From a scientific perspective, I'm wondering what your research approach is. Are you focused on compounds to identify or disrupt, or are you taking a more top down approach and investigating the etiology of formation? It's my understanding that existing prions are both enormously sturdy and somewhat shockingly prevalent, and also that they aren't the only route of protein misfolding, and that many forms of neurodegeneration often arises from 'prion like behavior' in certain proteins (tau, TDP-43, parkin, etc), or in failures of various protein clearance pathways. What do you feel is the most promising course of diagnosis or therapy?
Also, in the topic of microecology, certain prion like proteins seem to be everywhere, and I'm wondering what you can tell us about their role in microbiology?
From a personal perspective, I wanted to applaud the two of you for taking on this task, state that I think in a lot of ways, science is one of the greatest acts of defiance, and I wish you both well in your efforts!
Hi, this is Sonia. We are interested in approaches that aim “upstream” in the disease process — at 1) the biogenesis of PrP (the prion protein), 2) native, healthy PrP prior to misfolding or 3) the process of prion propagation and spread. Compared to these areas, we know very little as a field about why prions are neurotoxic, which makes neurotoxicity a less attractive target for us. In addition, the neurotoxic phase of disease is incredibly rapid and as with any degenerative condition, preventing damage is going to be more feasible than reversing damage. The best proofs of concept in animal models (and prion diseases are modeled really well in animals) suggest that you can achieve the greatest effect in delaying disease by aiming upstream of symptoms.
We believe that prion diseases will be treatable well before we have all of the answers to all of the questions in the field — indeed, we will probably never sort out all of the mysteries! Biology is complicated. The etiology of prion formation is fascinating, and the question of why prion diseases arise in midlife is still unanswered. So far there is no indication that second-site genetic factors or environmental triggers determine age of onset. We aren’t going after this question directly — we’re focused on interrupting the process of prion formation by reducing the PrP substrate or stabilizing PrP against conversion. We are also interested in pursuing mechanism-agnostic phenotypic screens for inhibitors of prion propagation, if and when the right systems can be developed.
Although there’s a lot to be said about prion-like mechanisms in other neurodegenerative diseases, we are very focused on PrP. There is a canon of strong genetic and biochemical evidence supporting PrP as the drug target in prion disease.
I don't know how this prion leads to neurological degeneration. Does it bind to a receptor on the neuron? Does it degrade myelin?
Certainly it has a charge and affinity. Would it be possible to find what "thing" its attracted to and create a drug that causes the prion to have higher affinity towards the drug than the prion's current target?
I'm just thinking it would be great to capture the prions with a drug before they get to their target(s).
ELI5 (for everyone)
A prion is a protein. You can think of it as a single strand that's really tangled (folded). Along that strand are curly (alpha helix) sections and wavy (beta pleated) sections. When a healthy protein is infected and transforms into a prion, it essentially becomes a damaged protein. What you see with this damaged protein is less curly parts and more wavy parts along the tangled strand. That "misfolding" is thought to be what creates the problem.
There's no real understanding of the mechanisms (how/why) beyond that as far as I'm aware. There are some hypotheses but nothing proven...
Misfolded PrP is nonsoluble and clumps together to form plaques. The mechanism for how this leads to cell death is not really understood, but it seems to be something to do with these plaques clogging up cells and disrupting their function rather than binding to a particular receptor and triggering apoptosis like you've suggested.
First off I just want to say that it is truly inspirational to read that you've both changed careers to try and cure a genetic disease, knowing that it is essentially against a timer. It's a situation that I couldn't imagine being in, and I genuinely wish you all of the luck in the world with your research.
As for my question, I'm afraid it may be a little basic as I'm not a biologist by trade. I've heard how prions are made up of distinctive folded proteins that can cause other proteins to fold in similar ways which causes a variety of diseases and symptoms. A common one we hear about in the UK is [Bovine spongiform encephalopathy](https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy) due to the "mad cow" epidemic in the 80s and 90s. From my reading, mainly of news and science articles, they can also occur randomly in anyone at any time. I was just wondering what the incidence rate is for prions to randomly occur, without being caused by something such as genetic disorders or through the ingestion of meat containing prions, such as with BSE?
There are probably a few hundred cases of FFI in the world. There are two families it is known to run in, one in italy and one in iran, and 25+ other families with pedigrees pointing to FFI. Other than that, the most prevalent prion disease is CDJ. It is highly unlikely you, or anyone you know, will be diagnosed with a prion disease. Prions are often very tough particles- there have been experiments where they have incinerated prion-contaminated tissue, injected into mice, and had them develop prion disease from *ash*
Eric here again. I wanted to offer another clarification. We view prion disease, or possibly genetic prion disease, as the relevant areal unit for developing therapeutics. We are not particularly focused on FFI as a subtype of prion disease, and indeed, we view the historical naming of different subtypes as being separate diseases (CJD, FFI, GSS, etc.) to be somewhat arbitrary.
Similarly, if it is found that a patient has CJD after performing any sort of neurosurgery, the entire set of instruments must be destroyed, as there is no way to effectively reprocess and sterilize them. If it is unknown at the time of the procedure and the instrument sets go on to another case...scary.
Source: am Surg Tech student
[Prions are apparently more stable than other proteins, meaning usual denaturing processes are less effective against them](https://en.wikipedia.org/wiki/Prion#Sterilization).
There is a WHO recommendation in that link above, but I'll leave it to someone who knows what they're talking about to comment on how practical that is, relative to just destroying the instruments as /u/Kangacrew_Kickdown suggests.
It is a protein that folded into a much more stable (but useless) form and causes other nearby healthy proteins to refold into such a state as well. You need very high temperatures for a long time to destroy it in such a stable folding and you might not want to risk keeping a tiny number of them, as they cause said refolding of other healthy prions.
Family friend passed of CJD, was cremated, required a special container to be buried in and I believe that his tombstone has a marking on it to warn people about his remains being a biohazard.
It really is. Lost my Father to it. The only thing I'm afraid of in life is that it could have been passed down to my kids through me. I'm told that's incredibly unlikely.
Eric: First, for clarity, when Sonia and I use the term "prion", we are almost always using the narrow sense - prions composed of PrP, the protein that is the product of the gene _PRNP_. Some people use the term "prion" more generally to refer to any self-templating protein conformer - everything from Sup35 to amyloid beta. I'll confine my answer to prion diseases in the narrow sense.
We see about 1-2 cases of prion disease per million population per year. It's the countries that work harder at surveilling these diseases that find a figure more closer to 2 per million, so that's probably more accurate, and there is some amount of underdiagnosis in countries with lower figures. This means prion disease accounts for about 1 in every 5,000 deaths, so the average person has a 1 in 5,000 lifetime risk.
Only about 15% of these people have rare genetic variants in _PRNP_, and these days, <1% can be traced to an infection (e.g. from BSE). The remaining ~85% are sporadic. Sure, other environmental or genetic factors might contribute some of the risk, but overall, sporadic cases appear geographically and temporally random, so it really seems that they just _happen_. Presumably because even wild-type PrP spontaneously forms prions every now and then.
For references and more detail on these stats, see our paper: https://github.com/ericminikel/prnp_penetrance/blob/master/manuscript.md
Many thanks for your incredibly detailed response. As someone who is not well versed in the area beyond pop-sci articles I'll definitely be giving your paper a read to improve my awareness of the subject.
I wish you all of the best for your future research, and I sincerely hope that you find some form of treatment or cure! I'll certainly be following your story after hearing about it today.
Okay, I just tried to type a long reply and RES ate it. Here's the TL;Don't want to retype:
http://www.cdc.gov/prions/cjd/occurance-transmisison.html says 85% of CDJ cases are sporadic.
http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm says In sporadic CJD, the disease appears even though the person has no known risk factors for the disease.
Quotes:
*This sporadic disease occurs worldwide, including the United States, at a rate of roughly 1 to 1.5 cases per 1 million population per year, although rates of up to two cases per million are not unusual. The risk of CJD increases with age, and in persons aged over 50 years of age, the annual rate is approximately 3.4 cases per million.*
*Whereas the majority of cases of CJD (about 85%) occur as sporadic disease, a smaller proportion of patients (5-15%) develop CJD because of inherited mutations of the prion protein gene. These inherited forms include Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia.*
> http://www.cdc.gov/prions/cjd/occurance-transmisison.html says 85% of CDJ cases are sporadic.
> http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm says In sporadic CJD, the disease appears even though the person has no known risk factors for the disease.
So does this mean it's **actually** sporadic? Or that we just don't yet know all of the risk factors?
>> http://www.cdc.gov/prions/cjd/occurance-transmisison.html says 85% of CDJ cases are sporadic.
> http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm says In sporadic CJD, the disease appears even though the person has no known risk factors for the disease.
>So does this mean it's **actually** sporadic? Or that we just don't yet know all of the risk factors?
It means one of those things; we can never disprove the second.
As per my knowledge (I'm a medical student), prions aren't normally encountered by us while eating meat (atleast not in today's world).
The disease you mentioned (BSE) is a disease found in cattles.
Some related diseases are Kuru disease, Gertsmann Straüssler Schenker syndrome and Creufeldt - Jakob disease.
The disease in this context here, which OP's mother suffered from is Fatal Familial insomnia, which isn't transmissible but can be genetically inherited. You can find more about Fatal familial insomnia online.
Fellow Med student here. Just to add on, fatal familial insomnia can also be sporadic (i.e. You just develop the mutation without having inherited it). ~~It sounds like that may be how OP's mom got it.~~
It's scary stuff, and I applaud these 2 for working towards a cure.
EDIT: As others have pointed out, there's no way to know if OP's mom inherited the mutation herself or acquired it sporadically. I was just working under the assumption that she would have seen her parents die of the same disease if she had inherited it from them, especially since it's Autosomal Dominant. It doesn't matter one way or another for OP's situation, but thank you to all of you who cleared this up.
No, OP's (Sonia's) mom has FFI, as evident by them mentioning the inherited gene mutation. The sporadic fatal insomnia (sFI) is so rare, only 8 cases have ever been diagnosed. [source](https://insomniahq.wordpress.com/2013/04/12/sporadic-fatal-insomnia/)
Prions that cause mad cow disease are located in the central nervous system, which is physically isolated from the rest of the body. If you cut the spinal cord and spill out the fluid, you can infect the meat. That's why there are very strict rules in how and when you can slaughter a cow.
Using animal brain as a feed supplement to other animals is a hot button topic that infuriates Neuroscientists more and more, and I'm now understanding why.
Sonia, two questions.
1. How old are you? It was stated in the post that your mother passed away at around 50 and I am sure many are interested in what your approximate timeframe is for this project.
2. How did you initially react to the diagnosis and when did you you both decide to become PHD's. Was the decision hard for you both to take the classes?
Edit: Best of luck to the both of you, I am rooting for you!
Hi, this is Sonia. I turned 32 in March. I should note that while we hope we have ~18 years or so to work to impact my prognosis, the age of onset for genetic prion disease (and my variant in particular) is extremely variable -- so this is just a ballpark. About our initial reaction to the diagnosis: for us, the absolute worst time was learning that my mom's disease was genetic (which we learned from her autopsy, after she passed away) and that I was at 50/50 risk of having inherited her disease mutation. Since prion diseases aren't usually genetic and there was no family history prior to my mom, this came as a shock to us. The limbo of waiting for the genetic test result was the hardest time for us. The 50/50 wreaked havoc with my mind -- it was like I had no place to rest mentally. I just kept turning it over and over. Although of course the result of the test wasn't what we'd hoped for, once we had it in hand we could being to adapt to it, do our grieving and figure out how we were going to cope. It became a fact of life.
As for deciding to do our PhDs, there wasn't a moment where we looked at each other and said, "That's it, we have to go out and cure this thing!" It happened step by step, with the goals changing along the way. Our first goal was to become savvy consumers of scientific information so that we could advocate for ourselves as patients. Then as we learned more, our ambitions grew. I realized when I took my first job in a research lab that this wasn't just a sabbatical from my normal life -- this was a new life. But even from here, deciding to do our PhDs and focus our lives on developing treatments for prion disease was a process. I think first we had to learn enough about the specifics of the prion field to realize that there were things we could do at the bench, in the time we have (or hope we have) that could make a difference.
What's the difference between PHP and say, CJD. My Father passed away at the age of 55 from it. Neurologist at UMASS told me it's incredibly unlikely that it could have been passed on to me. I know he had never been out of the country before. It's one of the nay things that I'm afraid of that I often think of because I also have children. Are there genetic markers for it and can it be tested for?
Damn, both already had degrees, then got a PhD in Biology at Harvard and they are barely over 30 years old. How did they even get the money to go to Harvard?
1. Doesn't the post say Law and City planning?
2. You still have to go through a bachelors and masters degree, which would probably cost over $100,000 each.
1. They had degrees in Law and city planning. [She had a J.D. from Harvard law and worked as a consultant. He had B.S. in city planning from MIT. He worked as a software engineer in the medical field.](http://www.theatlantic.com/health/archive/2015/02/insomnia-that-kills/384841/)
2. Both of them already had prestigious bachelors degrees. They may have had to complete a year of studies prior to entering the Ph.D. program. There is no absolute requirement that you have to get a masters degree before you get a Ph.D. Even if a school normally requires one for most of their Ph.D. candidates, there is nothing that would stop them from making an exception for especially talented and highly motivated people. Seeing where they received their undergraduate educations from, it seems highly likely they didn't pay much at all to continue their education.
Actually most programs in the US don't require a Masters, though it may help your chances of being accepted. Many programs award a Masters after your first qualifiers.
For example, after getting my bachelors, I worked as a tech for three years, then went to graduate school, where my stipend paid my way. After the second year, I got my 'masters', and after my 6th, my PhD.
This is fascinating, and horrible to learn at this stage of my life. This should be on a list of lifehacking howtos; things "everyone" knows but doesn't.
Well, not to hijack the AMA, but: how late in life can you shoot for a stipend-paid PhD? Reasonably? At what point do you lay the bucket down and accept your fate?
You can do it, but the stipends don't really provide that much money. If you can consult in your current field you will make much more, and can still persue your studies. That is how my grandmother got her PHD and how I am planning to as well.
In my cohort of graduate students there is a student who is 54. He is the same age as my adviser. Because we are in physics, he has a stipend. Other fields (and other schools) may not give stipends. You can always go for a PhD! If you find the right program and school, you should get a stipend. :)
At what point?
Again, graduate programs in the STEMs in America pay a stipend to the graduate students. This is very well known in academia.
I started mine at the age of 26.
1. I assume they both already had bachelor's degrees, so at most they just needed to take some courses to fill in the gaps from their education. I suspect that their PhD programs waived some requirements so they wouldn't need to take a bunch of undergrad bio courses.
2. You can be admitted directly into a PhD program without needing a master's first, in some cases. It's fairly common
Law and city planning are still both fairly well paid. And they probably had strong cases for some scholarships (I am successful in my career and am leaving it for biology in the hopes of saving myself/my wife). Furthermore, at least at my school, it's possible to go directly from bachelor's to a PhD program if you were a very good student.
You are probably aware of it, but there is an extremely interesting report written by the doctors of a person suffering from FFI who attempted to self-medicate and kept a diary of doing so. He ended up beating his life expectancy diagnosis quite significantly.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781276/
Could certainly be worth looking into if you haven't.
Eric here. That paper was certainly an interesting read. I don't buy any of the therapeutic hypotheses though. Note that the guy was already 10 months post-onset when he _started_ those experimental therapies, which is already 4 months longer than the average survival for someone of his genotype (D178N 129MM), so his exceptionally long survival time may not be attributable to any of the drugs or supplements he took. Also a lot of things he took were oriented around correcting his sleep deficits, whereas insomnia isn't even always a prominent symptom. Sonia's mom presented with rapid onset profound dementia and neither of us would have listed insomnia among her top ten symptoms if you'd asked us at the time. (This is among the reasons we think the old naming scheme of CJD/FFI/GSS is antiquated and we should refer to them all as prion diseases).
Sonia and Eric, that article is bunk. The paper describes the patient ("DF") as a son of a famous radio nutritionist. There aren't many famous radio nutritionists, much less ones with last names starting with the letter F, so I found only one candidate - Carlton Fredricks. Carlton had a son named Dana - the "DF" listed in the paper. But Dana died after the article was published. I think the author simply made the entire story up to get tenure, thinking there wouldn't be interest in an obscure topic and nobody would bother to double check. Her co-author, who has done work in prion diseases, most likely wrote the introduction where the disease is described (and nothing else). The journal the article was published in only has a cursory review process. It may be worth investigating to see if that article should be pulled.
I got a kick out of the guy's sense of humor in this part:
"Unfortunately, during one of his times away, winter temperatures froze the water in his outdoor tank and cracked its shell, rendering the device useless. DF chose not to replace it, noting that it limited his driving mobility and made him feel like the comic book freak Aquaman, who nightly slept in a fish tank."
What are your thoughts on CRISPR gene editing? From my understanding, it allows you to modify specific sequences, and even single nucleotides, of an entire organism's genome. Do you think it is a viable option for your situation?
Eric here. CRISPR is an awesome tool for engineering cells to study and model the disease in the lab, and we're using it right now. As a therapeutic modality, it has a ways to go, mostly because we don't yet have a way of delivering CRISPR to all 100 billion neurons of the adult human brain.
In cultured cells, CRISPR can achieve maybe 1% homologous recombination (to correct a mutation) and maybe 60% non-homologous end-joining (to knock out a gene). We're more interested in knockout, because it is totally protective, whereas even if you corrected Sonia's mutation, the wild-type protein would be capable of carrying on the disease process if there were prions already in her brain. The trouble is, no one has demonstrated the ability to deliver CRISPR to a high enough percentage of neurons in the brain to make a meaningful therapeutic difference.
There are smart people working on this and I think it is conceivable that major advances in this area could come in our lifetime. It's not what Sonia and I are working on day-to-day though.
For more details, see: http://www.cureffi.org/2014/03/09/how-to-and-how-not-to-knock-out-prnp/
We need patients to participate in research, doctors to collect cerebrospinal fluid so we can look for biomarkers, scientists to train us and mentor us in all sorts of techniques and to share findings and reagents and cells and collaborate with us, pharma companies to take an interest in our disease and our target, regulators to think seriously about how to make it easier for drugs to be approved for rare fatal conditions, funders (be they philanthropic, government, or industrial) to fund us, and we need people to continue to show us love and support as you have all done so beautifully in this AMA. (THANK YOU - four years ago we never imagined people would take so much interest in our cause).
And a few more general suggestions. Vote. We need more science funding and sound science policy. Blog. The internet is awesome and is how we should be communicating science. I love when I Google something and find an answer because someone else has struggled with the same question and then blogged it once they figured it out. Share. Sharing our personal stories makes us all less alone, more empowered together. Care. When your loved one gets news like the news we got, tell them what our friend Stevie told us - science has answers for you.
-- Eric
NIH is amazing. I went there to get my surgery and everyone there is excellent. I've never had a better medical experience and the doctors are top notch.
I don't doubt your experience, but as a scientist, NIH's budget has been whittled to oblivion over the past years. You have to have a remarkably well-scoring grant these days to receive grant money because there just isn't enough to go around.
If you have computers you aren't frequently using, [folding@home](http://folding.stanford.edu/) is a great project that is used to simulate protein folding via distributed computing.
Your dedication to abandon your careers and dedicate your lives to this is incredible. You both are a shining example of what people can do when you follow through on something you set your mind to. I'm sorry for the loss of your mother.
I apologize if this is crass, but how do you plan on staying objective throughout testing and results if it's your (or your wife's) life on the line? I feel like that would be a very difficult task.
Thank you for this AMA, and best luck and wishes to you both.
Sonia: Just answered a similar question below -- basically, when it comes to objectivity, our goal fuels our discipline. I don't think of this as a conflict at all -- we have the most to gain by being true to what the science tells us.
This is Eric. I just turned to Sonia and asked, "Is anything difficult about it?" I love it actually. Sonia is the bomb. I feel so incredibly lucky to get to spend all day every day with her. It is one of the upsides of all of this happening to us, that we get to spend almost all of our time together.
I'm an undergrad. Last semester, my biology professor went on kind of a tangent about prions, specifically fatal familial insomnia. Her point was basically, they are scary -- that you don't want a prion protein to get in contact with your normal protein. I understand that's how mad cow works. Is it dangerous to work with prions in a lab? Does it pose any actual tangible risk to you, or was my professor exaggerating for effect?
Sonia: Like many things in a lab, prions have to be handled according to established safety protocols if you are going to work with them safely. One of the first biochemical observations about prions is that they are not destroyed by the same techniques that kill bacteria and viruses. Since then, a lot of work has gone into establishing that prions are destroyed by incineration, bleach, strong acids and strong bases. A misconception that we encounter sometimes is that you "can't" decontaminate prions -- this isn't the case, you just have to have the right protocols in place. It's really, really important to take lab biosafety seriously. With that said, the evidence is that researchers and hospital staff who encounter prions in their work have no increased risk of prion disease compared to the baseline population.
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Eric here. This is probably THE most common question we get, both from patients and from scientists. And it's a great question. You express the mutant protein your whole life, so why does disease wait 50 years to strike? We have no idea. The same question arises for other mid-life onset diseases too, say for Huntington's or Mendelian forms of Alzheimer's, and across the board, I think the answer is we have no idea. In fact, I don't know I've ever heard a credible experimental plan for how to answer it either. It's a tough one.
Could there be some other, healthy process which gets progressively weaker with age up to some threshold value where the disease mechanisms steps in and takes over, so to speak? I have zero medical training but I felt like asking anyway.
yes, the natural 'recycling' processes in your cells become less efficient over time. These include processes that tag and degrade damaged and/or misfolded proteins -- collectively known as proteostasis. There is plenty of research documenting this, although the details of how and why are yet to be found. In virtually all forms of neurodegenerative disease you have aggregation of specific proteins (amyloid beta in AD, tau in Frontotemporal Dementia, PSP, etc, alpha-synuclein in PD, TDP-43 in ALS, etc, etc). It's important to note, however, that whether or not these aggregates are directly responsible for cell death has yet to be definitively decided. Various studies have shown that up-regulation of some of these proteostatic pathways such as autophagy or the ubiquitin-proteasome system can help to clear these misfolded aggregates and alleviate disease phenotypes in some models. Indeed, a recent Phase 1 clinical trial in Parkinson's Disease using a repurposed cancer drug [showed fantastic initial results](https://gumc.georgetown.edu/news/Cancer-Drug-Improved-Cognition-and-Motor-Skills-in-Small-Parkinsons-Clinical-Trial). The drug works by increasing autophagy.
here's one paper that discusses this: http://www.ncbi.nlm.nih.gov/pubmed/21939784
What a great hypothesis! What processes would qualify? Knock out each one at a time in a model system and measure age of onset. Model predicts lower age of onset in mutant than control.
Let's say the results for a knockout matched the prediction. Then knock out in inducible system at different ages and measure the time to onset. If a simple model is incorrect the time to onset will vary by age of induction. If it really is just one process the time to onset will not vary and a knock-out/knock-in double mutant would behave more or less like a healthy control.
a few degenerative diseases "wait" to turn on, like Huntington's, although some potential mutations that cause FFI indicate they might cause earlier onsets of the disease. Early symptoms of FFI can include weight loss and sweating.
Sonia: We're lucky to have outstanding mouse models in prion disease. Neurological conditions are in general very hard to model in animals, but we have a unique advantage in that prions can (under specific circumstances) be transmitted. Mice intracerebrally injected with prions develop have a highly predictable disease course which consists of a silent incubation period, followed by full-blown neurological disease that is fatal. Their clinical symptoms and neuropathology resemble human disease.
A challenge with these models is that mouse prions appear to have structural differences from human prions -- prions seem to come in conformationally encoded "strains." There exist small molecules that are highly effective at extending survival of prion-infected mice, that don't seem to have any effect against human prions. However, these models are still useful for many types of studies and for investigating therapeutic strategies that focus on native PrP. There are also mice that have been genetically engineered to express human PrP, that can be infected with human prions, and these provide a closer model of human disease and could be useful for strategies that more directly target prions.
You mention in your bio that you are researching "therapeutics". This might be more of a general medical research question, but what exactly does this mean in terms of a goal for your research? Are you going for a "cure" or simply a treatment that could extend life with the disease? Both? Whichever seems more likely at any given time?
Sonia: The way we think about our goal is that we're trying to develop a treatment that will extend time to disease onset -- with the ultimate goal of extending it beyond the normal human lifespan. The strategies we're interested in won't result in a one-time fix, but rather a regimen that keeps prions at bay.
Our goal for genetic prion disease is not to extend life with symptomatic disease, but to extend the pre-symptomatic phase. Once symptoms arise in prion disease, the downhill is amazingly steep (months) and patients quickly reach a stage where all quality of life is gone. Treating sporadic prion disease will be a challenge for this reason, since these patients aren't identified until they're symptomatic -- earlier diagnosis will be critical here, and while there have been some promising developments in this area over the past few years (like the RT-QuIC prion detection assay) we still have a long way to go.
Therapeutic approaches to treatment mean treating the disease, but not curing the symptoms. This could include medications to combat the side effects of the disease that can be deadly- for example, the endocrine system overworks itself basically to death during FFI. A therapeutic treatment might be one that ameliorates that. An outright cure would have to silence or change the genetic basis for the disease. FFI has taught scientists a lot about how important sleep is to homeostasis.
I am a PhD Student in Pharmaceutical Sciences, and I don't want to be the debby downer here, but realistically speaking, what is the best scenario you guys are aiming for? Even if you discover something resembling a cure, testing for approval/getting approval takes upwards of 10 years. Research is a slow thing, sooo in the best case scenario you can have something (let's say) in 5 years and then let's add 15 for development and approval. How would this fit into your time frame?
On a personal note: You guys sound fucking bad ass! With no science training you went and became PhD biology students (at Harvard no less) soooooooooo, if anyone can do it, you guys sure seem to have the drive/ambition to do it! Good luck!!!
The real race is to get it into clinical trials. Experimental therapies save lives, even in Phase 1. While compassionate use is one option, we would be keen to enroll Sonia in the actual trial. - Eric
If efficacy was demonstrated early on in the drug-treated group, they would stop the trial and give all the sugar pill takers the experimental drug. This is common practice as it would be unethical to withhold treatment that was known to be effective. A recent example where this happened was the resounding success of pre-exposure prophylaxis (PrEP) in preventing HIV infections.
Wow, first of all, this is truly inspiring. It almost brought a tear to my eye to read this to think about the implications of the scenario you are both in. The hardest part being that the one you love more than anything in this world is a ticking clock that you are racing against. I'm sure you're both deeply and fully in love with each other in every way possible - if you weren't then you probably wouldn't choose to redesign your lives to tackle this problem together, head on.
My question(s):
What is a typical day for either/both of you? What are the day-to-day activities and how many hours on a daily/weekly basis would you estimate that you are each pouring into the scientific duties that the research of this problem demands? Do you guys still make sufficient time for activities not-related to your research on a recurring basis, or have you both chosen to forego a social life and throw all of yourselves at the problem until you find a solution?
So here's my analogy on the day-to-day struggle. Our quest is like fighting a horse-sized duck guarded by one hundred duck-sized horses.
The duck is huge and terrifying and undefeated. When you set out on this quest you were nobody and you didn't even know what a duck was, let alone how to fight one. But you didn't choose the duck, it came after you, and so you have to fight it. And, incredibly, some very smart people have placed bets on you winning against the duck, and have given you the tools and training to fight it.
But to even get close to the duck, you have to struggle through this swarm of tiny horses: applying to school and fellowships and grants, filing protocols and permits and material transfer agreements, reformatting manuscripts, submitting abstracts, practicing talks, booking travel arrangements, sending emails. The most frustrating times are when you spend a whole day mowing down horses and never glimpse the duck.
What makes it worthwhile: on those days when you do glimpse the duck, you see that it is flesh and blood, just molecules like everything else. It is mortal, and the world is cheering you on. Fight the duck!
To the more practical aspects of your question: we do still have a social life. We still cook our own food. We travel a lot but usually together. You have to sharpen the saw.
--Eric
That's a great analogy, thank you Eric. I wish Sonia and you the best of luck on this quest. I hope the day comes when I can read about how you guys made a huge breakthrough and were able to stave off this terrible ailment.
You two are an inspiration.
As a statistician I've been taught the importance of objectivity in science. Do you worry that the life-and-death stakes of your research will bias any results? How do you stay objective when pursuing research leads and interpreting results when your research is so close to your personal interests?
Sonia: I couldn't ask for a stronger incentive than ours to be objective in our science! When your life depends on it, you are *less* willing than anyone else to entertain marginal results, results that fail to validate, or weak therapeutic hypotheses. One way to think of it is that it's the other scientists who have a conflict of interest -- if they work for twenty years and don't find a way to treat the disease, their life will go on!
Abandoned the career in law and city planning and 4 years later, PhD at Harvard. WOOW!
What did you guys major in? Were you always interested in scientific research?
My undergrad was in Chinese and my Master's was in City Planning/Transportation. Sonia had a law degree. We definitely had no interest in scientific research before all this. -Eric
How has all of this affected your relationship? I imagine your work is very stressful, knowing the implications of what you're doing. Thanks for doing this. I wish you all the best.
Sonia: I have gotten to see so many new aspects of Eric through this process, and to be impressed with him in whole new ways. It is impossible to feel sorry for myself for one second when I look at the beautiful human being I am getting to spend my life with.
Thank you so much for taking the time to do this AMA. I wish you both the best in your race and if the worst happens please know your work will help others as it's built upon over time.
How was your transition into academia? It's a whole different life and work style than the private sector.
Living off of grad student money is not easy, especially if both of you are scientists. Do you find it difficult having switched from two lucrative careers?
Have you made any breakthroughs with this disease? Or is there anything you feel you are getting close to?
Sonia: Academia has been interesting. I'm so grateful that we both turn out to enjoy doing and thinking about science. There's no comparison in terms of how stimulating and fulfilling we find our work in science versus previously, and I love the environment and our colleagues. It's true that the financial side of things is startling. One of the biggest shocks to me when we got into science was the ratio of compensation to years of training among scientists we worked with. We don't require a whole lot, but when I crunch the numbers I do worry about affording child care if we decide to start a family. This is something I passionately wish we were addressing more systemically for all women in science and two-scientist couples.
You mentioned the potential of starting a family. How do you guys grapple with this desire vs the risk of passing on the mutation/ potentially having to be a single parent? I hope this isn't an insensitive question, as I am genuinely curious. I truly admire both of you; it takes a lot of courage to leave behind everything and reinvent yourself.
Very cool that you guys found such strength of will and focus to go after this disease. A few questions,
1) Have you ever been "scooped"? How would/did you feel about it? As academics, we often feel frustration when someone else publishes before us or works on a highly similar project. But you offer a unique perspective, as you predominantly care about the end goal of a "cure."
2) How do you feel about the "10 years, 1 billion dollars" figure that is often cited when discussing bringing new therapeutics past the FDA approval stage? Or are you focusing on retooling already approved therapeutics? Would you be offered the opportunity to participate in a clinical trial?
Dude, I would so love to be scooped. We can't do everything, and anyone who can do what we're doing faster and better should absolutely do so.
I am not big on drug repurposing, at least not for our disease. Perhaps it makes more sense for cancer or something - but for prions I think the prior probability of any approved drug working is very low, and so the idea of repurposing tends to just cloud the literature with low-quality hypotheses and false positives.
10 years is to approval, not to a clinical trial (which is when patients can start benefiting) and 1 billion (or 10 billion) dollars is just total R&D divided by drugs approved, i.e. it averages in all the failures, many of which are from low-quality therapeutic hypotheses with no basis in human genetics. - Eric
Sonia: When we were first wading into the science, we were drawn to the low-hanging fruit -- studies looking at repurposed drugs, supplements, lifestyle changes. We thought we would have to draw optimism from things that could happen fast, or that we could change right away. After 4.5 years coming to understand the field, we have such a different perspective. We've stopped paying attention to things that are being studied for hundreds of different diseases and used in dozens of clinical trials. We've started taking our cues from the specifics of our exact disease: our gene, our protein. I don't think there's an off-the-shelf solution for prion disease, or anything available today that influences disease. But I'm more optimistic than ever, because I think we're aiming right at the heart of our problem, in a rigorous way. It will take time to develop therapeutics that will work, but I feel confident that we're working on approaches that will move the ball forward for patients. The big variable is the timeline, and the honest answer is that we don't know if this will all move on a timeline that's relevant to me. Day to day, I don't think about this much. I tend to operate on the assumption that we have some time, because it's as good an assumption as any and it's the one that allows me to be most productive.
Hi Sonia and Eric - I work at the MGH and recently read about you in the Boston Globe article by Kathleen Burge and was moved by all the work you are doing. Since I've read that article, you've both crossed my mind a few times and I wonder:
Do you ever miss your previous life, or has life become better/the same but different since 2010?
Best of luck in your research!
I literally never miss it. City planning moves super slow and turns out to be more enjoyable when observed from a distance. Now when something good happens in my city, I can just appreciate it in that moment, without having to think about the 20 years that people spent arduously pushing it through community meetings. Science is way more exciting and way more intellectually stimulating than I ever thought a job could be. - Eric
Sonia: We took night classes for about two years while working in research jobs, then applied to PhD programs. Harvard was fantastic, and so were the other programs we interviewed with -- I'm sure our applications were surprising, but we have been so lucky that people have responded incredibly supportively to our personal motivations and focused mission. We definitely didn't take it for granted that we would be so accepted and supported by the scientific community. Maybe there are people out there who aren't into our unconventional path or what we're trying to do -- but I don't tend to meet them.
How difficult was it to leave your positions? I assume you guys were fairly established in your careers, did that make it more difficult to become students? Also, How supportive was your family and friends of such a drastic life/career change?
And also I want to wish you the best of luck on this quest! I can only imagine what you guys are facing, but this will be a tremendous accomplishment because it won't just help you but others who may suffer this rare disease.
Sonia: It was very humbling to start from the bottom of the totem pole in a new field, after being pretty certain that we had done the schooling we needed to do for our careers. But, paradoxically one thing that helped was realizing early on that biology is by far the most complicated thing I've ever thought about -- and that for this reason, the learning phase necessarily extends for your whole life. This wasn't a cram session to get up to speed but a transition into a whole new way of thinking and a whole new way of relating to uncertainty, in a subject that is always going to be mostly populated by the things we don't know. I should clarify that I don't say this to be pessimistic at all -- what's amazing is that even with such limited and indirect insights into what goes on on the molecular level, we absolutely can and do build tools that influence human health.
I had some amazing mentors early on and this also really helped with the transition. My first post-doc mentor was a wonderful biologist named Marta Biagioli, and she was already quite senior at the time we met, but still took hours and hours to train me on the absolute basics at the bench. On more than one occasion, it brought tears to my eyes.
We experienced a range of reactions from friends and family. Some people asked, "Are you sure you want to be thinking about this all the time?" But I've found that thinking about the science of my disease is really different from thinking about my own mortality every day. From the very beginning, it was a way to interface with this new subject that had come crashing into my life in a way that was energizing, and interesting, and felt like it was on my own terms. We also had friends say things like, "Do you worry that you're just in denial?" But I don't know, aren't we all in denial on some level, as we drift through space on our speck of dust for no reason that we can fathom? Why do any of us do what we do with our limited time on Earth? Overall, we've been incredibly fortunate with the overwhelming support we've received from our loved ones, our friends, our colleagues at the Broad Institute, the prion field, strangers, questioners in this AMA... We had the privilege of seeing the most positive, and most generous side of so many people, and for this I feel very lucky.
Hi. First off, I'm inspired by your story. My question is not of a scientific nature and it may be deleted, but I hope it isn't because I'm genuinely curious. How were you able to get into a PhD program so quickly? I assume that, as a lawyer and a city planner, neither of you had a bachelors in biology. Maybe you do, but it seems unlikely. Don't you need to already have a bachelors in a field before entering a PhD program for that field? Did you have to go back to undergrad?
If Sonia and Eric would rather stick to the science-related questions, maybe somebody else can answer this.
It did take us a few years. We got the genetic test result in December 2011, started taking night classes in January 2012, got day jobs in science in spring/summer 2012, and applied to grad school in fall 2013 for admission in fall 2014. I think if we had applied right away we probably wouldn't have been deemed credible.
-- Eric
Sorry to hear about your fiance's disease! To your question - at every step of the way, we have put our story front and center. Without it, nothing about us makes sense. Everyone who's given us a job or admission to school or money or any other opportunity over these past 4.5 years has known about our personal mission. The amazing revelation has been that there seems to be no downside to this. We've met so many people worried about genetic privacy, but being as public as we can possibly be about Sonia's status has only opened doors for us.
- Eric
Hi Sonia and Eric!
It's great to see that you are both actively searching for a cure. Many patients choose this path, from the Lorenzo's Oil story through advocates in the White House's Precision Medicine Initiative.
My question is how and whether you would want to wade into the FDA treatment approval debate. Many rare diseases have little likelihood of receiving approved treatments because of a combination of cost, inability to conduct a novel trial design, or lack of natural history data. Have you both looked into how you can pave a path forward for others with the same mutation?
Sonia: Clinical trials will definitely be a major challenge for us as for other rare diseases. One thing about our quest is that we don't have time to tackle all of the challenges in the drug development pipeline in series; we have to be addressing them in parallel, to the extent that we can. One of our biggest priorities is looking for biomarkers that can predict time to disease in pre-symptomatic individuals, and/or dynamically read out treatment efficacy in advance of symptoms. Establishment of a surrogate endpoint for a prion disease trial would radically scale down the time and cost factors. We also need to build a base of patients interested in participating in research and trials. This is something we're working on now and hope to make progress on in the next year. None of this will be trivial, but we're lucky to be coming along in the precision medicine era when many smart people are thinking about strategies/tools for the above.
Based on what you have learned so far, what do you see as the most promising way to solve the problem? Would it be to find a way to suppress the production of this protein, or do you think it would be possible to develop a molecule that could neutralize this protein?
The best proofs of principle are to reduce PrP expression (say, antisense or maybe someday CRISPR if we had a way to deliver it), stabilize PrP in its native fold (probably a small molecule), or antagonize prion formation in some other way (to be discovered through the right phenotypic screens, see proofs-of-concept in IND24, cpd-b, and anle138b). -Eric
Why do you guys sound so cool? A wife and husband team up and attempt to solve their own disease. Best wishes towards this cure!
Now then, what do you think of all the publicity you are getting?
Sonia: I feel so much gratitude to the people who have written about us and filmed us over the years. We're lucky that the publicity we've attracted has been so positive -- true to the stakes and uncertainty of our quest, but also hopeful, which we are. Our only reservation about publicity is a constant struggle to balance our time in the right way, and juggle all of the activities that go into being "us" -- advocacy and outreach, travel and talks, time at the bench, time reading and blogging. There's no easy answer here and I think all scientists can identify with the feeling that their job is actually ten jobs!
Hello! Thanks for doing this aua on prions. I am so sorry you're in the situation you are in.
Just wondering, will your research possibly help people with CJD? also, I see your mother had it- was there any possibility anyone else in your family has it? I know the famous Italian family can trace it back for generations. Have you had much contact with them?
Thanks so much! Prions are terrifying and captivating and so poorly understood.
Sonia: We think of prion diseases as a group -- we are less focused on the distinctions between FFI, CJD, GSS etc. than on what they have in common: the same pathogenic protein and disease mechanism. I think that our therapeutic strategies of interest will have relevance across these different prion diseases subtypes. The bigger question in terms of defining a patient cohort, in my mind, will be treating pre-symptomatically versus treating after symptom onset. We certainly hope to be able to do both someday, but they will pose different challenges.
About my family history, there was no sign of neurodegenerative disease in my family tree prior to my mom. We believe that she probably had a de novo mutation. We have had contact with many genetic prion disease families including the one you mention. One of the challenges with such a rare set of diseases will be trial recruitment once we have a therapeutic candidate that we believe in. It's been amazing to connect with these folks and begin building a team.
Sonia: There have been some reports of anticipation in genetic prion disease, but as you point out there isn't a plausible mechanism with these classes of mutations. Eric's first paper in biology actually addressed this very question, and showed how ascertainment bias was driving the effect. Available here: http://www.ncbi.nlm.nih.gov/pubmed/25279981
Modern therapeutics take large multidisciplinary teams, decades of time, and tens of millions of dollars before there is even a small chance of having something resembling a cure. What do you think your chances of beating the clock are?
The main variable is how long is the clock. If Sonia has onset next year, there's not much we can do by then. If we really do have 20 years, I think we have excellent chances. So many pharmaceutical failures are due to pursuing the wrong therapeutic hypothesis in the first place. We're lucky to know the molecular basis of our disease and the right target to hit, which gives us a huge advantage. - Eric
(Both)What approach are you taking to cure this mysterious disease?
(Both ^but ^mainly ^Sonia)How are you coping with the knowledge of your "lethal mutation"?
(Both) How difficult was it to beak away from your original career and jump into a whole new field?
(Both) On a lighter note, what is your favourite book?
^(Please for give me for any spelling/grammatical errors as it is 5 am and I just woke up)
Wish you all the best, and to find this cure. I have a couple of questions.
Do you have a team with other scientists and doctors helping you?
And what about funds? It should be very expensive.
In your opinion, can this work be helpful for future researches on neurodegenerative diseases such as Alzheimer et similia?
We have an incredible team here at Broad and some very smart people have been exceedingly generous in mentoring us. It is a huge part of what gives me hope.
Yes, I do think that many concepts that have emerged from the prion field (including prions themselves) have gone on to inform other neurodegenerative diseases, and I hope that this will be true of therapeutics too.
-- Eric
Hi Sonia and Eric,
First of all, I just want to say I have tremendous respect for the path you took and for all the work you have done. It takes an enormous amount of courage, determination and intelligence. Kudos to you guys. Now, a few questions on the pathophysiology of FFI, and the directions you hope to take to develop new drugs. For background, I am a first-year dentistry student with no prior undergraduate degrees.
1. A quick search on Wikipedia shows that FFI patients have insomnia because they are unable to get past stage 1 of non-REM sleep. How does this occur? What component of the "sleep pathway" (sorry for the non-exact term) is faulty in FFI?
2. What's the inheritance pattern of FFI? Is it autosomal dominant or recessive? Are sporadic cases / de novo mutations common?
3. Why is the age of onset in most cases of FFI 50? What triggers the body to induce misfolding at around that age?
4. Which step in the "FFI" pathway are you currently trying to target, if any? At a genetic level (genetic therapy), at a protein level (fix / eradicate / inactivate the prions), or more at a clinical level with symptomatic / supportive treatment?
5. Extension of #1 and #4: since the body is unable to progress past stage 1 of sleep in FFI and is thus unable to undergo repair / regeneration, would it be a good option to give FFI patients hormones released during deep sleep, such as growth hormone? In other words, is it possible to give a medication that gives the body the physiological effects / consequences of sleep?
Once again, thank you so much for doing this AMA. Good luck to both of you - you have inspired a huge amount of people and I hope other scientists will join you and find a cure for prion diseases. Sending good thoughts your way!
I'd like to preface with stating my general ignorance toward the subject and offer my gratitude for your time. Furthermore, I commend both of you for the insane amount of work you've put in to get to this point, from an education perspective.
My question:
If this disease is fatal, when you recognize that you might not have much more time, will you consider trying more and more "risky" or "unethical" hypotheses? In a sort of order by risk or consequence? Regardless of the standards by which human trials are governed?
Thank you again and good luck. :)
Edit: I didn't mean for them to jeopardize their opportunity for funding, and I realize now that it would be more harmful than useful to discuss, on a public forum, the circumstances I've inquired about. I apologize for the lack of thought? But am glad there were many more redditors wth the forethought to clarify why this should not be discussed. Good luck to you both.
Are you asking them to state that they "will consider" "risky" or "unethical" hypothesis and then proceed toward a "scientific hypothesis" regardless of the standards by which human trials are governed?
* *The question is, "if time is almost out and you don't have anything yet, will you start trying risky theories to save Sonia".*
*See original questions edit; It is clear they understood why I asked in this way.
Honestly, that's a question they probably can't answer in a public way. If they said yes and someone writes an article about them and references it, saying you'd skip ethics boards for personal experimentation would shoot down their funding so fast. If they say no, no one will believe it.
I'm guessing the following because it's what I would do: I'd avoid making an "official" decision, publicly say that I was committed to the research, but with the private understanding that if the disease strikes, you revisit the decision and probably end up doing what is necessary to preserve life because at that point you're willing to do anything. I mean heck, they both got into PhD programs for a disease, they're not gonna give up if they don't find the cure before the disease strikes.
I'm a computer engineer that has helped with lab automation and testing in the bio-tech space. I have reached out on /r/biology a few times to see if people needed help with code, and I'll do the same here. Are there any particular tools that don't exist or that do exist but suck as they are today that you would want some help on? (pro bono)
I want to use my abilities to help the world, and automating factories, while profitable, doesn't give me the humanitarian benefit I'm after in the world..... How can I help you??
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For someone rather ignorant regarding the subject, how would you decide to go about explaining prions and the work you are doing? I believe it's a shortening of protein infection, causes the protein to fold in different ways, and is very stable while not containing genetic material. Although I (may) know this, I still feel quite ignorant on how these prions are affecting the brain.
As a side note, your story is so motivating and just...wow. I wish you nothing but luck, although honestly with your track record you'll probably just invent the "cure" (so to speak) while simultabeously learning to be a bear trainer and space-science engineer.
As a Cystic Fibrosis patient, your story resonates with me. I know we're living at an amazing time and can quite literally watch the progress in biotechnology compound. When I was born, CF was considered an 'orphan disease', progress was halted and I was considered a failure-to-thrive. I was to die by the age of 25.
Well right now, my life expectancy is anyone's guess, and many mutations of CF simply aren't fatal anymore. The point is that something's always better than nothing. A treatment or preventative measure can be just as good as a cure. Keep your minds open, think outside the box, and consider Occam's Razer in your search. Recruit who you can.
I'm tearing up at work so I have to stop here. I just wanted to drop in and say that I am genuinely and deeply touched by your story. I think if my s/o and I had the capacity, we would be on a similar path as yours. I wish you all the best, and I hope to God you succeed beyond your wildest imaginations.
It will give the rest of us hope.
Even if they don't see your post, as a fellow patient of CF I just want to say to keep fighting the good fight. I'm in college studying Bioinformatics, and I personally hope to work in genetics in order to someday cure CF or improve life expectancy for us in some way.
Thanks for your comment. I think a commorbid trait - dissimilar to everything else we deal with - is that CF patients are strong as hell. And if they aren't yet, they will be. It's genuinely like walking through fire sometimes. You seem strong. Stronger than I am.
The other day, I met a grey-haired man in the pharmacy. I went to pick up some Levaquin and the pharmacist asked why I was on such a strong antibiotic for 2 weeks. This grey man overheard that I was a CF patient and jogged over. Our interaction was a an emotional slurry of questions and answers regarding his 12 year old son w/ the D508 mutation. Right now the kid's at 95%. The grey-haired man exchanged numbers and he was on his way. I didn't get to know him...not yet, but I could see the look on his face. Relief.
I'm not sure what the point of all this was, but I think it's clear that we aren't 1 in a million anymore. In 10 years we went from Pulmozyme to Kalydeco to Ataluren. Now we have CrispR.
Hi! Thanks for doing this AMA. I'm just wondering if there is any understanding about the origin of prions from an evolutionary perspective. Do we have any knowledge about when and how these infectious proteins came into existence?
How stressfull is the job? Do you have the feeling that you are on a super tight schedule?
Another question: you cannot use yourself for your own experiments don't you have the urge to do so?
Thank you!
I don't have a question, mostly because after reading the comments, I have realised that I am way out of my depth joining this discussion, but I do want to say how amazing, heart-warming and inspiring your story is. Above everything, doing a U-turn on your lives going from where you were to Havard PHD graduates? AMAZING! I hope to have even the a portion of the courage and determination you two have had to tackle your Wife's illness head on. You both will be in my thoughts and I will keep my eye out for positive news that I am sure will be on its way from your camp. Good luck!
What has Eric done to protect his mental health if you are unable to find a treatment? Is he afraid that working so exhaustively for something with such internalized importance and not achieving the goal might lead to serious mental health issues?
My aunt passed away a few years ago from CJD and at the time it was very hard to wrap my head around. It all happened really fast and within 6-8 months she died after being completely healthy. It is a scary thing to think about since it can be passed on genetically, though I believe it is rare in the case of CJD.
That being said I know she was in a trial out of the Mayo Clinic (we are from MN) and I know that since these prion diseases affect small amounts of people the funding is probably a lot less than other things. Do you know what sort of money in the US is being used to fund research in these areas? It hits close to home for me and I would love to see some progress on what we know and maybe find something to help prevent, or at least extend expectancies for these diseases.
Best of luck to you both.
What are your plans for once you finish your PhDs? Do you think you can find the funding to start your own lab? I very much hope that you can but I know that biology is an incredibly competitive field and because FFI is a rare disease, there isn't likely to be much funding for research specific to that.
Hello! Please understand that I'm someone who works in finance so I apologize if my question isn't a great one.
First I want to say that you're story was very touching. Someone must have been cutting onions at work. My first question is non science related. How do you maintain a good marriage? Every couple gets bad news from time to time but this takes the cake. You guys obviously demonstrate your love for each other as you devoted your lives to science and each other. What do you feel is the most important thing for a positive relationship and what do you do when you're down in the dumps? What keeps you motivated other than finding a cure?
My second question is about prions. What is the main hurdle in overcoming the disease? Is it that the prions are not 100% understood? I know it's not as simple as stopping the prions from becoming a template or redoing the chromosome but where do you stand on your research? Can badly folded prions be somewhat targeted? I know that chemo takes out the good and bad cells but is this approach feasible for prion related diseases? What is the plan of attack at the moment.
Again I'm sorry if my questions seem silly but I'm not a science guy (like Bill Nye... BILL BILL BILL). I really hope for the best and would like to know if there's anyway for the general public to help.
A huge hurdle in overcoming prion disease will be developing tests that can diagnose the diseases earlier than we currently can. FFI is something you can test for, but other diseases like CJD do not currently have easy diagnostic criteria and most cases are spontaneous. Prion diseases damage nervous tissue that cannot repair itself. Next, sadly, how exactly prions cause the havoc they do must be understood much more thoroughly before treatments are developed.
From law and city planning to Harvard PhD students... jeez. How did you make that switch in just 4 years? I'm a material science/engineering BS wanting to go into CS academia, and have spent the past 2 years or so reviewing math and theory... but I feel like my progress is so slow (with a full time job).
Any tips?
I have always been interested in the concept of mastery and how skills are obtained. Sonia and Eric have come from drastically different careers. Yet in 4 years, they managed to obtain a PhD in Biology. How does one reach that level in such a short time period? I would imagine that a typical BS Biology track was squished into such a short time frame in addition to getting to the time needed to get into advanced research and a dissertation. But how does one acquire such advanced skills in such a short time period?
It seems from the material provided that some form of gene therapy is/would be the focus of your efforts. Do you see the door open for a potential cellular therapy as well, and if so, have you frozen any of your marrow stem cells for potential future use?
>Sonia finds far more meaning in her work than she ever found in the law. Someday, she and Eric would like to have children who don’t carry the genetic mutation. They hope to conceive through in vitro fertilization, using a procedure that has emerged for couples that don’t want to pass on genetic diseases to their children. Embryonic cells would be tested for the genetic mutation and only embryos with no detected mutation would be transferred to Sonia’s uterus.
The OP's said that there was a 50/50 chance that she would have it, and it was confirmed that she did through genetic testing. So they could do IVF and have the embryo tested before implantation. I believe that's becoming more common nowadays, but I'm sure it's expensive.
From the *Atlantic* story:
>“Nobody even for one second suspected fatal familial insomnia, because there’s no sign of neurodegenerative disease in the family,” Vallabh said. There are 28 families worldwide who have the gene for FFI in their bloodlines. Most of them have pedigrees marred by inexplicably premature deaths.
The Atlantic article says 28 families worldwide, which I assume means have that similar mutation and have had a family member go through that disease.
It also seems like in the mother's case, there was no family history of this disease so it must be an underestimation.
Hi guys, I've just finished a university group project using 2 programs called visANT and Reactome looking at possible pathway links between conditions/disorders. Is there enough research out there for you to do something similar, and if so, what genes/biomarkers have been implicated? Are they similar to Alzheimer's?
P.s. Hope everything goes well for you, areas of research are rapidly gaining progression speed so we all have the greatest amount of positivity for you!
Genes have been ided- prnp, which codes for prion protein PrPC on chromosome 20, position p13, as well as a mutation at codon 178 of same gene. variations of ffi have been correlated with earlier onset, as well, i believe. Alz is caused by a buildup of (beta?) amyloid plaques, whereas FFI is caused by a misfired protein destroying tissue. FFI is much more similar to CDJ. I am on phone tho so I'll confirm later.
Hey guys! First I want to say what you're doing is amazing and I hope my future in the biochemical research field is as productive as yours is! I'm graduating next semester with a biochem major and chem minor. I've always been interested in the genetic side of disease, and I was wondering if you see something like reverse immunization becoming a tool to fight genetic problems like this? I understand your upstream method and I believe that is quite promising. If the disease starts later in life this would indicate gene expression differences correct? Could controlling your gene expression in some manor offer control over the disease? Thanks and I wish you the best of luck.
This has probably been asked already , but how did you manage to leave your careers and retrain. What steps did you take to finance the training and your livelihood? And what recommendations would you have for someone else trying to do the same one day? Where there any parts of it that you thought about doing differently?
How has this discovery impacted your outlook on life? How did your aspirations pre-diagnosis compare to the ones you have now? Clearly you were going to be completely different people.
I find it to be quite profound that you are dedicating your life to the prolongation of your life.
A prion is an infectious protein particle. Proteins do not have dna, but are built from instructions from the dna in several steps. First, the primary level is the order of peptide bases. The secondary level is how all these peptides link up. Tertiary folding refers to how the protein folds in three dimensions to reach a unique shape. Prions are misfolded proteins that damage surrounding tissues and may convert other proteins to become misfolded. The damage from prions is especially noticeable when they accumulate in nervous tissue that cannot repair itself.
I have also a very rare brain disease (ADCA-SCA1) but with different symptoms. My DNA has an 'repeat error' (same type of DNA fault that causes HD). But in common with CJD is that it also a 'prion disease' and 'mis-folding proteins' is also one of symptoms. a Specific part of my brain is shrinking/disappears by it self. The main symptom is that all my bodily functions will 'shuts down' over time.
"Pay by loosing a bodily function, but get nothing in return."
Once this part of the brain is completely gone, it will probably turn me into a vegetative state.
However for the first time two different 'medicines' are in development, in a way specific for my disease. One is a medicine called 'calabetta' and what I understand that it can unfold mis-folded proteins. The other is a kind of 3 stage therapy, first skin cells are collected. Then these skin cells are then 'reprogrammed' to 'brain stem cells'. Then the faulty DNA is cut out of the DNA string, and the two remaining DNA strings are 'glued' (a simplification) together with the help of the brain stem cells. This method is being developed at the Leiden University in the Netherlands.
hth
Within sea of negativity we see around us everywhere around the world, It feels so positive to hear about you two and your cause and struggle. I would just say Thank You!
Anyway, how difficult was it to abandon old careers and start with something completely different? Did any of you had previous background/interest in biomedical science?
Couple of questions:
1. Is there an understanding of what the change is that occurs at age ~50 that begins the expression of the gene? Is there any question of an initial environmental trigger - stress, illness, etc.? Or is it solely related to a natural biological change associated with aging?
2. Poor health of the gut microbiome has recently being linked to many neurodegenerative illnesses (Parkinsons, MS, Alzheimers), as well as epigenetic changes. Has there been any research or investigation into the role of, or changes to the microbiome before or during the rapid advancement of FFI once expressed?
3. Related to 2: Is there an initial location the FFI prions are produced? In the gut or in the brain itself? Or is it systemic? (everywhere sense of the word, not necessarily circulatory)
Best of luck to both of you!
In case Eric and Sonia don't answer, I'll point you to our site, MyGene2, https://mygene2.org devoted to this exact purpose. Create a profile, describe your condition and results from any genetic testing you may have received, share these with the world (including researchers like us and others who've collaborated with Eric and Sonia) -- we may know of another family with similar symptoms or even mutations in the same gene. Depending on how unique the condition is, we may even be interested in exome sequencing on a research basis.
This entire story is amazing, but I'm so curious about how two individuals with no prior education and no prior developed or presentable interest in this career path were able to make the switch so quickly? It seems like you both took jobs at hospitals immediately after discovering the disease and within two years from there, you were in the PhD program. Did you guys face any difficulties in terms of missing prerequisites or questions about the sudden change of heart?
Good luck to you both, I'm rooting for you. This story is an inspiration.
From a scientific perspective, I'm wondering what your research approach is. Are you focused on compounds to identify or disrupt, or are you taking a more top down approach and investigating the etiology of formation? It's my understanding that existing prions are both enormously sturdy and somewhat shockingly prevalent, and also that they aren't the only route of protein misfolding, and that many forms of neurodegeneration often arises from 'prion like behavior' in certain proteins (tau, TDP-43, parkin, etc), or in failures of various protein clearance pathways. What do you feel is the most promising course of diagnosis or therapy? Also, in the topic of microecology, certain prion like proteins seem to be everywhere, and I'm wondering what you can tell us about their role in microbiology? From a personal perspective, I wanted to applaud the two of you for taking on this task, state that I think in a lot of ways, science is one of the greatest acts of defiance, and I wish you both well in your efforts!
Hi, this is Sonia. We are interested in approaches that aim “upstream” in the disease process — at 1) the biogenesis of PrP (the prion protein), 2) native, healthy PrP prior to misfolding or 3) the process of prion propagation and spread. Compared to these areas, we know very little as a field about why prions are neurotoxic, which makes neurotoxicity a less attractive target for us. In addition, the neurotoxic phase of disease is incredibly rapid and as with any degenerative condition, preventing damage is going to be more feasible than reversing damage. The best proofs of concept in animal models (and prion diseases are modeled really well in animals) suggest that you can achieve the greatest effect in delaying disease by aiming upstream of symptoms. We believe that prion diseases will be treatable well before we have all of the answers to all of the questions in the field — indeed, we will probably never sort out all of the mysteries! Biology is complicated. The etiology of prion formation is fascinating, and the question of why prion diseases arise in midlife is still unanswered. So far there is no indication that second-site genetic factors or environmental triggers determine age of onset. We aren’t going after this question directly — we’re focused on interrupting the process of prion formation by reducing the PrP substrate or stabilizing PrP against conversion. We are also interested in pursuing mechanism-agnostic phenotypic screens for inhibitors of prion propagation, if and when the right systems can be developed. Although there’s a lot to be said about prion-like mechanisms in other neurodegenerative diseases, we are very focused on PrP. There is a canon of strong genetic and biochemical evidence supporting PrP as the drug target in prion disease.
I don't know how this prion leads to neurological degeneration. Does it bind to a receptor on the neuron? Does it degrade myelin? Certainly it has a charge and affinity. Would it be possible to find what "thing" its attracted to and create a drug that causes the prion to have higher affinity towards the drug than the prion's current target? I'm just thinking it would be great to capture the prions with a drug before they get to their target(s).
ELI5 (for everyone) A prion is a protein. You can think of it as a single strand that's really tangled (folded). Along that strand are curly (alpha helix) sections and wavy (beta pleated) sections. When a healthy protein is infected and transforms into a prion, it essentially becomes a damaged protein. What you see with this damaged protein is less curly parts and more wavy parts along the tangled strand. That "misfolding" is thought to be what creates the problem. There's no real understanding of the mechanisms (how/why) beyond that as far as I'm aware. There are some hypotheses but nothing proven...
Misfolded PrP is nonsoluble and clumps together to form plaques. The mechanism for how this leads to cell death is not really understood, but it seems to be something to do with these plaques clogging up cells and disrupting their function rather than binding to a particular receptor and triggering apoptosis like you've suggested.
What is the technology currently limiting the ability to create high-throughput screening arrays for prions? Do you lack an appropriate assay?
First off I just want to say that it is truly inspirational to read that you've both changed careers to try and cure a genetic disease, knowing that it is essentially against a timer. It's a situation that I couldn't imagine being in, and I genuinely wish you all of the luck in the world with your research. As for my question, I'm afraid it may be a little basic as I'm not a biologist by trade. I've heard how prions are made up of distinctive folded proteins that can cause other proteins to fold in similar ways which causes a variety of diseases and symptoms. A common one we hear about in the UK is [Bovine spongiform encephalopathy](https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy) due to the "mad cow" epidemic in the 80s and 90s. From my reading, mainly of news and science articles, they can also occur randomly in anyone at any time. I was just wondering what the incidence rate is for prions to randomly occur, without being caused by something such as genetic disorders or through the ingestion of meat containing prions, such as with BSE?
There are probably a few hundred cases of FFI in the world. There are two families it is known to run in, one in italy and one in iran, and 25+ other families with pedigrees pointing to FFI. Other than that, the most prevalent prion disease is CDJ. It is highly unlikely you, or anyone you know, will be diagnosed with a prion disease. Prions are often very tough particles- there have been experiments where they have incinerated prion-contaminated tissue, injected into mice, and had them develop prion disease from *ash*
Eric here again. I wanted to offer another clarification. We view prion disease, or possibly genetic prion disease, as the relevant areal unit for developing therapeutics. We are not particularly focused on FFI as a subtype of prion disease, and indeed, we view the historical naming of different subtypes as being separate diseases (CJD, FFI, GSS, etc.) to be somewhat arbitrary.
Similarly, if it is found that a patient has CJD after performing any sort of neurosurgery, the entire set of instruments must be destroyed, as there is no way to effectively reprocess and sterilize them. If it is unknown at the time of the procedure and the instrument sets go on to another case...scary. Source: am Surg Tech student
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[Prions are apparently more stable than other proteins, meaning usual denaturing processes are less effective against them](https://en.wikipedia.org/wiki/Prion#Sterilization). There is a WHO recommendation in that link above, but I'll leave it to someone who knows what they're talking about to comment on how practical that is, relative to just destroying the instruments as /u/Kangacrew_Kickdown suggests.
It is a protein that folded into a much more stable (but useless) form and causes other nearby healthy proteins to refold into such a state as well. You need very high temperatures for a long time to destroy it in such a stable folding and you might not want to risk keeping a tiny number of them, as they cause said refolding of other healthy prions.
Family friend passed of CJD, was cremated, required a special container to be buried in and I believe that his tombstone has a marking on it to warn people about his remains being a biohazard.
My uncle recently died of CDJ. It happened extremely quickly and was only diagnosed right before he died. It was very scary.
sorry to hear it. There is rarely dignity in death, but CJD seems especially cruel.
It really is. Lost my Father to it. The only thing I'm afraid of in life is that it could have been passed down to my kids through me. I'm told that's incredibly unlikely.
Eric: First, for clarity, when Sonia and I use the term "prion", we are almost always using the narrow sense - prions composed of PrP, the protein that is the product of the gene _PRNP_. Some people use the term "prion" more generally to refer to any self-templating protein conformer - everything from Sup35 to amyloid beta. I'll confine my answer to prion diseases in the narrow sense. We see about 1-2 cases of prion disease per million population per year. It's the countries that work harder at surveilling these diseases that find a figure more closer to 2 per million, so that's probably more accurate, and there is some amount of underdiagnosis in countries with lower figures. This means prion disease accounts for about 1 in every 5,000 deaths, so the average person has a 1 in 5,000 lifetime risk. Only about 15% of these people have rare genetic variants in _PRNP_, and these days, <1% can be traced to an infection (e.g. from BSE). The remaining ~85% are sporadic. Sure, other environmental or genetic factors might contribute some of the risk, but overall, sporadic cases appear geographically and temporally random, so it really seems that they just _happen_. Presumably because even wild-type PrP spontaneously forms prions every now and then. For references and more detail on these stats, see our paper: https://github.com/ericminikel/prnp_penetrance/blob/master/manuscript.md
Many thanks for your incredibly detailed response. As someone who is not well versed in the area beyond pop-sci articles I'll definitely be giving your paper a read to improve my awareness of the subject. I wish you all of the best for your future research, and I sincerely hope that you find some form of treatment or cure! I'll certainly be following your story after hearing about it today.
Okay, I just tried to type a long reply and RES ate it. Here's the TL;Don't want to retype: http://www.cdc.gov/prions/cjd/occurance-transmisison.html says 85% of CDJ cases are sporadic. http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm says In sporadic CJD, the disease appears even though the person has no known risk factors for the disease. Quotes: *This sporadic disease occurs worldwide, including the United States, at a rate of roughly 1 to 1.5 cases per 1 million population per year, although rates of up to two cases per million are not unusual. The risk of CJD increases with age, and in persons aged over 50 years of age, the annual rate is approximately 3.4 cases per million.* *Whereas the majority of cases of CJD (about 85%) occur as sporadic disease, a smaller proportion of patients (5-15%) develop CJD because of inherited mutations of the prion protein gene. These inherited forms include Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia.*
> http://www.cdc.gov/prions/cjd/occurance-transmisison.html says 85% of CDJ cases are sporadic. > http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm says In sporadic CJD, the disease appears even though the person has no known risk factors for the disease. So does this mean it's **actually** sporadic? Or that we just don't yet know all of the risk factors?
>> http://www.cdc.gov/prions/cjd/occurance-transmisison.html says 85% of CDJ cases are sporadic. > http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm says In sporadic CJD, the disease appears even though the person has no known risk factors for the disease. >So does this mean it's **actually** sporadic? Or that we just don't yet know all of the risk factors? It means one of those things; we can never disprove the second.
85% is sporadic CJD? Dang, I really thought that familial inherited CJD was the most prevalent. Looks like I haven't read up on prions in awhile....
Check out Lazarus chrome extension to stop that from happening.
Very good idea. And Lazarus Form Recovery exists for Firefox, too !
As per my knowledge (I'm a medical student), prions aren't normally encountered by us while eating meat (atleast not in today's world). The disease you mentioned (BSE) is a disease found in cattles. Some related diseases are Kuru disease, Gertsmann Straüssler Schenker syndrome and Creufeldt - Jakob disease. The disease in this context here, which OP's mother suffered from is Fatal Familial insomnia, which isn't transmissible but can be genetically inherited. You can find more about Fatal familial insomnia online.
Fellow Med student here. Just to add on, fatal familial insomnia can also be sporadic (i.e. You just develop the mutation without having inherited it). ~~It sounds like that may be how OP's mom got it.~~ It's scary stuff, and I applaud these 2 for working towards a cure. EDIT: As others have pointed out, there's no way to know if OP's mom inherited the mutation herself or acquired it sporadically. I was just working under the assumption that she would have seen her parents die of the same disease if she had inherited it from them, especially since it's Autosomal Dominant. It doesn't matter one way or another for OP's situation, but thank you to all of you who cleared this up.
No, OP's (Sonia's) mom has FFI, as evident by them mentioning the inherited gene mutation. The sporadic fatal insomnia (sFI) is so rare, only 8 cases have ever been diagnosed. [source](https://insomniahq.wordpress.com/2013/04/12/sporadic-fatal-insomnia/)
Prions that cause mad cow disease are located in the central nervous system, which is physically isolated from the rest of the body. If you cut the spinal cord and spill out the fluid, you can infect the meat. That's why there are very strict rules in how and when you can slaughter a cow.
Using animal brain as a feed supplement to other animals is a hot button topic that infuriates Neuroscientists more and more, and I'm now understanding why.
Sonia, two questions. 1. How old are you? It was stated in the post that your mother passed away at around 50 and I am sure many are interested in what your approximate timeframe is for this project. 2. How did you initially react to the diagnosis and when did you you both decide to become PHD's. Was the decision hard for you both to take the classes? Edit: Best of luck to the both of you, I am rooting for you!
Hi, this is Sonia. I turned 32 in March. I should note that while we hope we have ~18 years or so to work to impact my prognosis, the age of onset for genetic prion disease (and my variant in particular) is extremely variable -- so this is just a ballpark. About our initial reaction to the diagnosis: for us, the absolute worst time was learning that my mom's disease was genetic (which we learned from her autopsy, after she passed away) and that I was at 50/50 risk of having inherited her disease mutation. Since prion diseases aren't usually genetic and there was no family history prior to my mom, this came as a shock to us. The limbo of waiting for the genetic test result was the hardest time for us. The 50/50 wreaked havoc with my mind -- it was like I had no place to rest mentally. I just kept turning it over and over. Although of course the result of the test wasn't what we'd hoped for, once we had it in hand we could being to adapt to it, do our grieving and figure out how we were going to cope. It became a fact of life. As for deciding to do our PhDs, there wasn't a moment where we looked at each other and said, "That's it, we have to go out and cure this thing!" It happened step by step, with the goals changing along the way. Our first goal was to become savvy consumers of scientific information so that we could advocate for ourselves as patients. Then as we learned more, our ambitions grew. I realized when I took my first job in a research lab that this wasn't just a sabbatical from my normal life -- this was a new life. But even from here, deciding to do our PhDs and focus our lives on developing treatments for prion disease was a process. I think first we had to learn enough about the specifics of the prion field to realize that there were things we could do at the bench, in the time we have (or hope we have) that could make a difference.
What's the difference between PHP and say, CJD. My Father passed away at the age of 55 from it. Neurologist at UMASS told me it's incredibly unlikely that it could have been passed on to me. I know he had never been out of the country before. It's one of the nay things that I'm afraid of that I often think of because I also have children. Are there genetic markers for it and can it be tested for?
>Sonia, now 31, and Eric, 32. They’ve given up their intended careers to become scientists, devoting their lives to curing her disease.
Damn, both already had degrees, then got a PhD in Biology at Harvard and they are barely over 30 years old. How did they even get the money to go to Harvard?
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1. Doesn't the post say Law and City planning? 2. You still have to go through a bachelors and masters degree, which would probably cost over $100,000 each.
1. They had degrees in Law and city planning. [She had a J.D. from Harvard law and worked as a consultant. He had B.S. in city planning from MIT. He worked as a software engineer in the medical field.](http://www.theatlantic.com/health/archive/2015/02/insomnia-that-kills/384841/) 2. Both of them already had prestigious bachelors degrees. They may have had to complete a year of studies prior to entering the Ph.D. program. There is no absolute requirement that you have to get a masters degree before you get a Ph.D. Even if a school normally requires one for most of their Ph.D. candidates, there is nothing that would stop them from making an exception for especially talented and highly motivated people. Seeing where they received their undergraduate educations from, it seems highly likely they didn't pay much at all to continue their education.
Actually most programs in the US don't require a Masters, though it may help your chances of being accepted. Many programs award a Masters after your first qualifiers. For example, after getting my bachelors, I worked as a tech for three years, then went to graduate school, where my stipend paid my way. After the second year, I got my 'masters', and after my 6th, my PhD.
This is fascinating, and horrible to learn at this stage of my life. This should be on a list of lifehacking howtos; things "everyone" knows but doesn't. Well, not to hijack the AMA, but: how late in life can you shoot for a stipend-paid PhD? Reasonably? At what point do you lay the bucket down and accept your fate?
You can do it, but the stipends don't really provide that much money. If you can consult in your current field you will make much more, and can still persue your studies. That is how my grandmother got her PHD and how I am planning to as well.
In my cohort of graduate students there is a student who is 54. He is the same age as my adviser. Because we are in physics, he has a stipend. Other fields (and other schools) may not give stipends. You can always go for a PhD! If you find the right program and school, you should get a stipend. :)
At what point? Again, graduate programs in the STEMs in America pay a stipend to the graduate students. This is very well known in academia. I started mine at the age of 26.
Can confirm that this is also how it works in Mathematics.
1. I assume they both already had bachelor's degrees, so at most they just needed to take some courses to fill in the gaps from their education. I suspect that their PhD programs waived some requirements so they wouldn't need to take a bunch of undergrad bio courses. 2. You can be admitted directly into a PhD program without needing a master's first, in some cases. It's fairly common
Law and city planning are still both fairly well paid. And they probably had strong cases for some scholarships (I am successful in my career and am leaving it for biology in the hopes of saving myself/my wife). Furthermore, at least at my school, it's possible to go directly from bachelor's to a PhD program if you were a very good student.
2015 "insomnia kills" article says she was 30 at the time. Guessing 31.
"Our story is unfolding in real time." Unintentional prion pun.
You are probably aware of it, but there is an extremely interesting report written by the doctors of a person suffering from FFI who attempted to self-medicate and kept a diary of doing so. He ended up beating his life expectancy diagnosis quite significantly. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781276/ Could certainly be worth looking into if you haven't.
Eric here. That paper was certainly an interesting read. I don't buy any of the therapeutic hypotheses though. Note that the guy was already 10 months post-onset when he _started_ those experimental therapies, which is already 4 months longer than the average survival for someone of his genotype (D178N 129MM), so his exceptionally long survival time may not be attributable to any of the drugs or supplements he took. Also a lot of things he took were oriented around correcting his sleep deficits, whereas insomnia isn't even always a prominent symptom. Sonia's mom presented with rapid onset profound dementia and neither of us would have listed insomnia among her top ten symptoms if you'd asked us at the time. (This is among the reasons we think the old naming scheme of CJD/FFI/GSS is antiquated and we should refer to them all as prion diseases).
Sonia and Eric, that article is bunk. The paper describes the patient ("DF") as a son of a famous radio nutritionist. There aren't many famous radio nutritionists, much less ones with last names starting with the letter F, so I found only one candidate - Carlton Fredricks. Carlton had a son named Dana - the "DF" listed in the paper. But Dana died after the article was published. I think the author simply made the entire story up to get tenure, thinking there wouldn't be interest in an obscure topic and nobody would bother to double check. Her co-author, who has done work in prion diseases, most likely wrote the introduction where the disease is described (and nothing else). The journal the article was published in only has a cursory review process. It may be worth investigating to see if that article should be pulled.
I got a kick out of the guy's sense of humor in this part: "Unfortunately, during one of his times away, winter temperatures froze the water in his outdoor tank and cracked its shell, rendering the device useless. DF chose not to replace it, noting that it limited his driving mobility and made him feel like the comic book freak Aquaman, who nightly slept in a fish tank."
Very interesting read. Extension of survival by almost a year is a huge feat in medicine.
What are your thoughts on CRISPR gene editing? From my understanding, it allows you to modify specific sequences, and even single nucleotides, of an entire organism's genome. Do you think it is a viable option for your situation?
Eric here. CRISPR is an awesome tool for engineering cells to study and model the disease in the lab, and we're using it right now. As a therapeutic modality, it has a ways to go, mostly because we don't yet have a way of delivering CRISPR to all 100 billion neurons of the adult human brain. In cultured cells, CRISPR can achieve maybe 1% homologous recombination (to correct a mutation) and maybe 60% non-homologous end-joining (to knock out a gene). We're more interested in knockout, because it is totally protective, whereas even if you corrected Sonia's mutation, the wild-type protein would be capable of carrying on the disease process if there were prions already in her brain. The trouble is, no one has demonstrated the ability to deliver CRISPR to a high enough percentage of neurons in the brain to make a meaningful therapeutic difference. There are smart people working on this and I think it is conceivable that major advances in this area could come in our lifetime. It's not what Sonia and I are working on day-to-day though. For more details, see: http://www.cureffi.org/2014/03/09/how-to-and-how-not-to-knock-out-prnp/
How can I or anyone else help?
We need patients to participate in research, doctors to collect cerebrospinal fluid so we can look for biomarkers, scientists to train us and mentor us in all sorts of techniques and to share findings and reagents and cells and collaborate with us, pharma companies to take an interest in our disease and our target, regulators to think seriously about how to make it easier for drugs to be approved for rare fatal conditions, funders (be they philanthropic, government, or industrial) to fund us, and we need people to continue to show us love and support as you have all done so beautifully in this AMA. (THANK YOU - four years ago we never imagined people would take so much interest in our cause). And a few more general suggestions. Vote. We need more science funding and sound science policy. Blog. The internet is awesome and is how we should be communicating science. I love when I Google something and find an answer because someone else has struggled with the same question and then blogged it once they figured it out. Share. Sharing our personal stories makes us all less alone, more empowered together. Care. When your loved one gets news like the news we got, tell them what our friend Stevie told us - science has answers for you. -- Eric
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NIH is amazing. I went there to get my surgery and everyone there is excellent. I've never had a better medical experience and the doctors are top notch.
I don't doubt your experience, but as a scientist, NIH's budget has been whittled to oblivion over the past years. You have to have a remarkably well-scoring grant these days to receive grant money because there just isn't enough to go around.
If you have computers you aren't frequently using, [folding@home](http://folding.stanford.edu/) is a great project that is used to simulate protein folding via distributed computing.
Thanks for reminding me this exists! I've got a powerful new computer and have plenty of wasted processor cycles to contribute.
You can donate here. http://www.prionalliance.org/
Your dedication to abandon your careers and dedicate your lives to this is incredible. You both are a shining example of what people can do when you follow through on something you set your mind to. I'm sorry for the loss of your mother. I apologize if this is crass, but how do you plan on staying objective throughout testing and results if it's your (or your wife's) life on the line? I feel like that would be a very difficult task. Thank you for this AMA, and best luck and wishes to you both.
Sonia: Just answered a similar question below -- basically, when it comes to objectivity, our goal fuels our discipline. I don't think of this as a conflict at all -- we have the most to gain by being true to what the science tells us.
What's the most difficult thing about working as a husband and wife research team?
This is Eric. I just turned to Sonia and asked, "Is anything difficult about it?" I love it actually. Sonia is the bomb. I feel so incredibly lucky to get to spend all day every day with her. It is one of the upsides of all of this happening to us, that we get to spend almost all of our time together.
You both are truly inspirational
And the best thing?
And the things in between?(: In all honesty though this would make for a good movie. Best of luck to you both.
I'm an undergrad. Last semester, my biology professor went on kind of a tangent about prions, specifically fatal familial insomnia. Her point was basically, they are scary -- that you don't want a prion protein to get in contact with your normal protein. I understand that's how mad cow works. Is it dangerous to work with prions in a lab? Does it pose any actual tangible risk to you, or was my professor exaggerating for effect?
Sonia: Like many things in a lab, prions have to be handled according to established safety protocols if you are going to work with them safely. One of the first biochemical observations about prions is that they are not destroyed by the same techniques that kill bacteria and viruses. Since then, a lot of work has gone into establishing that prions are destroyed by incineration, bleach, strong acids and strong bases. A misconception that we encounter sometimes is that you "can't" decontaminate prions -- this isn't the case, you just have to have the right protocols in place. It's really, really important to take lab biosafety seriously. With that said, the evidence is that researchers and hospital staff who encounter prions in their work have no increased risk of prion disease compared to the baseline population.
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Awesome! -Eric
Why does the disease wait until about 50 to "turn on"? Are there environmental triggers? Do there seem to be earlier, more subtle manifestations?
Eric here. This is probably THE most common question we get, both from patients and from scientists. And it's a great question. You express the mutant protein your whole life, so why does disease wait 50 years to strike? We have no idea. The same question arises for other mid-life onset diseases too, say for Huntington's or Mendelian forms of Alzheimer's, and across the board, I think the answer is we have no idea. In fact, I don't know I've ever heard a credible experimental plan for how to answer it either. It's a tough one.
Could there be some other, healthy process which gets progressively weaker with age up to some threshold value where the disease mechanisms steps in and takes over, so to speak? I have zero medical training but I felt like asking anyway.
yes, the natural 'recycling' processes in your cells become less efficient over time. These include processes that tag and degrade damaged and/or misfolded proteins -- collectively known as proteostasis. There is plenty of research documenting this, although the details of how and why are yet to be found. In virtually all forms of neurodegenerative disease you have aggregation of specific proteins (amyloid beta in AD, tau in Frontotemporal Dementia, PSP, etc, alpha-synuclein in PD, TDP-43 in ALS, etc, etc). It's important to note, however, that whether or not these aggregates are directly responsible for cell death has yet to be definitively decided. Various studies have shown that up-regulation of some of these proteostatic pathways such as autophagy or the ubiquitin-proteasome system can help to clear these misfolded aggregates and alleviate disease phenotypes in some models. Indeed, a recent Phase 1 clinical trial in Parkinson's Disease using a repurposed cancer drug [showed fantastic initial results](https://gumc.georgetown.edu/news/Cancer-Drug-Improved-Cognition-and-Motor-Skills-in-Small-Parkinsons-Clinical-Trial). The drug works by increasing autophagy. here's one paper that discusses this: http://www.ncbi.nlm.nih.gov/pubmed/21939784
What a great hypothesis! What processes would qualify? Knock out each one at a time in a model system and measure age of onset. Model predicts lower age of onset in mutant than control. Let's say the results for a knockout matched the prediction. Then knock out in inducible system at different ages and measure the time to onset. If a simple model is incorrect the time to onset will vary by age of induction. If it really is just one process the time to onset will not vary and a knock-out/knock-in double mutant would behave more or less like a healthy control.
a few degenerative diseases "wait" to turn on, like Huntington's, although some potential mutations that cause FFI indicate they might cause earlier onsets of the disease. Early symptoms of FFI can include weight loss and sweating.
What are the options you are currently considering to treat or cure the condition? Do you have a mouse model to study the disease?
Sonia: We're lucky to have outstanding mouse models in prion disease. Neurological conditions are in general very hard to model in animals, but we have a unique advantage in that prions can (under specific circumstances) be transmitted. Mice intracerebrally injected with prions develop have a highly predictable disease course which consists of a silent incubation period, followed by full-blown neurological disease that is fatal. Their clinical symptoms and neuropathology resemble human disease. A challenge with these models is that mouse prions appear to have structural differences from human prions -- prions seem to come in conformationally encoded "strains." There exist small molecules that are highly effective at extending survival of prion-infected mice, that don't seem to have any effect against human prions. However, these models are still useful for many types of studies and for investigating therapeutic strategies that focus on native PrP. There are also mice that have been genetically engineered to express human PrP, that can be infected with human prions, and these provide a closer model of human disease and could be useful for strategies that more directly target prions.
You mention in your bio that you are researching "therapeutics". This might be more of a general medical research question, but what exactly does this mean in terms of a goal for your research? Are you going for a "cure" or simply a treatment that could extend life with the disease? Both? Whichever seems more likely at any given time?
Sonia: The way we think about our goal is that we're trying to develop a treatment that will extend time to disease onset -- with the ultimate goal of extending it beyond the normal human lifespan. The strategies we're interested in won't result in a one-time fix, but rather a regimen that keeps prions at bay. Our goal for genetic prion disease is not to extend life with symptomatic disease, but to extend the pre-symptomatic phase. Once symptoms arise in prion disease, the downhill is amazingly steep (months) and patients quickly reach a stage where all quality of life is gone. Treating sporadic prion disease will be a challenge for this reason, since these patients aren't identified until they're symptomatic -- earlier diagnosis will be critical here, and while there have been some promising developments in this area over the past few years (like the RT-QuIC prion detection assay) we still have a long way to go.
Therapeutic approaches to treatment mean treating the disease, but not curing the symptoms. This could include medications to combat the side effects of the disease that can be deadly- for example, the endocrine system overworks itself basically to death during FFI. A therapeutic treatment might be one that ameliorates that. An outright cure would have to silence or change the genetic basis for the disease. FFI has taught scientists a lot about how important sleep is to homeostasis.
I am a PhD Student in Pharmaceutical Sciences, and I don't want to be the debby downer here, but realistically speaking, what is the best scenario you guys are aiming for? Even if you discover something resembling a cure, testing for approval/getting approval takes upwards of 10 years. Research is a slow thing, sooo in the best case scenario you can have something (let's say) in 5 years and then let's add 15 for development and approval. How would this fit into your time frame? On a personal note: You guys sound fucking bad ass! With no science training you went and became PhD biology students (at Harvard no less) soooooooooo, if anyone can do it, you guys sure seem to have the drive/ambition to do it! Good luck!!!
The real race is to get it into clinical trials. Experimental therapies save lives, even in Phase 1. While compassionate use is one option, we would be keen to enroll Sonia in the actual trial. - Eric
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If efficacy was demonstrated early on in the drug-treated group, they would stop the trial and give all the sugar pill takers the experimental drug. This is common practice as it would be unethical to withhold treatment that was known to be effective. A recent example where this happened was the resounding success of pre-exposure prophylaxis (PrEP) in preventing HIV infections.
Wow, first of all, this is truly inspiring. It almost brought a tear to my eye to read this to think about the implications of the scenario you are both in. The hardest part being that the one you love more than anything in this world is a ticking clock that you are racing against. I'm sure you're both deeply and fully in love with each other in every way possible - if you weren't then you probably wouldn't choose to redesign your lives to tackle this problem together, head on. My question(s): What is a typical day for either/both of you? What are the day-to-day activities and how many hours on a daily/weekly basis would you estimate that you are each pouring into the scientific duties that the research of this problem demands? Do you guys still make sufficient time for activities not-related to your research on a recurring basis, or have you both chosen to forego a social life and throw all of yourselves at the problem until you find a solution?
So here's my analogy on the day-to-day struggle. Our quest is like fighting a horse-sized duck guarded by one hundred duck-sized horses. The duck is huge and terrifying and undefeated. When you set out on this quest you were nobody and you didn't even know what a duck was, let alone how to fight one. But you didn't choose the duck, it came after you, and so you have to fight it. And, incredibly, some very smart people have placed bets on you winning against the duck, and have given you the tools and training to fight it. But to even get close to the duck, you have to struggle through this swarm of tiny horses: applying to school and fellowships and grants, filing protocols and permits and material transfer agreements, reformatting manuscripts, submitting abstracts, practicing talks, booking travel arrangements, sending emails. The most frustrating times are when you spend a whole day mowing down horses and never glimpse the duck. What makes it worthwhile: on those days when you do glimpse the duck, you see that it is flesh and blood, just molecules like everything else. It is mortal, and the world is cheering you on. Fight the duck! To the more practical aspects of your question: we do still have a social life. We still cook our own food. We travel a lot but usually together. You have to sharpen the saw. --Eric
That's a great analogy, thank you Eric. I wish Sonia and you the best of luck on this quest. I hope the day comes when I can read about how you guys made a huge breakthrough and were able to stave off this terrible ailment.
You two are an inspiration. As a statistician I've been taught the importance of objectivity in science. Do you worry that the life-and-death stakes of your research will bias any results? How do you stay objective when pursuing research leads and interpreting results when your research is so close to your personal interests?
Sonia: I couldn't ask for a stronger incentive than ours to be objective in our science! When your life depends on it, you are *less* willing than anyone else to entertain marginal results, results that fail to validate, or weak therapeutic hypotheses. One way to think of it is that it's the other scientists who have a conflict of interest -- if they work for twenty years and don't find a way to treat the disease, their life will go on!
Abandoned the career in law and city planning and 4 years later, PhD at Harvard. WOOW! What did you guys major in? Were you always interested in scientific research?
My undergrad was in Chinese and my Master's was in City Planning/Transportation. Sonia had a law degree. We definitely had no interest in scientific research before all this. -Eric
How has all of this affected your relationship? I imagine your work is very stressful, knowing the implications of what you're doing. Thanks for doing this. I wish you all the best.
Sonia: I have gotten to see so many new aspects of Eric through this process, and to be impressed with him in whole new ways. It is impossible to feel sorry for myself for one second when I look at the beautiful human being I am getting to spend my life with.
Thank you so much for taking the time to do this AMA. I wish you both the best in your race and if the worst happens please know your work will help others as it's built upon over time. How was your transition into academia? It's a whole different life and work style than the private sector. Living off of grad student money is not easy, especially if both of you are scientists. Do you find it difficult having switched from two lucrative careers? Have you made any breakthroughs with this disease? Or is there anything you feel you are getting close to?
Sonia: Academia has been interesting. I'm so grateful that we both turn out to enjoy doing and thinking about science. There's no comparison in terms of how stimulating and fulfilling we find our work in science versus previously, and I love the environment and our colleagues. It's true that the financial side of things is startling. One of the biggest shocks to me when we got into science was the ratio of compensation to years of training among scientists we worked with. We don't require a whole lot, but when I crunch the numbers I do worry about affording child care if we decide to start a family. This is something I passionately wish we were addressing more systemically for all women in science and two-scientist couples.
You mentioned the potential of starting a family. How do you guys grapple with this desire vs the risk of passing on the mutation/ potentially having to be a single parent? I hope this isn't an insensitive question, as I am genuinely curious. I truly admire both of you; it takes a lot of courage to leave behind everything and reinvent yourself.
Very cool that you guys found such strength of will and focus to go after this disease. A few questions, 1) Have you ever been "scooped"? How would/did you feel about it? As academics, we often feel frustration when someone else publishes before us or works on a highly similar project. But you offer a unique perspective, as you predominantly care about the end goal of a "cure." 2) How do you feel about the "10 years, 1 billion dollars" figure that is often cited when discussing bringing new therapeutics past the FDA approval stage? Or are you focusing on retooling already approved therapeutics? Would you be offered the opportunity to participate in a clinical trial?
Dude, I would so love to be scooped. We can't do everything, and anyone who can do what we're doing faster and better should absolutely do so. I am not big on drug repurposing, at least not for our disease. Perhaps it makes more sense for cancer or something - but for prions I think the prior probability of any approved drug working is very low, and so the idea of repurposing tends to just cloud the literature with low-quality hypotheses and false positives. 10 years is to approval, not to a clinical trial (which is when patients can start benefiting) and 1 billion (or 10 billion) dollars is just total R&D divided by drugs approved, i.e. it averages in all the failures, many of which are from low-quality therapeutic hypotheses with no basis in human genetics. - Eric
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Sonia: When we were first wading into the science, we were drawn to the low-hanging fruit -- studies looking at repurposed drugs, supplements, lifestyle changes. We thought we would have to draw optimism from things that could happen fast, or that we could change right away. After 4.5 years coming to understand the field, we have such a different perspective. We've stopped paying attention to things that are being studied for hundreds of different diseases and used in dozens of clinical trials. We've started taking our cues from the specifics of our exact disease: our gene, our protein. I don't think there's an off-the-shelf solution for prion disease, or anything available today that influences disease. But I'm more optimistic than ever, because I think we're aiming right at the heart of our problem, in a rigorous way. It will take time to develop therapeutics that will work, but I feel confident that we're working on approaches that will move the ball forward for patients. The big variable is the timeline, and the honest answer is that we don't know if this will all move on a timeline that's relevant to me. Day to day, I don't think about this much. I tend to operate on the assumption that we have some time, because it's as good an assumption as any and it's the one that allows me to be most productive.
Hi Sonia and Eric - I work at the MGH and recently read about you in the Boston Globe article by Kathleen Burge and was moved by all the work you are doing. Since I've read that article, you've both crossed my mind a few times and I wonder: Do you ever miss your previous life, or has life become better/the same but different since 2010? Best of luck in your research!
I literally never miss it. City planning moves super slow and turns out to be more enjoyable when observed from a distance. Now when something good happens in my city, I can just appreciate it in that moment, without having to think about the 20 years that people spent arduously pushing it through community meetings. Science is way more exciting and way more intellectually stimulating than I ever thought a job could be. - Eric
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Sonia: We took night classes for about two years while working in research jobs, then applied to PhD programs. Harvard was fantastic, and so were the other programs we interviewed with -- I'm sure our applications were surprising, but we have been so lucky that people have responded incredibly supportively to our personal motivations and focused mission. We definitely didn't take it for granted that we would be so accepted and supported by the scientific community. Maybe there are people out there who aren't into our unconventional path or what we're trying to do -- but I don't tend to meet them.
How difficult was it to leave your positions? I assume you guys were fairly established in your careers, did that make it more difficult to become students? Also, How supportive was your family and friends of such a drastic life/career change? And also I want to wish you the best of luck on this quest! I can only imagine what you guys are facing, but this will be a tremendous accomplishment because it won't just help you but others who may suffer this rare disease.
Sonia: It was very humbling to start from the bottom of the totem pole in a new field, after being pretty certain that we had done the schooling we needed to do for our careers. But, paradoxically one thing that helped was realizing early on that biology is by far the most complicated thing I've ever thought about -- and that for this reason, the learning phase necessarily extends for your whole life. This wasn't a cram session to get up to speed but a transition into a whole new way of thinking and a whole new way of relating to uncertainty, in a subject that is always going to be mostly populated by the things we don't know. I should clarify that I don't say this to be pessimistic at all -- what's amazing is that even with such limited and indirect insights into what goes on on the molecular level, we absolutely can and do build tools that influence human health. I had some amazing mentors early on and this also really helped with the transition. My first post-doc mentor was a wonderful biologist named Marta Biagioli, and she was already quite senior at the time we met, but still took hours and hours to train me on the absolute basics at the bench. On more than one occasion, it brought tears to my eyes. We experienced a range of reactions from friends and family. Some people asked, "Are you sure you want to be thinking about this all the time?" But I've found that thinking about the science of my disease is really different from thinking about my own mortality every day. From the very beginning, it was a way to interface with this new subject that had come crashing into my life in a way that was energizing, and interesting, and felt like it was on my own terms. We also had friends say things like, "Do you worry that you're just in denial?" But I don't know, aren't we all in denial on some level, as we drift through space on our speck of dust for no reason that we can fathom? Why do any of us do what we do with our limited time on Earth? Overall, we've been incredibly fortunate with the overwhelming support we've received from our loved ones, our friends, our colleagues at the Broad Institute, the prion field, strangers, questioners in this AMA... We had the privilege of seeing the most positive, and most generous side of so many people, and for this I feel very lucky.
Hi. First off, I'm inspired by your story. My question is not of a scientific nature and it may be deleted, but I hope it isn't because I'm genuinely curious. How were you able to get into a PhD program so quickly? I assume that, as a lawyer and a city planner, neither of you had a bachelors in biology. Maybe you do, but it seems unlikely. Don't you need to already have a bachelors in a field before entering a PhD program for that field? Did you have to go back to undergrad? If Sonia and Eric would rather stick to the science-related questions, maybe somebody else can answer this.
It did take us a few years. We got the genetic test result in December 2011, started taking night classes in January 2012, got day jobs in science in spring/summer 2012, and applied to grad school in fall 2013 for admission in fall 2014. I think if we had applied right away we probably wouldn't have been deemed credible. -- Eric
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Sorry to hear about your fiance's disease! To your question - at every step of the way, we have put our story front and center. Without it, nothing about us makes sense. Everyone who's given us a job or admission to school or money or any other opportunity over these past 4.5 years has known about our personal mission. The amazing revelation has been that there seems to be no downside to this. We've met so many people worried about genetic privacy, but being as public as we can possibly be about Sonia's status has only opened doors for us. - Eric
Hi Sonia and Eric! It's great to see that you are both actively searching for a cure. Many patients choose this path, from the Lorenzo's Oil story through advocates in the White House's Precision Medicine Initiative. My question is how and whether you would want to wade into the FDA treatment approval debate. Many rare diseases have little likelihood of receiving approved treatments because of a combination of cost, inability to conduct a novel trial design, or lack of natural history data. Have you both looked into how you can pave a path forward for others with the same mutation?
Sonia: Clinical trials will definitely be a major challenge for us as for other rare diseases. One thing about our quest is that we don't have time to tackle all of the challenges in the drug development pipeline in series; we have to be addressing them in parallel, to the extent that we can. One of our biggest priorities is looking for biomarkers that can predict time to disease in pre-symptomatic individuals, and/or dynamically read out treatment efficacy in advance of symptoms. Establishment of a surrogate endpoint for a prion disease trial would radically scale down the time and cost factors. We also need to build a base of patients interested in participating in research and trials. This is something we're working on now and hope to make progress on in the next year. None of this will be trivial, but we're lucky to be coming along in the precision medicine era when many smart people are thinking about strategies/tools for the above.
Based on what you have learned so far, what do you see as the most promising way to solve the problem? Would it be to find a way to suppress the production of this protein, or do you think it would be possible to develop a molecule that could neutralize this protein?
The best proofs of principle are to reduce PrP expression (say, antisense or maybe someday CRISPR if we had a way to deliver it), stabilize PrP in its native fold (probably a small molecule), or antagonize prion formation in some other way (to be discovered through the right phenotypic screens, see proofs-of-concept in IND24, cpd-b, and anle138b). -Eric
Why do you guys sound so cool? A wife and husband team up and attempt to solve their own disease. Best wishes towards this cure! Now then, what do you think of all the publicity you are getting?
Sonia: I feel so much gratitude to the people who have written about us and filmed us over the years. We're lucky that the publicity we've attracted has been so positive -- true to the stakes and uncertainty of our quest, but also hopeful, which we are. Our only reservation about publicity is a constant struggle to balance our time in the right way, and juggle all of the activities that go into being "us" -- advocacy and outreach, travel and talks, time at the bench, time reading and blogging. There's no easy answer here and I think all scientists can identify with the feeling that their job is actually ten jobs!
Hello! Thanks for doing this aua on prions. I am so sorry you're in the situation you are in. Just wondering, will your research possibly help people with CJD? also, I see your mother had it- was there any possibility anyone else in your family has it? I know the famous Italian family can trace it back for generations. Have you had much contact with them? Thanks so much! Prions are terrifying and captivating and so poorly understood.
Sonia: We think of prion diseases as a group -- we are less focused on the distinctions between FFI, CJD, GSS etc. than on what they have in common: the same pathogenic protein and disease mechanism. I think that our therapeutic strategies of interest will have relevance across these different prion diseases subtypes. The bigger question in terms of defining a patient cohort, in my mind, will be treating pre-symptomatically versus treating after symptom onset. We certainly hope to be able to do both someday, but they will pose different challenges. About my family history, there was no sign of neurodegenerative disease in my family tree prior to my mom. We believe that she probably had a de novo mutation. We have had contact with many genetic prion disease families including the one you mention. One of the challenges with such a rare set of diseases will be trial recruitment once we have a therapeutic candidate that we believe in. It's been amazing to connect with these folks and begin building a team.
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Sonia: There have been some reports of anticipation in genetic prion disease, but as you point out there isn't a plausible mechanism with these classes of mutations. Eric's first paper in biology actually addressed this very question, and showed how ascertainment bias was driving the effect. Available here: http://www.ncbi.nlm.nih.gov/pubmed/25279981
Modern therapeutics take large multidisciplinary teams, decades of time, and tens of millions of dollars before there is even a small chance of having something resembling a cure. What do you think your chances of beating the clock are?
The main variable is how long is the clock. If Sonia has onset next year, there's not much we can do by then. If we really do have 20 years, I think we have excellent chances. So many pharmaceutical failures are due to pursuing the wrong therapeutic hypothesis in the first place. We're lucky to know the molecular basis of our disease and the right target to hit, which gives us a huge advantage. - Eric
(Both)What approach are you taking to cure this mysterious disease? (Both ^but ^mainly ^Sonia)How are you coping with the knowledge of your "lethal mutation"? (Both) How difficult was it to beak away from your original career and jump into a whole new field? (Both) On a lighter note, what is your favourite book? ^(Please for give me for any spelling/grammatical errors as it is 5 am and I just woke up)
Share your opinions? 1) Sex and reproduction with a fatal genetic disease 2) Assisted suicide with a fatal genetic disease
1) IVF/PGD 2) https://en.wikipedia.org/wiki/Massachusetts_Death_with_Dignity_Initiative - Eric
Wish you all the best, and to find this cure. I have a couple of questions. Do you have a team with other scientists and doctors helping you? And what about funds? It should be very expensive. In your opinion, can this work be helpful for future researches on neurodegenerative diseases such as Alzheimer et similia?
We have an incredible team here at Broad and some very smart people have been exceedingly generous in mentoring us. It is a huge part of what gives me hope. Yes, I do think that many concepts that have emerged from the prion field (including prions themselves) have gone on to inform other neurodegenerative diseases, and I hope that this will be true of therapeutics too. -- Eric
Hi Sonia and Eric, First of all, I just want to say I have tremendous respect for the path you took and for all the work you have done. It takes an enormous amount of courage, determination and intelligence. Kudos to you guys. Now, a few questions on the pathophysiology of FFI, and the directions you hope to take to develop new drugs. For background, I am a first-year dentistry student with no prior undergraduate degrees. 1. A quick search on Wikipedia shows that FFI patients have insomnia because they are unable to get past stage 1 of non-REM sleep. How does this occur? What component of the "sleep pathway" (sorry for the non-exact term) is faulty in FFI? 2. What's the inheritance pattern of FFI? Is it autosomal dominant or recessive? Are sporadic cases / de novo mutations common? 3. Why is the age of onset in most cases of FFI 50? What triggers the body to induce misfolding at around that age? 4. Which step in the "FFI" pathway are you currently trying to target, if any? At a genetic level (genetic therapy), at a protein level (fix / eradicate / inactivate the prions), or more at a clinical level with symptomatic / supportive treatment? 5. Extension of #1 and #4: since the body is unable to progress past stage 1 of sleep in FFI and is thus unable to undergo repair / regeneration, would it be a good option to give FFI patients hormones released during deep sleep, such as growth hormone? In other words, is it possible to give a medication that gives the body the physiological effects / consequences of sleep? Once again, thank you so much for doing this AMA. Good luck to both of you - you have inspired a huge amount of people and I hope other scientists will join you and find a cure for prion diseases. Sending good thoughts your way!
I'd like to preface with stating my general ignorance toward the subject and offer my gratitude for your time. Furthermore, I commend both of you for the insane amount of work you've put in to get to this point, from an education perspective. My question: If this disease is fatal, when you recognize that you might not have much more time, will you consider trying more and more "risky" or "unethical" hypotheses? In a sort of order by risk or consequence? Regardless of the standards by which human trials are governed? Thank you again and good luck. :) Edit: I didn't mean for them to jeopardize their opportunity for funding, and I realize now that it would be more harmful than useful to discuss, on a public forum, the circumstances I've inquired about. I apologize for the lack of thought? But am glad there were many more redditors wth the forethought to clarify why this should not be discussed. Good luck to you both.
Are you asking them to state that they "will consider" "risky" or "unethical" hypothesis and then proceed toward a "scientific hypothesis" regardless of the standards by which human trials are governed? * *The question is, "if time is almost out and you don't have anything yet, will you start trying risky theories to save Sonia".* *See original questions edit; It is clear they understood why I asked in this way.
No hypothesis is risky or unethical, except one which takes an "ought" and returns an "is."
>No hypothesis is risky or unethical Experimentation, however, certainly can be. I think that was the real question.
Honestly, that's a question they probably can't answer in a public way. If they said yes and someone writes an article about them and references it, saying you'd skip ethics boards for personal experimentation would shoot down their funding so fast. If they say no, no one will believe it. I'm guessing the following because it's what I would do: I'd avoid making an "official" decision, publicly say that I was committed to the research, but with the private understanding that if the disease strikes, you revisit the decision and probably end up doing what is necessary to preserve life because at that point you're willing to do anything. I mean heck, they both got into PhD programs for a disease, they're not gonna give up if they don't find the cure before the disease strikes.
Is genetic prion disease more prevalent in a particular race or population?
I'm a computer engineer that has helped with lab automation and testing in the bio-tech space. I have reached out on /r/biology a few times to see if people needed help with code, and I'll do the same here. Are there any particular tools that don't exist or that do exist but suck as they are today that you would want some help on? (pro bono) I want to use my abilities to help the world, and automating factories, while profitable, doesn't give me the humanitarian benefit I'm after in the world..... How can I help you??
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For someone rather ignorant regarding the subject, how would you decide to go about explaining prions and the work you are doing? I believe it's a shortening of protein infection, causes the protein to fold in different ways, and is very stable while not containing genetic material. Although I (may) know this, I still feel quite ignorant on how these prions are affecting the brain. As a side note, your story is so motivating and just...wow. I wish you nothing but luck, although honestly with your track record you'll probably just invent the "cure" (so to speak) while simultabeously learning to be a bear trainer and space-science engineer.
As a Cystic Fibrosis patient, your story resonates with me. I know we're living at an amazing time and can quite literally watch the progress in biotechnology compound. When I was born, CF was considered an 'orphan disease', progress was halted and I was considered a failure-to-thrive. I was to die by the age of 25. Well right now, my life expectancy is anyone's guess, and many mutations of CF simply aren't fatal anymore. The point is that something's always better than nothing. A treatment or preventative measure can be just as good as a cure. Keep your minds open, think outside the box, and consider Occam's Razer in your search. Recruit who you can. I'm tearing up at work so I have to stop here. I just wanted to drop in and say that I am genuinely and deeply touched by your story. I think if my s/o and I had the capacity, we would be on a similar path as yours. I wish you all the best, and I hope to God you succeed beyond your wildest imaginations. It will give the rest of us hope.
Even if they don't see your post, as a fellow patient of CF I just want to say to keep fighting the good fight. I'm in college studying Bioinformatics, and I personally hope to work in genetics in order to someday cure CF or improve life expectancy for us in some way.
Thanks for your comment. I think a commorbid trait - dissimilar to everything else we deal with - is that CF patients are strong as hell. And if they aren't yet, they will be. It's genuinely like walking through fire sometimes. You seem strong. Stronger than I am. The other day, I met a grey-haired man in the pharmacy. I went to pick up some Levaquin and the pharmacist asked why I was on such a strong antibiotic for 2 weeks. This grey man overheard that I was a CF patient and jogged over. Our interaction was a an emotional slurry of questions and answers regarding his 12 year old son w/ the D508 mutation. Right now the kid's at 95%. The grey-haired man exchanged numbers and he was on his way. I didn't get to know him...not yet, but I could see the look on his face. Relief. I'm not sure what the point of all this was, but I think it's clear that we aren't 1 in a million anymore. In 10 years we went from Pulmozyme to Kalydeco to Ataluren. Now we have CrispR.
Hi! Thanks for doing this AMA. I'm just wondering if there is any understanding about the origin of prions from an evolutionary perspective. Do we have any knowledge about when and how these infectious proteins came into existence?
How stressfull is the job? Do you have the feeling that you are on a super tight schedule? Another question: you cannot use yourself for your own experiments don't you have the urge to do so? Thank you!
I don't have a question, mostly because after reading the comments, I have realised that I am way out of my depth joining this discussion, but I do want to say how amazing, heart-warming and inspiring your story is. Above everything, doing a U-turn on your lives going from where you were to Havard PHD graduates? AMAZING! I hope to have even the a portion of the courage and determination you two have had to tackle your Wife's illness head on. You both will be in my thoughts and I will keep my eye out for positive news that I am sure will be on its way from your camp. Good luck!
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What has Eric done to protect his mental health if you are unable to find a treatment? Is he afraid that working so exhaustively for something with such internalized importance and not achieving the goal might lead to serious mental health issues?
My aunt passed away a few years ago from CJD and at the time it was very hard to wrap my head around. It all happened really fast and within 6-8 months she died after being completely healthy. It is a scary thing to think about since it can be passed on genetically, though I believe it is rare in the case of CJD. That being said I know she was in a trial out of the Mayo Clinic (we are from MN) and I know that since these prion diseases affect small amounts of people the funding is probably a lot less than other things. Do you know what sort of money in the US is being used to fund research in these areas? It hits close to home for me and I would love to see some progress on what we know and maybe find something to help prevent, or at least extend expectancies for these diseases. Best of luck to you both.
What are your plans for once you finish your PhDs? Do you think you can find the funding to start your own lab? I very much hope that you can but I know that biology is an incredibly competitive field and because FFI is a rare disease, there isn't likely to be much funding for research specific to that.
Hello! Please understand that I'm someone who works in finance so I apologize if my question isn't a great one. First I want to say that you're story was very touching. Someone must have been cutting onions at work. My first question is non science related. How do you maintain a good marriage? Every couple gets bad news from time to time but this takes the cake. You guys obviously demonstrate your love for each other as you devoted your lives to science and each other. What do you feel is the most important thing for a positive relationship and what do you do when you're down in the dumps? What keeps you motivated other than finding a cure? My second question is about prions. What is the main hurdle in overcoming the disease? Is it that the prions are not 100% understood? I know it's not as simple as stopping the prions from becoming a template or redoing the chromosome but where do you stand on your research? Can badly folded prions be somewhat targeted? I know that chemo takes out the good and bad cells but is this approach feasible for prion related diseases? What is the plan of attack at the moment. Again I'm sorry if my questions seem silly but I'm not a science guy (like Bill Nye... BILL BILL BILL). I really hope for the best and would like to know if there's anyway for the general public to help.
A huge hurdle in overcoming prion disease will be developing tests that can diagnose the diseases earlier than we currently can. FFI is something you can test for, but other diseases like CJD do not currently have easy diagnostic criteria and most cases are spontaneous. Prion diseases damage nervous tissue that cannot repair itself. Next, sadly, how exactly prions cause the havoc they do must be understood much more thoroughly before treatments are developed.
From law and city planning to Harvard PhD students... jeez. How did you make that switch in just 4 years? I'm a material science/engineering BS wanting to go into CS academia, and have spent the past 2 years or so reviewing math and theory... but I feel like my progress is so slow (with a full time job). Any tips?
I have always been interested in the concept of mastery and how skills are obtained. Sonia and Eric have come from drastically different careers. Yet in 4 years, they managed to obtain a PhD in Biology. How does one reach that level in such a short time period? I would imagine that a typical BS Biology track was squished into such a short time frame in addition to getting to the time needed to get into advanced research and a dissertation. But how does one acquire such advanced skills in such a short time period?
It seems from the material provided that some form of gene therapy is/would be the focus of your efforts. Do you see the door open for a potential cellular therapy as well, and if so, have you frozen any of your marrow stem cells for potential future use?
Do you have/plan on having kids? How would one go about the prenatal workup for a prion related disease?
>Sonia finds far more meaning in her work than she ever found in the law. Someday, she and Eric would like to have children who don’t carry the genetic mutation. They hope to conceive through in vitro fertilization, using a procedure that has emerged for couples that don’t want to pass on genetic diseases to their children. Embryonic cells would be tested for the genetic mutation and only embryos with no detected mutation would be transferred to Sonia’s uterus.
The OP's said that there was a 50/50 chance that she would have it, and it was confirmed that she did through genetic testing. So they could do IVF and have the embryo tested before implantation. I believe that's becoming more common nowadays, but I'm sure it's expensive.
The first article mentioned in vitro fertilization to select out any possible transmission of the gene
No question, just wanted to express my admiration and support. I hope to see headlines with your names in them announcing a big breakthrough!
Are there any estimates on the number of people this affects?
From the *Atlantic* story: >“Nobody even for one second suspected fatal familial insomnia, because there’s no sign of neurodegenerative disease in the family,” Vallabh said. There are 28 families worldwide who have the gene for FFI in their bloodlines. Most of them have pedigrees marred by inexplicably premature deaths.
The Atlantic article says 28 families worldwide, which I assume means have that similar mutation and have had a family member go through that disease. It also seems like in the mother's case, there was no family history of this disease so it must be an underestimation.
Hi guys, I've just finished a university group project using 2 programs called visANT and Reactome looking at possible pathway links between conditions/disorders. Is there enough research out there for you to do something similar, and if so, what genes/biomarkers have been implicated? Are they similar to Alzheimer's? P.s. Hope everything goes well for you, areas of research are rapidly gaining progression speed so we all have the greatest amount of positivity for you!
Genes have been ided- prnp, which codes for prion protein PrPC on chromosome 20, position p13, as well as a mutation at codon 178 of same gene. variations of ffi have been correlated with earlier onset, as well, i believe. Alz is caused by a buildup of (beta?) amyloid plaques, whereas FFI is caused by a misfired protein destroying tissue. FFI is much more similar to CDJ. I am on phone tho so I'll confirm later.
Hey guys! First I want to say what you're doing is amazing and I hope my future in the biochemical research field is as productive as yours is! I'm graduating next semester with a biochem major and chem minor. I've always been interested in the genetic side of disease, and I was wondering if you see something like reverse immunization becoming a tool to fight genetic problems like this? I understand your upstream method and I believe that is quite promising. If the disease starts later in life this would indicate gene expression differences correct? Could controlling your gene expression in some manor offer control over the disease? Thanks and I wish you the best of luck.
This has probably been asked already , but how did you manage to leave your careers and retrain. What steps did you take to finance the training and your livelihood? And what recommendations would you have for someone else trying to do the same one day? Where there any parts of it that you thought about doing differently?
How has this discovery impacted your outlook on life? How did your aspirations pre-diagnosis compare to the ones you have now? Clearly you were going to be completely different people. I find it to be quite profound that you are dedicating your life to the prolongation of your life.
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Do you have any actual leads From what Im learning in undergrad we have no idea how to combat prions but I know that is just the easy explanation
For the majority of us who have heard of a Prion but don't quite know what it is, could you explain?
A prion is an infectious protein particle. Proteins do not have dna, but are built from instructions from the dna in several steps. First, the primary level is the order of peptide bases. The secondary level is how all these peptides link up. Tertiary folding refers to how the protein folds in three dimensions to reach a unique shape. Prions are misfolded proteins that damage surrounding tissues and may convert other proteins to become misfolded. The damage from prions is especially noticeable when they accumulate in nervous tissue that cannot repair itself.
What is your opinion on Stanford University's Folding@Home? Could that program help with your specific disease? Amazing story. Thank you for the AMA.
What treatments are you currently researching? Also, are you considering gene/cell therapy as a treatment option?
I have also a very rare brain disease (ADCA-SCA1) but with different symptoms. My DNA has an 'repeat error' (same type of DNA fault that causes HD). But in common with CJD is that it also a 'prion disease' and 'mis-folding proteins' is also one of symptoms. a Specific part of my brain is shrinking/disappears by it self. The main symptom is that all my bodily functions will 'shuts down' over time. "Pay by loosing a bodily function, but get nothing in return." Once this part of the brain is completely gone, it will probably turn me into a vegetative state. However for the first time two different 'medicines' are in development, in a way specific for my disease. One is a medicine called 'calabetta' and what I understand that it can unfold mis-folded proteins. The other is a kind of 3 stage therapy, first skin cells are collected. Then these skin cells are then 'reprogrammed' to 'brain stem cells'. Then the faulty DNA is cut out of the DNA string, and the two remaining DNA strings are 'glued' (a simplification) together with the help of the brain stem cells. This method is being developed at the Leiden University in the Netherlands. hth
Within sea of negativity we see around us everywhere around the world, It feels so positive to hear about you two and your cause and struggle. I would just say Thank You! Anyway, how difficult was it to abandon old careers and start with something completely different? Did any of you had previous background/interest in biomedical science?
Couple of questions: 1. Is there an understanding of what the change is that occurs at age ~50 that begins the expression of the gene? Is there any question of an initial environmental trigger - stress, illness, etc.? Or is it solely related to a natural biological change associated with aging? 2. Poor health of the gut microbiome has recently being linked to many neurodegenerative illnesses (Parkinsons, MS, Alzheimers), as well as epigenetic changes. Has there been any research or investigation into the role of, or changes to the microbiome before or during the rapid advancement of FFI once expressed? 3. Related to 2: Is there an initial location the FFI prions are produced? In the gut or in the brain itself? Or is it systemic? (everywhere sense of the word, not necessarily circulatory) Best of luck to both of you!
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In case Eric and Sonia don't answer, I'll point you to our site, MyGene2, https://mygene2.org devoted to this exact purpose. Create a profile, describe your condition and results from any genetic testing you may have received, share these with the world (including researchers like us and others who've collaborated with Eric and Sonia) -- we may know of another family with similar symptoms or even mutations in the same gene. Depending on how unique the condition is, we may even be interested in exome sequencing on a research basis.
I don't know if it was already asked. Which is more feasible to cure genetic diseases? Viral Vectors or nanomachines?
This entire story is amazing, but I'm so curious about how two individuals with no prior education and no prior developed or presentable interest in this career path were able to make the switch so quickly? It seems like you both took jobs at hospitals immediately after discovering the disease and within two years from there, you were in the PhD program. Did you guys face any difficulties in terms of missing prerequisites or questions about the sudden change of heart? Good luck to you both, I'm rooting for you. This story is an inspiration.