‘The awesome power of yeast’

Keywords: ageing research, cancer research, drug discovery, gene engineering, mitochondrial function, Nobel prizes, teaching, yeast-derived vaccines.

‘The awesome power of yeast genetics’ was a term generally believed to have been first used by Ira Herskowitz (1946–2003).¹ With thousands who have experienced the power of yeast genetics the phrase thrived and continues in new contexts today, not just yeast genetics. To date five Nobel prizes have been awarded to yeast researchers for their discoveries of important cellular mechanisms (Table 1). In this article we describe that awesome power that is available today (Fig. 1).

Table 1.  Nobel prizes awarded to yeast researchers.

Fig. 1.  Some applications of the awesome power of yeast. The background image shows yeast viewed by light microscopy.

Yeasts are the best studied eukaryotes. Our advances in genetics, molecular and cell biology have been greatly aided by yeast, in particular Saccharomyces cerevisiae, whose genome was the first eukaryotic genome to be sequenced. Much of the information on the contributions of yeast to biology is readily available on the Saccharomyces Genome Database.² This information has aided the characterisation of many genes and proteins in humans. Functional complementation of yeast gene deletants with human genes is often observed in yeast, further allowing insights into human proteins in health and disease. To a lesser extent, several Candida species have been similarly exploited and the information compiled on the Candida Genome Database.³

Due to the conservation of important fundamental processes of eukaryotes from yeasts to humans, yeast have played crucial roles in the study of several human diseases.⁴ The similarities such as age-associated loss of proteostasis makes them valuable models for diseases involving age-related proteinopathies. Through advanced synthetic biology approaches it is also possible to reconstruct yeast for the study of diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, prion disease, and cancers.^5–7

Yeast also offers unique opportunities to study diseases involving mitochondrial defects since it can grow with defective mitochondria.⁸ In addition, the conservation of cellular signalling and pathways from yeast to higher eukaryotes make it more highly useful in studying diseases involving a multitude of processes. For example, these attributes have been used in recent studies that have been outstanding in identifying compounds that can modify mitochondrial health.^9,10

The first viral subunit (for HBV and HPV) vaccines were made in yeast and they have been used safely for more than three decades. Since then, several important therapeutic proteins including vaccines have already been synthesised using yeast as a cell factory (Table 2).¹¹ In the 1980s, Macreadie and colleagues at CSIRO were involved in the development of the 2nd viral subunit vaccine for a poultry virus, infectious bursal disease virus.¹²

Table 2.  Some therapeutic proteins expressed in yeast for commercial purposes.¹¹

Can yeast be used to produce a COVID-19 vaccine? So far progress to the development of a yeast-derived COVID-19 vaccine has been slow compared to the many other COVID-19 vaccines. However, the efficacy of a yeast-derived receptor binding domain (RBD)-based COVID-19 vaccine looks to be promising.¹³ A challenge with producing human proteins in yeast is the type of carbohydrate added to proteins (glycosylation).¹¹ Human glycosylation is complex, while yeast adds high mannose. This challenge has now been met, by synthetic biology approaches. Pichia pastoris was re-engineered with genes involved in human glycosylation to produce up to 16 different types of mammalian glycosylation patterns. This has revolutionised the pharmaceutical industry and the use of P. pastoris for vaccine production.¹⁴ Corbevax is an example of a P. pastoris expressed subunit vaccine, for COVID-19. It is patent free and is regarded as an effective, low cost vaccine candidate.¹⁵

Protein interactions are immensely important for assembly of protein complexes and for cell signalling. The yeast two hybrid system, pioneered by Fields and Song (1989) has provided technologies to discover human protein–protein interactions, including their precise molecular interaction interfaces.¹⁶ Further, it is possible to use yeast displaying human protein interactions to find small molecules that disrupt these interactions.¹⁷ This is a powerful approach for drug screening since molecules found in such an approach must already have a degree of bioavailability.¹⁸

Yeast is also a useful model to study aging. Throughout their life most yeast species produce progeny by budding. With each bud that is released a bud scar is left at the surface and these scars can readily be stained with calcofluor white.⁸ In every generation, 50% of the population are newborn yeast, while the remainder have one or more bud scars. Flow cytometry is a very convenient means to be analyse or isolate yeast populations, which provides a convenient means of observing the ageing of yeast and can facilitate study of the expression of ageing-related genes.¹⁹

As noted by Dhakal (2021) proteostasis declines with aging and can readily be observed in yeast having the Alzheimer’s disease protein, amyloid beta.⁸ Anti-ageing drugs can readily be tested in such yeast models. For example, a study to screen several bioactive compounds found two excellent candidates (baicalein and trans-chalcone) that have potential to treat and prevent AD. Additionally, the synergistic activity of these two compounds in improving ageing health in the yeast that expressed amyloid beta was identified using such yeast models.²⁰

Yeast is GRAS (generally regarded as safe), fast growing and can be used as a convenient organism for teaching aseptic technique, metabolism, synthetic biology and cell biology.¹¹ Yeast are usually grown in rich media and the total absence of antibiotics, even for selection of transformants. Therefore, proper technique is required.

Yeast are eukaryotes and have the organelles of eukaryotes. There is beauty in the sight of mitochondria in live yeast, being able to look at them as structures resembling roots in a plant pot, rather the textbook image: an oval shape showing their cross section. Furthermore, the effect of mitochondria on growth can be readily demonstrated on media with a non-fermentable carbon source, and yeast lacking the ability to grow on such media can be observed. This lack of growth can happen when a mitochondrial inhibitor is added to the media (e.g. antimycin, oligomycin, erythromycin, chloramphenicol) or when the yeast contains a defect in its mitochondrial genome. This defect can include a point mutation or a deletion of a portion or all of the mitochondrial genome. Such mutants are known as mit⁻ or petite mutants.

So far, yeasts have proved to be an awesome research tool for studying human diseases, a very convenient biological factory for production of several important therapeutic proteins and a platform for screening drugs against human diseases. Important discoveries made in yeast have always provided solutions to big problems in simpler ways.

Data sharing is not applicable as no new data were generated or analysed during this study.

Ian Macreadie is the Editor-in-Chief of Microbiology Australia but was blinded from the peer-review process for this paper.

This study did not receive any specific funding.