Peter Walter (UCSF, HHMI) : Harnessing Serendipity


– In Conversation With Claudia Dreifus, New York Times.

 Peter Walter, a professor of biochemistry at the University of California, San Francisco, studies how proteins within cells communicate with one another. His contributions have been instrumental in shaping scientific understanding of how cells are organized and how they function.

While still a graduate student, Dr. Walter discovered the signal recognition particle, which guides proteins to their correct locations within cells. At U.C.S.F., his laboratory identified the inner workings of the unfolded protein response, which helps cells maintain properly configured proteins. Improperly folded proteins have been implicated in a variety of diseases, among them Alzheimer’s disease and cancer.

We spoke for two hours in February at his San Francisco home and more recently when he came to New York City to accept the Vilcek Prize, which honors the work of immigrant scientists and artists.

A condensed and edited version of the two conversations follows.

Q. Where did you grow up? Do I hear a Berliner accent?

A. Yes. I grew up in West Berlin during the Cold War years. My parents had a little chemists’ shop, which was like a second home to me. I think, in part, my scientific inclination was born in being around the fantastic materials there. That, and experimenting in the house.

It seemed natural for me to pick the chemistry track at university.

Unfortunately, the science instruction at the Free University of Berlin was, in the early 1970s, extremely proscribed. There was no room to discover the unknown, which to me is the essence of scientific inquiry. You were given protocols to follow. It was always clear what would happen at the end. You were graded on getting the expected outcome.

This did not engage me. What interested me more was something developing in America, a new field where people studied the chemistry of cells and how life worked. I tried to read all I could about this biochemistry. But I was hindered because most of the important papers were published in English.

So to improve my English, I did something audacious. I signed up as an exchange student at Vanderbilt University in Nashville.

What’s audacious about that?

Well, we Germans don’t tend to migrate — we stay pretty much in the place we come from. At 22, I’d never lived anywhere but Berlin. I told my mother I’d be back in nine months.

How did you like Nashville?

It was absolute culture shock — a very small town with a church on every corner. My host family, lovely people, believed that America had won the war in Vietnam.

The university, however — Vanderbilt was a revelation. At the laboratory of Professor Tom Harris, I was allowed to do real research. Here I was, this lowly exchange student, and I was given use of the most expensive equipment and complete freedom to design my own experiments.

At Vanderbilt, I began to appreciate something uniquely American: the possibility of personal reinvention.

And so, when one of the Vanderbilt trustees suggested I apply for my doctoral studies to Rockefeller University, where the students were free to design their own curriculum, I didn’t hesitate. And when I only made it to the Rockefeller wait list, I still hoped.

But then came some serendipitous luck: At the last moment, an accepted student opted for Harvard, and I was offered his place. So I told my mother that the nine months would be a little longer.

At Rockefeller, you ended up working in the laboratory of Gunter Blobel, who won the 1999 Nobel Prize in Medicine. What was he researching when you joined his group?

He was trying to understand how the protein machines inside the cells organized themselves, and how they knew where to go within the cells to perform their functions. Gunter’s idea was that, in nature, things don’t just happen. There’s a machinery inside the cell that’s important to its organization.

He proposed that the proteins had these chemical ZIP codes that directed them to their destinations. At the time, this was unproven, and many of Gunter’s rivals disparaged it.

I spent four years taking the process apart biochemically and discovered this signal recognition particle that directs the proteins to their correct location. This was an important step in proving the validity of Gunter’s ideas.

Few graduate students get to make such a significant discovery. Did the experience give you confidence?

I think it gave me the confidence to, in 1983, open my own lab shortly after graduate school. Once you realize you’re good at looking into the unknown, it no longer scares you. In my lab at the University of California, San Francisco, we took some of the research that Gunter pioneered further by studying the folded protein response of cells.

A cell is more than a bag of chemicals. It has a power plant, garbage disposal units, libraries, the genome, roads and traffic lanes. All the protein components produced have to fold up correctly within the cell. Proteins that are not properly folded can be toxic.

We discovered how cells determine if they have sufficient capacity to fold proteins into their appropriate three-dimensional shapes. Not having enough capacity to do this triggers the unfolded protein response.

Why is this important?

If cells can’t do it, they die. Thus, the unfolded protein response makes life-or-death decisions. It is connected to numerous human diseases like diabetes, neurodegeneration, cancer.

You had cancer six years ago. What did your time as a patient teach you about your lab work?

The treatment I got was pretty generic. It made me feel what an extreme dearth of knowledge we have about why cancer cells grow out of control and what we can do about it.

I am happy to say I’m disease free as I sit here. But I’ve had friends die because there was no treatment possible. So, we really need to understand what fundamentally goes wrong in these cells and how we can correct the defect. I think from that angle, yes, it gave my research a very strong new motivation.

Original Source : New York Times (NYT)

More Story : HHMI Bulletin

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Mysteries of misfolding: how does the prion protein misfold?

Image : NCBS News

Anusha Krishnan

Prions are strange, even by the standards of the biological world which regularly throws up bizarre creations. They are the agents that cause mad cow disease in cattle, scrapie in sheep, Creutzfeldt- Jakob disease (the equivalent of mad-cow in humans) and fatal familial insomnia. The term prion was coined from the words “protein” and “infection” to reflect its unique nature – an infectious protein, which does not require the all-important DNA or RNA molecules to copy and transmit biological information.

Prions are misfolded forms of regular cell proteins with a distinctive ability to convert their normally folded counterparts into more prions. If prions are deviant forms of normal proteins, sheer curiosity prompts one to ask – how are they formed? What causes these normal proteins to contort themselves into the prion form? Scientists Jogender Singh and Jayant Udgaonkar from the National Centre for Biological Sciences (NCBS, Bangalore) have a partial answer to this. Their work on the prion protein demonstrates that certain genetic mutations can destabilise the structure of the proteins and set it onto a “misfold path” leading to the aberrant 3-D conformation of a prion.

As with all proteins, prions are made of amino acids (the fundamental building blocks of proteins) that are chemically bonded to each other in a specific sequence. A simple analogy can liken them to beads of different sizes and shapes strung together. The ability to fold into a 3-dimensional structure such as a helix or a sheet depends on its constituent amino acids – much like how the physical and chemical attributes of the component beads allow the arrangement of such a string into a 3-D shape. Changing a single amino acid could drastically alter the folded form of a protein, just as changing a bead could affect the final form of a bead sculpture. Singh’s and Udgaonkar’s work shows that such single amino acid mutations in particular stretches of the normal protein sequence can spontaneously initiate misfolding into a prion.

The study utilised one of the first known prion proteins – simply dubbed “Prion Protein” or PrP – as a model to examine how naturally occurring amino acid mutations could disrupt normal protein structure to induce it to misfold. “We know that genetic or familial instances of prion diseases could be caused by single amino acid mutations in prion proteins. What we have tried to understand here is the mechanism of misfolding of the prion protein by studying the effects of familial mutations on the structure of the protein”, says Dr. Singh, the lead author in this investigation. The answer lies in a section of PrP named “α-helix 1” – a segment that is shaped like a helix. When this structure and an adjacent loop are destabilised due to pathogenic mutations, misfolding is facilitated in other parts of the prion protein, and the rates of PrP’s normal-to-prion conversion are increased. The instabilities cause the formation of flat sheet-like structures which further drive the transition of other helices within the protein into sheets.

“What is even more interesting is that none of the mutations we have studied are actually in the α-helix 1 region; but all of them destabilise this region”, says Dr. Singh. The results of this work also showed that the extent of misfolding in a mutant PrP was highly correlated with the extent of destabilisation in the α-helix 1 region wrought by the mutation.

The misfolded proteins now stick together to form spherical “oligomers”, whose subunits consist of the misfolded prions. The accumulation of such protein oligomers in nerve cells is the main cause of neuro-degenerative symptoms and ultimately, death, in patients with prion diseases. Research on other neurodegenerative disorders such as Parkinson’s and Alzheimer’s have noted a striking similarity between the toxic protein clumps (called amyloid plaques) within neurons found in these conditions and the prion oligomers in prion diseases. Therefore, these conditions are also increasingly being thought of as prion diseases or “prion phenomena”.

The research highlighted in this article elucidates the initiating steps of prion formation. This knowledge is of immense practical value as arresting these steps can stall the progress of prion formation and hence the disease it causes. Intriguingly, in another study Singh and colleagues showed that specific stabilization of the prion protein by mutation could completely inhibit its misfolding. Current therapies for prion diseases have taken the form of antibodies and other molecules that stabilise the helical structures in normal forms of potential prion proteins. These anti-prion drugs are highly potent in blocking further prion formation – they offer hope in not only surviving prion diseases, but may also prove therapeutic for Alzheimer’s or Parkinson’s.

About the study:

The paper appeared in the journal Angenwandte Chemie on 8th May 2015, and can be accessed here.

Original News : NCBS News