Let’s Talk About Heat Shock Proteins (While Waiting for the Summer)

 

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Do you sometimes wonder why scientists bother to study the development of fruit flies? Or why they care about how the cave fish has lost its eyes? Scientists might argue that it is because of curiosity, and because research is just great! Or because we gain insight into mechanisms of evolution or animal development, which will eventually let us better understand how species evolved and develop. For many people this motivation is valid enough. But others do not see any purpose in research if it is not to cure diseases or to make human life more comfortable or safer. Unfortunately, the relevance of research is not always apparent from the beginning. Sometimes it needs years, or even decades to understand the significance of certain findings! Here I want to tell the story of heat shock proteins - one out of many examples of how a study initially dismissed as irrelevant turned out to be a groundbreaking finding. 

Here I want to tell the story of heat shock proteins - one out of many examples of how a study initially dismissed as irrelevant turned out to be a groundbreaking finding.

The story of heat shock proteins started in the early 1960s in Italy. A scientist named Ferruccio Ritossa studied the puffing pattern of the polytene chromosomes* in the fruit fly Drosophila. He noticed a change in the puffing pattern after fly larvae were exposed to increased temperature. 


 (* Polytene chromosomes are oversized chromosomes which are commonly found in cells of the larval Drosophila salivary gland. Puffed up regions in these chromosomes indicate less condensed DNA and increased RNA synthesis (transcription) activity.

 Ritossa early 1960s; Source: (De Maio, Santoro et al. 2012) 

Ritossa early 1960s; Source: (De Maio, Santoro et al. 2012) 

It was already known at that time that puffs in these chromosomes indicate increased gene expression activity or as Ritossa described it: „These patterns can be explained in terms of variations of chromosome activity“. Hence, heat leads to increased synthesis of at that time unknown factors. It has been reported that Ritossa had difficulties to publish his findings; his studies were considered as not biologically relevant. Eventually, his heat shock studies were published in Experientia in 1962. The „unknown factors“ induced by heat were later identified as heat shock proteins. 

In the following decades a plethora of studies on heat shock proteins would be published. It turned out that these proteins are present in all studied organisms, including bacteria, yeast, humans and plants! Heat shock proteins are crucial for maintaining cellular homeostasis under stress but are also important under normal conditions by acting as molecular chaperones; they help other proteins – their clients − to fold correctly. Moreover, heat shock proteins play a role in diseases such as cancer and they have turned out to be a promising therapeutic target. Hence, many researchers have dedicated and are still dedicating their research to these versatile molecules. 

The concept of evolvability through heat shock proteins was proposed! 

Susan Lindquist was one of those researchers. Her studies on heat shock proteins are intriguing and far-reaching; they cover basic science but also lead to new approaches in applied science. Here I want to highlight her publication together with Suzanne Rutherford in the high impact journal Nature in 1998. Every student of developmental or evolutionary biology has probably read about this study in one of their textbooks. It describes that under normal conditions, one of the heat shock proteins called Hsp90 buffers genetic polymorphisms in Drosophila; proteins can fold and function normally even though they carry mutations which would result in morphological changes without the support of Hsp90. Yet in stress situations heat shock proteins are recruited to ensure vital functions. As a consequence there are not enough heat shock proteins to buffer all mutations. This is important for evolution: under stress situations morphological variations can occur within a population which might or might not be advantageous for the survival of the organism. Beneficial mutations will be maintained due to positive selection. Therefore, Rutherford and Lindquist concluded that Hsp90 acts as a capacitor for morphological evolution. The concept of evolvability through heat shock proteins was proposed! In further studies Susan Lindquist and others showed that this concept can also be applied to other species. One example of evolvability through heat shock proteins is the loss of eyes in the cavefish Astyanax mexicanus. It was assumed that the stressful transition from surface to cavefish led to an increased need for heat shock proteins, which uncovered genetic and as a consequence morphological variations – like variations in eye size. The fish population adapted to the cave and lost its eyes. 

 Surface fish (a, b) and cave fish (c, d) differ in many morphological traits, the most prominent being the loss of pigmentation and the loss of eyes in the cave forms. (Image reused with the kind permission from Copyright Clearance Center: Nature Communications.  The cavefish genome reveals candidate genes for eye loss . Suzanne E. McGaugh, Joshua B. Gross, Bronwen Aken, Maryline Blin, Richard Borowsky et al.,© Springer Nature 2014) 

Surface fish (a, b) and cave fish (c, d) differ in many morphological traits, the most prominent being the loss of pigmentation and the loss of eyes in the cave forms. (Image reused with the kind permission from Copyright Clearance Center: Nature Communications. The cavefish genome reveals candidate genes for eye loss. Suzanne E. McGaugh, Joshua B. Gross, Bronwen Aken, Maryline Blin, Richard Borowsky et al.,© Springer Nature 2014) 

Heatshock proteins do not only act as capacitors for genetic variations, but also as potentiators for cancer.

Ensuing studies revealed that heat shock proteins do not only act as capacitors for genetic variations, but also as potentiators for cancer. Tumour cells are usually under stress, and heat shock proteins help them to stay alive, since these proteins do not distinguish between a „good cell“ and a „bad cell“. In fact, HSP90 levels are increased in cancer cells; high HSP90 levels indicate a negative prognosis in breast cancer. This fact makes heat shock proteins a promising target in cancer therapy! 

I don’t know whether Ritossa had the slightest idea where his findings about the chromosomal puffing pattern in heat shocked flies would lead to. Looking back it is a story worth telling, since it emphasizes the impact of basic science and „simple“ model organisms. And I guess it is also a story about not getting discouraged if your research is not considered as worth doing it by some people. It might be appreciated by others! 

written by Petra Tauscher

 

References

[1] De Maio, A., M. G. Santoro, R. M. Tanguay and L. E. Hightower (2012). "Ferruccio Ritossa's scientific legacy 50 years after his discovery of the heat shock response: a new view of biology, a new society, and a new journal." Cell Stress Chaperones 17(2): 139-143. 

[2] Rohner, N., D. F. Jarosz, J. E. Kowalko, M. Yoshizawa, W. R. Jeffery, R. L. Borowsky, S. Lindquist and C. J. Tabin (2013). "Cryptic variation in morphological evolution: HSP90 as a capacitor for loss of eyes in cavefish." Science 342(6164): 1372-1375. 

[3] Rutherford, S. L. and S. Lindquist (1998). "Hsp90 as a capacitor for morphological evolution." Nature 396(6709): 336-342. 

[4] Schopf, F. H., M. M. Biebl and J. Buchner (2017). "The HSP90 chaperone machinery." Nat Rev Mol Cell Biol 18(6): 345-360.