Hacker News Reader

Comment by DoreenMichele | Hacker News Reader

In layman's terms: She had a particularly vicious form of cancer where the very cells that are supposed to protect your health -- your T-cells -- are the enemy. So they made three edits to donor cells and wiped out her compromised cells. Then gave her a bone marrow transplant afterwards to replenish her immune system with new cells.

I'm squeamish about genetic research, but this looks really good to me. I hope she recovers fully and there are no further complications, though I imagine it's too early to guess what her prognosis might be.

So there are already trials of base editing under way in sickle-cell disease, as well as high cholesterol that runs in families and the blood disorder beta-thalassemia.

That's a big deal for people with those genetic disorders.

View on HN

>I'm squeamish about genetic research

And I'm sad about millions upon millions of mostly well-meaning people, who died of ultimately preventable causes - if only we could push the research from the lab to clinic faster.

Everybody is prone to ageing, and very soon it will be our turn.

The challenge with genetics research is it could also result in the death of every human on the planet.

It’s an amazing power for good and bad.

You don't need to ban, say, clinical trials of gene therapy (especially with inert lipid nanoparticle carriers which do not replicate), to ban a quite narrow and not really clinically useful subfield called "gain of function research".

Why can't our legal system deter the obvious high-level publicly visible perpetrators of the recent "gain-of-function" fiasco is really some food for thought.

It’s more than broad weaponization of viruses that are a danger though.

Take for instance what we’re doing with plants. We make designer plants that provide food, and are immune from particular pesticides. We then spray the fields and all the other plants and bugs die (besides the immune plants).

What happens when it turns out some genetic inserts in the corn creates something like mad cow disease (but in humans) 3-5 years later? Turns out some protein the corn produced we thought was harmless caused massive issues.

Genetics has massive implications even if well meaning.

I think the ability to eliminate disease is massively powerful and a net good. That said, I’m concerned about the long term tail end risks of such work.

I don’t think you can ban it, because someone will do the work. And those that do the work will get a competitive advantage (eventually letting them “win”). I think it’s about mitigating risks by reducing / limiting mass adoption of genetic based technology without a very long window of analysis.

> I think the ability to eliminate disease is massively powerful and a net good.

One real-world example of this is genetically modifying the American Chestnut by splicing in genes of the Japanese Chestnut, which is resistant to the blight since it co-evolved with it. The resistance comes from how Japanese Chestnut trees respond to oxalis acid by walling it off, preventing the fungus from spreading.

> That said, I’m concerned about the long term tail end risks of such work.

One bleak science fiction novel that takes place in this kind of future, specifically an amped-up version of the corporate GMO food crop meddling you referenced, is The Windup Girl by Paolo Bacigalupi.

> What happens when it turns out some genetic inserts in the corn creates something like mad cow disease (but in humans) 3-5 years later? Turns out some protein the corn produced we thought was harmless caused massive issues.

Do you require similar safeguards with plants created by "classic" genetic engineering and random mutations occurring all the time? Such methods usually involve making tons of random mutations, which nobody tests for anything, until we manage to also get the one that we want.

Of course you rarely make a completely new protein by random mutations (different story with naturally evolving viruses), however, current genetic engineering of plants and animals for food is AFAIK not about completely new proteins too -- it's about turning off existing pathways, or about transferring existing proteins from one species to another.

As a general rule, we don't arrest people for things that aren't illegal.

... Unless by "deter" you just meant "make it illegal," in which case, agreed.

How could genetics research kill all humans?

Asking for a friend.

Eh, life forms can have a exponential growth curve, so virologist and bacterial genetic research can easily kill a large part of the population. But then we are well on the way for that, so who cares?

Developing a virus that kills a certain ethnic group seems like it could be possible.

Probably not. Genetics isn't nearly as clean a people imagine it to be.

Much easier to target one individual (and their whole host of genetic factors) than to target one genetic factor that can be associated with an ethnic group and pray that it doesn't either also express itself in an undiscovered way in other ethnic groups or have knock-on effects or the potential to mutate.

We aren't as genetically different as people imagine, and this sort of approach would be absolutely playing with fire.

One could even craft a virus that is targeting a certain behavioral anomaly like sociopathy, if its genetically clearly identify-able. All one would need is a proof-able potent carrier virus and once could reign in the destructive potential of humanity.

"No more bad boy behavior, or the bad boys vanish from the surface of the earth." behavioral deterrence via a biologic weapon.

What a fascinating nash equilibrium, the unsocial monsters, forced to be social, including applying gentle pressure, so they do not become history like there victims of the past. What a concept..

Then it mutates and kills us all..

>One could even craft a virus that is targeting a certain behavioral anomaly like sociopathy, if its genetically clearly identify-able.

It isn't, and I'd be surprised if it ever could be. There will always be statistical correlations (especially when looking at multiple genes in combination) but you can't conclude what a person's brain and mind are like just from their genome.

"Ethnic group"s are generally not homogenous and definitely not supported by genetic evidence in the way folks usually think about them.

That’s wildly over-apocalyptic for such a general statement. (biochemist)

Nonono that would be lovely, finally some evolutionary pressure. What's the real threat is breeding obligately obedient citizenry and immortal leaders. Which is the first thing practical genetic engineering will probably be used for.

“Will probably”

Has

I find the notion of stopping aging, and by proxy "natural death", a bad one. I welcome our turn.

This is suicidal thinking - you essentially want to die, but you wish it on some future you (certainly not the you of today, whose turn it probably isn't yet). I cannot see a world in which this could be deemed healthy.

Instead you want to avoid/deny eventual natural death for ever? Fight it? To be at peace with the process of aging and the thought of eventually dying is not the same as suicidal thinking.

> I cannot see a world in which this could be deemed healthy.

I cannot see a world in which fighting and avoiding natural death can take healthy forms. All matter decays. All things recycle. We have material bodies, hence we are part of the cycle of life. The old giving way to the new is a necessity for growth & evolution. I would even say it's beautiful. And healthy.

I think we will never agree. I see a death cult, you see acceptance of the natural order of things. It is a fundamental difference in viewpoint.

A death cult? Seriously? The fact I think the inevitability if death a good thing doesn't make me a worshipper. You're just being offensive.

Look, if you want to die, go right ahead. But leave me and my family out of it. We love our lives and each other and I'd like for us to live as long as we can. Proclaiming your disdain research in this field because "death is good" without elaborating on that (and when the obvious conclusion is the exact opposite, see: The deaths of children with cancer, the deaths of world-changing intellectuals like Von Neumann, the eventual deaths of every good person/pet that you know), does not come off in a flattering light for you.

The fact that you think dying is good is a feeling. It is based on an article of faith - it must be, because you cannot make coherent arguments for the necessity of death that aren't either based on faith or other issues that are solvable in ways that don't kill people.

I'm not "just being offensive". Death is harmful, and insisting it must happen is perpetrating death. If you insist this, you are perpetrating a harmful ideology that interferes with research into senescence and therefore contributes to suffering.

You're afraid, I get it. So am I. We'll all die someday. So will everyone and everything, at some point. It's not good or bad. It's not a matter of faith or ideology. It's scary and we don't want it and we fight it with everything we got. That's also a part of being alive.

I'm just concerned with the possibility of us "winning over death" and how it would transform everything. It's not another cure for an illness or another 100 years to live. It's no one ever going away without someone else making them. For better or worse. That's not a part of life. That's an entirely different existence.

I 'm totally with you. Most of human misery, suffering and malice is due to decline, loss, grief and death, and the awareness about them.

People who claim it would be bad to live long are either coping or had a chance at a decent life or believe it would somehow cause unsolvable problems.

To what extent is your view an adaptation to how things are currently (and I agree it can be good to have a positive outlook on things you can't change) and to what extent do you think it's a strong analysis of how things should be?

Let's say a mysterious virus spreads through the population, and edits all our DNA with the only effect that we all suddenly gain negligible senescence - people still die from accidents and acute diseases, but everyone retains the same level of general healthiness as a young adult with no aging. In that situation, would you be advocating that everyone take medicine to turn aging and death from aging back on?

Lmao. If we extrapolate your logic to few hundred years ago - you shouldn’t survive over 40 yrs. But I’m sure you can’t wait to retire at 60. So your perspective is simply a result of past scientific work in defeating ‘natural death’. And suddenly you think it’s a bad idea.

Thank you for explaining to me what I expect and think. It's much clearer to me now.

while a rude response, guy above does raise the point of well, yes I'd like to not die at 40. Medicine is good. But the talk of imortality is hubris. Is is to judge oneself the best or most worthy thing, and to deny our children and the nature of progess itself. As medicine has brought us extra life, death and re-generation have brought us us. And as us which have been given, we give to others through our death.

So whats the limit? Its a big question that dosen't need to be answered now, because immortality is not on the table. Another 20 or so years maybe. So maybe lets take care of the world we got before we fall into some delusional sense of godhood. (Just upload yourfselfs bros)

I feel like this type of medicine is more like a research study waiting for a perfect match patient than it is highly personalized treatment...

Is this technique broadly applicable? Or limited to very specific cases

It looks to me like a somewhat unique opportunity to risk it because without this treatment, she was dead anyway and in fairly short order. So it was a means for them to learn something with very little potential downside. Worst case scenario: The treatment kills her. And she was dying anyway.

From the article:

In Alyssa's therapy, each of the base edits involved breaking a section of genetic code so it no longer worked. But there are more nuanced applications where instead of switching an instruction off you can fix a defective one. Sickle-cell anaemia, for example, is caused by just one base change that could be corrected.

And I already quoted (in my previous comment) the next paragraph that indicates they are already doing trials. This is potentially a big deal and they seem to be pursuing it in a very reasonable and conservative fashion, which is always something that concerns me with this type thing. There's a lot of potential for terrible and horrifying abuse and that is not what I am seeing described here.

Seems like this particular version of gene editing only works with blood/marrow disorders? If someone had a single mutation affecting their colon or eye, would the same technique be appropriate?

Blood/bone marrow is relatively easy as you have a very clear delivery vehicle for your modified genes. Actually getting to the colon cells or retina is a lot harder, can’t just inject it into the blood and expect it to end up in the right place.

Yeah, those are valuable opportunities. You have to take risks to learn, but human life is to valuable to risk.

I remember looking into the state of the art around in utero and neonatal health when we got pregnant. I was astonished at how limited the knowledge is. I quickly realized the big gaps are just because it’s too risky to study. You can’t morally experiment on pregnant people and infants.

A "problem" with this treatment is that, for most patients, the current standard of care works. To the extent that this treatment is effective, it is likely effective for most leukaemia patients, including those who would respond well to current treatments. It is very plausible that this treatment (or a refined version of it) will eventually be shown to be superior to the current standard of care, in which case it would become the standard of care, and the current treatment will be relegated to the niche patient that does not respond to gene edited t-cells.

More broadly, the technique of precisely editing DNA of select cells to perform specific engineered tasks is very broadly applicable. But that is a technique for developing treatments, not a treatment itself.

> will eventually be shown to be superior to the current standard of care, in which case it would become the standard of care

How does this overturning occur? Do care providers agitate for change? Or is it typically a response to headstrong patients and families?

It starts with researchers convincing their ethical review board that they should be given the opportunity to experiment with the different approach.

That’s why new procedures almost always are done on patients who are as good as dead (gene editing to change one’s hair color won’t soon get past ethical review, for example, but if gene editing gets used in mainstream medicine, enough data may be collected to make a review board say it’s acceptable to give it a try)

The first experiments typically only prove the medicine or procedure works. Long term survival of the patient the exception. From there, it’s step by step towards treating healthier and healthier patients.

If it turns out the approach is better for the typical patient, patient groups (who may even have paid for part of the research) start lobbying for its use. If the new procedure is both better and cheaper, insurers also will lobby for it.

Isn’t this treatment simply accomplishing the same thing that the current treatment does but in a targeted way with hopefully much fewer side effects? When you have cancerous T cells the only option is to eradicate all of them and start over with a bone marrow transplant. Normally that would mean frying them with radiation or poisoning with chemo which also effects a lot of other tissue. This treatment is supposed to only kill the T cells.

That's my noob understanding too. This is a more precise form of autologous transplant.

I assume quick adoption of base editing for trickier cases, eg for T-cell acute lymphoblastic leukemia, like this patient had. Note that she had a previous transplant, using the more conventional treatment of her T cells. Just starting with base editing will be much less onerous to future patients.

This is one tough person. Surviving chemo then two transplants is amazing. Just thinking about it crushes my heart.

Source: Had bone marrow transplant 30+ years ago. My then experimental treatment became the default option (as applicable). Don't know much about biology or medicine, but I can repeat what I've heard and read.

Remember what "works" means in this case. Chemotherapy, or for other cancers, radiation, surgery that removes large, healthy parts of organs that might have a tumor. Chemotherapy has hosts of side effects, of course (hair loss, nausea, ruined immunity, CIPN, etc) some permanent for some people. It "works" when you look at what KPIs oncologists like, very reductionist things like "5-year overall survival" whilst you ignore things like quality of life both in the short term and long term.

We should be moving away from chemotherapy. It really is poison (cytotoxin) that has "treatment" of cancer as a side effect, just because it will readily kill cancer cells more than healthy cells whilst also taking a lot of the healthy cells with it. But, it's the "established" standard of care, which many doctors built their careers on, so I suppose it won't go away soon.

Surgery to remove part of an organ, followed by chemotherapy gave my mother a few more years of life. Are you suggesting there is some other alternative, currently accepted and understood, that would've worked better? Because while those side effects are terrible they are usually more temporary than the extension of life that they afford people. Face the question, would you rather chemo for a couple months and then live a couple years, or die in a couple weeks?

No, they are suggesting we should strive for better therapies.

Wiping out the recipients immune system and transplanting a donor system is in itself a common (advanced) practice since long, so the new part here is the tweaking of the donor system. Very interesting.

The edited cells did not replace her immune system. They were used to destroy it.

Then after that a bone marrow transplant was done to restore it.

Its coming within the decade for cancer vaccines. The trick is to be able to scale production and lower the turnaround time.

Wiping out your immune system and replacing it has something like a 50/50 survival rate even if you use your own cells. It's a hail Mary than usually either kills or cures.

I knew a guy with cancer that had this done. He survived the process, but unfortunately the cells they restored him with were not cancer free like they thought. He died anyway.

I think increasing the survival rate for these things could be very useful.

Resetting the immune system can be already done and it seems to help against auto-immune diseases such as lupus, but it is very dangerous. Once you destroy the immune system of the patient, and before it grows back from donor cells, the patient is fatally vulnerable even to normally banal pathogens such as the common cold. Keeping the patient isolated and alive in a hospital full of germs is a major challenge.

That is why this kind of therapy is only used when the patient faces death anyway.

> I'm squeamish about genetic research

Can you elaborate on what makes you squeamish about research?

Not OP, but something just feels unnatural and unsettling about changing humans, and especially for changing yourself. It feels like the uncanny valley where it just doesn't feel right. I'm agnostic so it's not for a particularly religious reasons, and it's purely an emotional response for me that's not grounded in logic at all, so I also just describe it as squeamish for no reason.

Thank you for a honest response. I think this is an underexplored topic - how many of our broad social policies were shaped mostly on the basis of sufficiently broadly shared visceral feeling.

Should we base ultimately coercive society-wide regulatory framework on mere "squeamishness", appropriately rationalized, or should we instead embrace a non-discriminatory, laissez-faire approach in this domain?

> how many of our broad social policies were shaped mostly on the basis of sufficiently broadly shared visceral feeling

All of them? I'm struggling to think of a counterexample.

Yeah, I'd say the phrases "broadly shared visceral feelings" and "broad social policies" point to nearly the same concept.

When I have these thoughts, I remind myself that typhoid is natural and penicillin is artificial.

A big part of progress is fighting and defeating the natural.

That said, not all genetic manipulation will end well.

Not the OP, but I think there are ethical concerns about genetic manipulation that do not amount to catastrophizing (e.g. 20th century eugenics is back!).

Maybe the conflation is the problem for me. I don’t see how research or even consensual application necessarily leads to “20th century eugenics”.

Consensual application is a huge assumption based on recent history.

The existence on non-consensual application would not change my opinion on the value of research.

I don't see how it doesn't. Look at human history.

I remain unconvinced that the inevitable existence of e.g., designer babies will inevitably lead to forcing people to have them.

Forcing no, but those who could afford to do it would engineer superior children, and society would rather quickly devolve into a caste-type social system or worse.

It is inevitable that more people will be able to exert more control over their reproduction. I agree that this is likely to amplify the human tribalism that already causes so many problems. I still don't see how that inevitably leads to “20th century eugenics” nor why we should discourage or fear research.

You haven't had children, have you? They don't neatly fit into plans or develop to top down desires.Thinking the children will be superior is extreme arrogance even if it all works out and they are born immune to cancer. It puts too much faith in one advantage determining all.

Under that catastrophic social model the elite should have been descendants of the elite from before the Bronze Age collapse, and heavy cavalry should have maintained their combat effectiveness over the masses even during the Infantry Revolution.

Simple put people think "its a slippery slope". Every step closer to the evolution of a new technology makes people think about all the bad ways it could be used. Many past leaders in chemistry probably thought their advances would lead to the holocaust.

Its not bad to think/talk about the possible negative consequences of bringing a new technology into this world.

If we get designer babies along with curing cancer I say "so be it".

Laws can be written to limit its use if we find it morally objectionable

The problem with old school eugenics was that it wasn't consensual. Like forced sterilizations and abortions.

If gene tech can make future generations healthier and smarter with informed choice by the parents, those future generations will look back in horror at the barbaric pro death & disease lobby of the 2020s.

>Can you elaborate on what makes you squeamish about research?

Yes, I for one can't imagine why editing the genes of humans would cause alarm. After all, who wouldn't want to have children that are smarter, more docile, and healthier? Or, for other people's children, who have qualities that make you uncomfortable and can't be edited out, like dark skin or homosexuality, you have the option to edit their reproductive ability so that such qualities can come to an end humanely, without violence.

In the same way, I can't understand are those people against longevity research. Who wants to die? Not me, and certainly not those in power. You know, the people in power earned their positions, they are good at it, and mortality just means someone new and inexperienced will fumble around at the job. For continuity and safety, immortal leaders will do a better job and keep us safe. I don't see why anyone would consider this a bad thing.

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

I am, of course, aware of these tropes. If you have any sincere objections to research, please enlighten us.

You think that sincerity is incompatible with satire?

When it is mixed with the stupidity you spouted , yes.

Of course not. Satire can be done very well and sincerely.

I'm not sure how satire is relevant to this exchange.

Have you ever tried making changes to a large, incredibly complex codebase with zero comments? Sometimes the changes you make don't have the expected results.

That sounds like an argument in favor of research.

Also, stateful code, no staging environment, no undo commit, prone to fatal runtime errors...

You’ve never made a change to such a codebase that was generated by a massively parallel evolutionary computer running for billions of years.

You could just as easily make the argument that there is probably no body of data more stable than existing genomes.

Some people are interpreting that more broadly than I intended it. I'm squeamish about this kind of medical gene editing in specific.

There is a genetic disorder that runs in my family. I used to be on a bunch of email lists for the condition. People with the condition routinely volunteer for drug studies in a desperate attempt to get help that current medical science can't provide them and/or to get free care for a condition that's very medically expensive.

People with serious medical conditions are all too often treated like lab rats whose lives don't really matter. Treating people like me humanely isn't a real high priority. Quality of life is not much part of the discussion. Keeping us alive a little longer is the only metric that seems to count and horrifying things get done in the name of it.

Very interesting, because T-cells are implicated in multiple sclerosis.

And probably other similar diseases.

The detective work going on with MS is fascinating. The blood work from the US military and what it has shown is really interesting - it’s not new news but was to me when I stumbled on it this year.

https://www.nih.gov/news-events/nih-research-matters/study-s...

I have long suspected that viruses are the underlying cause of most of the diseases that have eluded us for the last 50 years. HIV gave us insights into a novel way that viruses can operate. It makes sense to think that there are more ways than we imagined.

E/B virus is suspect in Type 1 Diabetes too. E/B Vaccination could eradicate a group of diseases potentially.

Reply on news.ycombinator.com