The Rise of Yeast as a Model Organism in Biology

For millennia, yeast has held a place at the table of history, transforming flour into bread, grapes into wine, and grain into beer. But yeast is much more than a building block for a good meal. It offers a glimpse into the fundamental questions about the inner workings of cells and into something much larger than itself—human biology.

In the latter half of the 20^th century, researchers relied on mammalian systems, including mouse and human cells, as representatives of higher eukaryotes. Yeast had not yet become a widely recognized model organism for studying fundamental biological processes.

One researcher, however, would begin to question this approach. In 1964, Leland Hartwell was a postdoctoral fellow in virologist Renato Dulbecco’s group at the Salk Institute working with polyoma virus-infected mammalian cells to study how the infection influenced cell growth and induced DNA synthesis. However, Hartwell remarked, “I felt like I wasn’t going to get anywhere with human cells…There just weren’t technologies to allow us to really ask fundamental questions.”

Hartwell eventually left the Salk Institute for a position at the University of California, Irvine, where he had received a grant to study the control of cellular DNA synthesis. Determined to pursue a different approach, he decided not to continue working with mammalian cells. “I spent a lot of time in the library looking for a eukaryotic organism that had [facile] genetics, because I was impressed by the success that had been made in studying gene regulation in bacteria and bacterial virus reproduction both using genetics.” His search ultimately led him to yeast.

The Genetic Rise of Budding Yeast in Labs

The groundwork for yeast as a genetic model had begun decades earlier from the 1930s through the 1950s. Researchers worked independently across continents to study Saccharomyces cerevisiae, commonly known as baker’s yeast, in earnest. At the Carlsberg Laboratory in Copenhagen, biologist Øjvind Winge led early efforts to study yeast through breeding experiments—classical genetics—initially motivated by the goal of combining desirable traits in brewing strains.¹

Around the same time, geneticists Carl and Gertrude Lindegren at the University of Southern Illinois conducted parallel breeding studies, contributing key insights into yeast biology, including yeast reproduction and mating types and the initial genetic map of yeast chromosomes.^2-4

Building on this foundation, Hartwell sought guidance from leaders in the field, geneticists Robert Mortimer at the University of California, Berkeley and Herschel Roman at the University of Washington, on working with yeast. Roman provided Hartwell with yeast strains and loaned him a micromanipulator—an essential but technically demanding tool used to separate the yeast spores from one another and let them each grow into a colony.

“[Yeast] is just a beautiful organism for doing genetics.”

—Leland Hartwell, Arizona State University

From there, Hartwell began studying the genetics of cell division and DNA synthesis in 1965.⁵ Three years later, Roman invited Hartwell to move his lab to the University of Washington; he eagerly accepted, in hopes that the classical genetics environment would help him better study cell division, especially since he was new to working with budding yeast.

“The hardest part was finding [yeast] that were specifically defective in the cell division process,” recalled Hartwell. Budding yeast cells grow by forming a small bud on their surface that enlarges over the course of the cell cycle. In many cell division mutants, this process is interrupted. Hartwell explained, “When they can’t divide, they accumulate synchronously.”

So, as Hartwell and his colleagues isolated temperature-sensitive mutants, they became very interested in photographing cells at 37°C, which is the restrictive temperature for yeast, as they were dividing. “I constructed a photomicroscopy setup where the cells could be incubating, and I could photograph them at the same time.”

He assigned this task to his student Brian Reid, and they quickly realized that the approach enabled them to visualize defects and identify cell division mutants. Now, they could pinpoint when in the cell cycle the defect occurred: Cells exposed to the restrictive temperature before a critical event would arrest in the first cycle, while those exposed after it would complete that cycle and arrest in the next.

“Photomicroscopy was the big breakthrough that allowed us to find cell division mutants,” said Hartwell. These observations allowed the team to describe the first cell division control (cdc) mutants, cdc1, cdc2, and cdc3, in budding yeast.⁶ From then on, Hartwell called the following period of discovery “a gravy train,” as the group kept finding and characterizing cdc mutants—more than 100.⁷ One of the key genes identified was CDC28, a critical regulator of the “start” G1 gene that controlled the initiation of the cell cycle, where yeast decided whether to mate or to divide. These advancements in understanding the control and operation of the eukaryotic cell cycle piqued the interest of the few others who saw utility in studying yeast.

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Enter Fission Yeast, Budding Yeast’s Relative

At the time, Paul Nurse was a doctoral student at the University of East Anglia, studying amino acid metabolism in the fungus Candida utilis. During this time, he struggled with a temperamental prototype amino acid analyzer, finagling the device by any means necessary to keep it functioning. While he kept one eye on the device, he read different papers, including Hartwell’s two papers from 1970 and 1973 describing cdc mutants. Nurse was already interested in studying cdc, but he remarked, “I wasn’t quite so sure about budding yeast as a model for this particular problem.”

When he finished his graduate studies in 1973, he left the amino acid analyzer behind and set his sights on yeastier pastures. Instead of budding yeast like S. cerevisiae, he decided to work with fission yeast Schizosaccharomyces pombe. This choice was largely driven by how S. pombe divides in the middle of the cell, which is much more typical of other eukaryotic cells. “I decided to follow Hartwell's process and approach and isolated mutants with fission [yeast] that were defective in the cell cycle.”

“One of the advantages of the yeast is you can do incredibly precise work, and you can test hypothesis very carefully. So, for any complex phenomenon, yeast is great.”

—Paul Nurse, Francis Crick Institute

But first, Nurse had to learn the genetics of fission yeast, so he spent a few months in Switzerland with geneticist Urs Leupold at the University of Bern. Then, he moved to Scotland as a postdoctoral researcher with zoologist Murdoch Mitchison at the University of Edinburgh who worked on the fission yeast cell cycle. “So, I was a bridge, if you like, between those two fields and applied genetics to fission yeast starting in about 1973.”

Because S. pombe divided in the middle, Nurse couldn’t look for cdc mutants based on bud size. Instead, he identified temperature-sensitive mutants that could not divide and became elongated. These early studies defined more cdc genes necessary for S-phase, mitosis, and cell division.^8,9 Then, Nurse wanted to know if any of these were involved in controlling the cycle itself, rather than just being a piece of cellular machinery needed to carry out individual steps within cell division.

He remarked that cytogeneticist Barbara McClintock’s approach of developing “a feeling for the organism,” was something he experienced as he spent much of his time examining yeast under the microscope. He could tell when the yeast were happy or unhappy, but also, he mainly looked for elongated cells with impaired cell cycle. Instead, in a serendipitous observation, he found the opposite—the yeast cells were smaller. These cells did not arrest but instead divided early before reaching their normal size.

“It took me about 15 seconds to realize [this observation] was important. But I’d never thought of it. That actually opened up the cell cycle control because it turned out that the cdc2 gene that you could mutate produced a wee mutant phenotype.” This wee mutant phenotype was named for its size and discovery in Scotland. Wee1 was a negative inhibitor, regulating cell size and division timing.¹⁰

Around this time in the 1980s, DNA technology became available, and many researchers, including Nurse, shifted from classic genetics to molecular genetics to better study these genes.

Looking for a CDC28 homolog in S. pombe, Nurse took a budding yeast library, put it onto a fission yeast cdc2 temperature-sensitive mutant, and cloned a DNA sequence from budding yeast. Upon further investigation, his team later determined that cdc2 in fission yeast was the homolog to CDC28 in budding yeast; it was necessary for G1 and mitosis.^11,12

While these yeast findings excited him, Nurse wanted to look for the human homolog of this gene. The idea seemed far-fetched, as yeast and humans probably diverged about 1.5 billion years ago. “Obviously, most people thought we were crazy, and we probably were,” said Nurse, who at that point worked at the Imperial Cancer Research Fund. Undeterred, Nurse and his team used a human cDNA library and inserted the entire catalog into S. pombe with a defective cdc2 gene. Nurse described it as “the dirtiest experiment you could imagine,” because he wasn’t sure it would even work—but it did. They observed that a human gene functioned similarly to yeast cdc2, effectively rescuing it and restoring its function: Could this be the human homolog they were looking for?

It took them a few more months to confirm the result using Sanger sequencing. When the computer printed out the results on the ticker tape, Nurse couldn’t believe his eyes. The findings revealed that the human and yeast proteins were over 60 percent identical. Because of these similarities, the mechanisms controlling the cell cycle were likely to be conserved in eukaryotes. They had found the human homolog: cyclin-dependent kinase 1 (CDK1).¹³

“One of the advantages of the yeast is you can do incredibly precise work, and you can test a hypothesis very carefully. So, for any complex phenomenon, yeast is great,” said Nurse, now at the Francis Crick Institute. “[Yeast] is just a beautiful organism for doing genetics,” added Hartwell, now at Arizona State University.

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The beauty of yeast also eventually caught the attention of neurobiologist Jasper Rine, then a graduate student at the University of Oregon, who was initially focused on zebrafish research. But he could not resist the siren call of yeast, which came in the form of a huge amount of lively conversation filtering through the vents in the adjacent room.

Rine had previously encountered yeast as a contaminant in his neuron cultures and dismissed them, thinking, “It’s a shame there’s nothing particularly interesting about them. They’re just so much easier to grow than neurons.” But to his surprise, the neighboring lab of Ira Herskowitz was studying yeast genetics.

Intrigued by their use of yeast to answer fundamental biology questions, he traded in zebrafish for budding yeast, working alongside Herskowitz to study the mechanism of cell-type switching during yeast mating. Together, they discovered the conserved gene family responsible for mating-type silencing, which they named silent-information regulator (SIR).¹⁴ Humans have a similar gene family known as sirtuins (SIRT1-7), which were later found to be involved in processes like metabolism and aging.¹⁵

Rine became part of the growing yeast research community, whose collective work and efforts encouraged scientists to use yeast to study other problems in cell biology. “It sort of felt like a grand adventure and that there were unlimited possibilities,” said Rine.

Sequencing the Yeast Frontier and Answering Modern Biological Questions

The ease of yeast’s genetic manipulation made it an attractive target for sequencing, especially with the rise of more rapid, automated sequencing. In the 1990s, a consortium of scientists came together and began in earnest to sequence a series of model organisms, including S. cerevisiae in 1996 and S. pombe in 2002.¹⁶ S. cerevisiae contained some 6,000 genes on 16 chromosomes.¹⁷ This milestone marked a dramatic expansion from the study of just a handful of individual genes in the preceding decades. Then, additional studies revealed that budding yeast and human amino acid sequences overlapped by approximately 32 percent, and roughly half of essential yeast genes could be replaced by their human counterparts.^18,19

The Establishment of Yeast as a Research Model From budding to fission, yeast shows that even the simplest organisms can teach researchers big lessons about life. A) What Makes a Good Model Organism? Researchers prefer model organisms that are easy to grow and maintain, have rapid life cycles, possess simple genomes, are easily genetically modified, and share numerous genes with humans.16,18 Which Types of Yeast Are Used as Models? B) Budding Yeast (Saccharomyces cerevisiae) Budding yeast reproduces by forming a small daughter cell, or “bud,” from the parent cell. Despite its tiny size, it has a compact, easily manipulated genome, making it an ideal system for studying genetics, cell division, and aging.6,7 C) Fission Yeast (Schizosaccharomyces pombe) Fission yeast elongates and splits in the middle, much like how human cells divide. It is a useful system for understanding cell cycle control and cellular responses to DNA damage and the process of DNA replication.10,13 D) What Has Yeast Taught Researchers? Despite early doubts about yeast, researchers worked diligently to demonstrate its potential, and yeast rose to the occasion as a model organism. Yeast research has helped scientists understand how cells work and has driven advances in medicine, biotechnology, and synthetic biology.

With clear links between yeast and human cell cycle control, the implications of these discoveries extended far beyond basic biology. The same genes that governed when a yeast cell divided were closely related to those controlling division in human cells. Rine, now a professor emeritus at the University of California, Berkeley, reflected that by studying yeast and the cell cycle, “It was obvious from the very beginning that it would have great lessons for cancer.”

In addition, yeast has become a powerful platform for biomedical discovery. Its rapid growth and genetic tractability enabled early high-throughput screening approaches, allowing scientists to model disease-associated mutations and identify compounds capable of restoring normal cellular function—experiments that would be far more complex in higher organisms. Plus, researchers engineered yeast for drug development and recently completed a decades-long project to construct a synthetic yeast genome to serve as a platform for enhanced biotechnology innovation.^20,21

Today, yeast continues to be a powerhouse in the biologists’ toolkit, expanding its utility from unraveling fundamental biology to areas such as drug discovery, functional genomics, and synthetic biology. Like the “little engine that could,” yeast rose above early skepticism, proving that even the smallest organisms can have enormous impact.