Face transplant recipient’s donor face now failing | Hacker News Reader

Face transplant recipient’s donor face now failing

latimes.com

134 pointshsnewman104 comments

This is to be expected. Any time we do any transplant immunosupressants are given to the recipient for the rest of their life, but this only slows the inevitable. Heart transplants recipients all get accelerated atherosclerosis. Lung transplant recipients all get long term fibrosis. We buy time with these procedures and do everything we can to keep them going, but if you have a transplant, you're in a really bad spot to begin with.

I wonder how long it will take until growing organs from the recipient's own stem cells is actually viable. There definitely is some interesting research, and it would completely circumvent the problems with the immune system.

This issue is why I started Forever Labs (YCS17). We bank your stem cells. Immunity presents many difficult problems to be solved. I’d rather worry about the therapeutic developments alone rather than add immunity on top of it.

I'm a little curious how something like this works within the economic framework of a startup. How do you reconcile the inherently long-term nature of your business (I might need my stem cells in a decade or two) with the inherent instability of a startup (you might go out of business within 3 years)?

The annual storage fees ($250/yr) cover our banking costs. The banking needs little more than invoicing to remain viable, and with the numbers we have banked, it could survive as a stand-alone entity, or would be an asset that could be acquired by another banking service. My cells are in there, as are those of many of my family members. I want them available 20 years from now. Of course, we aspire to mature beyond a startup, and are getting there. :)

What is the value prop for extracting and storing stem cells now vs. extracting them later? Is it just that you’ll have to extract less bone marrow now vs later? Isn’t there a decline in quality and quantity of viable stem cells when they’re stored?

There's actually a significant decline in quality and quantity that continues with age. That's why we cryopreserve them. If brought down to liquid nitrogen temp properly, they can remain viable nearly indefinitely.

Thanks for this. I had no idea this was the case, and have long operated under the erroneous belief that most transplants basically worked and left the recipient relatively problem-free afterward—well, at least as far as the transplant was concerned. It is odd to learn that transplants are a time-buying exercise.

I just finished up an introductory biology lecture series, and this suddenly makes less sense to me than it did before. What is it about the foreign cells that is identified as foreign by the host cells? The cells ought to be remarkably similar. They're human, with the same function/pluripotency using the same protein interactions. So why attack it?

There's a lot more to immune response than "does this look like a human cell?"

See, for example, blood types, where giving an A type person B type blood will cause serious issues.

Each human has a largely unique signature of HLAs (https://en.wikipedia.org/wiki/Human_leukocyte_antigen).

The whole point of this, evolutionarily, is so that a parasite that thrived in one human body won't necessarily thrive in another.

This is also why many species reproduce by sex.

Because it's part of the arms race with pathogens that has been going on for a billion years since multi-cellular life first appeared. Pathogens do lots of very clever things to hide from the immune system, so the immune system is tuned to detect very subtle changes. The body largely operates on zero-trust network models, except for a few locations where the benefit of a too-active immune system has serious consequences to the fitness of the organism. The eyes and the testicles are good examples of that in humans.

I guess auto-immune disease is an example of where it also goes the wrong way for somebody. Probably most of us know somebody with IBD, lupus, or any of the others. It's very common for the body to reject something benign, or ourselves.

Type 1 diabetes is a good example of this, where the body detects its own insulin producing cells as threats and eliminates them. Lots of the research in type 1 treatments isn't just about producing insulin, but figuring out how to prevent the body from destroying it again without all of the risks of immunosupressant drugs.

To add to this: if the immune system would just check that the cell is human then every invader would just evolve to pass that check. The only viable way to defend is to mark the cells as belonging to this specific human. That way even if some bacteria evolves to trick my immune system it's unlikely to also trick yours, and the infection can't spread.

Additionally, if the immune system would just check that the cell is human, then humans would be vulnerable to contagious cancer, such as the facial tumor disease suffered by Tasmanian Devils

https://en.wikipedia.org/wiki/Devil_facial_tumour_disease

Humans almost certainly are vulnerable to contagious cancer (there are a few known in other species: https://en.wikipedia.org/wiki/Clonally_transmissible_cancer) . We just haven't acquired/discovered any yet.

HTLV, EBV, HPV

you better believe we have! It’s just rare (thank goodness).

Those are cancers caused by viruses, and it's the viruses getting transmitted.

On the other hand, clonal transmission refers to the cancer cells themselves leaving sick individual A, entering healthy individual B, and continuing to reproduce there.

You could use transmissible preleukemia (eg CHIP in allo transplants) as an example if you wished.

Direct unassisted clonal transmission in humans seems likely but, as you noted, it hasn’t been documented to the extent that Tasmanian Devil facial tumors have.

Warts are a corner case. I’m not sure whether it’s been determined if some hosts end up increasing the fitness of the shed cells. If so, that’s quickly heading towards a globally transmitted precursor lesion.

This weirdly reminds me of public private key authentication

> except for a few locations where the benefit of a too-active immune system has serious consequences

For anyone else curious about this, https://en.wikipedia.org/wiki/Immune_privilege

This seems to answer it https://www.sciencealert.com/this-protein-could-explain-why-...

Dendritic cells 'teach' lymphocytes what a foreign invader is, right most of us know that from high school, but here's where it goes beyond me:

>They found that differences between the mice donor's and recipient's SIRPα gene correlated with the recipient's immune responses.

SIRPα isn't an unknown protein, already understood to bind to another protein called CD47 that triggers a range of immune responses in different white blood cells.

>Joining the dots, the researchers believe CD47 on monocytes – the white blood cells that grow into dendritic cells – interact with SIRPα receptors on foreign tissues, setting off the entire ID check process.

>"Once these cells are activated, then they turn around and activate the rest of the immune system, and that leads to the full-blown rejection of the organ," lead researcher Fadi Lakkis from the University of Pittsburgh told Liz Reid at 90.5 WESA.

Here's the paper https://immunology.sciencemag.org/content/2/12/eaam6202

This seems to be the relevant bit

>Using an elegant positional cloning approach, Dai et al. have identified polymorphisms in the mouse gene encoding signal regulatory protein α (SIRPα) to be key in this innate self-nonself recognition. They show that SIRPα receptor CD47 binds SIRPα variants with distinct affinities and propose this affinity sensing to be the mechanism that triggers dendritic cell maturation, the first step in the initiation of the alloimmune response. Given that the SIRPα gene is also polymorphic in humans, it remains to be seen whether human SIRPα variations influence transplantation success.

Probably has some sort of MAC address identifier that can detect whether something if different than the host DNA, but I have no idea nor experience in biology.

I’d say it’s probably more like some kind of checksum against the DNA. If the body detects something has been changed from what was there before it dispatches the white blood cells to kill it off. Immunosuppressants are a way to bypass the checksum, but only for some limited time. Maybe we need a way to change the checksum values altogether, but then the whole body could be rendered rejected and cease to function (death).

This is actually an issue in graft-vs-host rejection for bone marrow transplants.

I love tech analogies to biological functions.

It amazes me how much 'tech' is always running on a cellular/molecular level.

Thank you!

We always reach for the analogies that match our experience most closely. If this were 200 years ago, we'd say that the immune system was like a lock-and-key mechanism, or perhaps we'd say it was like a bank checking for correct signatures.

Indeed, I remember a kid's cartoon about our bodies when I was growing up that showed germs that had evolved the correct antigens as being spies passing through passport control with forged passports.

Indeed. I had read about it before but viewing these visualizations blew my mind:

https://www.youtube.com/watch?v=SMtWvDbfHLo (DNA transcription)

https://www.youtube.com/watch?v=TfYf_rPWUdY (mRNA translation)

https://www.youtube.com/watch?v=I9ArIJWYZHI (DNA replication)

Adding to some of the other comments: Leukocytes (immune cells) such as B and T cells will undergo "education" when they are developing. For example, B cells, before being released, will go through something called central tolerance in the bone marrow. If the B cell receptors bind a "self" antigen (markers that are associated with our own cells) while developing, it will go through negative selection and be destroyed. Of course, some B cells that bind self antigens do make it through in rare cases and this is what manifests as an autoimmune disease.

Thanks for this. I'm perpetually amazed at how mind-bogglingly complex the human body is.

> while developing, it will go through negative selection and be destroyed

Can you share more about how this process works? Even just a link would do. Thank you!

https://en.wikipedia.org/wiki/V(D)J_recombination

I think Khan Academy does a good job of explaining it: https://www.youtube.com/watch?v=EsQyCHs4IBY

Proteins on the surface of cells identify them as “self” or “not self”. MHC (major histocompatability complex) plays a large role.

So why attack it?

There is more in your body than just your cells. We are in the infancy of understanding stuff like this, but my WAG is that donor tissue can be rejected because it contains hostile microorganisms that didn't make the radar of the medical staff for whatever reason.

> donor tissue can be rejected because it contains hostile microorganisms

Citation? That sounds both convenient and implausible (medical science has a long way to go in many areas, but microscopy/microorganism detection is pretty far along).

Humans Carry More Bacterial Cells than Human Ones

https://www.scientificamerican.com/article/strange-but-true-...

FYI: WAG stands for Wild Ass Guess. They usually don't involve citations.

> I just finished up an introductory biology lecture series, and this suddenly makes less sense to me than it did before.

The immune system is one of the most complicated and wonderful pieces of biology. It's also scary in the ways that it can malfunction and the challenges it presents to modern medicine.

> What is it about the foreign cells that is identified as foreign by the host cells?

The MHC system is a major determinant of histocompatibility.

https://en.wikipedia.org/wiki/Major_histocompatibility_compl...

https://en.wikipedia.org/wiki/Human_leukocyte_antigen

https://en.wikipedia.org/wiki/Histocompatibility

MHC is an adaptive immune function used to detect foreign antigen that was evolved as a means to combat intracellular pathogens. This cell-surface machinery collects and presents foreign antigens from inside the cell at the cell surface for discovery by immune cells that come into contact. If something "foreign" is found on the MHC, the immune system targets the cell for deletion and upregulates the immune system for further attack.

The genes that code the MHC proteins vary widely between individuals. This can be beneficial as viruses struggle to evolve in a way that evades all MHCs in a population.

Unfortunately, the MHC proteins are themselves a highly reactive antigen that triggers the immune system. Luckily, the body learns during a process called "negative selection" to cull any immune cell receptors that recognize your own MHCs:

https://en.wikipedia.org/wiki/Thymus (search "negative selection").

If any of your own T-cells match your own MHC, they're killed. Unfortunately, your body doesn't know the shape of MHC proteins from donor tissue and can't learn to kill any TCRs that match. And these proteins are incredibly, incredibly polymorphic:

https://en.wikipedia.org/wiki/Human_leukocyte_antigen

Search "variability", then multiply the numbers -- you're not going to find an exact match for you anywhere, unless you have an identical twin. This is why donor databases exist. If you can find a match for one of the variants, it reduces the product of these multiples.

It's very hard to find a tissue match.

When you transplant foreign tissue, it's an antigen.

Fun fact: did you know your immune system genes aren't at rest and are actually evolving right now? Your immune cells run stochastic hill climbing. It's wild. Check out somatic recombination:

https://en.wikipedia.org/wiki/V(D)J_recombination

The immune system is incredibly complicated.

You post made me wonder about a lot

> Unfortunately, the MHC proteins are themselves a highly reactive antigen thahttps://www.airships.net/hindenburg/interiors/t triggers the immune system. Luckily, the body learns during a process called "negative selection" to cull any immune cell receptors that recognize your own MHCs:

This is very interesting that this process is split into two separate domains / privilege levels. That way you can't have a fork bomb that would overwhelm the MHC production process.

> Unfortunately, your body doesn't know the shape of MHC proteins from donor tissue and can't learn to kill any TCRs that match.

Maybe we'll combat this in the future by finding a way to donate or genetically engineer a whole bone from the organ donor, thus having bone marrow matching the donated organ. If we could get localized immune suppression on only those parts, that would be cool. I guess those leukocytes would be attacked immediately.

> https://en.wikipedia.org/wiki/V(D)J_recombination

Wow.

My understanding is that most cells in the human body regenerate. What I don't understand is how cells that are part of the transplant regenerate. Do they use the host or the transplanted DNA to regenerate?

Cells (re)generate by splitting, there's no other way. For non-mobile tissue, the tissue regenerates itself from whatever DNA the cells in that tissue have locally. There are some types of cells that are "manufactured" in one place and "shipped" throughout the body (e.g. blood cells in bone marrow) but for the transplanted tissue any new cells would still have the donor DNA forever.

Also, that applies for chimeric humans that happen to have two different DNA sets from two different fertilized eggs; some parts of their body will forever have different DNA than other parts.

> Also, that applies for hymeric humans

Seems like this: https://en.wikipedia.org/wiki/Chimera_(genetics)

Yep, that's the correct term, English isn't my main language.

Now makes more sense. Thanks for the explaination

It's no one thing, but a combination of factors that allow the immune system to identify and attack foreign cells that have entered the system. Think of it like one of those incredibly stupid algorithms that pass for AI today. Except this algorithm is "trained" over millions of years by the host organism dying when it fails to properly classify hostile foreign biomass. Over that long a time it gets to be pretty good, but not 100% flawless: autoimmune disorders like multiple sclerosis result when the immune system incorrectly attacks the body's own tissues, and allergies result when the immune system overreacts to foreign material, such as food or pollen, entering the body.

> Any time we do any transplant immunosupressants are given to the recipient for the rest of their life, but this only slows the inevitable.

Is this true that it is inevitable? My understanding, from my girlfriend attending medical school (only M1), is that for many types of transplants, when immunosupressants are taken properly, it is unlikely that the organ will ever be rejected.

For example, only 10-20% of patients who receive a kidney transplant will experience rejection[1].

[1] https://columbiasurgery.org/kidney-transplant/organ-rejectio...

“Only 20%” and “unlikely to ever be rejected” are worlds apart.

Modern immunosuppressive therapy for, for instance kidneys, has dropped the five year acute rejection rate from 50% to 20%. About 8-10% in the first year.

You can get a 5% 10-year non-rejection rate only in the most hand-picked groups (adheres to meds, no underlying systemic disease, and no chronic nephropathy). That sub-population exists, but it’s pretty uncommon.

People without underlying disease generally dont need or get replacement organs. These are all complex cases. Only in the most rare of circumstances does an otherwise totally healthy person need a new kidney.

Focal glomerulosclerosis destroys kidneys in a completely healthy person.

> “Only 20%” and “unlikely to ever be rejected” are worlds apart.

The parent comment I responded to stated it was "inevitable." "Inevitable" and "only 20%" are many more worlds apart than "unlikely to ever be rejected" and "only 20%".

"Unlikely" is a bit subjective, but it is well below a coin flip.

I cited a source for the statistics. If you disagree, can you please cite your source?

Even if there is no acute rejection event, long-term accumulation of damage from the host's immune system attacking the graft at a low background level is still very likely. Immune suppression has to walk a tightrope that in addition to being very thin is also constantly moving around. Each time you get sick, if your immune suppression is too aggressive, you might just die. If it's not aggressive enough, the pro-immune signalling generated in response to the infection might override the immune suppression and trigger rejection of the graft. Any other event that triggers or suppresses an immune response also has similar risks associated with it.

It's kind of similar to how diabetes patients need to constantly monitor their blood sugar and manually adjust their insulin levels to compensate, but on a longer time scale (generally weeks to months rather than minutes to hours). But with diabetes, at least you have the potential for almost direct control over your blood sugar levels (by regulating food intake). There is no such direct control for your level of immune activity, nor is there a simple and quick blood test to measure whether immune suppression is at the right level.

In short, anyone with a transplant is walking a wobbly tightrope of immune suppression for the rest of their life, and they sometimes don't even know they've fallen off until they hit the ground.

(Source: I have previously worked in a lab studying transplant rejection and trying to, among other things, develop such a simple and quick blood test: https://www.ncbi.nlm.nih.gov/pubmed/24725967)

There was some talk a while back about using a modified form of HIV to suppress immune response for transplant recipients. Any update on that?

I don't have any specific knowledge about that. Our lab was mainly focused on diagnostics for transplant rejection, with the idea being that a quick and easy test for rejection would allow immune suppression to be adjusted more accurately and more often, since the current standard test is a tissue biopsy manually inspected by a specialist, which is not something you can do very frequently for a number of reasons.

I recently listened to this podcast. https://news.ycombinator.com/item?id=21051174 It is about widespread fraud in the drug industry. During the interview it was mentioned that some people are seeing organ failure due getting fraudulent drugs from abroad. It is possible that this is not what happened in this case, but it seems plausible. To anyone who has the time, listen to this podcast. It was really educational and scary, pharmaceuticals fraud is no joke.

*The interview discusses the material in Katherine Eban's book Bottle of Lies.

Interestingly the EU is working on building a verification service for pharmaceuticals but some countries are pushing back.

The human brain is wired to make connections, but it's important to step back and realize the universe of "plausible" explanations are almost infinite.

It is nothing more than rank speculation that these two stories are somehow related. The world is teeming with junk science like this, and it can be dangerous and even fatal. (E.g. anti-vexers). That's why I think it's important to recognize it when you see it, and call it out. Even more-so if you find yourself possibly espousing damaging speculation without a scintilla of evidence.

The evidence is the podcast/interview. It is not known the extent to which generic drugs are affected. But in almost all the Indian plans investigated there was evidence of fraud, and I believe evidence of fraud was found in 80% of Chinese generic pharmaceutical plants. Additionally according to the author of the book there have already been cases of organ rejections due to fraudulent generics.

Before dismissing my comments out of hand maybe you should look at my evidence.

I'm sorry but GP is completely correct and you are just reacting defensively.

He didn't claim that your evidence was faulty, but that there is nothing to connect these two stories. You're making a link that does not exist.

In fact, when you say

> It is possible that this is not what happened

you are making it seem quite likely that this is indeed what happened. With no supporting evidence.

It's exactly what anti-vaxers do.

How much of this is mitigated by donor/recipient compatibility (haplotypes? is that the right word?)? Is there no such thing as a purely compatible donor?

A 100% compatible donor is a identical twin or clone. Besides the MHC haplotypes which govern large parts of the immune response to ‘self’ there is the actual makeup of the rest of the genetic material which may be presented as antigens and then recognised as foreign

Yes identical twins are fully compatible. The first kidney transplant was done between identical twins and the the recipient lived with no anti-rejection medications for decades from what I recall.

There have been instances of kidney transplants between identical twins to withdraw immunosuppressants after some time.

Absolutely terrible that's happening, though. Hopefully with further genetic research and being able to grow new organs, these issues will go away.

Tarleton, who now lives in Manchester, N.H., told the Boston Globe she has no regrets about the transplant because it dramatically improved her life. She has learned to play the piano and banjo, wrote a memoir and has spoken to many groups about her life. She lost 20 pounds and began walking five miles a week.

“I had such a low quality of life prior to my face transplant. Do I wish it had lasted 10 or 20 years? Of course,” she said.

I was on an email list and a woman who had two lung transplants described some of what she had been through and also asserted she would do it again and had no regrets.

You have to understand these are people who have no other viable options. However bad this is, the alternative is worse.

I wrestle with these questions because I wish we were looking for better answers. I am in no way interested in telling people who have had transplants that they were wrong to choose that for themselves.

But transplants are dramatic, heroic, headline grabbing procedures. Helping people keep their organs functioning so they don't need a transplant has much less capacity to grab headlines and fascinate the public and so on.

We increasingly put our time and effort into really dramatic medical procedures that are very expensive and have a golly, gee whiz factor. I think we are likely largely overlooking better paths that would give a higher quality of life in many cases because they have less razzle dazzle.

> her estranged husband doused her body with lye after beating her with a baseball bat

I'm periodically shocked when I'm reminded of how wide is the spectrum between good and bad.

I so do not want to click on this link in case there are pictures. I really do not want to see what this looks like.

Are there pictures?

There's one pre-surgery photo.

I'm with you. These kind of images stay with me forever, particularly at 4 o'clock in the morning.

There's a pic and it's not so pretty. What's much worse to me is the description of what her husband did to her. Consider skipping this one altogether.

I'm a live and let live, everyone has their own pain and their own story, we all are just doing our best sort of guy... But I want to string that guy up.

It appears he's already dead.

https://www.ibtimes.com/who-carmen-tarleton-lye-attack-victi...

Quoting the linked article:

“I have fully forgiven him and I don’t have the same attitude that a lot of people have with his treatment of me,” Tarleton said. “I have moved on so well and in so many ways. I feel like, for me, it ends a big chapter in my life.”

More than what happened to her, what stands out to me is that she's moved on. That's strength. There are things that no one can take away.

I wouldn't be so eager to highlight these statements.

Self-blame is very common in victims of domestic abuse, and when one suffers from it they're predisposed towards "forgiveness". It's really a compensation for feeling somehow responsible for their own abuse, which is very unfortunate.

I'm glad she seems to have found some closure in his death though.

You move on so it doesn't steal anymore of your future. It's the only thing you can do. Stewing about it just lets it take yet more of your life when the cost has already been too high.

In most cases, no, the people trying to bleed you emotionally with their pity party for you aren't going to do a damn thing to help improve your quality of life. They will only add to your suffering.

Shutting them down as efficiently as possible as just part of protecting yourself from yet more damage in a cold, cruel world full of assholes.

At some point I think practically speaking people are broken beyond repair, at least compared to the amount of good you could do for other people with the same amount of resources.

> I'm a live and let live, everyone has their own pain and their own story, we all are just doing our best sort of guy... But I want to string that guy up.

I don't think empathy and punishment are at odds with each other. It's perfectly possible (and, I think, healthy) to have deep compassion for both victims and perpetrators, while still taking the right corrective measures.

Depending on what exactly "stringing up" entails, I might be right there with you.

It's incredibly sad that a horribly abused dog viciously attacks humans; it didn't didn't deserve that life. You still put it down.

Yeah not good, how can men bring themselves to such violence against women. I am sitting here as I write this looking at my wife and cant for the life of me fathom doing such a ghastly act to her or even a woman that I don't know, no matter what I believed (real or imaginary) their transgressions where against me. I don't know the back story but if he was capable of doing this, she probably left him for good reason as I cant imagine this was the first incident. A person has the right to leave if they feel you are no longer the right person for them, sometimes it happens in pretty shitty ways, but it does not justify physical harm to that person.

I am just left speechless, there really should be a death penalty for intentionally maiming a person to the point that they will live the rest of their life in suffering and sorrow. No one deserves the fate this woman has been left with. I am sorry she will have to endure another transplant.

> I am sitting here as I write this looking at my wife and cant for the life of me fathom doing such a ghastly act to her or even a woman that I don't know.

Not trying to 1-up you but I can't imagine how anyone could do this to anyone.

Edit: to those curious what happened to the husband. 30 to 70-year sentence (age 52 at the time), died in prison. https://www.vnews.com/Man-Convicted-of-Maiming-Vermont-Woman...

It's so sad what she had to experience

Yeah, it is an incredibly terrible story. Sometimes in fiction (books, movies, etc) I think how unrealistic some depictions of cruelty can be, but then I read stories like this and remember that fiction rarely captures the actual levels of cruelty people are capable of.

There's one of her from an interview a few years back, scar tissue from chemical burns.

I mean, in medicine most "fixes" for harsh problems are temporary; nothing is permanent as in the end we all are going to die sooner or later. There's a good reason to think not in terms of "people cured" but in metrics like QALY (quality-adjusted life years) gained - even if this transplant fails tomorrow, it has given that poor woman 5 years of significantly improved (according to her own experience) life quality, and that was a good and valuable thing to achieve even if it turns out that it can't last.

> “We all know we are in uncharted waters,” Tarleton said. “I would rather not have to go through a catastrophic failure.”

If anyone hasn't been through some tragic medical shit in their life, pay attention to that. You'll understand it later.

This is what gets me. Take care of yourself, because you don't know what kind of Sword of Damocles is hanging over your head.

A lot of us think we are invulnerable when we are young. I had a college friend who died of brain cancer a few years after graduating. I myself had a kidney failure a few years ago and now on dialysis. In the snap of a finger your life can change.

Health and time are the two biggest things people take for granted, particularly when they're young

“There are so many unknowns and so many new things we are discovering,” said Dr. Bohdan Pomahac, director of plastic surgery transplantation at Brigham and Women’s and one of Tarleton’s surgeons. Still, he said, “It’s really not realistic to hope faces are going to last (the patient’s) lifetime.”

What's the mortality rate on transplants? If you keep doing the same surgery over and over, won't the patient eventually die on the operating table?

I'm curious to know how much face transplants cost in the US, and if insurance covers any of it.

I know some of the face transplants were funded by the department of defense.

As potential treatment regime for wounded soldiers who usually are prone to such horrific injuries.

Paywalled.

I did not see a paywall.

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