A Prion Love Story | Hacker News Reader

A Prion Love Story

newyorker.com

145 pointsirollboozers12 comments

My PhD is focussing on addressing fundamental questions in how prions behave like they do.

Often in medicine edge cases provide insight into a more general mechanism or process (e.g. Li Fraumeni and p53/cancer, retinoblastoma and Rb). Part of my work is considering the idea that prion diseases may be very pure examples of a more general process observed in a huge range of neurological diseases, from ALS to Alzheimers to Huntington's to Parkinsons.

While there is some fantastic work going on at the clinical/in vitro side, I hope that a more general understanding of the physical processes governing phenotype will help provide a broader class of treatments.

WRT Eric and Sonia's passion for the research - I've done research in a range of areas, and I've never found a puzzle as fascinating and as engaging as this. I keeps me up at night. I go through flashes of theories and ideas that I have notebooks full with possible hypotheses and associated experiments. The putative overlap in related and unrelated areas of research, from oxidative damage to epigenetic regulation to arguments relating to 3D diffusion within the cellular environment, is extensive and both a source of inspiration and trepidation. Basically, I can entirely relate to that constant feeling of engagement and interest. My work has accidentally become my hobby, and it's awesome.

I hate to be a negative nancy, but for most of these diseases I'm not convinced the answers are in the biophysical properties of amyloids. I still hold out that biophysics might hold answers for the PrP diseases - mad cow; kuru; FFI, the subject of the OP - but for most of these other conditions (alzheimer's, diabetes, Gelsolin Amyloidosis - not parkinsons, which is, contrary to common grantwriting trends, is not an amyloid), I'm increasingly convinced that amyloid is not, in the general case, causal, because amyloid is a general protein fold. There's amyloids that are not cell-malfunction-related and probably functional (in melanosomes[0], secretory granules[1], and which bacteria use to grow their extracellular matrices[2]), there's amyloids that aren't toxic except for causing physical disruption (beta-2 microglobulin blocks kidney nephrofunction), and there's amyloids which are just garbage binned proteins (bacterial inclusion bodies[3]). Probably in the ur-times, early proteins, which were likely overwhelmingly hydrophobic[4] aggregated as amyloids as an easy, thermodynamically favorable, self-assembling superstructure, that is regulateable merely by producing to concentrations above the critical concentration.

[0] Fowler, et al, PLOSBio 2005, the data are terrible - long story, but I basically redid the experiments and got cleaner, sensical results - but the conclusion is probably true. [1] Maji, et al, Science 2009 [2] Cherny, et al, JMB 2005 [3] Wang, et al, PLOSBio 2008 [4] Mannige, et al, PLOSCompBio 2012

I have more detailed reasons to believe the things that I do, if you'd like to hear more, feel free to contact me. I especially have some interesting tips on where to look with PrP (I did a short, unpublished project on it that was inconclusive, but the ideas are intriguing). Long story short, if you are dead set on being a biophysicist, and you want to really make a difference, focus on the PrP diseases, the other ones are, in my highly opinionated opinion, red herrings. Otherwise, focus on the biology. Also, learn your chemistry well, in either case. Good luck with your PhD. It's a minefield out there.

Physician here, great article.

Let me say that on the spectrum of diseases if I rank them from weak to strong in terms of our ability to defeat them:

Bacteria - Virus - Prion

We are so far from being able to treat prion diseases, it is an entirely different order of magnitude of difficulty than our ability to treat viruses.

Where do fungi and parasites fall on that spectrum?

For the most part before bacteria.

What's really cool is that the two people got funding for their research on Microryza, a YC company: https://www.microryza.com/projects/can-anle138b-delay-the-on...

these diseases are terrifying, I used to work on the biophysics of diabetes, which has similar properties at the molecular level - and in our lab we had people working on alzheimer's and prion biophysics... After a long time, I'm not sure we know enough to have glimpses of where to begin, besides the obvious (currently, non-solution of) gene therapy.

http://www.ted.com/talks/russell_foster_why_do_we_sleep.html

I hope they get a chance to speak at TED themselves.

With no intention of trivializing a genuinely inspiring story ...

   [Deckard picks up paper unicorn.]
   Gaff's voice:	It's too bad she won't live. But then again, who does?
   Deckard :	Gaff had been there, and let her live. Four years, he figured. 
   He was wrong. Tyrell had told me Rachael was special: no termination date.
   I didn't know how long we had together. Who does?

Hope in the face of utter uncertainty. Now that's fortitude!

For those who are interested and able, a link to donate: http://www.prionalliance.org/donate/

(I am not affiliated)

Inspiring. I wish them both the best of luck.

bookmarked for later read. One of my neighbors worked in Charlie Prusiner's lab as a postdoc (I lived a couple blocks from UCSF), and i remember being baffled by how she described her research and thinking I should do some remedial reading.

Reply on news.ycombinator.com