Franken-Yeast: Designing Life, Defining Life

Recently, a group of scientists(1) published a paper detailing their progress in synthesizing genes(2) and successfully inserting their man-made chromosomes into yeast cells. In order to synthesize DNA, scientists write out a genetic blueprint for a gene, and predict how it will behave by modeling its behavior with computer software. Then the gene design is broken into smaller segments, and commercial DNA labs generate copies of these segments. The shorter segments are assembled into complete genes, and then inserted into living yeast cells. Their offspring are an extraordinary strain of common brewers yeast: Saccharomyces cerevisiae(3).

All living cells are loaded with DNA, and we only understand how a fraction of it works. When the human genome was first examined, as little as 3% of the DNA was recognized, and the rest looked like gibberish. Even Francis Crick said this unfamiliar DNA was “little better than junk.” Further research has revealed that these stretches of DNA perform complex functions, like switching genes on and off, and sending signals to other genes. But the purpose and interactions of every segment of DNA is still not clear.

By designing and creating replacement chromosomes, and successfully folding this man-made DNA into yeast cells that can reproduce, scientists are clarifying the roles of the most essential genes required to sustain life.

But this is not the first time that brewers yeast (S. cerevisiae) has stood at center stage as scientists investigate the secrets of life. Two hundred years ago, the behavior of yeast was used to demonstrate that fermentation was a simple, predictable chemical process. Then, later, closer study revealed that fermentation was the result of a living process — yeast was alive!

Be he alive or be he dead,
I’ll break his bones to make my bread

In the late 1600s, Anton van Leeuwenhoek was building handheld microscopes, and drawing detailed illustrations of the miniature world he through his lenses. van Leeuwenhoek faithfully recorded what he saw, making detailed drawings of everything from fleas to blood flow in capillaries. And when van Leeuwenhoek examined beer beneath his lens, he saw yeast cells, and drew those too. However, looking at beer through his microscope was just one stop in a long survey, and he didn’t give yeast much more thought.

“Gist,” Dutch for “yeast”, as drawn by Anton van Leeuwenhoek

And until the Enlightenment got into full swing, nobody else thought much about yeast, either. In Samuel Johnson’s 1755 Dictionary, yeast was defined as “the ferment put into drink to make it work.” But yeast would come into focus soon. As Enlightenment scientists investigated natural phenomena, old ideas were put to the test. One enduring idea was “spontaneous generation,” accepted as fact at least as far back as Aristotle’s time. For example, people believed that a piece of meat left alone would spontaneously generate maggots. Wheat, eventually, would produce mice. But these “Just So” explanations for natural phenomena evaporated in the sunlight of the scientific revolution. Observation and experiment revealed that maggots are born of eggs laid by flies, and baby mice are only produced by mother mice.

Antoine Lavoisier(4) was a French scientist who, with his wife, Marie, advanced the understanding of chemistry. One of his greatest contributions was to validate the theory of the conservation of mass. “Conservation of mass” is the principle that matter is never created nor destroyed; it is only transformed. The Lavoisiers devised experiments to demonstrate that the weight of the components of a chemical reaction were the same before and after the reaction. Lavoisier was able to measure masses with such precision that he could demonstrate when gases had reacted with metals. In 1789, he turned his attention to fermentation. Here, his ideas of conservation of matter were confirmed: as sugar ferments, each measure of glucose produces two units of alcohol and two units of carbon dioxide.

The molecular formula for glucose is C6H12O6. Ethyl alcohol takes the form C2H6O, and carbon dioxide, CO2. So, Lavoisier demonstrated that the combined mass of the glucose was equal to the combined mass of carbon dioxide and ethanol produced:

C6H12O6 = 2(C2H6O) + 2(CO2)

Voilà, chemistry! Discrete and exact; what goes in equals what comes out.(5)

But what exactly yeast was, or how it performed fermentation, exactly, wasn’t clear. Yeast was still considered inanimate, a chemical catalyst that speeded fermentation, but was unaffected by it.

Only a few years later, the view of yeast would change entirely. By 1835, microscopes were powerful enough that scientists could observe yeast cells growing and budding — not behavior typical of inert chemicals. Louis Pasteur discovered that although most fermentation followed the simple formula that Lavoisier outlined (C6H12O6 = 2 (C2H6O)+2 (CO2), there were other substances produced by fermentation, including glycerin and succinic acid. He also noted that the population of yeast cells grew as fermentation progressed. These observations led Pasteur to say,

La fermentation c’est la vie sans air; c’est la vie sans oxygen libre.
Fermentation is life without air; it is life without free oxygen.

And since then, yeast has served as a model organism for exploring cell biology. Like us, yeast is a eukaryote: a complex cell, with its DNA packaged in a nucleus. It is easy and cheap to grow. It lives a fairly simple life and reproduces rapidly. And although yeast is a fungus, many of the genes in yeast are identical to those in mammal cells, performing similar jobs. Studying how changes in yeast genes affect its development can illuminate the role of similar genes in other animals.

Yeast was one of the first eukaryotes whose DNA was fully sequenced, nearly twenty years ago. But teasing out the roles of all of its genes has taken years. By manipulating genes in yeast, scientists have been able to learn what different genes do: “what happens if we swap this for that?” And the tools for making these changes have become much more powerful and precise. But genes have evolved in living organisms over millions of years, in a slow, iterative process. Although the phrase “junk DNA” isn’t used much anymore, there are still many sequences of DNA that are not well understood.

Now, scientists can tailor a gene from the bottom up, confident that they know what each component will do. Scientists can insert very specific code into these designer yeast genes, and include short sequences that mark the yeast as synthetic. By observing how this designer yeast grows and reproduces, we understand better how each gene works, and as importantly, how those genes interact with each other and the whole organism.

So, in a new way, yeast is endearing itself to humans. In addition to making our existence more delicious, yeast helps us understand the nature of life itself.

Need more yeasty goodness? Read Part 1: A Nation of Minions

Notes:

1. http://syntheticyeast.org/
2. DNA, genes, chromosomes: Genes are discrete segments of DNA that provide instructions for making proteins, or other cellular functions. Chromosomes are large collections of genes. S. cerevisiae contains 16 chromosomes. Each of us Homo sapiens carries 46 chromosomes. Shrimp have 86–92 chromosomes.
3. The species name comes from the Latin word for beer, cervisiam. Same root as cerveza.
4. Lavoisier’s career was cut short by the guillotine in 1784, courtesy of Jean-Paul Marat and the French Revolution.
5. Another example of Lavoisier’s innovative experiments demonstrated that water was a compound, not an element. He forced water vapor through a red-hot gun barrel. The oxygen in the water bound to the hot iron, forming rust, and leaving only free hydrogen to emerge at the far end of the barrel.