who directed The Rockford Files, The A-Team, and The Commish.

Card, Orson Scott | Xenocide (1999) (F)
The story of an attempt to control a highly adaptive virus on planet Lusitania.

Carroll, Sean | Endless Forms Most Beautiful: The New Science of Evo Devo and The Making of the Animal Kingdom (2005) (NF)
A look at developmental biology and its relationship to evolution documentation of how genes that regulate embryonic development have "evolved", creating new body patterns and better adaptations for survival.

Carson, Rachel | The Sea Around Us (1951) (NF)
Recommendations regarding the care of the oceans that are still timely more than 50 years later.

Carson, Rachel | Silent Spring (1962) (NF)
Carson's classic expose of poisons in the environment and how they accumulate in the tissues of animals.

Case, John | The First Horseman (2001) (F)
The influenza epidemic from 1918 may be released again by a bioterrorist.

Case, John | The Genesis Code (2001) (F)
Women are being inseminated with cell samples containing DNA from relics associated with Christ.

Close, William T. | Ebola: Through the Eyes of the People (paperback 2001) (NF)
A documentary novel written by Glenn Close's father that chronicles the first emergence ofEbola in a Catholic mission in Zaire.

Colborn, Theo, et al. | Our Stolen Future (1997) (NF)
The impact that synthetic chemicals in the environment have on human reproduction,development, and disease.

Cook, Robin | Terminal (1993) (F)
A Harvard medical student investigates a clinic with a 100 percent cure rate for a rare cancer.

Cook, Robin | Acceptable Risk (1995) (F)
An interesting link between antidepressant drugs and the Salem witch trials.

Cook Robin | Chromosome 6 (1997) (F)
Genetic research, primate development, and cloning for transplantation.

Cook, Robin | Toxin (2001) (F)
An investigation of the beef-packaging and slaughterhouse industries and Eco 0157 infections.

Cornwell, Patricia | Portrait of a Killer: Jack the Ripper Case Closed (2002) (NF)
Cornwell uses current forensic techniques to amass evidence indicating that Walter Sickert, a well-known London artist, was Jack the Ripper.

Cousins, Norman | Head First: The Biology of Hope and the Healing Power of the Human Spirit (1990) (NF)
The author's own account of the use of humor therapy to overcome cancer.

Crichton, Michael | The Andromeda Strain (1969) (F)
A satellite returns from space with an unknown pathogenic "organism."

Crichton, Michael | Five Patients: The Hospital Explained (1970) (NF)
The positives and negatives of the health care system seen through the lens of five actual case studies.

Crichton, Michael | Jurassic Park (1990) (F)
A new type of theme park complete with cloned dinosaurs goes awry.

Crichton, Michael | Congo (1994) (F)
An investigation of a research team attacked by an "unknown" species.

Crichton, Michael | Timeline (1999) (F)
Time travel to the medieval past goes awry.

Darnton, John | The Experiment (1999) (F)
A story of cloning, genetic disease, and ethical issues.

Darnton, John | Neanderthal (2001) (F)
A group of Neanderthals is found in the present.

Darwin, Charles | Origin of Species (1859) (NF)
Darwin's original work that presented natural selection as the mechanism for evolution.

Davidson, Osha G. | The Enchanted Braid: Coming to Terms with Nature on the Coral Reef (1998) (NF)
Evaluation of the condition of Earth's coral reefs reveals that 10 percent are beyond help, and another 30 percent are in serious danger.

Dawkins, Marian Stamp | Though Our Eyes Only? The Search for Animal Consciousness (1993) (NF)
An account of what is currently known about animal consciousness.

Dawkins, Richard | The Ancestor's Tale: A Pilgrimage to the Dawn of Evolution (2005) (NF)
Moving backwards in time, the evolution of humans and many other organisms is traced with fossils, DNA, and comparative anatomy to "the beginnings". ("Good graphics and photographs")

Dawkins, Richard | The Blind Watchmaker: Why the Evidence of Evolution Reveals a Universe Without Design (1986) (NF)
A discussion that supports Darwinism as an explanation of our existence to counter intelligent design supporters.

Dawkins, Richard | The Selfish Gene, 2nd ed. (1989) (NF)
Dawkins makes the case that our genes maintain us in order to make more genes.

Dawkins, Richard | River Out of Eden: A Darwinian View of Life (1995) (NF)
Looks at genetic and mitochondrial evidence for evolution and takes "gene's eye view" of natural selection.

Dethier, Vincent | To Know a Fly (1989) (NF)
Cartoons and humor relate stories of curiosity and the excitement of the scientific method.

Diamond, Jared M. | The Third Chimpanzee: The Evolution and Future of the Human Animal (1992) (NF)
Diamond takes a look at human evolution to determine how we became more than a chimpanzee.

Diamond, Jared M. | Guns, Germs, and Steel: The Fates of Human Societies (1997) (NF)
An investigation into human nature, history, and politics to explain how Europe conquered the New World, Africa, and Asia.

Dillard, Annie | Pilgrim at Tinker Creek (1998), Teaching a Stone to Talk: Expeditions and Encounters (1983) (NF)
Collections of essays on Dillard's observations of nature.

Dixon, Bernard, ed. | From Creation to Chaos: Classic Writing in Science (1989) (NF)
A collection of writings that depict the major scientific investigations of the last 150 years.

Djerassi, Carl | Cantor's Dilemma (1989) (F)
Two scientists who win the Nobel Prize for cancer research are suspected of falsifying data.

Dorris, Michael | The Broken Cord: A Family's Ongoing Struggle with Fetal Alcohol Syndrome (1989) (NF)
The story of the author's adoption a young Native American boy who suffers from fetal alcohol syndrome.

Doyle, Rodger P. | The Medical Wars (1983) (NF)
Disease and its causes.

Dugatkin, Lee Alan | Cheating Monkeys and Citizen Bees: The Nature of Cooperation in Animals and Humans (1999) (NF)
An explanation for why animals help each other.

Durden, Kent | Gifts of an Eagle (1972) (NF)
The author's account of rescuing a Golden Eagle nestling.

Eckert, Allan W. | The Great Auk (1963) (F)
A fictional but believable story about how humans contribute to the extinction of a species.

Eckert, Allan W. | The Silent Sky: The Incredible Extinction of the Passenger Pigeon (1983) (NF)
Eckert delivers a novel wrapped around man's role of the extinction of the passenger pigeon.

Ehrlich, Paul | The Population Bomb (1976) (NF)
A treatment of the population explosion without consideration of the possibility of technological developments.

Eiseley, Loren | The Immense Journey (1957) (NF)
A collection of essays on evolution from an anthropologist's viewpoint.

Ellis, Mel, et al. | The Land, Always the Land (1998) (NF)
Essays on nature—one chapter for each month of the year.

Feynman, Richard P. | "Surely You're Joking, Mr. Feynman!" Adventures of a Curious Character (1999) (NF)
A book of anecdotes about the Nobel-prize winner's life that a layman can understand and that entertains while it educates.

Fossey, Dian Gorillas in the Mist (1983) (NF)
Fossey's own story of working with gorillas in the remote African rain forest.

Frank-Kamenetskii, Maxim D. | Unraveling DNA: The Most Important Molecule of Life (1997) (NF)
What was known about DNA and the field of molecular genetics as of 1996.

Franklin, Jon | Molecules of the Mind: The Brave New Science of Molecular Psychology (1987) (NF)
The link between chemical imbalances in the brain and mental illness.

Gallo, Robert | Virus Hunting: AIDS, Cancer, and the Human Retrovirus: A Story of Scientific Discovery (1991) (NF)
A defense against the charges of unethical behavior that were made during Gallo's discovery of the AIDS virus.

Garrett, Laurie | The Coming Plague: Newly Emerging Diseases in a World Out of Balance (1995) (NF)
Garrett's dissertation on emerging and reemerging diseases.

Gear, Kathleen, and W. Michael | People of the Wolf (1994), People of the Fire (1992), People of the Earth (1994) (F)
A husband-and-wife anthropologist team writes about native North Americans before written history.

Goodall, Jane | In the Shadow of Man (1983) (NF)
Goodall's story of her work with chimpanzees.

Goodall, Jane | Through a Window: My Thirty Years with the Chimpanzees of Gombe (1990) (NF)
The sequel to In the Shadow of Man.

Goodall, Jane | Reason for Hope: A Spiritual Journey (1999) (NF)
An extension of Goodall's first book with more emphasis on her philosophy.

Gould, Stephen Jay | Ever Since Darwin: Reflections in Natural History (1977), The Panda's Thumb: More Reflections in Natural History (1980), Hen's Teeth and Horse's Toes (1983), The Flamingo's Smile: Reflections in Natural History (1985), Bully for Brontosaurus: Reflections in Natural History (1991), Wonderful Life: The Burgess of Shale and the Nature of History (1998), The Mismeasure of Man (1999) (NF)
Essays on evolution and natural history.

Grace, Eric S. | Biotechnology Unzipped: Promise and Realities (1997) (NF)
Provides the basics about DNA and an explanation of genetic engineering.

Hagen, Joel, Douglas Allchin, and Fred Singer | Doing Biology (1997) (NF)
Documents the discovery of the cause of beriberi, the process of chemiosmosis, the details of Krebs cycle, and much more.

Hamer, Dean | Living with Our Genes: Why They Matter More Than You Think (1998) (NF)
A look at the possible connections between our genes and our personalities, sexual orientation, high-risk behavior, etc.

Heersink, Mary | E. coli 0157: The True Story of a Mother's Battle with a Killer Microbe (1996) (NF)
A mother writes about the bacterial infection that nearly killed her son after he ingested improperly cooked hamburger on a scout trip.

Heinrich, Bernd | Ravens in Winter (1989) (NF)
The author's observations of the behavior of ravens over several Maine winters.

Heiser, Charles Bixler | Of Plants and People (1992) (NF)
A collection of essays on ethnobotany.

Henig, Robin | A Dancing Matrix: Voyages Along the Viral Frontier (1993) (NF)
A slightly dated treatment of emerging viruses and how our behavior predisposes us to viral epidemics.

Henig, Robin | The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, the Father of Genetics (2000) (NF)
The story of Mendel and the three scientists who later rediscovered his work.

Hoover, Helen | Gift of the Deer (1966) (NF)
The story of a family's experiences with a whitetail deer family that visits them for several years.

Hoover, Thomas | Life Blood (paperback 2000) (F)
A clinic in the tropics is recruiting young women for fertility experiments to produce children "sold" through adoption agencies.

Horner, John | Digging Dinosaurs: The Search That Unraveled the Mystery of Baby Dinosaurs (1999) (NF)
A look at dinosaur fossils and the people who look for them.

Hoyle, Fred | The Nature of the Universe (1960) (NF)
A collection of radio talks on astronomy done by the author, a famous British astronomer, in the 1950s.

Huxley, Aldous | Brave New World (1932) (F)
A provocative piece of futuristic science fiction.

Johanson, Donald | Lucy: The Beginnings of Humankind (1981) (NF)
A history of paleoanthropology precedes a description of finding and analyzing Lucy.

Jones, Steve | Darwin's Ghost (2000) (NF)
Wonderful and easy to read, updated version of Origin of Species using Darwin's exact table of contents (and many of Darwin's original words) but replacing the 1800s examples with modern ones that support Origin's arguments concerning natural selection.

Karlen, Arno | Napoleon's Glands and Other Ventures in Biohistory (1984) (NF)
A discussion of how disease has affected human history.

Keller, Evelyn Fox | A Feeling for the Organism: The Life and Work of Barbara McClintock (paperback 1984) (NF)
A biography of Nobel-prize-winner McClintock, whose work on transposable genes was decades before its time.

Kingsolver, Barbara | The Poisonwood Bible (1999) (F)
A story told through the voices of four daughters of a Baptist missionary to the Congo.

Kingsolver, Barbara | Prodigal Summer (2000) (F)
Nature themes run throughout the telling of three stories set in Appalachia.

Kolata, Gina | Flu: The Story of the Great Influenza Pandemic (2001) (NF)
Story of how the flu virus killed 40 million people at the end of World War I, researching survivors' stories and analyzing the causes of this terrible epidemic and its legacy.

Koontz, Dean | Seize the Night (1998), Fear Nothing (1998) (F)
The main character is forced to do his detective work at night because he has xeroderma pigmentosa, a genetic disease that makes him unable to repair genetic damage that results from exposure to ultraviolet light.

Krakauer, Jon | Into Thin Air: A Personal Account of the Mount Everest Disaster (1997) (NF)
Krakauer was part of the ill-fated Mount Everest expedition that resulted in nine deaths.

Kyle, Stephen | Beyond Recall (2000) (F)
A virus is released on the world by a bioterrorist.

Lax, Eric | The Mold in Dr. Florey's Coat: The Story of the Penicillin Miracle (2004) (NF)
The true story about the development of the drug penicillin after its discovery by Alexander Fleming. ("an interesting but hard read")

Leakey, Richard, and Roger Lewin | The Sixth Extinction: Biodiversity and Its Survival (1996) (NF)
There is uncertainty about the causes of the first five mass extinctions, but man is the culprit of the present sixth mass extinction of species.

LeGuin, Ursula | The Left Hand of Darkness (1999) (F)
The story of an envoy from Earth who goes to another planet to establish a relationship between the two planets.

Leopold, Aldo | Sand County Almanac and Sketches Here and There (1949) (NF)
A series of essays on the plants and animals associated with the author's Wisconsin farm.

Leroi, Armand Marie | Mutants: On Genetic Variety and The Human Body (2003) (NF)
Relates variability to human embryology and growth discusses race and strange genetic conditions such as those of the ostrich-footed people and conjoined twins.

Levay, Simon | The Sexual Brain (1993) (NF)
A discussion of current knowledge about sex and the brain.

Levi-Montalcini, Rita | In Praise of Imperfection (1988) (NF)
Autobiography of one of two scientists who received the Nobel prize in 1984 for isolating a nerve growth factor in mice.

Lorenz, Konrad | King Solomon's Ring (1952) (NF)
A view of animal behavior through the eyes of the "father of ethology."

Lynch, Patrick | Carriers (1996) (F)
An organism that is one hundred times more contagious than Ebola is hatching in the rainforest.

Lynch, Patrick | Omega (1997) (F)
Superbugs (bacteria resistant to all known antibiotics) are on the loose in Los Angeles, and only a superantibiotic can control them.

Lyons, Jeff | Altered Fates: Gene Therapy and Retooling of Human Life (1995) (NF)
A historical treatment of the potential of and issues associated with gene therapy.

Lyons, Jeff | Playing God in the Nursery (1985) (NF)
A cautionary discussion about the use of extreme efforts to save premature and handicapped babies.

Maddox, Brenda | Rosalind Franklin: The Dark Lady of DNA (2003) (NF)
A very personal look at a brilliant scientist who never got the credit she deserved for her X-ray crystallographs of DNA that helped Watson and Crick solve the mystery of the double helix.

Maples, William | Dead Men Do Tell Tales: The Strange and Fascinating Cases of a Forensic Pathologist (1994) (NF)
Dr. Maples tells the stories of his strangest, most interesting, and most macabre cases.

Marion, Robert | Was George Washington Really the Father of Our Country? (1994) (NF)
Speculation on the effects that genetic disorders and disease may have had on historical characters like JFK, Lincoln, Bonaparte, etc.

Marr, John S. | The Eleventh Plague (1999) (F)
The 10 plagues of Egypt are visited on the world by a bioterrorist.

Massie, Robert K. | Nicholas and Alexandra (1995) (F)
Massie, the father of a hemophiliac, writes a fictionalized account of Nicholas II, the lastRussian tsar, and his wife, Alexandra.

Mawer, Simon | Mendel's Dwarf (1998) (F)
Mendel's great-great-great-nephew is a prominent genetic researcher who suffers from achondroplastic dwarfism. A disturbing ending and erotic passages may make this book inappropriate to use with students.

Mayr, Ernst | The Growth of Biological Thought: Diversity, Evolution, and Inheritance (1982) (NF)
Discusses man's attempts to classify and understand the diversity of life forms on Earth.

Mayr, Ernst | Towards a New Philosophy of Biology: Observations of an Evolutionist (1988) (NF)
Merges the science of biology, philosophy, and evolution.

Mayr, Ernst | One Long Argument: Charles Darwin and the Genesis of Modern Evolutionary Thought (1991) (NF)
An analysis of Darwin's evolutionary theories and their impact on science.

Mayr, Ernst | This Is Biology: The Science of the Living World (1997) (NF)
Traces the development of biology from ancient Greeks to age of biotechnology, weaving in relationships to history and ethics.

Mayr, Ernst | What Evolution Is (2001) (NF)
Argues evolution is not a theory but a fact—provides evidence interesting populational evidence and ends with "How Did Mankind Evolve?"

McGrayne, Sharon Bertsch | Nobel Prize Women in Science: Their Lives, Struggles, and Momentous Discoveries (1993) (NF)
The story of 14 women who have either won the Nobel prize or contributed to the win by another scientist.

McGrayne, Sharon Bertsch | Prometheans in the Lab: Chemistry and the Making of the Modern World (2001) (NF)
From nylon to fertilizer to DDT, stories of nine chemists to bring home the excitement and importance of their work in the modern world.

McNamee, Gregory, ed. | The Sierra Club Reader (paperback 1995) (NF)
A collection of writings from The Sierra Club.

Mitchell, W. J. T. | The Last Dinosaur: The Life and Times of a Cultural Icon (1998) (NF)
A look at the evolving image of the dinosaur.

Mones, Paul | Stalking Justice (1996) (NF)
Mones chronicles the first time DNA fingerprinting evidence was used in the U.S. to convict a serial murderer.

Montgomery, Sy | Walking with the Great Apes: Jane Goodall, Dian Fossey, Birute Galdikas (1991) (NF)
The stories of three great female primatologists who have given their lives to studying another primate species.

Morris, Desmond | The Naked Ape: A Zoologist's Study of the Human Animal (1967) (NF)
An examination of man from the scientist's point of view.

Morris, M. E. | Biostrike (paperback 1996) (F)
A runaway freighter filled with lethal bacteria must be stopped.

Mowat, Farley | Never Cry Wolf (1963) (NF)
Mowat tells about his adventures with a family of wolves.

Mowat, Farley | Woman in the Mists: The Story of Dian Fossey and the Mountain Gorillas (1988) (NF)
The story of Fossey's life with the gorillas of Rwanda, Africa, and a theory on why she was murdered.

Mullis, Kary | Dancing Naked in the Mind Field (1998) (NF)
A description of the author's adventures on the way to inventing PCR.

Nesse, Randolph M., M.D., and George C. Williams | Why We Get Sick: The New Science of Darwinian Medicine (1995) (NF)
Describes illness as important to honing our adaptations to our environment (development of fever, sneezing, etc.) and hypothesizes new ways to treat problems based on Darwinian principles.

Noble, Holcomb | Next: Coming Era in Medicine (1988) (NF)
A prediction of the future of medicine and technology.

Oldstone, Michael | Viruses, Plagues, and History (1998) (NF)
The impact of communicable diseases on history.

Oppel, Kenneth | The Devil's Cure (2001) (F)
A prison inmate may possess the cure for cancer in his blood, but getting it may be more than Dr. Laura Donaldson bargained for.

Peattie, Donald C. | Flowering Earth: Wood Engravings by Paul Landacre (1991) (NF)
A reprint of the 1939 book on the history of the plant kingdom.

Perutz, Max F. | Is Science Necessary? Essays on Science and Scientists (1989) (NF)
A book of essays by a Nobel-prize-winning molecular biologist.

Peters, C. J., et al. | Virus Hunter: Thirty Years of Battling Hot Viruses Around the World (1997) (NF)
C. J. Peters saw most of the emerging viruses during his CDC years and lived to tell the story.

Plotkin, Mark J. | Tales of a Shaman's Apprentice: An Ethnobotanist Searches for New Medicines in the Amazon Rain Forest (1993) (NF)
Plotkin has attempted to learn all he can about the medicinal uses of plants from South American shamans before they become extinct.

Pohl, Frederick | Chernobyl (1987) (F)
The author traveled to Moscow to collect the facts used in this fictionalized account of the Russian nuclear disaster.

Poole, Joyce | Coming of Age with Elephants: A Memoir (1996) (NF)
The story of elephants, their habitat, and how humans endanger them.

Preston, Richard | The Hot Zone (1995) (F)
A frightening story of an Ebola outbreak.

Preston, Richard | The Cobra Event (1997) (F)
A bioterrorist story of the dispersal of genetically engineered pathogens.

Preston, Richard | The Demon in the Freezer: A True Story (2002) (NF)
The history and eradication of the small pox virus.

Quammen, David | Flight of the Iguana: A Sidelong View of Science and Nature (1988) (NF)
A collection of nature essays that originally appeared in Outdoors magazine.

Quammen, David | The Song of the Dodo: Island Biogeography in an Age of Extinctions (1996) (NF)
A study of island biogeography and how it impacts extinction and conservation.

Quinn, Daniel | Ishmael, 5th ed. (1995), The Story of (1996), My Ishmael: A Sequel (1997) (F)
Quinn's unusual storyteller relates stories of a spiritual journey with ecological overtones as told to three different students.

Raup, David M. | Extinction: Bad Genes or Bad Luck (1991) (NF)
Theories on extinction.

Reichs, Kathy | Deja Dead (1997), Death du Jour (1999), Deadly Decisions (2000) (F)
Reichs is a forensic anthropologist whose main character, Temperance Brennan, is the same and who splits her time between North Carolina and Canada just like Reichs.

Restak, Richard | Receptors: The Brain Has a Mind of Its Own (1994) (NF)

Rhodes, Richard | Deadly Feasts: The "Prion" Controversy and the Public Health (1997) (NF)
A look into decades of research into diseases like kuru, scrapie, and mad-cow disease.

Ridley, Matt | Genome: The Autobiography of a Species in 23 Chapters (2000) (NF)
The story of one gene on each of our chromosomes and how it affects development.

Ridley, Matt | Nature Via Nurture—Genes, Experience & What Makes Us Human (2003)(NF)
Explores nature versus nurture arguments, and presents emerging evidence that intricate relationships between genes and the environment make them dependent upon each other.

Roberts, Royston M. | Serendipity: Accidental Discoveries in Science (1989) (NF)
A collection of stories about accidental discoveries that have changed science.

Roueche, Berton | Eleven Blue Men and Other Narratives of Medical Detection (1953), The Orange Man and Other Narratives of Medical Detection (1971) (NF)
A collection of essays on medical disorders and their detection.

Ryan, Frank | Virus X: Tracking the New Killer Plagues Out of the Present and into the Future (1997) (NF)
A less sensationalized story of emerging and reemerging viruses than Laurie Garrett's book.

Sacks, Oliver | The Island of the Colorblind (1997) (NF)
The author studies total colorblindness and a rare type of paralysis in light of their appearance in Pacific Island populations includes anthropology, botany, and medicine.

Sagan, Carl | The Dragons of Eden: Speculation on the Evolution of Human Intelligence (1977) (NF)
A somewhat dated look at the evolution of the human brain.

Sagan, Carl | The Demon-Haunted World: Science As a Candle in the Dark (1996) (NF)
A look at how science works and how scientific critical-thinking skills can be used in other disciplines.

Sagan, Carl, and Ann Durian | Shadows of Forgotten Ancestors: A Search for Who We Are (1992) (NF)
A look at the evolution of man starting with the Big Bang.

Sayre, Anne | Rosalind Franklin and DNA (1978) (NF)
Franklin did not live to share the Nobel prize for the discovery of DNA structure, but her contributions were invaluable.

Schlosser, Eric | Fast Food Nation: The Dark Side of the All-American Meal (2001) (NF)
A disturbing look at the empty and excess calories, unhealthy menus, and dangerous practices and processing that may affect those who dine at fast food restaurants.

Schreiber, Whitley, et al. | Nature's End: The Consequences of the Twentieth Century (1986) (F)
A cautionary tale of what will happen if we continue to destroy the environment at the rate we did in the twentieth century.

Shnayerson, Michael and Mark Plotkin | The Killers Within:The Deadly Rise of Drug-Resistant Bacteria (2003) (NF)
Focusing on staph, strep, and enteric bacteria, antibiotic resistance is explained and cautions made concerning drug overuse in both humans and livestock. Suggestions on both lessening the problems and searching for new antibiotic sources are discussed.

Silverstein, Herman | Threads of Evidence (1997) (NF)
A look at forensic technology with examples from actual cases.

Slack, J. M. W. | Egg and Ego: An Almost True Story of Life in the Biology Lab (1999) (NF)
Words of wisdom for anyone wanting to enter the field of science.

Stone, Irving | The Origin: A Biographical Novel of Charles Darwin (1980) (F)
A fictionalized biographical account of Darwin's life.

Sykes, Brian | The Seven Daughters of Eve: The Science That Reveals Our Genetic Ancestry (2001) (NF)
How decoding mitochondrial DNA answers questions of human origins.

Thomas, Lewis | The Lives of a Cell: Notes of a Biology Watcher (1978), The Medusa and the Snail: More Notes of a Biology Watcher (1979), The Fragile Species (1992), The Youngest Science: Notes of a Medicine-Watcher (1984) (NF)
Thomas's collections of essays on life.

Vonnegut, Kurt | Galapagos (1987) (F)
A futuristic, end-of-the-world story set in the Galapagos Islands.

Wambaugh, Joseph | The Blooding (1991) (F)
A novel based on the case of the first use of DNA fingerprinting evidence in a British rape and murder investigation.

Warner, William | Beautiful Swimmers: Watermen, Crabs, and the Chesapeake Bay (1976) (NF)
The story of life on the Chesapeake Bay.

Watson, James | The Double Helix (1968) (NF)
Watson's account of the events that led to the discovery of DNA structure.

Watson, James | DNA: The Secret of Life (2003) (NF)
A history of DNA from Mendel to genome sequencing.

Weinberg, Samantha | A Fish Caught in Time: The Search for the Coelacanth (2000) (NF)
The history of the search for the coelocanth.

Weiner, Jonathan | The Beak of the Finch: A Story of Evolution in Our Time (1994) (NF)
The story of Rosemary and Peter Grant, who have observed beak evolution for 20 years in finches on Daphne Island in the Galapagos.

Weiner, Jonathan | Time, Love, and Memory: A Great Biologist and His Quest for the Origins of Behavior (1999) (NF)
A biography of Seymour Benzer, the man who discovered how to use viral DNA to map a gene.

Weissman, Gerald | The Woods Hole Cantata: Essays on Science and Society (1985) (NF)
A collection of essays that highlight the parallels between science and society.

White, Ryan, and Ann Marie Cunningham | Ryan White: My Own Story (1991) (NF)
A biography of Ryan White, one of most famous AIDS victims.

Wills, Christopher | Yellow Fever, Black Goddess: The Convolution of People and Plagues (1997) (NF)
A look at how disease has affected history in addition to a analysis of current diseases.

Wilson, Charles | Extinct (1997) (F)
The Gulf Coast is terrorized by a megalodon, "assumed to be extinct" ancestor of the great white shark (only bigger).

Wilson, Edward O. | The Diversity of Life (1992) (NF)
A look at the loss of diversity, its effects, and some solutions.

Wilson, Edward O. | Sociobiology: The New Synthesis: Twenty-fifth Anniversary Edition (2000) (NF)
A description of the then-new science of sociobiology (the study of the biological basis of social behavior).

Wimpier, Eric P. | Why Geese Don't Get Obese (and We Do): How Evolution's Strategies for Survival Affect Our Everyday Lives (1998) (NF)
Takes a look at how animals (including humans) have evolved strategies to help them survive.

Zimmer, Carl | At the Water's Edge: Fish with Fingers, Whales with Toes, and How Life Came Ashore and Went Back to Sea (1998) (NF)
The history of vertebrate evolution with elaborate examples.

Zimmer, Carl | Parasite Rex: Inside the Bizarre World of Nature's Most Dangerous Creatures (2000) (NF)
A thorough look at parasites.

Zimmer, Carl | Evolution: The Triumph of an Idea (2001) (NF)
A history of evolution for the layperson.

Zimmerman, Barry E. | Killer Germs: Microbes and Diseases That Threaten Humanity (1996) (NF)
A graphic treatment of emerging and reemerging diseases.

Tricia Glidewell has taught AP Biology for 24 years in Atlanta and has served as an AP Reader and Table Leader for 12 years. She has been a College Board consultant for 15 years, teaching one-day workshops and weeklong summer institutes to new and experienced teachers all over the Southeast. She received the Outstanding Biology Teacher Award for the state of Georgia in 1999.

Carolyn Schofield Bronston has taught at Spring Branch's Memorial High School and Tyler's Robert E. Lee High School in Texas. Traveling as a consultant for the College Board since 1979, she also reads the AP Exam each June, authored the Teacher's Guide—AP Biology, created the AP Teacher's Corner, is a member of the Biology Development Committee, and serves as the AP Biology content advisor for AP Central. She is a winner of the Presidential Award for Excellence, the OBTA for Texas, the Tandy Award, and the Texas Excellence Award.


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Author summary

In most fields of science, medicine, and technology research, men comprise more than half of the workforce, particularly at senior levels. Most previous work has concluded that the gender gap is smaller today than it was in the past, giving the impression that there will soon be equal numbers of men and women researchers and that current initiatives to recruit and retain more women are working adequately. Here, we used computational methods to determine the numbers of men and women authors listed on >10 million academic papers published since 2002, allowing us to precisely estimate the gender gap among researchers, as well as its rate of change, for most disciplines of science and medicine. We conclude that many research specialties (e.g., surgery, computer science, physics, and maths) will not reach gender parity this century, given present-day rates of increase in the number of women authors. Additionally, the gender gap varies greatly across countries, with Japan, Germany, and Switzerland having strikingly few women authors. Women were less often commissioned to write ‘invited’ papers, consistent with gender bias by journal editors, and were less often found in authorship positions usually associated with seniority (i.e., the last-listed or sole author). Our results support a need for further reforms to close the gender gap.

Citation: Holman L, Stuart-Fox D, Hauser CE (2018) The gender gap in science: How long until women are equally represented? PLoS Biol 16(4): e2004956. https://doi.org/10.1371/journal.pbio.2004956

Academic Editor: Cassidy Sugimoto, Indiana University Bloomington, United States of America

Received: November 29, 2017 Accepted: March 14, 2018 Published: April 19, 2018

Copyright: © 2018 Holman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: R code used to collect and analyse the data, as well as a compact summary of our dataset, is archived at https://github.com/lukeholman/genderGapCode. A web app allowing exploration of the data can be found at https://lukeholman.github.io/genderGap/. The complete dataset is archived at the Open Science Framework (https://osf.io/bt9ya/). Data used to validate the gender assignment method (and which are thus not primary data for this study) were obtained from a third party these data are currently in preparation for publication and will be publicly available after that time.

Funding: School of BioSciences, University of Melbourne. Start-up funds provided to Luke Holman. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ISI, Institute for Scientific Information MeSH, Medical Subject Heading NSF, National Science Foundation OA, Open-Access STEMM, Science, Technology, Engineering, Mathematics, and Medicine


The origins of quantum biology

Quantum biology is usually considered to be a new discipline, arising from recent research that suggests that biological phenomena such as photosynthesis, enzyme catalysis, avian navigation or olfaction may not only operate within the bounds of classical physics but also make use of a number of the non-trivial features of quantum mechanics, such as coherence, tunnelling and, perhaps, entanglement. However, although the most significant findings have emerged in the past two decades, the roots of quantum biology go much deeper—to the quantum pioneers of the early twentieth century. We will argue that some of the insights provided by these pioneering physicists remain relevant to our understanding of quantum biology today.

1. Introduction

There is growing evidence that a number of specific mechanisms within living cells make use of the non-trivial features of quantum mechanics, such as long-lived quantum coherence, superposition, quantum tunnelling and even quantum entanglement—phenomena that were previously thought to be relevant mostly at the level of isolated molecular, atomic and subatomic systems, or at temperatures near absolute zero, and were thereby not thought to be relevant to the mechanisms responsible for life. It is important at the outset of this review, and before we delve into the origins of quantum biology, to make clear that what is currently understood by the term ‘quantum’ in quantum biology does not simply mean quantization: the discretization of electron energies to account for chemical stability, reactivity, bonding and structure within living cells. Clearly, quantization applies to all matter at the microscopic scale and has long been assimilated into standard molecular biology and biochemistry. Today, quantum biology refers to a small, but growing, number of rather more specific phenomena, well known in physics and chemistry, but until recently thought not to play any meaningful role within the complex environment of living cells. For an up-to-date discussion on recent advances in quantum biology and what it means, see for example [1–3].

One of the most celebrated examples of the non-trivial role that quantum mechanics might be playing in biology is the claimed long-lived quantum coherence observed in the transport of exciton energy in photosynthesis [4–6]. While this subject remains controversial, a more established role for quantum mechanics is found in the tunnelling of electrons and protons in enzyme catalysis [7–9]. Beyond these examples of quantum biology, quantum entanglement has been implicated in avian navigation [10–12], while quantum tunnelling has been proposed to be involved in olfaction [13] and mutation [14,15]. More speculatively, some have suggested a link between quantum coherence and consciousness [16,17], though this view has little support within the neurobiology community.

But while the current interest in quantum biology and the study of the phenomena and mechanisms mentioned above only emerged in the past two decades [18], the origins of the subject go much further back, to the quantum pioneers of the early twentieth century. We will argue that some of the insights provided by a number of these physicists remain relevant to our understanding of quantum biology today.

Quantum biology's origins are often traced back to 1944 and the publication of Erwin Schrödinger's famous book, What is Life? [19]. But even before this, several other quantum physicists had already made inroads into biology. For example, the German physicist Pascual Jordan published a book a year before Schrödinger's, entitled Physics and the Secret of Organic Life [20], in which he had posed the question ‘Sind die Gesetze der Atomphysik und Quantenphysik für die Lebensvorgänge von wesentlicher Bedeutung?’ (‘Are the laws of atomic and quantum physics of essential importance for life?’). In fact, Jordan had been thinking about this question for over a decade and had been using the term Quantenbiologie since the late 1930s. The murky origins that motivated and sustained his interest in quantum biology are inextricably linked to his political sympathies with Nazi Germany and play an important role in explaining why the field did not flourish further after the war ended.

Quantum biology was in fact born shortly after the development of quantum mechanics itself. By 1927, the mathematical framework of the new quantum mechanics was in place, owing to the efforts of Bohr, Heisenberg, Pauli, Schrödinger, Dirac, Born, Jordan, Fermi and others. Flushed with their success at taming the atomic world, and with the arrogance of youth on their side, many quantum pioneers strode out of their physics laboratories and away from their blackboards to seek new areas of science to conquer. Microbiology along with the emerging field of genetics and the chromosome theory of inheritance were still unexplored territories, and a growing number of biophysicists and biochemists began to show more than a passing interest in these subjects. It was only natural therefore for many to ask whether the new atomic physics might also have something to say about the building blocks of life.

Advances in experimental physics around this time were also posing new questions. Just as Robert Hooke's microscope had opened up a new world of the very small in the mid-seventeenth century, so new techniques and key experiments in the decades between the two world wars were helping lay the foundations of an even smaller, molecular, biology. These included the discovery of X-ray mutagenesis by H.J. Muller in 1927, Theodor Svedberg's measurement of the atomic weights of proteins by using his famous ultracentrifuge in the mid-1920s and, later, the crystallization of a virus by W.M. Stanley in 1935. These and other breakthroughs promoted a feeling of optimism that, with the tools of quantum mechanics, the secrets of life could finally be laid bare.

However, not everyone was so confident that the principles of physics and chemistry would be sufficient to explain biology. One such critic was Niels Bohr himself and yet, as we shall see, it was Bohr's pessimism regarding the importance of quantum mechanics in unlocking the secrets of life that would, paradoxically, influence and inspire the men who would lay the foundations of quantum biology.

At the same time as the quantum revolution was taking place in physics, enormous strides were being made in biology through neo-Darwinian synthesis, which brought together the rediscovered principles of Mendelian heredity with the mutations identified by Hugo de Vries and Thomas Hunt Morgan [21]. However, many mysteries remained, particularly surrounding the nature of the heritable material. Microscopic studies at the end of the nineteenth century had associated visible chromosome fibres with Mendel's heritable factors, by this time called ‘genes’. Biochemical studies had established that chromosomes consisted of proteins and nucleic acids but how the genetic information was written into ordinary chemicals and then inherited remained a complete mystery. Moreover, although the idea of vitalism, which maintained that there is some vital ‘life force’ that endows organisms with a special quality absent in inanimate matter, had retreated under the influence of nineteenth century advances, such as Wöhler's synthesis of urea, many scientists and philosophers clung to the belief that some aspects of life required principles outside of classical science. For example, in 1907, the French philosopher Henri Bergson first published his Creative Evolution, in which he argued that heredity and evolution were driven by an ‘élan vital’ or ‘vital impetus’ peculiar to the living [22]. Many scientists remained similarly unconvinced that the extraordinary dynamics of life and heredity could be accounted for by classical sciences such as thermodynamics, organic chemistry and physics.

2. The organicists

Another factor influencing the birth of quantum biology is more subtle and has to do with the philosophical movement of organicism that was popular with many of the leading scientists of the time. Organicism was a reaction to two opposing schools of thought in biology. The first was mechanism, whose origins go at least as far back as the French Philosopher René Descartes, who maintained that all living organisms 1 are essentially machines, differing in complexity but not in principle from those machines that had driven the Industrial Revolution. The movement tended to be reductionist in the sense that it maintained that in biology, just as in all inorganic phenomena, the whole is no more than the sum of its parts. According to the mechanists, all life should ultimately be explainable in terms of the fundamental building blocks of matter and the forces that connect them, each obeying deterministic physical and chemical laws. The opposing position to this is that of vitalism, which has deep roots in the religions and mythologies of the ancient world.

The organicists sought a middle ground. They accepted that there was something mysterious about life but claimed that the mystery could in principle be explained by the laws of physics and chemistry—it is just that these had to be new laws, as yet undiscovered. One of the early proponents of organicism was Ludwig von Bertalanffy, who is generally accepted to have founded the interdisciplinary field called general systems theory, which has since been applied to everything from biology to cybernetics. His work is considered to be among the forerunners of systems biology. In his 1928 book Kritische Theorie der Formbildung (Critical Theory of Morphogenesis) [23], he claimed that there was a need for new organizational principles to describe life. His ideas influenced many other scientists, including the German physicist Pascual Jordan, who was one of the authors of the famous 1925 Dreimännerwerk (Three-man paper), together with Max Born and Werner Heisenberg. This classic paper introduced the world to matrix mechanics, the mathematical framework on which quantum mechanics is built. The following year, Jordan moved to Copenhagen to work with Niels Bohr.

In 1929, Bohr delivered a lecture to the Scandinavian Meeting of Natural Scientists entitled ‘The atomic theory and the fundamental principles underlying the description of nature’ [24]. After mainly focusing on the successes of quantum mechanics in describing the nature of the atomic and subatomic world, he moved on to consider whether it might have something to say in biology:

Before I conclude, it would be natural at such a joint meeting of natural scientists to touch upon the question as to what light can be thrown upon the problems regarding living organisms by the latest developments of our knowledge of atomic phenomena which I have here described. [24]

It was not clear what Bohr was hinting at with his remark about ‘the problems of living organisms'. He was around this time still attempting to clarify his philosophical views, particularly on the measurement problem in quantum mechanics, as well as his ideas on ‘complementarity’, which we discuss further below. Indeed, in his 1929 lecture, he had emphasized in his typically vague way that

… the development of the atomic theory has… first of all given us a recognition of laws which cannot be included within the frame formed by our accustomed modes of perception the lessons we have learned by the discovery of the quantum of action open up to us new prospects which may perhaps be of decisive importance, particularly in the discussion of the position of living organisms in our picture of the world. [24]

But, despite the ambiguity of these words, Bohr was nevertheless a hugely charismatic and inspiring figure and his interest in the link between quantum mechanics and life encouraged Pascual Jordan to develop his own ideas further. After returning to Germany, having taken up a post at the University of Rostock, Jordan maintained a regular correspondence with Bohr about the relationship between physics and biology over the next couple of years. Their ideas culminated in what is arguably the first scientific paper on quantum biology. It was written by Jordan in 1932 and appeared in the German journal Die Naturwissenschaften the article was entitled ‘Die Quantenmechanik und die Grundprobleme der Biologie und Psychologie’ (‘Quantum mechanics and the fundamental problems of biology and psychology’) [25].

Jordan incorporated the organicism approach into his thinking by claiming that life's missing laws were the rules of chance and probability (the indeterminism) of the quantum world that were somehow scaled up inside living organisms. He called this his ‘amplifier theory’ and based it on Bohr's notion of the ‘irreversible act of amplification’ that is required in order to bring the fuzzy quantum reality into sharp focus by ‘observing’ it. Jordan believed that living organisms were uniquely able to carry out this amplification in a way that was conspicuously different from inanimate matter, such as a Geiger counter. While this all seems somewhat vague—and it was—the important point is that Jordan was convinced he could extend quantum indeterminism from the subatomic world to macroscopic biology. He even made a connection with free will by suggesting a link between quantum mechanics and psychology.

Jordan's insistence that living organisms have a unique ability to amplify the quantum into the macroscopic world does have a lot of resonance with modern views of quantum biology. However, he went much further and, in doing so, ultimately discredited the entire field by attempting to link his theories to Nazi philosophy in a mutual legitimization. And unlike what was at least claimed by other German scientists, such as Heisenberg, Jordan's political views were not merely those of a man capitulating to the insidiously hostile intellectual climate of 1930s Germany in order to ‘fit in’. Jordan was genuinely sympathetic to fascism and Nazi ideology. Indeed, his biological speculations became increasingly politicized and aligned with Nazi ideology. He even claimed that the concept of a single dictatorial leader (Führer), or guide, was a central principle of life:

We know that there are in a bacterium, among the enormous number of molecules constituting this … creature … a very small number of special molecules endowed with dictatorial authority over the total organism they form a Steuerungszentrum [steering centre] of the living cell. Absorption of a light quantum anywhere outside of this Steuerungszentrum can kill the cell just as little as a great nation can be annihilated by the killing of a single soldier. But absorption of a light quantum in the Steuerungszentrum of the cell can bring the entire organism to death and dissolution—similar to the way a successfully executed assault against a leading [führenden] statesman can set an entire nature into a profound process of dissolution. [25]

This attempt to import Nazi ideology into biology is both fascinating and chilling. Yet Jordan correctly pointed out that inanimate objects were governed by the average random motion of millions of particles, such that the motion of a single molecule has no influence whatsoever on the whole object. This insight, as we will see, is usually credited to Erwin Schrödinger, who later claimed that life was different from inorganic chemistry because of its dependence on the dynamics of a small number of molecules. Jordan similarly argued that the few molecules that control the dynamics of living cells within the ‘Steuerungszentrum’ have a dictatorial influence, such that quantum-level events that govern their motion, such as Heisenberg's uncertainty principle, are amplified to influence the entire organism.

In August 1932, the same year that Jordan published his Naturwissenschaften paper, Niels Bohr delivered another key lecture, at the International Congress on Light Therapy in Copenhagen, Denmark [26]. Like Jordan, he was influenced by the organicists' view that the mysterious ingredient of life was yet to be discovered but rather than opting for quantum indeterminacy, Bohr claimed that the mystery ingredient was a quantum concept he had helped to conceive: complementarity. Often referred to as wave–particle duality, this was for many of its founding fathers the central tenet of quantum mechanics. Indeed, for Bohr, the notion of complementarity went deeper than merely describing the dual nature of quantum entities, and he would later in life attempt to expand it into a broader philosophical notion. But, in its simplest form, it can be applied, for example, to the nature of light, which can exhibit both wave-like and particle-like properties, but never both at the same time: the properties are complementary. Bohr attempted to extend this notion into biology by arguing that there was an analogous complementarity between the functionality of life and our ability to study it. On a fishing trip in the Baltic around 1932, Werner Heisenberg reports a conversation on Darwinian theory in which Bohr suggests the following: ‘On the one hand, it states that, through the process of heredity, nature tests [every new living form], rejecting the great majority and preserving a few suitable ones. … But there is the second assertion: that the new forms originate through purely accidental disturbances of the gene structure. This claim is much more questionable …’ [27, p. 114]. Several decades and a world war later, in the early 1960s, Heisenberg was considering the same question when, at a meeting on the banks of Lake Starnberg in Germany and listening to a lecture about mutation and selection, he pondered whether, ‘something like intention were associated with Darwinian mutation… We could ask whether the aim to be reached, the possibility to be realised, may not influence the course of events. If we do that, we are almost back with quantum theory. For the wave function represents a possibility and not an actual event. In other words, the kind of accident that plays so important a role in Darwinian theory may be something very much subtler than we think, and this precisely because it agrees with the laws of quantum mechanics’ [27, pp. 242–243].

In 1931, another young German physicist, Max Delbrück, came to Copenhagen to work with, and be inspired by, Bohr. Despite an early interest in nuclear physics, Delbrück became fascinated by biophysics and the emerging field of molecular biology in particular. In 1935, he was one of three authors (the others being the Russian biologist Nikolay Timofeev-Ressovsky and the German biophysicist Karl Zimmer) of the landmark paper [28] that also became known as the Dreimännerwerk, in which they proposed that the idea of target theory, introduced by Friedrich Dessauer in Germany in the 1920s, could be used to deduce the size of a gene based on its susceptibility to ionizing radiation such as X-rays. They assumed that a quantum of radiation would hit and affect a localized ‘target’ of just a few molecules within the cell. Their paper, ‘Über die Natur der Genmutation und der Genstruktur’ (‘On the Nature of gene mutation and gene structure’) would become the inspirational starting point for Erwin Schrödinger's book, What Is Life? [19]. Delbrück went on to have a huge influence on molecular genetics. He left Nazi Germany in 1937 and settled in America, where he eventually became a US citizen. He won a Nobel Prize in 1969 for the discovery that bacteria develop resistance to viruses as a result of advantageous genetic mutations.

3. The Cambridge Theoretical Biology Club

The interest in the physical basis of life was not limited to mainland Europe. In the summer of 1932, an interdisciplinary group of scientists at the University of Cambridge set up the Theoretical Biology Club with the ambitious aim of solving ‘the great problem’ of whether life could be explained by the actions of atoms and molecules. The group's aim, like its counterparts in Germany and Austria, was to explore whether the ‘new physics’ (i.e. quantum mechanics) could provide novel laws in biology. It also hoped to merge reductionist biology with an organicist philosophy, though in this case inspired by the thinking of the great twentieth century philosopher Alfred North Whitehead.

Members of the group included some of the most influential scientists in early twentieth century biology, including biochemist Frederick Gowland Hopkins, who was awarded the Nobel Prize in Physiology or Medicine in 1929 (with Christiaan Eijkman for the discovery of vitamins), Joseph Woodger, who had translated Bertalanffy's 1928 book into English, mathematician Dorothy Wrinch, who attempted to deduce protein structure using mathematical principles, developmental biologist Conrad Waddington, along with the great evolutionary biologist and geneticist J.B.S. Haldane. In 1934, Haldane wrote a paper entitled ‘Quantum mechanics as a basis for philosophy’ [29], which opens arguing that

Biologists have as yet taken but little cognizance of the revolution in human thought which has been inaugurated by physicists in the last five years… . [29, p. 78]

While never advocating vitalism, he goes on to point out that

It has been suggested that while the laws of physics are not violated in living organisms, life takes advantage of the uncertainty principle to make certain events more probable than they would otherwise have been. [29, p. 81]

He clarifies his position by arguing that, at the molecular level, life differs from inanimate matter in that it can be influenced on the macroscale by single events at the quantum level,

If bacteria are heated or poisoned with certain reagents, the number of survivors falls off exponentially. This is taken to mean that the life of the cell depends on a single unstable molecule, whose change involves its death. As the transformation of such a molecule involves the uncertainty principle, this principle plays a large part in the life of bacteria. But higher organisms, even protozoa, behave as if their life depended on a number of similar molecules. The uncertainty principle in this form plays a less important part in their lives. They are protected from it by the laws of statistics, just as are large material particles consisting of many molecules. [29, p. 82]

By the closing years of the 1930s, a number of highly influential scientists on both sides of the Atlantic were examining the implications of the ‘new physics’ for biology, driven by a growing mechanistic picture of biology at the smallest scales, but under the umbrella of organicism. However, the Second World intervened to curtail any further progress.

Meanwhile, Pascual Jordan became increasingly politicized and evermore determined to link his ideas in quantum biology with Nazi ideology, with the conviction that, ‘after the victory, it could stand as a symbol and representation of the unbounded means of power of the new Reich’ [32, p. 270]. In 1941, he published the book Die Physik und das Geheimnis des organischen Lebens (Physics and the Secret of Life) [20], in which he continued to pose the question ‘Are the laws of atomic and quantum physics of essential importance for life?’ However, after Germany's defeat, Jordan's highly politicized ideas became anathema. The other matchmakers of the proposed marriage between biology and fundamental physics were scattered to the four winds in the aftermath of the Second World War and physics, shaken to its core by the atomic bomb, turned its attention to more traditional problems.

But the plans for a union were not entirely abandoned. One of the pioneers of quantum mechanics, Erwin Schrödinger, had fled Germany when the Nazis gained power. He settled in Ireland, where in 1944 he published a book whose title posed the question ‘What is life?’ [19], to which we now turn.

4. Order from order

By the 1940s, it was known that heredity was governed by genes, but nobody yet knew what genes were made of. Schrödinger was impressed by the extraordinary high fidelity of genetic inheritance, which had been shown to be associated with mutation rates of less than 10 –8 per gene per generation. He claimed that high fidelity of heredity could not be accounted for by the classical laws, because genes were too small.

Schrödinger's argument starts from a consideration of the laws of classical physics and chemistry, such as those of thermodynamics or the gas laws. He called these ‘order from disorder’ laws to reflect the fact that their orderliness is a product of underlying disorderly molecular dynamics. He pointed out that their accuracy is limited by 1/√N, where N is the number of particles involved. So, a balloon filled with a trillion particles deviates from the strict behaviour of the gas laws by only one part in 1 million, thereby providing relatively accurate gas laws for such macroscopic systems. However, a balloon filled with only 100 particles will deviate from orderly behaviour by one part in 10 (or 10% accuracy), and will thereby experience significant deviations from the gas laws. For example, all the molecules in the balloon will sometimes, randomly, move towards its centre, causing the balloon to contract while at a constant temperature, thereby violating Boyle's law. This, he argued, created a problem in understanding the physical basis for the fidelity of heredity because genes were known to be too small to be subject to the order from disorder laws. Using target theory, he estimated the size of a gene as no bigger than a cube of sides 300 Å containing a maximum of about 1 million atoms, so the level of noise in heredity if based on the order from disorder principle should be about one in 1000, or 0.1%—clearly much higher than the observed mutation rates. Schrödinger concluded that the accurate laws of heredity could not be founded on these order from disorder classical laws. He argued that genetic information had to be encoded at the molecular level as ‘an unusually large molecule which has to be a masterpiece of highly differentiated order, safeguarded by the conjuring rod of quantum theory’ [19, p. 68]. Schrödinger called this principle on which he claimed life depended ‘order from order’, arguing that ‘incredibly small groups of atoms, much too small to display exact statistical laws, do play a dominating role in the very orderly and lawful events within a living organism’ [19, p. 20]. On the nature of genes, he claimed that genetic information must be encoded by a ‘more complicated organic molecule in which every atom, and every group of atoms, plays an individual role, not entirely equivalent to that of many others (as is the case in a periodic structure). We might quite properly call that an aperiodic crystal or solid … ’ [19, pp. 60–61]. Like Jordan's amplifier principle, Schrödinger claimed that life was sensitive to the dynamics of small numbers of particles, and indeed, its structure and dynamics were encoded at the atomic level. He even suggested that ‘mutations are actually due to quantum jumps in the gene molecule’ [19, p. 34], where here we must be clear that what Schrödinger meant by ‘quantum jumps’ is quantum tunnelling through a finite potential barrier, rather than the old notion of quantum jumps of electrons between energy levels.

Schrödinger's book influenced both James Watson and Francis Crick, the co-discoverers of the DNA double helix, and was a factor in their decision to investigate the nature of genes. According to Watson, ‘this book very elegantly propounded the belief that genes were the key components of living cells and that, to understand what life is, we must know how genes act’ [31, p. 13]. But the years following the publication of Schrödinger's book saw the discovery of the DNA double helix and the meteoric rise of molecular biology, a discipline which developed largely without reference to quantum phenomena. Gene cloning, genetic engineering, genome fingerprinting and genome sequencing were developed by biologists who, by and large, were content to ignore the mathematically challenging quantum world. Physicists similarly dismissed the possibility that quantum effects could play a role in biology, particularly as demonstrating them in inorganic physical systems required an extraordinary level of control that could only be achieved by maintaining systems at temperatures close to absolute zero in a vacuum and shielded from environmental perturbations. Quantum phenomena such as tunnelling or quantum interference effects depend on a system being well isolated from its surroundings. This was considered to be unsustainable for biologically relevant time scales within a hot, wet and complex system such as a living cell.

There were, however, occasional forays into the borderland between biology and quantum mechanics. When Watson and Crick published their structure of DNA they speculated that mutations could be caused by tautomerization of DNA bases from their common imino forms to the rare enol forms, which could produce incorrect base pairs during DNA replication. The idea received a quantum twist from the Swedish physicist Per-Olov Löwdin, who proposed [32] that quantum tunnelling of protons could generate the tautomeric bases, thereby providing a physical mechanism for Schrödinger's speculation that random point mutations might have a quantum origin. But few geneticists knew of or were influenced by Löwdin's work. Thus, the prevailing view by the 1960s—not only among biologists but among biophysicists and biochemists too—was broadly dismissive of the notion that quantum mechanics played any kind of special role in living systems.

An example of the attitude at the time can be found in the writing of Christopher Longuet-Higgins, a British theoretical chemist who made major contributions to molecular chemistry using mathematical modelling and analysis. In 1962, Longuet-Higgins wrote a paper entitled ‘Quantum mechanics and biology’ [33], in which he was scathing of attempts to justify the importance of quantum mechanics in biology:

Nowadays, we smile at the concept of a ‘vital force’ governing the growth of living matter, but a few years ago it seemed that this force was coming back into biochemistry under the assumed name [of quantum biology] … One might envisage strange forces of a quantum mechanical nature…where atoms are deftly rearranged by some sort of tunneling effect. But when a biochemist begins to use quantum-mechanical language in this nebulous way, we may justifiably suspect that he is talking nonsense. There was, I remember, some discussion a few years ago about the possible occurrence of long-range quantum-mechanical forces between enzymes and their substrates. It was, however, perfectly right that such a hypothesis should be treated with reserve, not only because of the flimsiness of the experimental evidence but also because of the great difficulty or reconciling such an idea with the general theory of intermolecular forces. [33, p. 209]

Longuet-Higgins’s stance was very typical of the attitude towards quantum biology in the second half of the twentieth century, and, to a large extent, this scepticism was wholly justified.

Let us then summarize the role of the early quantum pioneers. The organicists, such as von Bertalanffy, were convinced that the deterministic classical laws of physics and chemistry were insufficient to account for the phenomena of life and that there was a missing ingredient yet to be discovered. Quantum physicists, such as Bohr, Schrödinger and Jordan, took this as a cue and suggested that quantum physics was that missing ingredient. They seized on the notions of complementarity and the uncertainty principle to claim that measurement and quantum randomness may play a role in evolution, perhaps even providing some directional control to the evolutionary process. However, this claim has largely been discredited and nearly all biologists remain wedded to the notion that there is no directionality in the mutational driver of evolution. What remained were vague ideas about a central role that some physicists such as Eugene Wigner ascribed to life, or rather to consciousness, as the magical ingredient necessary to solve the measurement problem [34]. This idea has also been largely discredited.

On the other hand, both Jordan and Schrödinger identified a real point of contact between quantum and biological processes that is highly relevant to today's work in quantum biology: macroscopic biological phenomena may be triggered by the dynamics of relatively small numbers of particles whose behaviour will be ruled or at least influenced by the non-trivial quantum phenomena such as uncertainty. Jordan wrote of a ‘very small number of special molecules endowed with dictatorial authority over the total organism’ [20, p. 157] whereas Schrödinger insisted that ‘incredibly small groups of atoms … play a dominating role in the very orderly and lawful events within a living organism’ [19, p. 20]. Schrödinger went on to point out that this reliance on the dynamics of small numbers of particles separates biological systems with their order from order principle from macroscopic inanimate systems dominated by laws obeying the order from disorder principle. These ideas were picked up by some biologists, such as Haldane, who similarly insisted that ‘higher organisms, even protozoa, behave as if their life depended on a number of similar molecules' [31, p. 82]. Although, reflecting the interests of their times, these quantum pioneers were particularly interested in the role of the uncertainty principle in life, their insights are transferable to the non-trivial quantum mechanical phenomena, such as coherence, tunnelling and entanglement, which are the focus of most modern quantum biology. Also significant is Schrödinger's claim that ‘The living organism seems to be a macroscopic system which in part of its behaviour approaches purely mechanical (as contrasted to thermodynamical) behaviour to which all systems tend, as the temperature approaches the absolute zero and the molecular disorder is removed’ [19, pp. 68–69]’. In this, Schrödinger was essentially pinpointing the role of the randomizing influence of thermal motion, what we refer to today as ‘environmental decoherence’ [35], which is what separates the quantum from the classical world, an insight that is often traced back to the work of Dieter Zeh [36]. Schrödinger is essentially claiming that living systems somehow circumvent decoherence, an idea that resonates with modern work on the role that environmental noise may play in maintaining coherence in living cells.

However, by and large, most biologists continued to believe that life is adequately accounted for by all the familiar statistical laws of classical chemistry and physics. In 1993, a collection of eminent scientists from around the world (Steven Jay Gould, Lewis Woolpert, Stuart Kauffman and many others) gathered for a meeting at Trinity College in Dublin, Ireland, to celebrate the half-centenary of his famous 1943 lecture on which the book What is Life? [19] is based. The book, What is Life: The Next Fifty Years [37], is a collection of essays written by the participants of the meeting. Yet, in most chapters, quantum mechanics is hardly, if at all, mentioned. Schrödinger's bold proposal for a marriage between the disciplines appeared to have been forgotten.

During the 1960s and 1970s, there remained, however, a few physicists who entertained the possibility that quantum mechanics played a key role in biology. For example, the German-born British physicist Herbert Fröhlich proposed a theory in which quantum mechanical coherence, now known as Fröhlich coherence, plays an important role in biological systems [38--40]. A biological system that attains such a state of coherence is known as a Fröhlich condensate. He argued that biological organization was facilitated by coherent excited states at the molecular level, driven by the flow of energy provided by metabolic processes that generate molecular vibrations in terahertz range. While highly controversial, there is a current interest in testing this hypothesis experimentally using available sources of intense terahertz radiation [41].

5. Current thinking

Despite Fröhlich's work, most quantum physicists in the second half of the twentieth century became increasingly sceptical about the possibility of non-trivial quantum effects playing a significant role in biology, particularly from studies of open quantum systems and the role of decoherence in destroying the coherence necessary for non-trivial quantum effects. From a theoretical perspective, a microscopic biological system, such as a biomolecular complex within a cell, must necessarily be treated as an open quantum system in the sense that it is never isolated from its environment. Instead, it must be continuously supplied with energy from its surroundings to maintain its low entropy and out-of-equilibrium state, as well as being subject to the inevitable random thermal noise of its environment. Therefore, it was expected that any delicate quantum effects, such as quantum superposition and coherence, will very rapidly dissipate (decohere), resulting in the suppression of any well-controlled quantum dynamics. These considerations drew physicists and biologists (who considered the question at all) to conclude that quantum phenomena would be unlikely to play a significant role in biology.

Nevertheless, it is being increasingly recognized that, just as Jordan and Schrödinger argued, living systems may after all depend on the dynamics of small numbers of molecules that are extremely well localized (extending across just a few nanometres—the scale of biomolecules such as proteins) and can take place over very short time scales (often of the order of picoseconds). This relative isolation in space, complexity and time could allow non-trivial, purely quantum mechanical processes to play an important role in living systems before decoherence induced by the surrounding environment can wash them away. There is now growing evidence that this is indeed the case.

The status of quantum biology changed dramatically in the last decades of the twentieth and early twenty-first centuries with sound experimental evidence for quantum coherence in photosynthesis and quantum tunnelling in enzyme action, together with strong theoretical arguments and some experimental evidence supporting the role of quantum entanglement in avian navigation and quantum tunnelling in olfaction. Theoretical and experimental approaches have also explored the role of proton tunnelling in the generation of DNA base tautomers [14]. Figure 1 shows a timeline charting the major discoveries and publications in quantum biology.

Figure 1. Timeline of key landmarks in the development of quantum biology (QB) throughout the twentieth and early twenty-first centuries. The boxes refer to the following sources: 1929 [24], 1932 [25], 1941 [20], 1944 [19], 1953 [42], 1963 [32], 1966 [43], 1974 [44], 1976 [45–48], 1989 [49], 2000 [50], 2007 [4]. FMO, Fenna–Matthews–Olson.

The past few years have seen a rapidly growing interest among a still small but expanding group of theoretical quantum physicists and chemists, experimental biochemists and spectroscopists who are carrying out serious theoretical and experimental studies of quantum effects in biology.

In fact, the situation is probably even more interesting than this. Work in quantum information theory has shown that environmental (thermal) noise in stationary non-equilibrium systems may actually support the existence of quantum coherence, allowing, as Schrödinger predicted, the dynamics of living systems to approach those of ‘purely mechanical (as contrasted to thermodynamical) behaviour to which all systems tend, as the temperature approaches the absolute zero and the molecular disorder is removed’ [19, p. 69]. Recent work has demonstrated that the retention of quantum dynamics in biological systems is intricately connected with environmental fluctuations taking place at biologically relevant length and time scales [51–55].

This recent research adds an extra layer to the insight of Jordan and Schrödinger that phenomena involving small numbers of particles subject to biological amplification (such as the hereditary material) were prime candidates for quantum biology. The new research expands the role of quantum biology to more complex systems in which quantum dynamics might be enhanced, rather than washed away, by a finely tuned and constructive interplay between the quantum system and its surroundings.

Quantum biology has come a long way from the insights of the quantum pioneers of the early twentieth century. Phenomena such as quantum tunnelling and quantum coherence are now widely accepted as being involved in vitally important processes for all living cells, such as energy transfer and enzyme action. The debate has now shifted from the question of whether quantum coherence and tunnelling are involved to the role that they play. Other areas of quantum biology, such as olfaction, magnetoreception or mutation, remain more speculative, at least partly because the experimental systems are not as tractable to precise physical measurement.

What remains indisputable is that the quantum dynamics that are undoubtedly taking place within living systems have been subject to 3.5 billion years of optimizing evolution. It is likely that, in that time, life has learned to manipulate quantum systems to its advantage in ways that we do not yet fully understand. They may have had to wait many decades, but the quantum pioneers were indeed right to be excited about the future of quantum biology.

Data accessibility

There are no data in this historical review article.

Authors' contributions

Both authors contributed equally to this article and have read and approved the final submission.


Gene name errors are widespread in the scientific literature

The spreadsheet software Microsoft Excel, when used with default settings, is known to convert gene names to dates and floating-point numbers. A programmatic scan of leading genomics journals reveals that approximately one-fifth of papers with supplementary Excel gene lists contain erroneous gene name conversions.

The problem of Excel software (Microsoft Corp., Redmond, WA, USA) inadvertently converting gene symbols to dates and floating-point numbers was originally described in 2004 [1]. For example, gene symbols such as SEPT2 (Septin 2) and MARCH1 [Membrane-Associated Ring Finger (C3HC4) 1, E3 Ubiquitin Protein Ligase] are converted by default to ‘2-Sep’ and ‘1-Mar’, respectively. Furthermore, RIKEN identifiers were described to be automatically converted to floating point numbers (i.e. from accession ‘2310009E13’ to ‘2.31E+13’). Since that report, we have uncovered further instances where gene symbols were converted to dates in supplementary data of recently published papers (e.g. ‘SEPT2’ converted to ‘2006/09/02’). This suggests that gene name errors continue to be a problem in supplementary files accompanying articles. Inadvertent gene symbol conversion is problematic because these supplementary files are an important resource in the genomics community that are frequently reused. Our aim here is to raise awareness of the problem.

We downloaded and screened supplementary files from 18 journals published between 2005 and 2015 using a suite of shell scripts. Excel files (.xls and.xlsx suffixes) were converted to tabular separated files (tsv) with ssconvert (v1.12.9). Each sheet within the Excel file was converted to a separate tsv file. Each column of data in the tsv file was screened for the presence of gene symbols. If the first 20 rows of a column contained five or more gene symbols, then it was suspected to be a list of gene symbols, and then a regular expression (regex) search of the entire column was applied to identify gene symbol errors. Official gene symbols from Ensembl version 82, accessed November 2015, were obtained for Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Escherichia coli, Gallus gallus, Homo sapiens, Mus musculus, Oryza sativa and Saccharomyces cerevisiae [2]. The regex search used was similar to that described previously by Zeeberg and colleagues [1], with the added screen for dates in other formats (e.g. DD/MM/YY and MM-DD-YY). To expedite analysis of supplementary files from multi-disciplinary journals, we limited the articles screened to those that have the keyword ‘genome’ in the title or abstract (Science, Nature and PLoS One). Excel files (.xls and.xlsx) deposited in NCBI Gene Expression Omnibus (GEO) [3] were also screened in the same way (files released 2005–2015). All URLs screened, results and scripts used in this study are currently available at SourceForge (https://sourceforge.net/projects/genenameerrorsscreen/). Scripts were run on Ubuntu v14.04 LTS with GNU bash, version 4.3.11. These findings were verified manually by downloading and checking Excel files from every paper and GEO file suspected to include gene name errors.

Supplementary files in Excel format from 18 journals published from 2005 to 2015 were programmatically screened for the presence of gene name errors. In total, we screened 35,175 supplementary Excel files, finding 7467 gene lists attached to 3597 published papers. We downloaded and opened each file with putative gene name errors. Ten false-positive cases were identified. We confirmed gene name errors in 987 supplementary files from 704 published articles (Table 1 for individual listings, see Table S1 in Additional file 1). Of the selected journals, the proportion of published articles with Excel files containing gene lists that are affected by gene name errors is 19.6 %. Of the journals selected, Molecular Biology and Evolution, Bioinformatics, DNA Research and Genome Biology and Evolution exhibited the lowest proportion (<10 %) of affected papers (Fig. 1a). Journals that had the highest proportion of papers with affected supplementary files were Nucleic Acids Research, Genome Biology, Nature Genetics, Genome Research, Genes and Development and Nature (>20 %). There was a positive correlation between 2015 journal impact factor (JIF) and the proportion of supplementary gene lists affected (Spearman rho = 0.52, two-sided p value = 0.03), which might be due to larger and more numerous datasets accompanying high-JIF papers. Of note, BMC Bioinformatics, the forum where the Excel gene name issue was originally reported [1], continues to suffer, with gene name errors present in 13.8 % of papers with Excel gene lists. Indeed, the number of papers with gene name errors continues to be a problem (Fig. 1b). Linear-regression estimates show gene name errors in supplementary files have increased at an annual rate of 15 % over the past five years, outpacing the increase in published papers (3.8 % per year). We screened 4321 Excel files deposited to NCBI GEO [3], identifying 574 files with gene lists and finding that 228 (39.7 %) of these contain gene name errors. These are listed in Table S1 in Additional file 1.

Prevalence of gene name errors in supplementary Excel files. a Percentage of published papers with supplementary gene lists in Excel files affected by gene name errors. b Increase in gene name errors by year


6. Supplementary information

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With the exception of movies (see section on preparing the movies) and large tables, all supplementary information, including movie titles and captions, should be collated into a single PDF file. If your table is very large, or you wish readers to be able to export and/or manipulate the data, we would prefer you to submit it as a Microsoft Excel file.

Use a separate numbering system from that used in the main article and use the format Fig. S1, Fig. S2, Table S1 etc. If a supplementary figure relates to a particular figure in the text, please cite it as close to this figure as possible. For the convenience of readers, please place each figure next to the corresponding legend in the supplementary information PDF. Please include a legend for each figure and a title for each table.

Please note that supplementary information files are not copyedited by JEB and therefore authors must ensure that all files are checked carefully before submission and that the style of terms and figures conforms to that of the article. Modification of supplementary information after publication will require a formal correction.

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Abstract

Synthetic biologists come in two broad classes. One uses unnatural molecules to reproduce emergent behaviours from natural biology, with the goal of creating artificial life. The other seeks interchangeable parts from natural biology to assemble into systems that function unnaturally. Either way, a synthetic goal forces scientists to cross uncharted ground to encounter and solve problems that are not easily encountered through analysis. This drives the emergence of new paradigms in ways that analysis cannot easily do. Synthetic biology has generated diagnostic tools that improve the care of patients with infectious diseases, as well as devices that oscillate, creep and play tic-tac-toe.

Those familiar with academia know that disputes over trademarks can be more intense (and, in a prurient sense, more interesting) than disputes over substance. Synthetic biology has such a dispute in the making.

The title 'synthetic biology' appeared in the literature in 1980, when it was used by Barbara Hobom to describe bacteria that had been genetically engineered using recombinant DNA technology 1 . These bacteria are living systems (therefore biological) that have been altered by human intervention (that is, synthetically). In this respect, synthetic biology was largely synonymous with 'bioengineering'.

In 2000, the term 'synthetic biology' was again introduced by Eric Kool and other speakers at the annual meeting of the American Chemical Society in San Francisco 2 . Here, the term was used to describe the synthesis of unnatural organic molecules that function in living systems. More broadly in this sense, the term has been used with reference to efforts to 'redesign life' 3,4,5 . This use of the term is an extension of the concept of 'biomimetic chemistry', in which organic synthesis is used to create artificial molecules that recapitulate the behaviour of parts of biology, typically enzymes 6 . Synthetic biology has a broader scope, however, in that it attempts to recreate in unnatural chemical systems the emergent properties of living systems 7 , including inheritance, genetics and evolution 3,4,5,8 . Synthetic biologists seek to assemble components that are not natural (therefore synthetic) to generate chemical systems that support Darwinian evolution (therefore biological). By carrying out the assembly in a synthetic way, these scientists hope to understand non-synthetic biology, that is, 'natural' biology. This motivation is similar in biomimetic chemistry, where synthetic enzyme models are important for understanding natural enzymes.

More recently, an engineering community has given further meaning to the title. This community seeks to extract from living systems interchangeable parts that might be tested, validated as construction units, and reassembled to create devices that might (or might not) have analogues in living systems 9 . The parts come from natural living systems (that is, they are biological) their assembly is, however, unnatural. Therefore, one engineering goal might be to assemble biological components (such as proteins that bind DNA and the DNA sequences that they bind) to create, for example, outputs analogous to those of a computer.

A common ground between the 'synthetic biology' and engineering communities lies in the global strategy by which scientists come to understand their subject matter, make discoveries and overturn paradigms. Synthesis offers opportunities for achieving these goals that observation and analysis do not. The use of synthesis in a way that complements analysis will be a main theme of this review (Box 1).

Synthetic biology already has many accomplishments to its credit. The effort to generate synthetic genetic systems has yielded diagnostic tools, such as Bayer's branched DNA assay (described in a later section), which annually helps improve the care of some 400,000 patients infected with HIV and hepatitis viruses 10,11,12 . These and other artificial genetic systems now support primitive genetic processes, including replication with the possibility of mutation 13,14 , selection 15 and evolution. Synthetic biology has also generated some interesting toys from biomolecular parts, including systems that oscillate 16 and that carry out simple computations 17 .

For engineering purposes, parts are most suitable when they contribute independently to the whole. This 'independence property' allows one to predict the behaviour of an assembly. Therefore, it makes sense to structure this review to follow the search for independently interchangeable parts.

This search turns out to be interesting. In molecular science, it is well known that the simplest building units (the atomic parts) do not always contribute independently to the behaviour of a molecular assembly (the whole). In the macroscopic physical world, building units often do, especially if they are designed to do so (as in modular software assembly, for example). Ultimately, synthetic biology succeeds or fails as an engineering discipline depending on where independence approximations become useful in the continuum between the atomic and macroscopic worlds.

As a science, synthetic biology can be evaluated in different ways. By measuring the insights, discoveries and paradigm shifts that are driven by synthetic biology, we ask here whether the synthetic approach has contributed in a way that is not easily possible by analysis alone.

Seeking interchangeable parts: DNA

As described by Watson and Crick 52 years ago, DNA has a modular structure. In a reductionist sense, DNA can be described as two antiparallel strands. Each strand is assembled from four different nucleotide building blocks, which are themselves assembled from sugars, phosphates, and nucleobases. These are, in turn, assembled from carbon, nitrogen, oxygen, phosphorus and hydrogen atoms.

In the Watson–Crick model, nucleotide pairs contribute independently to the stability of a duplex. In reality, this is a good approximation. DNA duplexes can be designed with considerable success by applying just two rules: A pairs with T, and G pairs with C. A second-order model does very well by adding only the effect of adjacent base pairs into the calculation 18 . Although some diversity in nucleic acid structure and function is not captured by such simple rules (for example, that of Z-DNA 19 , G QUARTETS 20 , and catalytic RNA 21 ), most molecular biologists only use this diversity occasionally.

The elegance of the Watson–Crick model has caused most molecular biologists to overlook the chemical peculiarity of such rules. No other molecular system can be described so simply. For example, the behaviour of a protein is generally not a transparent function, linear or otherwise, of the behaviours of its constituent amino acids, even as an approximation. The power of the Watson–Crick rules was nevertheless sufficient to lead to complacency by most of those who learned the double helix structure molecular recognition in DNA was a 'solved problem'.

The role of the DNA backbone in molecular recognition. This complacency was only dislodged through synthesis of nucleic acids. Starting in the 1980s, some synthetic biologists began to wonder whether DNA and RNA were the only molecular structures that could support genetics on Earth or elsewhere 3,22,23 . Other biologists, seeking technological goals, attempted to replace modules in the DNA structure to create DNA analogues that would, for example, passively enter cells, but could still support the 'A pairs with T, G pairs with C' rule, with the aim of disrupting the performance of intracellular nucleic acids in a sequence-specific 'antisense' way 24 .

This antisense idea was simple in cartoon form. The phosphate backbone was thought to be largely responsible for the unsuitability of DNA as a drug: the repeating backbone phosphates prevented nucleic acids from partitioning into lipid phases, an event believed to be essential for molecules to enter cells passively. The phosphate–ribose backbone is also the recognition site for nucleases. This knowledge, and the fact that the Watson–Crick model proposed no particular role for the phosphates in molecular recognition, encouraged the inference that the backbone could be changed without affecting pairing rules.

The effort to synthesize non-ionic backbones changed the established view of nucleic acid structure. Nearly 100 linkers were synthesized to replace the 2′-deoxyribose sugar, starting with the first by the Pitha 25 and Benner 26 laboratories. Nearly all analogues that lacked the REPEATING CHARGE showed worse rule-based molecular recognition. Even with the most successful uncharged analogues (such as the polyamide-linked nucleic-acid analogues (PNA) created by Nielsen and his group 27 ) molecules longer than 15 or 20 building units generally failed to support rule-based duplex formation. In other uncharged systems, the breakdown occurs earlier 28 .

This discovery was unfortunate for the antisense industry, but it had a marked effect on our understanding of DNA. The repeating charge in the DNA backbone could no longer be viewed as a dispensable inconvenience. The same is true for the ribose backbone of RNA: although several backbones (such as THREOSE DNA or LOCKED NUCLEIC ACIDS) work as well or better than ribose 24,29,30 , most of the replacements work less well. The backbone is not simply scaffolding to hold the nucleobases in place it has an important role in the molecular recognition that is central to genetics.

Evolution of genetic molecules. The above example illustrates how synthesis drives discovery and paradigm change. The failure to obtain non-ionic DNA analogues that retain rule-based pairing led scientists to think about the chemical structures that might be needed to support Darwinian evolution.

In particular, a genetic molecule must be able to suffer change (mutation) without markedly changing its overall physical properties. Again, this feature is infrequent in chemical systems (in proteins, for example). But because charge dominates the physical properties of a molecule, a repeating charge should allow appendages (the nucleobases, in the case of DNA and RNA) to be replaced without changing the dominant behaviour of a genetic system 31 . This has led to the suggestion that a repeating charge might be a universal feature of genetic molecules that work in water 31 .

Furthermore, the discovery that ribose was one of the better backbone sugars for supporting molecular recognition 24,32 had implications for the origin of life on Earth. In the mid 1990s, Miller had commented that because of the ease with which ribose decomposes as a sugar on heating 33 , ribose could not have supported the first genetic system on Earth. The results from synthesis, which indicated that ribose is especially good for genetics, drove efforts to find prebiotic routes to ribose that would overcome its intrinsic instability 34,35 .

Creating synthetic genetic systems. Synthesis focusing on the nucleobases also generated discoveries. The Watson–Crick pairing rules arise from two rules of chemical complementarity. The first, size complementarity, pairs large purines with small pyrimidines. The second, hydrogen-bonding complementarity, pairs hydrogen-bond donors from one nucleobase with hydrogen-bond acceptors from the other.

If nucleobase pairing were indeed so simple, it should be possible to move atoms around within the nucleobases (on paper) to synthesize unnatural nucleobases that would still pair following rules of size and hydrogen bonding complementarity, but differently from the natural nucleobases. Indeed, by shuffling the hydrogen-bond donating and accepting groups, one can easily generate eight additional synthetic nucleobases, forming four additional base pairs (Fig. 1).

Parts of the nucleobases of DNA can be used as interchangeable building modules. The blue units are the hydrogen bonding donor (D) collections of atoms. The red units are the hydrogen bonding acceptor (A) collections of atoms. a | The four standard nucleobases are shown. b | Shuffling the hydrogen bond donor and acceptor modules generates eight additional nucleotides, which constitute a synthetic genetic system. These synthetic bases have been used in an artificial genetic system that can support Darwinian evolution. A, adenine C, cytosine G, guanine Pu, purine Py, pyrimidine T, thymine.

In this case, synthesis showed that nucleobase pairing is as simple as the Watson–Crick model implies. A synthetic genetic alphabet with up to 12 independently replicatable nucleobase pairs can be supported by an extended set of Watson–Crick rules 36 . Furthermore, a small amount of protein engineering converts natural polymerases into polymerases that accept components of an expanded genetic alphabet in a polymerase chain reaction 14 . This created, for the first time, a synthetic genetic system that can be repeatedly copied, with the level of mutation needed to support adaptation and evolution.

By searching for synthetic systems that could recreate such emergent properties, synthetic biologists have discovered a great deal. For example, it was proposed that DNA polymerases scan the minor groove of a DNA duplex to look for unshared pairs of electrons as a recognition feature 37 . It was likewise proposed that this scanning of the minor groove was essential for the high fidelity of DNA replication. Efforts to obtain polymerases to support the evolution of the artificial genetic system led to the discovery that minor-groove scanning is not an essential feature of all polymerases.

Today, the effort to make a synthetic chemical system that is capable of Darwinian evolution is an important focus of the National Science Foundation's Chemical Bonding Program. Here, the details of the chemical structures of nucleobases that are essential to support genetics have been determined, with the goal of repairing specific chemical problems that limit the use of specific components of an expanded genetic alphabet. For example, several components of an artificial genetic system suffer from EPIMERIZATION this has been rectified by adding nitro substituents to the nucleobases 38 . Another component of the artificial system, iso-guanosine, has a minor TAUTOMERIC form that cross bonds with thymidine, creating a significant number of mutations in polymerase chain reactions. This defect was solved by replacing a nitrogen in the structure by a carbon atom 39 .

Because it provides rule-based molecular recognition that is orthogonal to the recognition provided by natural DNA, this synthetic genetic system is found today in the clinic. As part of the Bayer VERSANT branched DNA diagnostic assay 40 , synthetic biology helps to manage the care of approximately 400,000 patients infected with HIV and hepatitis viruses each year 10,11 (Fig. 2).

The target RNA molecule to be detected (the analyte) is attached to the plastic of a microwell (bottom) by the hybridization of the analyte to a series of capture probes. This complex then captures, through hybridization, a target probe, which in turn hybridizes to a pre-amplifier molecule, thereby 'sandwiching' the analyte between the capture probe and the pre-amplifier. The pre-amplifier captures a branched DNA dendrimer (amplifier) that contains several signalling molecules on each branch. As a consequence of the branching, a single analyte assembles a large number of signalling molecules in the microwell. These assays use the expanded genetic alphabet shown in Fig. 1. When standard nucleotides were used to assemble the signalling nanostructure, significant noise was seen, because non-target DNA that was present in the biological sample was captured by the probes in the microwell even in the absence of analyte. Incorporating components of the artificial genetic alphabet in the dendrimer reduced the noise. As a consequence, the assay now helps manage the care of some 400,000 patients annually, detecting as few as eight molecules of the analyte DNA in a sample.

Seeking interchangeable parts: proteins

The amino acid as a building module in proteins. The synthetic biology of nucleic acids is successful because the repeating charge in the backbone enables the nucleotide parts to be exchanged independently (although we acknowledge the fact that some RNA structures, such as G-rich sequences, are themselves problematic to engineer). Proteins, unfortunately, do not have a repeating charge engineering them has therefore been more difficult.

Proposals to engineer proteins, for which the interchangeable unit is the amino acid, is as old as recombinant DNA technology 41,42 . This idea was discussed in an engineering context in 1983 by Kevin Ulmer, then director of exploratory research at Genex 43 . In Ulmer's vision, synthetic biologists would first alter the behaviours of proteins by replacing amino acid BUILDING MODULES in the natural proteins. The replacements would come from the standard set of 20 natural amino acids, and would be chosen using primitive design principles to meet specific goals defined by the properties desired in the synthetic protein. Such primitive principles might, for example, place charged residues at the top and bottom of α helices, or strategically alter amino-acid size complementarity in the active site of an enzyme.

Design based on such primitive rules was expected to frequently fail. Failure, however, would drive the development of better design rules 44 . This would generate a cycle, involving the setting of a goal, the replacement of amino acids to create proteins to meet the goal using the improved design rules, followed by success and failure, refinement of the design rules, and the setting of new goals. This process might go on for decades, and perhaps even generate some of the emergent properties that characterize biological systems. This vision remains largely unrealized. The 20 years of experience since Ulmer presented his vision has shown that the behaviour of a protein is not a simple combination of independent contributions from the constituent amino acids 45 .

The failure of the independence approximation was, in large part, expected 46 . First, amino acids in a folded polypeptide sequence strongly interact with others, even amino acids distant in the polypeptide chain 47 . More seriously, even the simplest of molecular interactions are poorly understood. Today, chemical theory still cannot retrodict the freezing point of water 48 , the solubility of simple salts in water 49 , or the packing of crystals of simple organic molecules 50 . Protein folding is, in one view, an aggregate of these particular processes. A theory that cannot manage the particulars is not expected to manage the whole. Nevertheless, the synthetic effort will be crucial for demonstrating and overcoming these limitations of theory.

Serious efforts are under way to improve the computational tools needed to design and engineer proteins 51,52,53 . Some have attempted to improve design principles by examining ROTAMERS of amino acids, where different arrangements of side-chain atoms are used as the building modules, rather than the amino acids themselves 54 . Small protein folds have focused the simplification of design issues 55 . These include elegant examples from the laboratories of Imperiali, Allemann and Mayo.

Today, the technology of amino-acid replacement is done using a combination of calculation, design, screening, selection, and luck 56 . Even so, the outcome has been positive 57 many useful enzymes have emerged by means of amino acid replacement, including polymerases used for DNA sequencing 58 , reverse transcriptases that use PCR to amplify synthetic genetic systems 14 , and enzymes in commercial laundry detergents 59 . But these are far from a synthetic biology that captures the emergent properties of living systems.

The protein-folding unit as the building module. Proteins are built from secondary structure units, including the α helix and the β strand 60 . This gave rise to the idea that such secondary structural elements might serve as interchangeable parts to support protein design 61 .

Kaiser and his many students have been especially successful in using the amphiphilic helix as the interchangeable building unit. In an amphiphilic secondary structure, hydrophobic and hydrophilic amino-acid side chains are arranged in the sequence so that a hydrophilic side of the unit can face water, while a hydrophobic side can be buried in the protein fold. Such amphiphilic structures are expected to pack spontaneously in water.

Using this strategy, DeGrado et al. designed an artificial polypeptide that reproduced some of the folding and biological properties of mellitin, a protein from the sting of a bee, without reproducing its exact sequence 62 . The designed peptide was amphiphilic, and the model proposed that its hydrophobic side buries itself in the hydrophobic membrane of a cell. Amphiphilic helices as units have frequently been exploited since then 63 . Analogous approaches have used the β strand as the architectural module 64 .

Several laboratories have worked to create emergent biological properties, including templated replication, by using secondary structural elements as interchangeable building modules. For example, the Ghadiri laboratory designed a peptide by assembling α helical coiled coils to obtain a peptide ligase 65 and a peptide replicator 66 (Fig 3).

a | A de novo designed peptide ligase. α-helical peptides A and B bind to the electrostatically complementary α-helical peptide C to form the C·A·B ternary complex, which is composed of two coiled coils. Peptide A has a modified amino terminus that reacts with the chemically modified carboxyl terminus of peptide B on formation of the ternary complex. The reaction of peptides A and B is a ligation that forms the product C·P (C·P * represents the chemical reaction between A and B to produce P). b | Peptide replicator schematic based on the reaction illustrated in part a, showing the reaction of peptide A with peptide B on formation of a ternary complex with peptide C. Peptides A L , B L , and C LL are composed of L-amino acids, whereas peptides A D , B D , and C DD are composed of D-amino acids. Peptides C LL and C DD are produced autocatalytically in a template-directed fashion through the reaction of precursors A L with B L , and A D with B D , respectively. Therefore, this replicator is stereochemically selective, only producing products (C LL and C DD ) that are isomerically pure. Part b modified, with permission, from Ref. 65 © American Chemical Society (2001) and from Nature Ref. 66 © (2001) Macmillan Magazines Ltd.

Much of this work falls squarely within the definition of biomimetic chemistry, in that it reproduces isolated behaviours of natural biological systems. This includes using amphiphilic helices as design elements to create a synthetic enzyme that catalyzes the decarboxylation of oxaloacetate 67 . Further work with modular design has improved this artificial enzyme 68 . A wide range of catalytic activities are now being sought in this fashion based on the modular assembly of secondary structure building units. These include artificial enzymes that catalyze ester hydrolysis 69 , oxidize phenol using molecular oxygen 70 and catalyze aldol reactions 71 .

Despite these successes, helices and strands remain challenging as building modules to support synthetic biology in proteins. Even when amphiphilic elements assemble in water to form a fold, the interior packing is often dynamic (a 'molten globule'). Subsequent design, trial and luck are required to refine the dynamic core to make it rigid. More trivially, many protein design projects have failed simply because proteins have a tendency to precipitate. The backbones of proteins do not carry a repeating charge (like nucleic acids do) instead, the repeating unit is a dipole (the amide linkage), which is well suited for self-aggregation. Much of protein design, therefore, is an effort to design peptides that remain dissolved in water.

It has been suggested that natural selection might have used secondary structural elements as interchangeable parts in constructing new proteins. Vestiges of such swapping might be detectable in very ancient steps for the construction of proteins 72 . But the recent widespread recruitment of function (proteins that share 50% sequence identity can catalyze very different reactions 73 ) seems to have arisen primarily through point mutation, insertion and deletion.

The natural protein as the engineering unit. As we move from the atomic to the macroscopic world, the next step considers folded proteins as interchangeable parts. The biosphere contains proteins that have a wide diversity of physical and catalytic properties. For several decades, metabolic engineers have asked whether these can be reassembled as building modules to create new pathways that capture at least some of the emergent properties of biological systems. This might be done without needing to solve the difficult problem of constructing artificial proteins from scratch.

The simplest idea behind metabolic engineering has been to simply redirect the metabolism of a cell by altering its genetic makeup 74 . This has long been achieved by non-rational means fermentation strains obtained by classical screening and selection are widely used in industry (in the synthesis of citric acid, for example) 75 . The advent of recombinant DNA technology has led to enhanced efforts to pick and choose enzymes from a range of organisms and then to assemble these enzymes into a single organism to produce products that might not be native to the organism. For example, Fukui et al. 76 constructed a strain of the bacterium Ralstonia eutropha that was able to produce poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) from fructose (Fig. 4a). The strain was engineered by introducing genes for various steps in the pathway from two other microorganisms in addition to R. eutropha.

a | The combination of enzymes from three sources in a Ralstonia eutropha host generated a strain that produced large amounts of a poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) polymer from fructose. All enzymes from Ralstonia eutropha are shown in black, whereas those from Areomonas caviae and Streptomyces cinnamonensis are shown in green and red, respectively. Modified, with permission, from Ref. 76 © American Chemical Society (2002). b | The combination of enzymes from three sources in an Escherichia coli host generated a strain of the bacterium that produced a precursor for artemisinin, an antimalarial drug. The challenge of this experiment lay in the need to curtail the pathway to recognize and avoid metabolite toxicity, while optimizing the yield of the desired product. The general methodology for the pathway design was to use an engineered mevalonate pathway that is absent in E. coli, rather than the DXP (1-deoxy-D-xylulose 5-phosphate) pathway that is native to the organism. The synthetic operons used are depicted, and the engineered pathway metabolites are shown in red. In the engineered mevalonate pathway, the fan of genes from ERG12 to ispA exist on multiple plasmids to tune the pathway for optimization of the product while avoiding metabolite toxicity. As depicted at the bottom of the figure, the E. coli strain DYM1, a strain deficient in isoprenoid synthesis, was used, because the DXP pathway was found to limit product yield, probably owing to an unrecognized link between the pathway and physiological control elements in the organism. Enzymes used (isolated from Saccharomyces cerevisiae unless otherwise noted): ADS, amorphadiene synthase atoB, acetoacetyl-CoA thiolase (E. coli) dxs, 1-deoxy-D-xylulose 5-phosphate synthase ERG12, mevalonate kinase ERG8, phosphomevalonate kinase HMGS, HMG-CoA synthase idi, IPP isomerase (E. coli) ippHp, IPP isomerase (H. pluvialis) ispA, FPP synthase (E. coli) ispC, 1-deoxy-D-xylulose 5-phosphate reductoisomerase MVD1, mevalonate pyrophosphate decarboxylase tHMGR, truncated HMG-CoA reductase. Pathway intermediates: AA-CoA, acetoacetly-CoA A-CoA, acetyl-CoA CDP-Me, 4-diphosphocytidyl-2-C-methyl-D-erythritol CDP-ME2P, 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate DMAPP, dimethylallyl pyrophosphate DXP, 1-deoxy-D-xylulose 5-phosphate FPP, farnesyl pyrophosphate G3P, glyceraldehyde 3-phosphate HMB4PP, 1-hydroxy-2-methyl-2-(E)-butenyl 4-pyrophosphate HMG-CoA, hydroxymethylglutaryl-CoA IPP, isopentenyl pyrophosphate Mav-P, mevalonate 5-phosphate ME-2,4cPP, 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate MEP, 2-C-methyl-D-erythritol 4-phosphate Mev-PP, mevalonate pyrophosphate. Adapted, with permission, from Nature Biotechnology Ref. 77 © (2003) Macmillan Magazines Ltd.

An analogous example comes from the Department of Synthetic Biology at the division of Physical Biosciences at the Lawrence Berkeley National Laboratory 77 . Here, researchers developed a strain of Escherichia coli that could synthesize amorphadiene, an isoprenoid precursor for the antimalarial drug artemisinin. The pathway combined the acetoacetyl-CoA thiolase (encoded by the atoB gene) from E. coli, an isopentenylpyrophosphate isomerase from Haematococus pluvialis, and several enzymes from Saccharomyces cerevisiae (Fig. 4b). The Gates Foundation is now funding the scaling up of this process as part of its mission to generate inexpensive drugs for the third world.

As Khosla and Keasling noted 78 , metabolic engineering generally requires more than simply throwing enzymes together in a cell. Achieving a synthetic goal (here, a strain that produces a particular product) requires the management of complex metabolic and regulatory processes. In pursuit of this goal, one cannot help but learn about metabolism and its emergent behaviours, including the regulation of metabolism and the extent to which enzymes drawn from various sources can be combined independently. So, synthesis drives discovery and learning.

Using genes and genetic elements. One way to search for interchangeable parts is to identify the parts that are used in natural evolution. The archetypal example of modularity in evolution is found in genetic regulatory and signalling pathways. Here, combinations of proteins often function as molecular switches, that is, they are stimulated by upstream events (ligand binding, a chemical reaction, or the movement of components into new locations) and generate an output, which can then serve as an input for another switch. Recruitment and the exchange of individual proteins in such pathways throughout eukaryotic evolution has generated many logical networks that control cellular behaviour 79 .

Given this natural precedent, one goal for synthetic biology is to take the proteins themselves as building modules and synthesize artificial regulatory circuits that have preselected inputs and outputs. As before, the motivation is not so much to construct 'toys', but rather to use the challenge of a synthetic goal to discover principles that connect the chemistry of signal transduction to emergent regulatory properties in complex biology.

Several examples show how this might be done. In signal transduction pathways that involve receptor tyrosine kinases, tyrosine-containing motifs are autophosphorylated. These then dock to the Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains of adaptor proteins, which, in turn, activate signalling pathways that generate specific cellular responses. The signal created by these events depends on the details of the adaptor proteins. For example, the SH2 domain of the growth factor receptor-bound protein 2 (GRB2) adaptor is flanked by two Src homology 3 (SH3) domains. These bind proteins, such as the guanine nucleotide exchange factor son of sevenless homolog 2 (SOS2) and GRB2-associated binding protein 1 (GAB1) docking protein, which then help to activate the Ras and phosphatidylinositol 3'-kinase pathways, respectively. GRB2 therefore couples the phosphorylated motifs to signalling pathways that lead to cell survival, growth and proliferation. Different combinations lead to the opposite outcome. For example, autophosphorylated death receptors bind adaptors, such as fas (TNFRSF6)-associated via death domain (FADD) this is followed by an analogous signalling process that promotes cell death through apoptosis.

In an intriguing study from Pawson's group 80 , growth-promoting and death-promoting modules were rearranged. In this work, the phosphotyrosine recognition domains of GRB2 — either SH2 domain or ShcA phosphotyrosine-binding domain — were fused to the death effector domain of FADD. When the construct was transformed into fibroblasts, the synthetic adaptors re-routed the signals that normally lead to growth so that they instead resulted in cell death. Here, the synthetic goal confirmed the power (and, to some extent, the underlying correctness) of a modular model of regulation by this system.

It is clear that this type of restructuring of existing regulatory components will be used in the future to rewire signalling more generally. Here, the analogy with the construction of electrical circuitry has been used by Hasty et al. 81 , who recently reviewed some of the spectacular accomplishments in this area (summarized in Box 2).

Synthetic biological 'toys' can also be created. For example, an artificial oscillatory network (a 'repressilator') was constructed in E. coli by Elowitz and Leibler 16 (Fig. 5) These synthetic biologists placed into an E. coli host three transcriptional repressor systems that are not together part of any natural biological system, and coupled these to the synthesis of green fluorescent protein. The fluorescent output of the cell oscillated as a function of time, providing a visual signal of the state of the oscillator in the cell. The oscillation period of hours was longer than the time typical to complete a cycle of cell division. This indicates that the state of the oscillator was transmitted from generation to generation, and became a property of a colony of cells.

a | Schematic showing the regulation pattern that forms the basis of a repressilator. Three gene–promoter pairs are arranged so that the product derived from the expression of the gene following a promoter is a repressor for the next promoter in the cycle. Black connecting lines show that promoter PLlacO1 controls the transcription of the gene tetR-lite, the tetracycline repressor protein TetR represses PLtetO1, which is the next promoter in the sequence. PLtetO1 in turn controls the transcription of cI-lite, and the protein CI represses the promoter PR. Finally, PR controls the expression of lacI-lite, and the lactose repressor protein LacI represses PLlacO1, completing the cycle. The suffix '-lite' refers to the presence of tags that increase the degradation rate of the proteins. b | The luminescence pattern of a reporter plasmid that carries GFP under the transcriptional control of the PLtetO1 promoter, when the reporter construct is transferred to an Escherichia coli in the presence of the repressilator. As the experimental trace shows, the oscillation of the TetR repressor expressed from the repressilator results in the time dependent oscillation of GFP expression. Bars at the bottom of the diagram show the timing of cell division events. The period of the oscillations is longer than the cell division time, and the cycle of oscillations continues in the subsequent generations. Adapted, with permission, from Nature Ref. 16 © (2000) Macmillan Magazines Ltd.

The repressilator is, of course, a synthetic equivalent of oscillation systems that are found throughout biology 82 . The goal of producing a synthetic oscillator might therefore lead to a deeper understanding of natural oscillators. For example, the repressilator showed noisy behaviour. This might arise from stochastic fluctuations of its component molecules, which are present in very few copies in individual cells. It might also reflect an interaction between the synthetic parts, or between the synthetic parts and the natural parts of the chemically complex biological host. For this type of network design to lead to an improved understanding of naturally occurring networks, we need to go back to analysis. A detailed analytical study of the synthetic system is needed, just as it was for the synthetic genetic systems or for the synthetic metabolic pathways described above.

Other toy systems have emerged in the past year. Some of these involve biomolecules other than proteins. For example, a molecular automaton that plays tic-tac-toe interactively against a human opponent has been built using deoxyribozymes as the modules 83 . The system is based on a network of 23 molecular-scale LOGIC GATES and one constitutively active deoxyribozyme. These are arrayed in nine wells (3 x 3), which correspond to the game board. To make a move, the molecular automaton analyzes the input oligonucleotide that is associated with a particular move by the human opponent and indicates a move by fluorescence signalling in a response well.

Where are the hazards of synthetic biology?

A provocative title such as 'synthetic biology' suggests a potential for hazard. Accordingly, the past year has seen a call for an 'Asilomar for synthetic biology' 84 , a reference to a conference in Monterey in 1975 that considered the public hazards of the recombinant DNA technology that supports the synthetic biology discussed above.

Much of what is currently called synthetic biology is congruent with the recombinant DNA technology discussed in Asilomar 30 years ago. This includes bacteria that express heterologous genes, proteins in which amino acids have been replaced, and cells with altered regulatory pathways. Placing a new name on an old technology does not create a new hazard.

Those seeking to create artificial chemical systems to support Darwinian processes are, however, creating something new. We must consider the possibility that these artificial systems might cause damage if, for example, they escape from the laboratory. A general principle in biology is relevant for assessing this potential for hazard. The more different an artificial living system is from natural biological systems, the less likely it is that the artificial system will survive in the natural world. A living organism survives when it has access to the resources that it needs, and is more fit than competing organisms in recovering these. Therefore, a completely synthetic life form that has eight nucleotides (Fig. 1) in its genetic alphabet would find survival very difficult if it were to escape from the laboratory. What would it eat? Where would it get its unnatural nucleosides?

This general principle also applies to less exotic examples of engineered life. The 30 years of experience with genetically altered organisms since Asilomar have indicated that virtually any human-engineered organism is less fit than its natural counterpart in a natural environment. If they survive at all in the environment, they do so either under the nurturing of an attentive human, or by ejecting their engineered features. Therefore, an E. coli engineered to play tic-tac-toe might survive in the human intestine, but would probably do so by jettisoning its game-playing skills.

Losing genetic information is much easier than obtaining new information. By contrast with the power of Darwinian processes implied by the Jurassic Park principle ('life finds a way'), Darwinian processes are highly conservative when it comes to creating new functions. When tackling new problems, Darwinian systems take small steps from what they already have they are not innovators on a large scale. Extinctions are one consequence of this, occurring when the environmental challenges change too fast for Darwinian processes to keep pace.

This is seen, for example, with natural life. The Ebola virus would spread more rapidly if it became airborne and less virulent, as would anthrax bacteria that were transmissible from an infected human host to an uninfected human. The fact that these features have not emerged in these infectious agents indicates the difficulty that Darwinian evolution has in generating such novel properties in existing organisms. In fact, the most hazardous type of bioengineering is the type that is not engineering at all, but reproduces exactly an already existing virulent agent. The synthesis of smallpox virus 85 is perhaps the riskiest recent example of synthetic biology.

The discussion so far presumes an absence of malice. Suppose one actually wanted to do damage? Would one genetically engineer E. coli carrying ricin to create a threat? Or place fuel and fertilizer in a rented truck and detonate it outside a Federal Building? We know the answer to this question for one individual Timothy McVeigh used the latter method to damage the federal building in Oklahoma City a decade ago. We do not know it for all individuals.

At the 2004 International Meeting on Synthetic Biology in Boston, one discussion centered on the 'hacker culture', referring to those who create computer viruses. As is the case whenever resources are diverted from productive to non-productive activity, computer viruses and spam cause human deaths. What if a group of people set out to create an airborne Ebola virus? And what if a synthetic biologist, having set the man-on-the-moon goal of creating such a virus, to learn more about how viruses become airborne, told (through the published literature) the biohacker how to do it?

However, the potential benefits of synthetic biology must be juxtaposed with this hazard. History provides only a partial guide. For example, in 1975, the City of Cambridge banned recombinant DNA research in an effort to manage what it perceived as a danger in this technology. In the same decade, an ill-defined syndrome noted in patients having 'acquired immune deficiency' was emerging around the planet as an important health crisis. Without the technology that had been banned by the City of Cambridge, it would have been difficult to learn what the human immunodeficiency virus was, let alone have compounds in hand today that manage the infection. Today, as SARS, bird influenza, and other infectious disease emerge from animal populations, recombinant DNA technology is what distinguishes our ability to manage this threat today and what was possible a century ago.

This might be the last time that a short review on synthetic biology will attempt to span work that ranges from organic chemistry to intercellular interactions. Even in 2005, much has been done to do justice to the individual topics discussed here. Several of these are mentioned in Box 3.

Truly interchangeable parts have, so far, been obtained only by applying synthetic biology to nucleic acids. Here, the independence approximation seems to be adequate because of the repeating charge on the backbone, which remains constant while the information-containing nucleobases are changed. The repeating charge dominates the physical properties of the molecule overall, allowing the pieces to be replaced independently.

Because of the robustness of the interchangeable parts in expanded genetic information systems, we suspect that an artificial chemical system that supports Darwinian evolution — the bridge between non-life and life 86 — will first be obtained with these. Here, the man-on-the-moon goal cannot help but deepen our understanding of the relationship between chemistry and life.

To obtain the same with proteins will require the development of basic chemical theory, including a better understanding of the behaviour of water, the dissolution of salts in water, and the packing of organic molecules. A well-targeted set of experiments, coupled with the appropriate theory, would help this system develop more rapidly. As with the synthetic biology of nucleic acids, chemistry will drive the development of the field.

Folded protein modules behave with sufficient independence to be useful building modules in synthetic biology. Here, we expect a substantial amount of exciting work over the next few years, as synthetic biologists struggle with the chemical reality, determine which modules behave independently, and define synthetic goals accordingly. Here, synthesis will demonstrate its power as a complement to analysis in the development of theory and the modification of paradigms associated with genetic regulation. The setting of ambitious synthetic goals cannot help but deepen our understanding of the intimate relationship between chemistry and life at the regulatory level, and better understand the emergent properties of complex biological systems.

Box 1 | What synthesis can do that observation and analysis cannot

The scientific method captures the full range of human activities. Life scientists can apply it to observe the foraging strategies of moose 87 , or to use X-ray crystallography to determine the molecular structure of the ribosome 88 , although the intellectual procedures involved in each case have little in common.

However, one theme is universal: it is easy for human scientists to convince themselves that data contain patterns that they do not, conclude that patterns support models when they need not, and believe that models are truth, which they are not. These observations are not pejorative. They reflect the same processes in the human mind that enable it to be effective and creative. Therefore, although the 'scientific method' that is taught in school emphasizes unfiltered observations, analyzing data with an open mind and conducting value-neutral experiments, the outcome of science does not depend on how well it meets this largely fictional idea, but rather how well scientists manage the values and filters that come naturally with human thought.

Synthesis offers one way to manage these. Synthesis defines an ambitious 'put-a-man-on-the-moon' goal. By doing so, it forces scientists and engineers to cross uncharted terrain in pursuit of the goal. This requires the solution of unscripted problems that are not normally encountered through either observation or analysis. Furthermore, the problems cannot be ignored if they contradict a paradigm. With analysis, if the data contradict the theory, the data are (as often as not) discarded to protect the theory. If one does this when putting an orbiter around Mars, however, the orbiter crashes 89 . For this reason, synthesis drives the evolution of paradigms, however this elusive term is defined 90,91 .

This is well illustrated in chemistry, which has long had powerful synthetic tools. For example, the late Robert Woodward credited the discovery of the rules underlying the orbital symmetry of molecules, for which Roald Hoffmann and Kenichi Fukui won the Nobel Prize in Chemistry in 1981, to problems encountered during the synthesis of vitamin B12 (Ref. 92). Because vitamin B12 is a large molecule with many sterogenic (chiral) centers, the synthesis of B12 was, for chemistry at that time, the equivalent of a 'man-on-the-moon' goal. Accomplishing this goal led not only to a synthetic route to a complex molecule, but more importantly to a greater understanding of chemical bonding something that was not accessible by simply observing the structure of B12. It also drove the development of modern analytical tools, such as high-performance liquid chromatography.

Similarly powerful synthetic tools are not available for many other fields. Planetary scientists and stellar physicists cannot, today, synthesize new planets or new stars to test theories and models about these systems. Biology, by contrast, has developed those tools over the past quarter century. During this time, in Barbara Hobom's sense of the term, biologists have been synthesizing parts of living systems to test their ideas. The combination of chemistry, biology and engineering is now at the point where the 'man-on-the-moon' goal is approachable: creating artificial Darwinian systems. One of the metrics of the success of synthetic biology will be how well the effort to assemble existing biological parts into machines, and how well the effort to create artificial systems that reproduce the emergent properties of living systems drives new discoveries and new theories.

Box 2 | Engineering regulatory circuits

The engineering of molecular circuits has recently been reviewed by Hasty et al. 81 this article should be consulted for more details of the cases briefly reviewed below, and for further examples.

In one experiment in yeast, Lim and his co-workers rewired Mapk signalling 93 and an actin regulatory switch known as N-WASP 94,95 . N-WASP carries an output region that (in isolation) stimulates the polymerization of actin by binding the actin-related protein (Arp) 2/3 complex (see part a of the figure). This activity is autoinhibited, however, by means of two modules from N-WASP, a highly basic (B) motif and a guanosine 5'- triphosphatase (GTPase)-binding domain (GBD). These bind to two activating inputs, the phosphoinositide Pip2 and the activated GTPase Cdc42, where the respective binding disrupts autoinhibition. Because the two activating inputs function cooperatively, N-WASP behaves as an 'AND' gate the output is positive (actin is polymerized) only if both Pip2 and Cdc42 inputs are present.

Lim and co-workers then attempted to reprogram the input control of N-WASP. They tethered an unrelated modular domain–ligand pair (a PDZ domain and its cognate C-terminal peptide ligand) to the end of the N-WASP output domain (see part b of figure). They expected this to create an unnatural autoinhibitory interaction that could be relieved by the competitive binding of an external PDZ ligand. Under basal conditions, this synthetic switch was not activating. The unnatural autoinhibitory interaction was then removed by adding the PDZ ligand. The maximal activity was close to that of the isolated output domain. The result was the same switch, but one that was turned on by a different activator.

The synthetic biologist then attempted to construct AND gates by tethering two unnatural modular domain-ligand pairs to the N-WASP output domain, replacing the two natural modules (B and GBD). A total of 34 constructs were synthesized and examined for their gating behaviour.

As expected for any real chemical system, the output depended on the concentrations of the input molecules, and was not predictable in an engineering sense. Some switches showed little basal repression. Others could not be activated. A few showed antagonistic gating, with one input activating and the other repressing. A few showed 'OR' gating, where one or the other input generated a positive output.

Nevertheless, about half of the synthetic constructs showed positive AND gating, where both inputs were required to generate a positive output. This input-output relationship was analogous to that seen with native N-WASP, but was obtained from a synthetic system, by using unnatural activators. Figure modified, with permission, from Ref. 95 © (2004) Elsevier Science.

Box 3 | Other directions in synthetic biology

As synthetic methods emerge, the various activities that can lay claim to the title of 'synthetic biology' has expanded beyond what can be covered in a single article. Listed here are just three other themes in the discipline, each with a leading reference.

One example is the 'top-down' approach towards synthetic biology that is being pioneered by Venter and his colleagues 96 . These authors have stripped genes from a living bacterium to determine the minimal set of genes that is required to support a cellular life form. Determining the minimal biological functions required to sustain life will be important for understanding primitive organisms in both a functional and evolutionary context. In addition, synthetic biologists who are practicing a 'bottom-up' approach will find this information crucial for designing synthetic biological systems that include all the necessary components — either in the form of genes or their synthetic equivalents — that are required to sustain life or a desired biological property.

Various types of artificial life that live in silico 97 have been suggested as being a form of 'synthetic biology'. This approach involves using simulations to evolve computational analogues of the emergent behaviours of living systems. Many of these artificial life forms compete for resources (such as computer processor cycles) within a computer, and therefore evolve.

Yet another type of synthetic biology uses individual cells as interchangeable parts, and attempts to engineer cell–cell communication. This has recently been reviewed in Ref. 98.


The Art of Theoretical Biology

This beautifully crafted book collects images, which were created during the process of research in all fields of theoretical biology. Data analysis, numerical treatment of a model, or simulation results yield stunning images, which represent pieces of art just by themselves. The approach of the book is to present for each piece of visualization a lucid synopsis of the scientific background as well as an outline of the artistic vision.

Franziska Matthäus studied biophysics at the Humboldt University in Berlin and received her PhD from the Polish Academy of Sciences in Warsaw. She worked as a postdoc, group leader and junior professor in Heidelberg and Würzburg and now holds the Giersch-Professorship Bioinformatics at the Goethe University Frankfurt, affiliated with the Frankfurt Institute for Applied Sciences (FIAS). She is interested in the chemical and mechanical regulation of cell motility, and uses a combination of image and data analysis as well as mathematical models to better understand how collective behavior or patterns emerge from internal regulation and cell-cell interaction.

Sebastian Matthäus studied communication design at the University of Applied Sciences in Potsdam, Germany. Since 2006 he is founder and head of the graphic design firm called “Grenzfarben” in Berlin, Germany. He is an expert in illustration & animation, works for large German newspapers and firms, but also supports interactive exhibitions.

Dr Sarah Anne Harris is Associate Professor of Biological Physics at the University of Leeds. She has always been interested in understanding how biological systems perform their amazing functions within the confines of the laws of physics. While her undergraduate degree is in Physics from the University of Oxford, she then obtained her PhD from the School of Pharmacy at the University of Nottingham in 2001. She is now in the Theoretical Physics group in the School of Physics and Astronomy, and part of the Astbury Centre for Structural Molecular Biology. Her research uses high performance supercomputing to model how biological molecules move and interact.

Thomas Hillen, Dr. rer. nat., is Professor and Associate Chair Research at the Department of Mathematical and Statistical Sciences at the University of Alberta in Canada. He studied at the Universities of Münster and Tübingen in Germany, before he moved to Canada in 2001. He has published five textbooks and over 80 journal publications. Currently, Dr. Hillen is President of the Canadian Applied and Industrial Mathematical Society (CAIMS). Dr. Hillen’s research is focused on mathematical modelling of cancer and cancer treatment. He is motivated to use advanced mathematical methods for the common good.


The title et al - Biology

The American Biology Teacher

The American Biology Teacher is designed to support the teaching of K-16 biology and life sciences. The journal features articles related to biology as a whole, ethical issues in biology, and teaching strategies for classrooms, labs, and fieldwork.

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