This is a must-read, a very interesting article about a very terrible disease. Dr. Kaplan is a professor at UPenn where I'm a Bioengineering major. He gave a lecture to one of my classes about FOP and it was so inspiring to see how much progress he has made on a disease with only a handful of cases that was supposed to be impossible to cure. Imagine trying to cure a muscular disease where you can't even biopsy the muscle of your patients! Dr. Kaplan is an amazing man I hope he kills FOP in his lifetime.
Agreed, and fascinating. To me, an article like this is better than any action novel. Found myself on the edge of my seat trying to figure out how far he'd managed to get! I think it's a perfect look at how building on other people's science is how we really get things done. What if he'd overlooked that paper that unlocked everything for him?
This snipped sums it better: "To be displayed in human form, skeletons have to be re-articulated or pieced back together with fine wires and glue. As a result of the bridges of bone that formed from FOP flare-ups, Harry Eastlack's skeleton is almost completely fused into one piece, which proved little challenge for the articulator's craft"
I think basically, the family agrees to an autopsy and there is a branch of medicine, pathology, which specializes in obtaining and preparing tissue samples, primarily for investigation into the causes, progression, and severity of disease. They are the ones that "scoop out the brain" then mount them on slides, stain, etc. With whole skeletons, I'm not sure - usually after autopsy, the "parts" are either put back into the body or otherwise interred in a container. I think maybe the family arranges something w/ the embalmer to remove the muscle and connnective tissue from the skeleton.
I think yes, the process is more or less this, really
After tissue is removed and preserved (samples), then in this case I believe the removal of soft tissue is done chemically, probably with a caustic substance.
Yes, this is as far as I go imagining this. Or maybe there are biological means as well
I saw a show where people make skeleton models and they used a type of bug to clean off the bones. Using certain chemicals would make the bones rubbery, whereas the bugs would leave a perfectly clean bone.
As the article mentions, Harry Eastlack's skeleton is on display -- along with many other medical anomalies -- at the Mütter Museum in Philadelphia. It's an interesting museum and definitely worth a visit if you are nearby:
This is a fantastic article that is extremely well written and does an excellent job of conveying the science. I think one of the more interesting side-effects of cheap DNA sequencing tech is that we're starting to find out that while any individual rare disease is rare, in aggregate, rare diseases are actually quite common. This also means that many common diseases (especially ones whose causes have eluded researchers) may actually be a constellation of rare diseases that look the same from our 20,000 foot view.
Fortunately, cancer is one such disease and it has the advantage of a healthy funding stream plus significant public mindshare. I suspect many of the techniques we are just starting to use to discover the causes of cancer and personalize therapy will start to be applied to rare diseases. These diseases will effectively get to capitalize on all the "infrastructure" that we've been working on without having to bear the cost burden of the inevitable 10's of thousands of dead ends that come with this kind of work.
To expand on your comment "rare diseases are actually quite common", I was struck by this in the article:
More than 7,000 such diseases exist, afflicting a total of 25 million to 30 million Americans
That's almost 10% of Americans! I suppose this shouldn't have been surprising given the Birthday Paradox [1], but the ~1/10 statistic puts things into perspective for me.
That means most of them must be mild. Because, clearly, 10% of Americans don't have something as serious as FOP. There's probably a long tail of increasingly rare and increasingly mild diseases, so that the cutoff is arbitrary.
Mild, or self-limiting or otherwise transitory. I know (closely) three people in two different countries who have a 15/100,000 disease that is self-limiting.
It wouldn't be very surprising to learn that every single person has some kind of genetic defect -- perhaps dozens -- but usually the compensatory mechanisms are strong enough to mask them, at least while you're young and strong overall. It makes a lot of sense that health should be a spectrum or a kind of dynamic equilibrium, rather than a binary on-off condition.
I know someone with FOP, and this pretty much fits his experience. His is a mild case, but he carries crutches because his knee sometimes locks from one of his attacks -- muscle sprain in childhood -- and he needs its support. He's also talked about the pain going to the doctors becomes at times, because pretty much everything is handled by specialists, or with their consultation, and he just wants to get on with life.
One of the things that this article doesn't touch on, though, is the difficulty in getting treatment and effective care for comorbid diseases. Because these diseases, especially things like FOP, can manifest in odd ways, they tend to lump all of the other abnormalities together, even if the other symptoms run completely counter to what the disease does to others. So, standard diagnostic batteries for the other diseases aren't run, even if such a diagnostic would be useful in managing body issues that can and do come up. Thankfully, though, he's managed to get a decent amount of day-to-day coping skills with his other disease (Ehlers-Danlos Syndrome) from the internet. It still would be nice for him to get a firm diagnostic, so that interactions and symptoms could better be monitored.
The fact that the subject of the OP was diagnosed fairly quickly struck me; more often than not, as you mention, rare diseases are misdiagnosed or completely missed. I've often wondered if someone hasn't done a long term statistical analysis of the probability of seeing rare diseases. It's one thing to think you have a rare disease (and is statistically very unlikely), but if you are a doctor seeing already self-selected ill subjects, wouldn't that change the probabilities significantly? I know modern medicine is quite mentally taxing, and most doctors are trained to be conservative, but maybe just emphasizing the fact that the statistics are different for the population of people seeing doctors might go a long ways to convince doctors not to automatically lump illnesses into the most common categories.
That, and making the tests cheaper (like all of them, virtually zero cost; who wouldn't just throw every test they can think of at a problem if the tests were dirt cheap).
A fascinating, excellently written article; a prime example of high-quality, long-form writing I enjoy reading.
A very human story that includes one of the most intriguing forms of "hacking" I know of--working to understand and manipulate our complex biology to improve human life.
It is fascinating the ways in which studying rare diseases leads to discovering more information about how our bodies work under normal conditions--discovery that may not have been realized otherwise.
What amazed me is that Jeanne Peeper was able to essentially do a pre-internet Kickstarter and raise funds for Kaplan to perform his research, hold a conference, and hire a geneticist.
With the power of the internet and how easy it is to set up a phpBB forum, sufferers of rare diseases don't have to live in isolation any more.
AT the moment, not really, but the communities of rare diseases often have put together a nonprofit foundation for fundraising, etc. The grants are really not big and don't really fund serious research in that they are a fraction of a typical NIH R01, R23 or K grant, and typically do not cover indirect funding (i.e. the slice of the pie the university or hospital takes for "overhead").
I think there is a scientific "kickstarter"-like startup that made the rounds here on HN a while back, though - maybe that could fit the bill? the name escapes me at the moment though.
> A rare disease is defined as any condition affecting fewer than 200,000 patients in the United States. More than 7,000 such diseases exist, afflicting a total of 25 million to 30 million Americans.
Can that really be true? 1 in 10 Americans has a rare disease?
I haven't been able to find a good source, but here's what the NCBI says:
"In part because data on many conditions are limited to case reports or special population studies, no well-supported estimate exists for the number of people collectively affected by rare diseases. A 1989 government report stated that 10 million to 20 million Americans had a rare condition (NCOD, 1989); the corresponding estimates in 2009 range from 25 million to 30 million (see, e.g., ORDR, 2009). The estimates were not accompanied by analyses or substantive citation of sources." http://www.ncbi.nlm.nih.gov/books/NBK56184/
The links in the footnotes lead to 404s, but this might be what they're referring to: http://rarediseases.info.nih.gov/asp/resources/ord_brochure....
It doesn't cite sources though and it calls it an estimate. It also says disease or condition, so I'm guessing it includes minor stuff that most people wouldn't really consider a disease. For example, my friend and her mom both have weird ridges on their thumbnails; definitely rare but it doesn't affect their health. Things like that are probably included in the estimate.
Why not? If 7,000 diseases exist and 30 million Americans have them, then that's an average of about 4,300 people with each disease, far bellow the 200,000 threshold. Obviously, they aren't all near the average, but there's plenty of headroom.
I know this is a stupid question, but the article states there are more than 7000 (but presumably less than 8000) diseases effecting 1 in 200000 or fewer, with 25-30 million suffers in the USA.
With a population of 300 000 000, * 7000 / 200 000, shouldn't that be about 10 million?
I was wondering about that stat - their estimates suggest that of the 7,000 "rare diseases" which affect <200,000, they each affect, on average, around 4,000 people. Would be interesting to see how that distribution looks on a graph.
You misread it - it says a rare disease is a condition affecting fewer than 200,000 patients in the United States., not 1 in 200,000 or fewer (in other words: those rare diseases aren't that rare; according to this definition, 1 in 1,500 people can suffer from a rare disease)
So, the math should be 7,000 rare diseases times at most 200,000 sufferers per rare disease = at most 1,400,000,000 sufferers for all rare diseases combined. The actual number will be way lower because many of those 7,000 will be much rarer, because some people may have more than one rare disease and because there simply aren't that many people in the USA.
From farther down in the article: "'I’ve seen 700 patients with FOP around the world, and it’s clear that there’s a lot of different ways to divide patients,' Kaplan said. One identical twin might be only mildly affected, while the other would be trapped in a wheelchair. Some patients developed a frenzy of bones as children, and then inexplicably stopped. 'I’ve seen it go quiet for years and years.'"
Wow. That's an important clinical clue, that discordance between identical twins. That suggests that the disease is not best described by a single-gene mutation, strong expressivity
simple Mendelian model. And that means that there is something else going on in the clinical expression of the disease besides the gene mutation, which might provide some traction for effective treatment.
The last part of the article sums up some interesting ways that insights from rare disease research can help physicians better understand human physiology and perhaps come up with ways to treat more common diseases. A very interesting read.
It could also be difference in circumstance. Note that the bone growth occurs as a response to muscle damage, so a more active child who suffers a higher incidence of standard bumps and bruises would be more likely to have more ossification.
Yes - I think people refer to this as penetrance. I.e. there may be an overall inheritance pattern but additional factors (environment, additional genes, exposures) are needed to cause the expression of the abnormal gene. A lot of conditions are autosomal dominant but incomplete penetrance, and researchers can roughly quantify the percent penetrance of specific conditions.
For me, one of the most important things to take away from this story is the possible link to osteoporosis (& a cure for it, although not directly stated). Looking into a disease that affects almost no one might help find a cure for a different one that affects one in ten people.
This is why we must also fund the study of "pure science" - of studying things purely for the sake of learning, with no idea ahead of time if we will learn anything "of value" or not.
Because there is so much that we don't understand yet, that it is impossible to study the "why" of anything that exists in the world without stumbling across something of more practical value.
Wow. See also "Tupac Shakur and the End of the World", a short story about a similar condition, caused by a latent virus and triggered by minor injuries. Everyone dies.
I hadn't realised when I read it that there was a real-world equivalent ...
The Mayo doctors didn’t tell Peeper’s parents that. All they did say was that Peeper would not live long.
It's unclear from the article how much was known yet, but if they knew the growths could be triggered by bruises and other insults, I sure as hell would've wanted to be told.
It is tragic that certain individuals lives are effectively destroyed by losing a genetic lottery, but in the end genetic diversity allows a species as a whole to adapt and deal with unexpected changes in their environment. Even for mutations like FOP there's the possibility that it could benefit humans in the long run.
Perhaps a slightly altered form of expression would allow for faster bone regeneration or a reduced chance of osteoporosis. The most relevant example I can think of is Sickle Cell Anemia. Having homozygosity for the mutation causing SCA leads to a multitude of complications and higher risk of death, but heterozygous humans have a significant increase in resistance to Malaria. Mutations are a blessing to some members of a species and a curse to others, but without them life as we know it would never have existed.
Yeah I feel that way about a lot of articles on the web. And this article for example I didn't read until it had several hundred points on HN which implies it would almost certainly be worth the read.
I skip over tons of articles on news websites and have been wondering for years if it would be possible to filter the headlines on news sites to avoid even seeing the 'human tragedy' stories that fill the news these days.
>Does anyone else feel this way about this and other things?
I'm finding this hard to articulate, so I'm just going to "speak".
I've felt the way you describe at times, but think it's good to face such things. I was forced to face crippling illness and death in people very close to me several times before I turned 30.
These possibilities are in us. There's no matter of deserve in play, it just is.
I don't continue to look and read about something like this to gawk and be entertained or desensitized, but to become slightly more educated, thankful and just maybe prepared.
Would be nice to know why I'm being down voted for having an opinion on an article I'm not used to reading that I deem as being quite emotionally upsetting.
Are other people devoid of emotion and enjoying reading it?
It's possible you're getting downvoted because of the way you phrased your post.
>> At the same time so upsetting that I am unable to completely read it all.
At first I interpreted this as, "[it is] so upsetting [because] I am unable to read it all". It makes it sound like you're complaining that the page didn't load all the way, or something. I had to read it a few times to understand what you meant. It could have been less ambiguous worded as, "At the same time, I am unable to completely read it all because it's so upsetting". If a reader misinterprets this sentence, the rest of the post becomes incomprehensible.
>> Time to Google if this is 'normal'
"this" is a bit vague here. What do you want to know is normal? Being upset by articles in general? Being upset by articles specifically about rare diseases? Being upset by this specific article?
>> Starts to Google.
Narration is the kind of thing I'd expect to see in a chat room, but not HN. It makes your tone much less formal, and some might see that as inappropriately flippant for a serious topic.
>> Does anyone else feel this way about this and other things?
"about this" is vague, again. The "and other things" clause makes this question so broad that it becomes tautological. "Does anyone else feel [upset] about [things that are upsetting]?"
I didn't mean anything around the page loading, just that simply was interested if people found the story of the girl's experiences heavy to read on an emotional level. Thus I was interested if I am emotionally weak dealing with this compared to others, why that is and if it's normal to be so shocked by something.
Your comment didn't add anything to the discussion. You liked but couldn't finish reading the article... well, how is that useful information, why would anybody care about what you read? The comment is fluff and noise, not worthy of occupying space higher up in the thread among posts with real informational value. The downvotes weren't for having the opinion, they were for making a post that conveys no interesting content or information.
(I didn't downvote, but I understand the mindset of those that do.)
It is an interesting and well written article about a disease more than 99% of us are fortunate enough never to have.
I think the downvotes you are recieving reflect how on the internet much of the discussion going on is a result of people merely reading the title, and maybe half a paragraph and then moving onto the comment sections to argue about points that were already covered in the article itself.
Which, judging purely by your comment, you appear to have done.
It shows the value of rare genetic disorders for biological and medical research, but I'm not sure it speaks for or against eugenics, it's a complex question...
Look at it from the point of view of an eugenics proponent: this disease is a good example of a genetic condition that you don't want spreading in future generations. Once we have treatments for the 7000 rare diseases mentioned in the article, we will have removed the evolutionary pressure that was keeping these diseases rare. Some eugenics supporters are afraid we are heading towards a society where everybody has to undergo a dozen lifelong treatments due to medicine effectively undermining the process of natural selection.
I can also imagine parents suffering from this disease, not wanting to pass it on to their children. So people affected might strongly disagree with you...
I guess you could say taking any position to an extreme is bad. However each of these diseases opens paths to future cures. It helps us understand human body better. And those cures will open ways to more ideas, etc. Without diseases we'll never have a chance to explore. I'm not negating those defects don't leave their parents in despair, but I speak from a position of a similar though magnitudes way milder defect (hip displacement). Eugenics taken to extreme would have discarded me.
Eugenics on small scales does have some advantages, though I fear it would bring advantages in a way that will only widen inequalities i.e. only people with money would have enough money for it. Rich people wouldn't just have money, but also best looks and best health.
Eugenics on large scales is on the other hand simply disastrous as it leaves monoculture and erradication of anything perceived as abnormal.
This assumes that by removing the disadvantage that it automatically confers an advantage to those that are treated. They still need a genetic advantage to flourish. Granted there may be an uptick in people that carry the defect by the shear fact that it is no longer an disadvantage but that does not translate into a society where everyone suffers from this defect. Unless they carry some latent advantage that could not be recognized because of the sever genetic disadvantage. I prefer to look at it as we have moved past that disadvantage in much the same way that we moved passed smallpox, some of smallpox was nature and immunity the other half was eradication. I see us doing the same thing, just speeding up the timetables now that we know some of the mechanics to do so.
I know next to nothing about the dynamics of gene transmission (if someone does please shed some light), but it seems quite obvious that the less evolutionary pressure you have against a gene, the more prevalent it will become.
My intuition is that evolutionary pressure works against entropy. Without the pressure, the genome would evolve towards a state of maximum entropy, i.e. a particular mutation would reach a prevalence of about 50%. But of course there will always be some sort of evolutionary pressure.
I would expect more of a random walk. I suppose that very slowly genes would mutate by themselves, but as far as having certain genes spread, two kids multiplied by 50% chance equals the same number of people with the gene, generation after generation.
Let's consider a simplified model, where there are only two different bases (A and G instead of A, T, G, C) and assume that the probabilities of mutations A->G and G->A are the same. Let's consider a single base mutation[1]. No matter what the mutation probability is, and no matter what the initial distribution is, I expect that the population will converge to about 50% A and 50% G. I guess you would agree.
Now if we make this very wrong model a bit less wrong by including the four base types A, T, G, C, we can expect that each allele will be found in about 25% of the population. And that is for single base mutations only. A mutation that depends on the precise value of 5 different bases would be displayed by a much smaller share of the population (1/4^5 = 0.1% I guess).
Of course people don't get born with fully random genomes like that, the vast majority of these mutations would not yield a living embryo. But still, the intuition we can get from this is that without evolutionary pressure, a particular mutation will eventually be found in a fraction of the population that is inversely proportional to the complexity of the mutation (in most cases that would be far from the 50% of my initial intuition).
No idea how close these layman's speculations are from the reality...
>Some eugenics supporters are afraid we are heading towards a society where everybody has to undergo a dozen lifelong treatments due to medicine effectively undermining the process of natural selection.
So if you get cancer and there is a cure for it, you won't forego treatment to help natural selection work? What type of twisted logic is that?
People should not be treated because it would spoil the gene pool
but rather
We certainly want to treat diseases, but this will spoil the gene pool unless we prevent the spread of bad genes
Solutions to prevent the spread of bad genes range from quite evil (forced sterilization has been used extensively before WWII but I have never heard of something as bad as denying treatment) to slightly controversial, e.g. screening of embryos [1].
By the way, I have just stumbled on the Wikipedia page on dysgenics [2], which is more specifically what this argument is about.
What is a bad gene today can as easily be a reason for the survival of a species as it can be a reason for the opposite. We may or may not be able to predict the effect of a gene on a population. But the question is not that.
The question is whether a person with 'bad' genes should have children or not. My answer - it is none my business! Whether a person has good or bad genes, he/she should be free to procreate. It is their choice. Provide pre conceptional counselling and let them decide.
I agree on most of your points. A gene that is a burden under present conditions might prove a gift in a different environment or against a future disease, and anyway nobody should choose for someone else if they can have children or not.
However the question is not if someone should have children or not. Genetic screening technologies are moving fast, as is our understanding of the human genome. The real question, that will take more and more importance in our society is Do I want to screen my sperm/ovum/embryos when I decide to have a child? and maybe Should genetic screening be mandatory in certain cases?
>Should genetic screening be mandatory in certain cases?
You find a "bad" gene, you tell the subject about it and inform them that their children might/will have it too/will have a certain condition.
If at all required, mandatory screening and advisory would be the extreme limits of what should be allowed(But what conditions would require mandatory screening and how are you going to screen two people before they have sex? Think about the logistics and the invasion of privacy!). Even in those cases, the government shouldn't have the power to sterilize the subject.
You can run educational campaigns. Teach people this stuff with sex-education or have married couples take a course(you will still miss out on a lot of people).
Eugenics takes away a basic right of a life form.
Update:
I understand that you may be speaking about people who have been diagnosed as having a certain genetic condition. If a disease has the capacity to cause public harm, there are exceptions made to the professional secrecy that a doctor is supposed to maintain. This involves informing relatives/a potential spouse about a condition that the patient may transmit. In cases of infectious diseases, quarantine and isolation procedures are well established. But most are for infectious conditions which can harm the public. So if the off-springs of individuals with bad genes can infect large number of people with some contagious condition, isolation protocols may apply. But that is still hypothetical.
If we dream up an horrendously bad genetic condition which can disrupt the human race, someone is going to come with horrendous regulations to prevent that. But the truth is most people suffering from "bad" gene induced conditions do not lead a normal life(do not have kids). If the sufferer of a genetic condition can easily have kids, then that condition may not be that "bad". Carriers of such genes could do with some pre conceptional counseling.
Sorry, I misstated THE question. It should be whether regulation rocreative behavior of people is our business at all. That and the point about counseling stands.
whether regulation of procreative behavior of people is our business at all
That's the question of whether genetic screening should be made mandatory in some cases... I don't think so, for the reasons you mentioned.
But I'm more interested in the other question, regarding voluntary screening of sperm/ovum/embryos... I wonder how big this will become in our lifetime, and how people will react to it.
Thank you for your time and effort to explain this.
Well, honestly, this smells national socialism from a mile.
Which genes are bad? Is it really that genes are bad? What about their mutations?
I have (not really suffer) ehlers-danlos type 2. Which is genetic disorder. Some people with it - like me - are lucky and have it really benign. It doesn't really affect my life in any way. It doesn't affect lifespan in my case. Then there are some others - with exact same gene mutations - who suffer constant pain to the point they would like to die (literally). Not to mention constant medical emergencies.
Now, I have almost no problems because of eds. And one benefit - apparently I have lower risk of colon cancer. (there is more bile in the system which is laxative which helps preventing colon cancer, plus the colon is built differently, in my case causing "stuff" to move quicker). So, how would you know my gene mutation is good or bad?
And how do you know that if you change it, something else won't be totally messed up instead? There is always the problem of unintended consequences.
Not to mention that once you would open this pandora box, you'd also need to deal with prospect parents demanding "gene therapy" for their future kid because of a gene they think is bad. Like with cosmetic surgeries. People with gene A have higher risk of being short, so please doctor, please, let's "fix" that. Our boy can't be short! Can't have red hair! Can't have 40% higher risk of being depressed or obese too.
I'm confused why this debate even surfaces. Of course you don't forcibly sterilize people.
I imagine the modern eugenics argument is about manipulating chromosomes rather than forcing people to not reproduce. IE, once we can selectively make the perfect human from a genetic standpoint (considering only using genes that promote intelligence / stamina / longevity / etc) that it becomes unethical to continue playing the genetic lottery and having children with FOP or down syndrome or some other life destroying condition.
Which I guess says sterilize everyone and grow people in tubes (or wombs until we can get that far). At least it is fair!
Totally! I think your example is a good illustration of the difficult questions we will face as genetic screening becomes more and more practical and affordable, thanks a lot for sharing. (I can't help but wonder what you would say to a doctor that tells you, "So do you want me to press this little button to make sure your children won't have the same condition?")
However, it might also be that in the long term, the quality of the gene pool objectively deteriorates. Taking it to the extreme, imagine if nobody can grow older than five years without medical assistance... I guess this is also something we should consider.
>imagine if nobody can grow older than five years without medical assistance
I think that way before that happens we'll have something like "virtual", "immortal" "bodies".
In other words I think that before we need all that medical care the original William Gibson's idea that we'll all end up stored somewhere in a computer memory connected to a network will happen. No body or genes really needed - we just "sit" in RAM, interact with others via network and are - immortal. Ray Kurzweil says it may even happen in our lifetimes. Heard Stephen Hawking mentioning something similar. Reaching point that we can live forever and don't really need our body for that. Or our body can be strengthened by armor, hardware of various types, to be much better and advanced than our bodies are.
This reminds me a little bit the dilema local Government in Paris had in 1890s -- what we'll do with all the horse dung if the number of horses grows at the current rate? And then cars came along and it was all irrelevant.
Seems to me it's also the same with depopulation. Who cares if there will be 20 billion of us in 50 years if we finally start colonizing other planets and the Moon?
Cancer is a very poor example when talking about eugenics since 1) most forms of cancer are non-hereditary and 2) cancer also rarely requires lifelong treatment, instead you either get cured or die (it can resurface though even when you think you are cured).
And for eugenics to work you do not need to die, just not get any kids, which is why Sweden used to have people sterilized.
One of the strongest arguments against eugenics is that when it has been applied in practiced it has brought out some of the worst sides in humans.
"lifelong treatment" means that it's not cured. You have lingering effects that are barely held at bay by your drug cocktail. It's not a state to look forward to.
I interpreted your comment as a rude remark dismissing a long explanation from jkn for why this article could easily be used as an argument for eugenics.
EDIT: BTW, down voted your comment above for being offtopic. So is this one so I wont blame anyone if they downvote.
