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Using Yeast to Understand Protein Folding Diseases: an Interview with Susan Lindquist

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Disease Models & Mechanisms 1, 17-19 (2008) doi:10.1242/dmm.000810 A MODEL FOR LIFE Using yeast to understand protein folding diseases: an interview with Susan Lindquist Susan Lindquist is a founding editor of DMM, whose pioneering work in yeast has advanced our understanding of protein folding in disease, including Parkinson’s, Huntington’s and prion diseases. Here, she discusses her personal approach to model organism research and scientific leadership. rotein shape is vital to its func- of. It’s not just regulated at the level of tran- tion. Pathological processes, such scription, which was the hot thing at the as neurodegeneration, stress tol- time; it’s regulated at the level of preferential erance and prion diseases, often translation, selective RNA turnover, selec- result from the misfolding of pro- tive removal of polyadenylation, and prefer- Pteins. Who could have imagined that re- ential transport of RNAs from the nucleus. search carried out in a unicellular organism, We uncovered a whole slew of regulatory such as yeast, would yield discoveries rele- mechanisms and found that they worked in vant to the treatment of complex human an incredibly orchestrated way. That was neurological diseases? Susan Lindquist great, but we didn’t know what the proteins DMM imagined that this simple eukaryote could were doing. At that point we needed to reveal plenty about protein folding and know what the proteins were doing and ge- pathology, and she was right. netics is a powerful tool for that. As soon as I heard about the new yeast What characteristics led you to focus on methods, I signed up for the Cold Spring yeast as a model organism? Harbor course on yeast. Gerry Fink [who de- the organism are just wonderful for experi- I leapt from working on Drosophila to veloped baker’s yeast as a model for studying mental manipulation. It can grow either as working on yeast literally the moment I the fundamental biology of all organisms and a haploid or a diploid, so you can cover or heard about the technique devised by Terri is a Professor of Genetics at MIT and a uncover the effects of mutations any time Orr-Weaver, Jack Szostak and Rod Rothstein. Member at the Whitehead Institute] was one you want. It is very easy and cheap to grow. They had figured out how to put a mutation of the teachers. I remember at the time the It has a small genome, so it wound up being into a piece of DNA and target it back into senior faculty didn’t spend much time advis- the first higher organism to have its genome the genome, replacing the gene in the chro- ing junior faculty. The only time someone sequenced. Another great thing about it is mosome with what you wanted [Orr- did stop by to give me advice was after that it actually does things in an amazing Weaver, T. L., Szostak, J. W. and Rothstein, R. hearing I was going to start working on yeast number of ways, just like human cells do. It J. Yeast transformation: a model system for – three years into my assistant professorship. is a simple, little organism but it has all of the Disease Models & Mechanisms the study of recombination (1981). Proc. He said: “that is ab- cellular compart- Natl. Acad. Sci. USA 78, 6354-6358] [using solutely crazy, don’t My idea is to use the right ments – the endo- yeast as a model organism]. I thought, “Wow! switch organisms, organism for the particular plasmic reticulum, a It is just absolutely fabulous.” don’t do something membrane-bounded We had been working on heat-shock pro- completely different question you are trying to get nucleus, vesicle traf- teins and using them as a system to study right in the middle of at and move around a lot ficking – as well as gene expression, asking ‘how does an or- the tenure clock.” But chromatin structure, ganism rapidly and completely change its I went ahead and decided to do it. (As a transcription factors, specific mechanisms pattern of gene expression in response to a woman, at that time, I hadn’t really thought for regulating the cell cycle, and many dif- specific stimulus?’ We did a lot of satisfying it was likely I would get tenure anyway. So I ferent types of signal transducers. All of these and interesting work at a time when very thought it was too good to pass up.) I’m so work in much the same way as they do in little was known about how organisms can glad I did. That capacity to go in and knock higher organisms. Bacteria do a lot of things control what proteins they will make. We out a gene using site directed mutagenesis quite differently. Don’t get me wrong, bac- found that the expression of heat-shock pro- was just a transforming thing in terms of ex- teria are great to work with, too. They grow teins is regulated at every level you can think perimental elegance. Since then, and indeed even faster! And for studying many truly fun- before then too, many things were done to damental problems in biology they are ter- Susan Lindquist is a Professor at the Massachusetts make the [yeast] organism more manipulat- rific. But there are many layers of biology, Institute of Technology and Whitehead Institute of able. It all started with brewers wanting to and particularly many problems related to Biomedical Research, and an investigator in the Howard Hughes Medical Institute. make better beer about a hundred years ago. specific human disease mechanisms, that (e-mail: [email protected]) But it continued because certain aspects of cannot be studied in bacteria. But in yeast, Disease Models & Mechanisms 17 A MODEL FOR LIFE Susan Lindquist protein trafficking – in and out of the homologues. We send [our collaborators] test different combinations of therapeutic nucleus, through the secretory pathway, into expression clones or viruses, which are then strategies initially derived from genetic organelles – the control of growth and divi- cloned into these other systems. [This analysis in yeast, nematodes and rat neurons. sion, responses to diverse stimuli, mito- process] has validated the effects of some of These are the big scheme things that I chondrial respiration, all this is very similar. our genes on toxicity due to α-synuclein. So would like to do and they are enabled by the There are obviously many differences I think this is really exciting – that’s one fact that this pluripotency technology [the between humans and yeast. It goes without billion years of conservation for a basic cell ability to manipulate cells into discrete saying: a yeast cell is not a neuron. But you biological process. mature lineages] has come about. It lets us can study much of basic eukaryotic cell make a wide leap. New imaging techniques biology in yeast. For example, we are study- How do you think recent technical ad- are also fabulous. We have not yet been on ing neurodegenerative diseases. Why would vances, for example genomics, will influ- the forefront of imaging, but I’d like to get anyone think to study a neurodegenerative ence the future model organisms? there. One of my postdocs is attempting disease in yeast? Many of the problems in Technologies are incredibly enabling. some amazing things in collaboration with these diseases derive from problems in Certainly the genome sequencing that has Matt Lang’s group here at MIT. protein folding and trafficking and that is been done has opened up many more or- Another thing that is terrific is the entry largely the same in yeast as it is in neurons. ganisms to study, it’s absolutely tremen- of different types of people into this field. To the extent that the problems are the same dously empowering. Invertebrates, verte- The physicists have brought in all kinds of [between yeast and other organisms] it is brates, and other fungi become powerful interesting ideas in terms of technologies. really great to be able to study it in yeast and you get access to doing things with Engineers too – tissue engineering and mi- because they are so fast to work with and pathogens that were [previously] very diffi- crofabrication – so that you can study because a host of very clever people have cult. I think now we need to develop other processes in parallel in large numbers much created such amazing tools to work with tools to work with these organisms. There more rapidly. Thinking about the circuitry DMM them. We’ve then been able to move from are many things that you might want to of the cell, engineers bring a whole different yeast into neurons largely through the help study in another organism. For example, [let perspective to it. It’s a phenomenal time for of collaborators, who have been wonderful. us take] a pathogenic organism. We have biology right now and it’s such a shame that It is great having a group of people to inter- been doing some looking at Plasmodium we – and by this I mean the entire scientific act with who have expertise in very different falciparum, one of the organisms that causes community – are so pinched in terms of areas. malaria. It’s very difficult to manipulate ge- funding. netically. It’s hard to grow [and] it has a very How do you approach the great distance complicated life cycle. But there are certain If you were to begin a completely new between a yeast cell and a mammal? aspects of the biology of P. falciparum that project, what would it be? The major way we’ve done it is with collab- one might be able to study by transposing its I would want to tackle the malaria problem orators.
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