# Planet Earth/7c. How did Life Originate?
## The Miller–Urey experiment

Stanley Miller arrived at the University of Chicago in 1951 despite a family tragedy of the preceding years. Miller grew up in Oakland California, and with his brother fell in love with the science of chemistry. In 1947, while in college studying chemistry, his father, who had supported his studies, suddenly passed away, leaving him to ponder his future education, without his father’s financial support. The faculty and the University of California supported his application to attend graduate school, and he was lucky enough to receive a teaching assistantship at the University of Chicago to further his education. Miller was initially assigned to the lab of Edward Teller, the Hungarian scientist who worked on the development of the hydrogen bomb in the 1950s. But the lab was not a happy place for Stanley Miller, who struggled. He grew up believing he was a chemical whiz kid, but now struggled to find a research topic of interest. Edward Teller was no help, as he was often researching bigger and more destructive atomic bombs, with funds from the United States Government. Miller was disillusioned about the prospect that chemistry was a field of science only set about to build bigger bombs and create larger atoms. One day he sat in a lecture by Harold Urey, the Nobel Prize winning chemistry professor who studied isotopes, and had discovered deuterium. Urey discussed in his lecture the origin of the solar system, and hinted at the strange mystery of the origin of life on Earth. The lecture gave Miller an idea, a topic, rather than studying atomic bombs, he would study the origin of life. He convinced Harold Urey to allow him to be his advisor, and switched labs. Urey was hesitant, as he knew that the study of the origin of life from inorganic chemical reactions was likely a difficult subject to get into for the young scientist, but the eager Stanley Miller convinced his advisor to give him some space in the lab. He had an idea and wanted to test it out.
Miller begin by recreating small lab versions of the atmosphere and ocean of the early Earth, which he knew from geological evidence was anoxic, lacking free oxygen gas. He used purified water (H$_2$O), methane (CH$_4$), ammonia (NH$_3$) and hydrogen (H$_2$). The gasses were filled in a sealed sterile glass flask and connected by a tube to a half-filled flask of water, which he placed over a source of heat to produced water vapor, below the gas filled flask he cooled the gasses, so that precipitation of water would cycle down another tube back to the water filled flask. Along this tube he had a valve to sample the condensed liquid that formed here. One of the key introductions he made to the gas-filled flask was an electrical spark. This spark he imagined represented lighting in the gas atmosphere of Earth. Once completed the experiment was set to run in the lab. Fellow students laughed at his simple experiment, with the crackle of sparks and burning flame below the flask, it looked like a science experiment that you would see in Frankenstein’s lab, not the lab of a Nobel Winning chemist. Harold Urey was equally worried that the experiment was pointless, how could inorganic chemicals of just those ingredients generate life. Miller watched the experiment each day, making notes of the process. Soon the color in the water changed to a pinkish color, and then a darker brown color, and the gas filled flask turned black. Taking samples, Miller analyzed the mixture produced, and what he discovered amazed the world.
He found traces of hydrogen cyanide (HCN), formaldehyde (CH$_2$O), and carbon dioxide (CO$_2$), but also larger strings of carbon molecules like glycine (NH$_2$-CH$_2$-COOH), but also many types of amino acids, like adenine, a nucleobase found in DNA, as well as carbohydrates like ribose (the backbone molecule for RNA).
In the nearly 70 years since Miller conducted his experiment, scientists have confirmed that these more complex organic molecules can be synthesized from such a simple experiment. Furthermore, the addition of sulfur, which was likely present in the atmosphere from volcanic activity as either hydrogen sulfide (H$_2$S), or sulfate (SO$_4$$^{2-}$), has led to other novel organic molecules being synthesized. With amino acids and a source of carbohydrates, like ribose there was at least the raw ingredients for life. All that was missing was the appearance of RNA (ribonucleic acid), to bind these amino acids and carbohydrates together into self-replicating molecules, which requires the coordination of three types of ribonucleic acids. This is where the experiments have failed.
Complex RNA molecules are much more challenging, and yet unproven to synthesize in a lab from such simple inorganic matter. These more complex molecules required an additional input of energy and raw materials as well as different processes. It is still a mystery what these steps are in the recipe of life.
Scientists have introduced electromagnetic radiation, in the form of intense light, evaporation (which appears to be a critical process), as well as sources of other materials like phosphate. It has also been shown that the mineral calcium apatite, which consists of phosphate and calcium ions, increased ribose formation from formaldehyde and glycolaldehyde in hot water (near 80 °C). Ribose is a vital ingredient for more complex RNA molecules. The pH of the water used in the experiments is also very critical, as well as the length of time the experiment is allowed to run. Running such prebiotic laboratory experiments have gotten scientists close to replicating life using the proposed conditions of an early Earth. But these experiments have yet to produce simple RNA based life form, lifeforms as simple as self-replicating viruses. The odd thing about these laboratory experiments is that scientists have created life, but they have had to cheat a little in the process of making that life, using material that may not have been present on early Earth— cellular membranes.

## Synthetic Life

Most people would say that Craig Venter is a bit of rebel; insubordinate he has never shied away from his self-beliefs and intense drive. Born in 1946 in Salt Lake City, and later moved to San Francisco, he was an average student, and attended community college in California after graduating from high school. Unlike Stanley Miller, Craig Venter was not some chemistry whiz kid, and spent most of his free time surfing or sailing on the ocean, and hanging out on the beach, barely passing classes with Cs and Ds. With the outbreak of the Vietnam War in the 1960s, he realized that he would likely be drafted, and so he decided to enlist in the Navy and trained to be a medic in San Diego California. His attitude did not change while in the Navy, and he ended up shipping out after a messy court-martial, and sent to field hospital to the city of Da Nang along the coast of Vietnam.
It was a dangerous place to be, as on January 30th of 1968 North Vietnam forces launched the Tet Offensive attacking hundreds of cities along the coast, from Quang Tri in the north to Saigon at the south. The major offensive attack resulted in significant causalities of both sides of the war. Craig Venter was staffing the overwhelmed hospital as the city became the heart of a war zone. Death was all around him, as the injured and dying poured into the Navy clinic, while firefights erupted on the streets outside. Watching so many people die around him, he became deeply depressed, and one day he could take it no longer, he swam out into the sea away from the coast of death. Wondering, as he swam, if he should ever return back to shore. Return to a world where people suffered and died. As the waves of Earth’s ocean lifted and sank, his tiny floating body, up and down in the vast void between liquid ocean and gas atmosphere. He pondered his purpose in life. And in the void, he grabbed hold of a purpose— he would save people. On returning from Vietnam and the bloody war, he finished his degree at the community college, got married, and enrolled at the University of California for graduate studies in physiology and pharmacology, rather than becoming a medical doctor, he felt he could save more people by developing new medicines that cured diseases and millions of people, rather than treating individual patients. After graduate school, his talents and drive got him a job teaching at the State University of New York, but he was still brash, divorcing his wife, and marrying one of his students. In 1984, he started working at the National Institutes of Health (NIH), and later came under the leadership of James Watson (one of the 1962 Nobel Prize winners in Physiology and Medicine for the discovery of the molecular structure of DNA). The project of the National Institutes of Health was to sequence the various individual nuclides that compose an individual DNA molecule from a human cell. The project was the fledgling Human Genome Project, which begin in 1990, to map the individual genes that compose a human DNA molecule.
Craig Venter had developed a method to slice the large molecule into smaller and smaller pieces, and analyze these sequences by entering the information into banks of computers. Each workstation looking at individual smaller and smaller pieces, like a factory. They were set up to map out each series of nuclides, the individual code of genetic material in the complex DNA molecule found in a human cell. Venter clashed with many of his supervisors, who recognized his brilliance and ambition, but struggled to contain his ego, and opinions. About a year into the project, Venter quit, and formed a private company, with the intention of filing a patent on the human genome, and beat the government funded scientists to the race. This turn of events shocked the world, with the idea that a company could own the knowledge of life. Venter’s talent at decoding the complex organic matter that makes life possible resulted in major breakthroughs in not only decoding the DNA molecules found in living animals and plants, but also in building new strands of DNA (and RNA) to synthesize new lifeforms.
In 1995, his team decoded the genetic script for the bacterium Haemophilus influenzae the bacteria that can cause deadly pneumonia and meningitis, especially in infants and babies. They followed up with a complete genome sequence of Mycoplasma genitalium, a sexually transmitted bacteria that lives on human genitals (which also lacks a cellular wall, and is the tiniest known bacteria yet discovered). These simple celled bacteria, had significantly smaller numbers of genes than the human DNA genome, and Venter wondered if he could create a cell that was even simpler, synthetically.
What is the simplest lifeform? What is the smallest amount of genetic information needed for life? Where Stanley Miller experiments asked how to create life from inorganic matter, Venter asked from the other side, what is the simplest life-form that can exist? In other words, if he could take these complex molecules apart to map and study them, could he and his team re-assemble them back together to create new lifeforms, ones that could be directed to make new medicines or vaccines? The ability to do so would revolutionize medicine.
Venter and his large team set about synthesizing life in 1995. The task was deceptively simple, make a molecule of DNA, then setting it about to see if it would reproduce if fed and cared for. They would then select from of these cultured replicated cells, and map the genome to see if the synthetic life would express the same genes as they set within the initial molecule they created in the lab and inserted into the first cell. The major problem they faced, and one that countless researches have faced before is with the cellular membrane. If RNA or DNA is made, it must be protected by some type of membrane, otherwise it would quickly fall apart due to the environmental conditions, particularly in an environment with free oxygen, or slight changes in temperature. The breakage of carbon-carbon bonds by oxidation or heat can break apart these complex molecules quickly before they have a chance to replicate, thus a protective membrane is required. The researches planned to use a bacterial membrane, and insert their synthetic molecule into the empty membrane, much like how a virus infects bacteria cells to make copies of itself. Time after time, the cultured cells were not their synthesized molecule, and the ability to insert their synthesized molecule into an empty cell proved nearly impossible. They tried for 15 years, with large teams of researchers, attempting to prove to the world that it was indeed possible.
In July of 2010, the team finally announced their success, in a paper published in Science entitled “Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome.” The cultured cells (which held only 582,970 base pairs) held the watermark of their names, etched into the genetic code of a synthetic lifeform. In the years since this amazing discovery, pharmaceutical companies have clamored for the technology to use for synthesizing medicine and vaccines, while the general public has come to fear the technology with an eversion to “genetically” modified food. Since 2010, we are living in a world in which humans are able to synthesize life, much like an engineer would build a car.
These break throughs, as well as other experiments conducted in labs indicates that the origin of life on Earth was achieved through multiple complex steps facilitated by the unique properties of Earth’s gas chemistry of the atmosphere, liquid chemistry of the ocean, and the solid chemistry of the Earth’s rocky surface, facilitated by the lack of oxygen. The emergence of an RNA-world, where life first appeared as self-replicating macromolecules of strings of carbon, with hydrogen, oxygen, nitrogen, phosphorus and sulfur, is thought to have occurred very early in Earth’s history. However, with the advent of an oxygen-rich ocean and atmosphere later in Earth’s history, these early life-forms were likely destroyed and went extinct, leaving behind only those organisms that developed a protective cellular membrane, with first true life forms— bacteria.
Bacteria meet all the definitions of life. They exhibit growth and development, they reproduce, they pass on variable genetic information with the heredity of traits, they are able to evolve and change through each generation, they exhibit homeostasis with stable conditions inside the cell, they can metabolize food by gaining energy from chemical reactions, they have cellular bodies with a membrane, and they respond to the external environment, and lastly, they have very short lifecycles between birth and death able to rapidly reproduce, but also quickly perish with death.
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