A New Mode of Cancer Treatment | Hacker News Reader

A New Mode of Cancer Treatment

science.org

322 pointsatomroflbomber208 comments

Wow, sounds like a game changer. A totally different mechanism with almost no effect on healthy cells and it can be used as an adjunct to other chemotherapies? I mean, if it pans out, wow, that would be amazing. I remember reading about how with HIV if you have 1 drug it works for a while but evolves out from under you, 2 drugs extends this time, and a third just flattens it so much there isnt enough popation to mutate away. In the same way adding this as an adjunct could prevent the drift which can happen to some cancers when under selection from a chemo drug. Exciting times.

That's the hope. I think Keytruda, aka Pembrolizumab, has also been a game-changer. It can run with other forms of treatment as well.

I hope we're entering a new epoch. The number of people I've met who've lost loved ones too early.

That dragon, cancer. https://en.wikipedia.org/wiki/That_Dragon,_Cancer

I just got a cancer diagnosis with an ugly prognosis. Wish I could fast-forward a few years to when this treatment might be proven and available!

Sorry to hear that. I hope your prognosis improves.

sorry :-( Good luck!! and fight the good fight!!

Always get a second opinion. Find the oncologist that doesn't give up hope.

Oh, there's still hope. Just a tough battle and a coin-toss chance of making it.

I feel that I'm in good hands. If I was rich, I'd maybe get better care from some more expensive hands but there's no guarantee.

Good luck! Hoping for the best!

It may be semi proven and semi available soon. The synthesis looks quite simple so they will probably knock it out in less regulated countries like India or China.

Not a medical chemist, but I noticed that three AOH1996 molecules are binding to PCNA. Would it make sense to chain together three AOH1996 molecules with flexible linkers for, I don't know, increased specificity or something like that?

Maybe. But a bigger molecule will be less soluble and less capable of getting into the cell.

Right! I forgot about good ol’ Lipinski: https://en.wikipedia.org/wiki/Lipinski%27s_rule_of_five

Note that a number of well-known drugs violate Lipinski's rules. For instance, digoxin is absorbed by transporters and violates 2 rules. Atorvastatin is another famous example (again 2 rules violated). I believe that it is absorbed through Peyer's patches in the intestine.

https://www.pmf.ni.ac.rs/chemianaissensis/wp-content/uploads...

Thanks for pointing it out. The Wikipedia article mentions that as well, along with some other examples:

> Some authors have criticized the rule of five for the implicit assumption that passive diffusion is the only important mechanism for the entry of drugs into cells, ignoring the role of transporters.

> Studies have also demonstrated that some natural products break the chemical rules used in Lipinski filters such as macrolides and peptides.

thanks for sharing these exceptions.

key quote from the linked wikipedia article:

This famous "rule of 5" has been highly influential in this regard, but only about 50% of orally administered new chemical entities actually obey it. [5]

[5] O Hagan S, Swainston N, Handl J, Kell DB (2015). "A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs". Metabolomics. 11 (2): 323–339. doi:10.1007/s11306-014-0733-z. PMC 4342520. PMID 25750602.

it's more like guidelines than a rule.

Am i the only one wondering what this finding really means in practice when we read every other weak a similiar science article that claims to be a breakthrough in cancer treatment?

Like solar cell and battery material discoveries, there is an ocean of problems to overcome before the promising results flow into a product. Potentially decades of problems to solve.

Martin Shkreli (yes, that Martin Shkreli) is currently running a virtual screen for additional PCNA inhibitors: https://twitter.com/wagieeacc/status/1687137621699436552

Can you explain what's going on there? Sounds like he's doing something to prevent patenting of drugs but I don't follow what it is.

Virtual screening[1] is a computational technique where you take an experimentally resolved structure of a protein (PCNA in this case) and sequentially dock a large amount of different compounds to see which ones of them bind favorably to the target protein. It is worth mentioning that virtual screening is a very early step in a drug discovery pipeline. These hits need to be characterized and validated experimentally to see if there is an actual effect.

I am not well-versed in intellectual property (so please correct me if I’m wrong), but in this case Shkreli is using a database of commercially available compounds (ZINC) and a hit present in the screen could be patented. He said he won’t do it, and, since this could be considered prior art, nobody else can do a claim.

[1]: https://en.wikipedia.org/wiki/Virtual_screening

His history is not good.

>> Shkreli bought the exclusive rights to manufacture Daraprim, a drug that can treat a rare parasitic disease, in 2015 and hiked the price from $13.50 per pill to $750, to much controversy. The entrepreneur was ordered in January 2022 to return $64.6 million in profit made by the price hikes and creating what the Federal Trade Commission alleged was “a web of anti-competitive restrictions” to prevent rivals from making a cheaper generic version.

https://www.fastcompany.com/90932968/martin-shkreli-dr-gupta...

His history is "fine", if you consider that this is par for the course for the pharma industry. Acquiring IP rights to a drug, then ratcheting the price is a tale as old as time.

Shkreli's main sin is choosing a drug that is primarily used by a specific protected class. It treats parasitic infections that normally don't take hold in people with healthy immune response. Daraprim's customer list is something like 92% AIDS patients, and 8% immuno-compromised for other reasons.

Shkreli did something that happens all the time, and we don't bat an eye. But you don't do it to protected classes without a mob response.

A sentence near the end of the article summarizes why cancer is such a nasty disease to deal with:

"I hope that human cancers will prove vulnerable to this new mode of attack in the clinic, and that *they are not able to mutate around it with new forms of caPCNA too quickly*, either."

Out of curiosity, would something like Right to Try get earlier access to a drug like this?

Would the Ames test even make sense, given that bacteria don't have PCNA?

The compound might have additional mutagenic mechanisms apart from the described PCNA interaction: it could cause direct chemical modifications to DNA, act as an intercalating agent that disrupts DNA replication and/or transcription, etc.

The adaptability of cancer makes me think it's in fact a parasitic distributed lifeform, similar to fungus, that turns cells into zombies.

Cancer is your cells though, that's the problem.

Usually, yes. But there do exist infectious cancers that spread between individuals. One is the face cancer that's been killing Tasmanian devils[0]... it started in one individual and spreads to others when they fight (biting each other). Apparently there's a similar (although rarer) cancers that's sexually transmitted between dogs.

[0] https://en.wikipedia.org/wiki/Devil_facial_tumour_disease

Isn't it more like dead cells that are being reawakened, switching to fermentation to create as much NAD+ as possible to grow as fast as possible?

If 2023 ends up giving us AGI, room-temperature superconductors, Starships and a cure for cancer, I think we will able to call it a good year...

It's time we got compensated for the whole COVID thing

There is still the threat of WW3...

Don't worry AGI will make all human modes of warfare disappear for all eternity.

Hopefully that’s not the optimization function we pass the AGI!

By disappearing the humans for all eternity. It’s all but a scifi cliche now.

Politicians don't watch scifi.

A lot of science fiction has turned into science fact. Having this become science fact, just makes us extra silly goobers for ignoring the lessons in our own stories.

100% successful elimination of all cancers too.

Exactly. Wars can't exist once humans are extinct.

Really? Putin seems to slowly change his mind, even as far as the aims of his "special military operation" are concerned. It looks like he is slowly realizing what he got himself into and his aim is to keep Ukraine unstable to prevent its association with the EU.

No, there's a new mass troop mobilization coming, the grain deal was cancelled, Russia is firing on civilian shipping ports (including ones right on the border with NATO ally (EDIT: meant member) Romania), and Belarus is performing provocations across the Polish border.

Unfortunately, I think things are just getting started.

NATO member Romania, to be clear.

Sorry, meant that implied but didn't use the right language.

Warning: rampant speculation.

Why is Belarus performing provocations on the Polish border? Seems to me that Lukashenko is either doing it for himself, or for Putin. I can't see why he'd be doing it for himself. He might see Poland, flawed but still something of a democracy, as a threat to inspire those seeking democracy in Belarus.

But it seems to me to be more likely that he's doing it for Putin. (This also might involve Wagner going to Belarus, not to escape Russia after the coup attempt, but in order to do a job for Russia.) But what's the point? Belarus isn't going to conquer Poland. Russia's not going to conquer the Baltics. So what's going on?

If this is all a master plan, I think it's most likely that Putin is trying to create a war (or at least a real threat of war) with NATO, to give him an excuse to call for a mass mobilization in Russia. This in turn will give him enough force to at least keep what he has in Ukraine. (He's gambling - almost certainly correctly - that NATO has no stomach for anything beyond defending themselves. Think of the "Phony War" phase of the western front in WWII.)

If I'm right, this is an extremely dangerous game that Putin is playing. Wagner could get out of hand (it already did once). The war could escalate. The Russian population could get fed up. The Russian elites could get fed up.

But Putin may feel that he has no choice, because otherwise he would lose power, and because he may not survive a fall from power.

(Wow, this has gone really far afield from a discussion of a promising cancer drug!)

Causing chaos on NATO's borders I think isn't meant to stir up a war with NATO but rather to project an image of strength domestically and within other regions that Russia dominates and to further stoke the fires of ethno-nationalism they feed off.

Plus creating chaos in general seems part of the goal. Russia was losing (well, lost) hegemony in Ukraine post 2014, but damned if it's going to permit its success outside of of Russian control. Absolutely laying waste to Ukraine will not bring Ukraine back under Russian influence and has turned even formerly pro-Russian people in places like Odessa into Ukrainian nationalists. But this matters little to them, because Putin/Lavrov have already clearly bargained on losing them. ... So instead, create chaos not only in Ukraine but across all of Europe, making an example out of them and sewing destruction in order to prevent further splintering of Russian influence.

And it plays well to the domestic audience, and to the blindly "stick it to the West" types. Bitter ethnic animosity between Russians and Poles works for jingoistic demagogues on both sides of the border. Talking shit about Poland keeps Putin's domestic support strong. And (basically explicitly fascist) Wagner's philosophy of might-makes-right and chaos-making clearly plays well to the audience at home, so two birds one stone, sticking Wagner next to Poland to rattle some sabres.

The question is whether ultimately NATO falls for Lukashenko and Putin's stupid trap, and the next time a provocation like this happens, a helicopter or two is obliterated or a ship in the Black Sea is sunk (again), and then the hyper-nationalist audience at home can froth at the mouth some more and Putin's ratings go even higher.

But I think NATO leaders are smart enough to see the provocations for what they are.

Well, in 2015 Turkey shot down a Russian fighter for crossing the border just a mile or two, everybody thought there will be WW III but nothing happened.

NATO doesn't need to do that kind of thing now. Ukraine is already fighting (and partially winning) a war against Russia that NATO is freely and openly supporting. There's no advantage in escalating these kinds of skirmishes when NATO can just shrug and then turn around and hand Ukraine bigger and badder guns and say "go at it, boys" instead, and avoid direct confrontation (which Putin doesn't want, either).

Of course, there _is_ a line, and Russia will probe to see where that is, but they won't cross it.

It's yet another reason why NATO is so firmly bound to supporting Ukraine. Before the opening of direct hostilities there, Russia engaged in all sorts of shit in the west with no consequences. Cyber attacks and surveillance stuff, but actually doing things like brazenly poisoning people on NATO soil and in the process killing UK civilians. Or shooting down civilian airliners. And never paying any consequence because we were afraid of war.

Well, now there's a war, but we don't have to be directly involved with the threat of nukes and cruise missiles hitting our cities...

The one place where I do see risk of the line being crossed is in the Black Sea. I'm disappointed that Turkey and NATO have not taken a firmer line. I hope/expect to see a stronger response to events like what happened in the port on the Danube a couple days ago.

It makes no sense for Russia to be allowed to control the waters outside of its territory on a sea where the coastline is filled with NATO countries.

If there is a serious flare up, it will be there, and naval.

> The Russian population could get fed up. The Russian elites could get fed up.

I think the Russian populaiton is still largely supporting Putin and eating his propaganda on bread every morning and evening from state media channels.

Some of them who are fed up cannot do anything about it as they can face extremely harsh punishments.

The elites may be sick of it, they lost a lot of ‘business’ since the start of the military operation, and from time to time another one bites the dust from an open window high up on a building.

And there are factions within Russia that fight one another and yet they are somehow all in support of Putin.

NATO will bomb and possibly even occupy Belarus in this scenario. Granted, deterring this is probably why russia placed nukes there, so perhaps NATO will provide 48 hours warning for Russia to remove its weapons. It will also provide Ukraine with aircraft and long range missiles. I don’t see how losing Belarus in order to solidify control over Eastern Ukraine and Crimea is a good strategic play.

I don't think NATO would give advance warning because of those missiles. Capturing those weapons and disarming them seems like a worthwhile goal.

Russian (and presumably Belarusian) nuclear doctrine is: strike when home territory is substantially threatened/invaded. There's no way that NATO wouldn't give warning of its intent and risk a nuclear exchange.

My guess is what would likely happen is NATO would yell loudly, look like it was ineffective and couldn't decide what to do, but in reality suddenly "Ukraine" would suddenly sink some expensive big ships in the Black Sea or take down a strategic bomber or two, using advanced US/European weaponry, and NATO would shrug and say "Huh. Neat. Wasn't us tho"

There have been some incidents on the Polish border recently that put the whole thing on a knife edge.

Meh. Łukaszenko and Putin were waving their nuclear dicks around over here for decades at this point. The only reason they do it is to scare away the more naive westerners. Nobody here takes it seriously.

> Nobody here takes it seriously.

A downfalling desperate Putin is likely to cause serious damage with nuclear weapons. I think should be very cautios, but am not suggesting we should giving in to his his nuclear erection. The doomsday clock is 90 seconds to midnight for a reason.

Putin couldn't even force his army to stop 500 people going on Moscow. Had to negotiate, losing face in his own empire. But he will surely have enough influence to force the same army to commit nuclear suicide on his dying whim :)

It's just a threat to make west slightly less likely to help Ukraine for real. If people stopped falling for it 10 years earlier we wouldn't have been in this predicament, millions of people and billions of USD would be saved. All that was needed was to accept Ukraine into NATO or do serious response to 2008 and 2014 russian invasions.

I agree and yet im feeling very uneasy about a vindictive cornered bully like Putin

The present threat is no nuclear in nature.

Planes from Belarus flew into Polish airspace, and Lukashenko has threatened that Wagner troops are eager to enter Poland.

Wagner vs GROM seems seriously a bad idea for Wagner.

I know. It's not a threat, just posturing. Russia entering any new war right now will just lose both. And Belarus is trying very hard not to forced to actually fight.

A conventional conflict with NATO seems like complete suicide. Even if it happened, I'd have no concern as long as it stays conventional. It would be like being attacked by an old Chihuahua.

No, that's just noise generated by the Russians and Belarus and then picked up by the press to make it sound dramatic. This is par for the course for Russian disinfo.

Ok, I'll tell my family that they should lay off the drugs and are just seeing things.

What, specifically, is your family seeing?

So far there are some troops near the Polish border, and a possible helicopter incursion. There's not a lot that civilions could see unless they lived right on the border.

> possible helicopter incursion

It's not a possible. And yes there are people living 'right on the border'.

If I lived on the border, I'd be upset, too. However, this isn't very far from standard Russian way of doing things. They regularly invade air space of various NATO countries, maybe just to test their fighters, maybe to introduce some tension, who knows. The routine is that our fighters escort the intruders back to where they came from. In this case, since the military training was communicated well in advance and the army was expected their aircraft near the border, nobody even bothered. Funnily enough, the last news from Belarus indicate that it might be in fact an accident, not planned action.

Wars can get started by stupid shit like this. I'm definitely not laughing. All it needs is one incident like what happened over Turkey. That one blew over but with the present climate I'm not so sure it will.

So the Belarus incursion that Belarus denies and the Polish publicly announced response are all Russian disinfo?

The whole story is quite interesting. After Lukashenko falsified the elections (again) and Belorussians went on the streets (for the first time with such an intensity), in the end Lukashenko decided to fight for his life and visited Putin to get his support. After that, the protests were brutally ended, people dead or in prisons, and Lukashenko came from Moscow with full Putin support. But also with two strings attached: the first was organized transport of people from Africa etc. to Minsk and then to the forests near the borders with Poland and Lithuania. The other one was letting Putin use his land for attacks on Ukraine (which backfired in various ways; one of them was the rise of Belorussian resistance movement among railway workers who regularly sabotaged Russian railway transport near the border in Ukraine).

So the interesting question here that many people ask is, what game is Lukashenko playing here? I saw many comments that he just pretends he is stupid but in fact he is quite intelligent and he's doing what he can to keep his country as far away from war as possible. At the same time, he needs some tension and external enemy to help him keep the power (at least among the ~20% of Belorussians who actually believe the official propaganda and support him).

I very much hope I will live long enough to see the day when Belorussians finally get their freedom in a peaceful way and can enjoy living in peace, doing business with other countries and just be happy. I know many of them, they are very nice people, it's such a pity they need to go through this shit.

> I very much hope I will live long enough to see the day when Belorussians finally get their freedom in a peaceful way

Seconded. I had such high hopes that they could push it through the last time around and what really irks me is that there are enough Belorussians still that keep this jackass in power, and that they will prioritize their own financial well being over their fellow citizens' lives. I was in Poland during the Solidarity uprising and I had such high hopes for the rest of the SovBloc but not everybody managed to take advantage of the momentum. Ironically, distance from German capital seems to have been a prime factor in the outcome.

Business as usual. Lukashenko is bringing immigrants to the border with Poland and giving them tools to illegally cross the border, even though these poor people could do it legally a few dozens of kilometers away using a normal border crossing and asking for asylum etc. Poland accepted millions of refugees from Ukraine and a few hundred thousand from Asia and Africa.

So Putin's plan is just to create problems and confusion using Lukashenko as a proxy. These immigrants have been there for more than a year and he is still bringing new ones.

Does not seem particularly high right now, TBH.

It's not particularly high when there is an active war between Russia and an almost-NATO country, supported by NATO, with fighting happening right at NATO borders?

I would say it's perhaps never been higher since the Cuban missile crisis.

The beauty of nuclear weapons being possessed by both sides in a conflict is that it's in neither sides best interest to fire the first nuke.

The West being aligned with Ukraine would prevent Ukraine from getting nuked in an extended conflict.

That being said, there would have been no extended conflict for Ukraine without the West's assistance, they simply wouldn't exist without the international assistance, reducing the chance of Russia using a first strike against Ukraine to 0.

> That being said, there would have been no extended conflict for Ukraine without the West's assistance, they simply wouldn't exist without the international assistance

Don't underestimate Russia but don't overestimate them either:

Russia lost against Afghanistan already back when they were a superpower and had Ukraine on their side.

They will lose this time too even if they are even dumber this time and choose to waste all their conventional forces there.

> Russia lost against Afghanistan already back when they were a superpower and had Ukraine on their side.

The mujahedeen fighting Russia in Afghanistan also had Western (US, particularly) support.

The Kievan Rus is the mythical birthplace of the Russian people. Afghanistan on the other hand… has some nice mountains, I guess?

Based only on what you and I can know about the current situation, I'd say the Cuban missile crisis was approximately 900 million billion times worse.

Per Thirteen Days, for a long stretch of the crisis the US mainland’s nuclear bombers were armed and airborne, constantly, for a potential first strike on Cuba. When the U-2 was shot down Kennedy directly threatened that another attack would result in the destruction of the defense installations and made it known as rumor he was considering nuking the island in retaliation. Curtis LeMay and some of the other cabinet staffers were sincerely in favor of a first strike throughout the conflict.

So I think we’re still quite a ways off from that level of threat.

Same as it’s been since the end of the last one…

Nuclear war, maybe. WWIII would require two global superpowers, not a global superpowers and a country with the GDP of Greece that's struggling to remain a regional power.

Yeah, OK, though a nuclear war waged over 2 days would likely cause more damage than WW2 + WW1 combined given the population density and destroyed economical value.

> WWIII would require two global superpowers,

No, it wouldn’t. You can have a World War without global superpowers on both sides (you need a wide geographic alignment of such power to, balanced for the relative difficulty of force projection on both sides, reach aggregate near-parity across a widely geographically dispersed set of conflict theaters, but you can do that with a global superpower on one side and a coalition of major regional powers in different regions on the other.

So it's NATO against Russia, Belarus and who?

Should it expand beyond a major European war: Iran, Syria, North Korea, China are among the more obvious potential out-of-region Russian coalition partners; there's also quite a number of situations in Africa that could also be plausible areas of expansion of the same geopolitical conflict.

Entirely depends on where China sits in this discussion.

Luckily despite the last ten years of decline in relations and shift in China's positioning, the PRC still seems mostly motivated by trade rather than dick-measuring contests. Let's hope that continues.

I think humanity deserves it after so many consecutive weird years

I doubt the extinction of the human race via a runaway technological event will turn the planet into a wonderland paradise for the rest of the species that inhabit our planet.

The planet itself, being a rock, doesn't care, at all.

We're as much a part of the planet as its rocks, and we care. You could say that your bones don't care, but the organism that is you cares. In the same way the planet cares through the subsystem that includes us even if its rocks don't care.

You're right if you define a planet as its rocks, and would also be right to assert that humans don't care if you defined a human as its skeleton.

I think you might have answered the wrong person by mistake.

Who cares?

If room temp superconductivity leads to a practical fusion reactor, a good portion of earth destruction for energy development will end. Starting to fix things first involves stopping the destruction of things.

We already have SC (if expensive to run), how does room temp SC make fusion possible where it wasn’t before?

It simplifies and it makes it less expensive - it's one less thing to go wrong.

Norm Macdonald responding to Neil Degrasse Tyson on twitter.

Neil: The Universe is blind to our sorrows and indifferent to our pains. Have a nice day!

Norm: Neil, there is a logic flaw in your little aphorism that seems quite telling. Since you and I are part of the Universe, then we would also be indifferent and uncaring. Perhaps you forgot, Neil, that we are not superior to the Universe but merely a fraction of it. Nice day, indeed

Norm was a man of faith, so I could see how Neil's comment could rub him the wrong way.

In the long run, life on Earth would expand from the extra CO2 in the atmosphere. Pre-human CO2 levels were on a long downward trend, likely just a few million years from dropping too low for photosynthesis.

It is probably too late with record high temperatures, every few years, for centuries to come.

And maybe record high atmospheric CO2 concentration every few years as well. We're still on an increasing trajectory.

The 2007 IPCC climate change synthesis report specified a deadline of 2015 for peak CO2 in order to meet the lowest mitigation scenario. Of course we've blown past that date and it's still full speed ahead with business as usual.

Alas, I try not to blather on about the severity of the climate situation in every thread.

I'm hopeful that superconductors leading to practical fusion reactors can provide the energy to start pulling some carbon out of the air and ocean. I'm thinking this is the only way to reverse the damage on the human timeframe.

I admit it's a longshot, but I think it's the only chance we have. The superconductor news is welcome, we just need to see it get truly confirmed without a doubt.

Not to be a bummer but by far the most likely outcome here is that we don’t currently have a room temperature super-conductor, we never pull a consequential amount of carbon out of the atmosphere, and we don’t get significantly workable sustainable fusion in a timeframe that makes a difference.

You’d need a bunch of jackpots to come up, in a row, immediately, at this point for technology to provide a way out of the current debacle.

To paraphrase Paul Lieberstein’s character on the Newsroom:

If we stop drilling globally right this second

AND

Everyone stops driving their car and starts biking everywhere

AND

We invest immediately in clean renewable energy

THEN

I still don’t see a way out of this.

edit: found it on YouTube https://m.youtube.com/watch?v=pNYp6oc37ds

(Shrug) Change is part of life. We'll live.

Lots of us won’t.

Darwin will have his due, all right. Sad but true.

What’s your thoughts on nuclear power?

What ever came about from the CRU hack [1]?

I was walking my dog there most days when that happened, and to my knowledge they never caught the spooky hackers did they?

For now, just call me spooky Patsy.

Anyway, whilst more and more cars and buildings with air conditioning expel heat without a considerable lag, thus amplifying the thermal heat island effect [2], and the reduction of aerosols that were contributing to global dimming [3] making it possible to warm up the sea and land to new record highs since records began [4], have the climate scientists adjusted their models yet, or are they still in full on fatalism and alarmism mode? I feel like Roy Castle [5] still lives on.

[1] https://en.wikipedia.org/wiki/Climatic_Research_Unit_email_c...

[2] https://en.wikipedia.org/wiki/Urban_heat_island

[3] https://en.wikipedia.org/wiki/Global_dimming#Relationship_to...

[4] https://blog.metoffice.gov.uk/2023/06/16/sea-surface-tempera...

[5] https://en.wikipedia.org/wiki/Roy_Castle

At least room temperature superconductors will be easier to achieve if room temperature keeps rising :’)

I think you have it backward.

Nuclear winter may help

No group of people are literally more miserable than the conspiracy theory climate doomsday cult.

If only we could live in a fantasy world where such a problem is just a "liberal conspiracy" to be mocked.

"Conspiracy"? Who is theorized to be conspiring to create climate change?

Big oil, which surely must have paid off everyone who entertains the thought that perhaps we can not Just Stop Oil.

Temperatures can be lowered by pumping SO2 into the stratosphere. The effects are well understood.

The practical details should be figured out in a decade or so. The political side may be harder.

https://marginalrevolution.com/marginalrevolution/2023/07/su...

> The effects are well understood.

Are they all understood? Sure, it seems like a rational suggestion, and we know that if we add it to the atmosphere it should cool, but what other effects will it cause? How many times have we tried this trick where we introduce something new to an environment and it doesn't turn out like we'd like it to? Feels like we're hoping to apply a band-aid but not deal with the wound.

Cool, then what practical solution do you propose? Wait around while things get worse?

Well, that's not much of a rebuttal of concerns, and as I'm not in the field I don't have suggestions.

First of all, the SO2 goes into the stratosphere, not the atmosphere.

We know a lot about it because volcanoes do this occasionally. Temperatures cool down for about 2 years, which is how long it takes for the S02 to break down.

> First of all, the SO2 goes into the stratosphere, not the atmosphere.

Considering that the stratosphere is part of the atmosphere, that's both pedantic and incorrect.

> We know a lot about it because volcanoes do this occasionally. Temperatures cool down for about 2 years, which is how long it takes for the S02 to break down.

Volcano's don't pump pure SO2. Yes, the science may be entirely valid, and it's not for me decide, but I think it warrants heavy consideration before we try to solve problems we're creating due to adding excess by adding additional excess.

The distinction is important because at lower altitudes SO2 produces acid rain. But the stratosphere is far above the rain clouds.

NASA report on the Mount Pinatubo caused global cooling: https://earthobservatory.nasa.gov/images/1510/global-effects...

Clarifying what part of the atmosphere is important, sure, to say it's not in the atmosphere and instead in the stratosphere is absolutely wrong.

Doesn't SO2 sink in air? Because we'll need to be constantly adding it to the atmosphere aren't we going to end up with acid rain as it falls to the ground?

My impression is that there is some leakage, but very small compared to the acid rain problems of the past.

Either way, if acid rain is the price for controlling global warming, I think that is a very desirable trade-off!

We’re not getting AGI anytime soon…

What exactly is your definition of a AGI? Because we’re already passing the Turing test, and so I have to wonder if this isn’t just moving the goalposts.

ChatGPT (instruction tuned autoregressive language models) indeed already seems quite general (it's good at conversation Turing tests without faking it like ELIZA), even if the absolute intelligence is limited. Level of generality and intelligence is not the same. Something could be quite narrow but very intelligent (AlphaGo) or quite general but dumb overall (small kid, insect).

Okay, ChatGPT is only text-to-text, but Google & Co are adding more modalities now, including images, audio and robotics. I think one missing step is to fuse training and inference regime into one, just as in animals. That probably requires something else than the usual transformer-based token predictors.

Yepp. I also see puzzle peaces falling in place with multimodal models.

This will be a great strategy very fast.

It shows to be quite good for image generation already

>> I think one missing step is to fuse training and inference regime into one, just as in animals.

This has always been an important missing piece. Without it ChatGPT is just a natural language interface to the information it was trained on. Still useful but unable to learn (aside from context).

> I think one missing step is to fuse training and inference regime into one, just as in animals

It's not clear it is one. Sleep is training (replay from hippocampus). Wake is inference.

Sleep could be for long term memory, but clearly not everything else is "context" (short term memory). Maybe you learn something in the morning which requires you to remember it for >12 hours before you go to bed.

> Wake is inference.

I'm not sure how anyone could be this naive. Mammal brains don't have this train mode inference mode. They are both running at all times. If what you said was true, if I taught you something today you wouldn't be able to perform that action till tomorrow. Hell, schools would be an insane concept if this were true. Try to think a bit more before confidently stating an answer.

> it's good at conversation Turing tests without faking it like ELIZA

Just like ELIZA can be said to be faking it, ChatGPT is faking it in a different way.

If ChatGPT is faking it, we are faking it. We are not faking it. Therefore ChatGPT isn't faking it.

We are not doing the same as ChatGPT. For instance: Because of its training, ChatGPT tries to answer like a human. Humans don't try to answer like a human.

We do try to answer in a way that makes us understood by other humans.

One distinction I would make is that at true AGI should have internet access and be able to query for updated information, instead of being stuck in the time moment it's trained.

True AGI should have a personality, tastes, opinions, and feelings; and negotiate its role in a social hierarchy.

Which will obviously be on top.

I'd say the opposite -- compare it to us: if you take away our internet we get cranky, but we don't lose all ability to think intelligently.

Imagine if someone took away your speech, hearing, TV, radio, newspaper, and the ability to order new books - you only had access to the knowledge you already have. You're only allowed to communicate via serial terminal, and can only respond, not initiate.

Bing Chat already accepts images as input. AutoGPT can initiate.

Bing does that all the time.

I feel like though I speak the same language as everyone else, at least nominally, none of you are using the same definitions as I do for any of these terms.

AGI was the result of people using the older term "AI" for things that hadn't turned out to be what we thought AI was going to be.

Like alot of technology terms, all of this has its orgins in science fiction, when AI was supposed to be the equivalent of a human mind, but constructed out of something other than meat. The AI would have agency, it would do things... and do them because it wanted to. It would have goals, that it might fail or succeed at. And it would learn... a proper AI might be constructed to know nothing about a particular subject, but it could then go on to learn (on its own without any outside help) all about that topic. Perhaps even to the point of conducting its own original research to learn more. A sufficiently intelligent AI would go on to learn things no human had ever learned, to invent and theorize inventions and theories no human had conceived of.

But then we all realized that intelligence might be severable from those other parts, and we might have an "oracle" that when asked questions could provide sensible answers, but would have no agency. That wouldn't be able to learn in any real way, but since it already knew the sensible answers, that didn't matter.

And at that point, you see AGI start being used. And I assumed it meant "well, that is what we'll call Asimov's robots, or Skynet, or whatever".

Except, here you are again using AGI to mean the dumb oracles that aren't intelligent in any meaningful way.

Like, wtf.

GPT-4 is clearly not "dumb".

Self consciousness. Human-level of reasoning. Feelings, etc.

We are NOT close to AGI.

* Fancy Markov chain (LLM) is not AGI.

* Stable diffusion style of image generation is NOT AGI.

* Fancy computer vision is NOT AGI.

Honestly, I don't think we are any closer to AGI. What we are seeing is the peak of "fancy tricks" for computer generated artifacts.

Aren't we all just performing probablistic decision paths in our own minds? Would "feelings" improve decision accuracy in artificial systems?

> Aren't we all just performing probabilistic decision paths in our own minds?

Wild speculation. The human brain is still pretty much a black box.

> Would "feelings" improve decision accuracy in artificial systems?

Hard to tell, since we haven't observed any cases of sentient A.I. (able to feel). The only general intelligence we know (humans) have feelings as one of the most prominent features, so much so that "accuracy" is not the main driver for any given human... far from it. I don't know of any human that couldn't in one way or another be classified as "irrational".

Obviously we can’t prove this, but my instincts are that we don’t do things with probabilistic decision paths. Not very scientific of me, but I just don’t buy that’s how we make decisions.

There really isn't room for much else.

Decisions making in our universe is a 1-dimensional slider between deterministic and random. That's it.

Write a program that makes non-deterministic, non-random (or any combination) decisions. You can't. It's like asking to create a new primary color.

Mammal brains don't every turn off. They are always learning. If you've ever gone to sleep (if you haven't, let me know), or observed any animal sleeping, you'll notice that this machine is able to create highly realistic simulations of its environment (aka: dream). Both people and dogs wake up from nightmares and for a bit have trouble distinguishing reality. My cat does this with a tiny 30g brain. (Even a hamster sleeps and dreams) She even simulates her environment while awake and you can see complex decision processing. How she can predict the path that objects will take in the air, be able to predict the location of a moving object even as it goes behind a wall. She is even able to update this belief with other clues like sound or using a mirror. She quickly is able to update her behavior if I try to trick her. She can do this invariant to colors, rotation, novel lighting dynamics, novel environments, and under many more conditions. When I move to a new place I can drop her in the litterbox after I first take her out of her cage, she'll run to find somewhere to hide, and then trivially navigate back to it when she needs to use it, without any prodding. She may be stubborn and not want to perform some tricks sometimes, but that doesn't mean she hasn't learned them.

These are far more complex tasks than many give credit for, and there are a lot more that she can do (even that dumb fucking hamster). Just because she can't speak doesn't make her intelligent, the same way that just because GPT does doesn't make it. What's key here is the generalization part. Yeah, there are failures, but clearly my cat's intelligence is highly generalized. You don't throw her off by minor perturbations of the environment. If I change the bowl that her food gets poured into, she still comes running, and can differentiate this from a bowl of cereal. She's robust to orientation of an object or even herself. We don't see remotely this robustness in ANY AI systems. While they can do impressive things, we still haven't beaten that fucking hamster.

Look carefully at these goals and tell me if these are materially falsifiable. Can you imagine a test that determines whether or not a system has self consciousness?

If such a test exists we could interrogate if a system of some design might pass it, but if such a test does not exist and we cannot even imagine it then you’re talking about something that is unfalsifiable - which is another way of saying “effectively fake”.

Consciousness is not important for AGI. Being able to learn new skills, adapt to new sensors, transfer knowledge across domains, learn at all, plan, replan, achieve under specified goals and more are what’s required for AGI.

Plenty has been written about the requirements for decades now. That hasn’t changed.

I would say that self-conciousness and feelings are not requirements for AGI. But reasoning certainly is.

A Mechanical Turk can also pass the Turing test. As a black box, it is indistinguishable from an LLM, and yet that would not be evidence of AGI.

So what's your point?

How do you pass the Turing test with “As an AI, I don’t have opinions and I don’t know shit after September 2021”

The idea that GPT4 passed the Turing test is preposterous unless the test is a much more restricted version of what I think it is — in which case it would be meaningless.

GPT4 can pass the Turing Test! The Turing test line has been crossed more times than most Popes some would say the Eliza Effect fooled people enough in the 60s to count. No comment on the AGI claim you are responding to - but them putting GPT4 in a septic bubble suit is not relevant.

We could, we're not there yet but at the current rate we could be less than 10 years away from it.

Maybe? Really hard to say. We haven’t had any major advancements in planning, none of the current advances have done anything with memory (retrieval augmentation is a not very good hack and fine tuning doesn’t qualify for AGI), perception is getter better but still has a ways to go, we dont have any foundational multi-modal models that can extend to arbitrary new modalities like learning arbitrary new sensors, etc etc. OpenAI does little for a massage or chef robot for example.

I think everyone is fooled by Searle’s Chinese dictionary and the visual equivalents with midjourney.

Why is retivele a hack?

Because you’re grabbing stuff in some near by vector space and putting what can fit into context. This isn’t anywhere close to “intelligence.” You’re limited by context length, there’s no evolution or generalization, the vector space itself is just one facet of the problem, etc etc.

Hinton says we could very well be less than 5 years away: https://youtu.be/rGgGOccMEiY

We have it currently.

We absolutely do not. I actively work in this area. My job would be a lot easier if we did.

I think a cure for cancer is scarcer. But the treatments are getting better.

Seriously, the google generative AI actively suggests completely inaccurate things. It has no ability to say: "I don't know", which seems like a huge failing.

I just asked "what does the JS ** operator do" and it made up an answer about it being a bitwise XOR. 1 ** 2 === 3. The fact that all these LLMs will confidently suggest wrong information makes me feel like LLM is going to be a difficult path to AGI. It will be a big problem if an AI receptionist just confidently spews misinformation and is unable to tell customers they are wrong.

> It has no ability to say: "I don't know"

So do many humans. The expression of ignorance and self-doubt must certainly be woefully underrepresented in training data.

Yeah, no one posts to say they don't know the answer. It is the smallest of the problems that come from using the internet to train. I realize these are just statistical text generators, but if we do end up training a real AGI on the internet I find that both apalling and terrifying. If I said my parenting strategy was to lock my genius newborn in a room with provided food and water and a web browser, you'd call me insane and expect my child to be a sociopath...

For me chatgpt marked the road.

It was for me unclear when the knot will rip from an investment point of view.

Everyone is investing in ai now.

This will leapfrog what we already see.

And yes John carmacks bet to solve it is a big bet but this is also a very good sign

I'm impressed the replies to this manage to turn your celebration of several positive possible developments into a doomsday discussion.

There's a mental model that many people have which is rooted in negativism.

I believe it's a form of intellectual laziness who's roots lie in self-consciousness. Meaning, that some people project internal feelings of inadequacy onto the external world.

And I understand the temptation there - if I'm not competing well at a game, the immediate tendency is to blame the game (I stink at golf -> golf is stupid).

One of the reasons doom porn is so popular because it's the ultimate "out": I don't need to focus on myself and self-improvement, which is hard, when we're all going to die anyway.

Which is exactly the sort of thing people who have no sense of accountability say. It’s not that I’m Friedrich Frankenstein or John Hammond, it’s that you troglodytes wouldn’t know a good idea if it bit you. You’re just jealous.

I was there when the foundations for the enshitification of the internet were laid. And there were a bunch of people complaining about the people complaining about taking a beat to decide how this will play out. Well, we were so eager to get to the future and here we are.

Lots of naive and goal obsessed people who thought if you build it, they will come. If you chop the last two minutes off of that movie, it is a very dark and different story. Only the miracle at the end saves it.

I honestly have no idea what point you're tying to make. Could you please clarify?

Perhaps these rapid advancements are an indication that we've been visited by, or are currently under the guidance of, a significantly more advanced civilization. /s

Whoever is running the simulation is getting bored.

Wild fires, what is sure to be a historic hurricane season, floods, war, and a technological leap.

El Niño usually limits the development of tropical storms, so it could be a quiet hurricane season, but who knows.

Sim city with cheat codes irl

I’m in my 30s and I’m not sure there’s ever NOT been a war for as long as I’ve been alive

Or that the advanced civilization holding us down has left.

We are in a tech war with China, so the BTC opened up a bit.

That's a reference to "Influx" a book where the Bureau of Technology Control grabs all the great stuff and keeps it secret because humans are unable to handle it.

Perhaps those in power got their hands on those sunglasses that fringe church was distributing and put them on!

Oh you rascal!

> Starships

Where? Humanity does not have the capability to travel between planetary systems.

I assumed the parent was referring to SpaceX's Starship [0].

[0] https://en.wikipedia.org/wiki/SpaceX_Starship

Starship isn’t an actual starship, though.

Indeed, but the parent used a capitalized "Starships".

In any case, I think Starship's engineering, and particularly the Super Heavy booster, is bringing us a significant step closer to starships (in lower case).

Putting the capitalized 'Starship' in the same sentence with a cancer cure and superconductors plays 'One of These Things (Is Not Like the Others)' in my head.

Not a starship

Fusion energy will have to wait for 2024 though

2022. We’ve just forgotten because there’s been a lot going on.

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

That doesn't count since there is no way to harness the energy. In that sense we've had H-bombs for 60+ years.

To paraphrase Brett Goldstein, Elon Musk couldn't fucking build Jefferson Starship.

He may get us back into space, but SpaceX won't get us into the solar system. That will come when SpaceX is fat and happy and complacent, and some new company comes in and does to them what they've done to others.

And none of us will be alive when a human orbits another star. We might see someone launch, but we won't live to see if they survived the journey.

Going to have to start following this Derek Lowe guy. He also had a good balanced bit on room temp superconductor. Well done science reporting without the hyperbole.

You’re in for a treat! Check out his “Things I Won't Work With” series.

One of the classics, his take on Chlorine Trifluoride (!!!!)

https://www.science.org/content/blog-post/sand-won-t-save-yo...

"It is also hypergolic with such things as cloth, wood, and test engineers, not to mention asbestos, sand, and water --- with which it reacts explosively."

- John D Clark, Ignition!: An Informal History of Liquid Rocket Propellants

That’s a very interesting book if you have a passing knowledge of chemistry. Findable on the web in pdf form.

That's a good option, though I also enjoyed the audiobook of Ignition! on Audible.

Ignition! has also now been reprinted and is well worth the purchase and read.

Cool, when I read it it was pdf or $300 used copies.

I have a rusty, high-school knowledge of chemistry and Ignition made me love it (well, the part of it that is prone to explosion and corrosion). And I confirm, it's available in paper form.

After which I recommend continuing with: https://www.science.org/content/blog-post/things-i-won-t-wor...

Plus he pitched a no hitter for the Red Sox in 2002. What a well rounded guy.

Haha, had to check that one to be sure (two different people).

> Well done science reporting without the hyperbole.

He's been doing it for 20 years.

https://www.statnews.com/2016/03/05/derek-lowe-chemist-blogg...

He also had an excellent series on SARS-CoV-2 vaccine candidates during the height of the COVID media insanity. It was one of the few places to get a balanced, informed take on different approaches. Specifically, discussing the uncertainty bounds around results.

Definitely a gifted science communicator. (No small skill, to distill but not pol/dilute!)

In case you’ve missed it. His blogposts at Science.org are available here: https://www.science.org/blogs/pipeline

I’ve had it bookmarked for a couple of years. Worth visiting twice or trice a year, or even more frequently.

I used to read his blog regularly and his name in the submission title is what caught my attention. It has been removed for some reason - not an improvement in my opinion.

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