I'm making drugs for cats | Hacker News Reader

I'm making drugs for cats

trevorklee.substack.com

170 pointsklevertree98 comments

My beloved calico who passed away near the beginning of the pandemic suffered from stomatitis. I opted for full dental extraction after pharmaceutical intervention proved ineffective. She eventually passed away from an aggressive mouth cancer, which is not uncommon in cats with stomatitis.

I loved that cat, she got me through grad school, and losing her was miserable. My gratitude to anyone working on stomatitis treatments.

I'm sorry to hear about your calico. Stomatitis is really a terrible disease.

aggressive mouth cancer? my calico ten years ago succumbed to a horrible oral bone cancer's complications. to hell with cancer, and it's kinda retarded (literal meaning of the word) how slowly progress is made.

Huh? Retarded just means "slow" literally. So, if I get your meaning, it's absolutely not "kinda" retarded, it's depressingly/horribly/saddeningly/hopelessly retarded. And I do not recommend putting "kinda" together with "retarded" if you want to be received positively.

(I'm sorry for what you and your calico endured. F cancer)

good catch (seriously) of the inadvertent cliche reinforcing "kinda". (yeah eff cancer)

I mean, it depends on the accent, but some people use "kinda" as a filler word without any strong meaning. I didn't perceive "kinda" to qualify "slow" in that sentence to imply it's "a little slow", given the sentence was written to assert that progress is slow.

Then just say "kinda slow". Easy. If you want to use a charged word, it's on you to make your intention easily understood. If that's too much for you, then just use a safe and well-understood word.

Then just say "unspeedwise". Easy. If you use ungood words, it's on you to not lead others to thinkcrime. If that's too much for you, just use the safe and well-understood A vocabulary.

According to both Merriam Webster and Oxford (not the OED, but the regular one) there are two definitions for retarded, both of which are offensive, and neither of which mean slow.

Good to know! I was interpreting parent generously.

Don't use dictionaries that change the definitions of words for political means. Retard means slow. A retard chamber, for example, contains retardant that is meant to slow the spread of fire.

There is a perpetual movement to take words and shuffle them around as a form of purity spiraling. People who don't want to work build entire careers out of pretending moral outrage. Play their game and you give them power. Next thing you know, the words that were okay to say are verboten and you're the next one crushed under the wheel of progress.

> Next thing you know, the words that were okay to say are verboten

So what? There are a hundred words your ancestors used that you never will. How has it changed your life one iota to have never uttered cockalorum, twitter-light, or grumpish?

> There is a perpetual movement to take words and shuffle them around

Yes, this has happened for all time.

> Yes, this has happened for all time.

No, that's a modern side effect of critical theory and grievance agitators. Nice try, though.

There's some rich irony in trying to deny the existence of pejoration and semantic drift, while claiming your political enemies are out of touch with reality.

Words starting out as factual and neutral, then acquiring a negative connotation, then falling out of use except as insults is literally a tale as old as time.

> The word "idiot" comes from the Greek noun ἰδιώτης idiōtēs 'a private person, individual' (as opposed to the state), 'a private citizen' (as opposed to someone with a political office), 'a common man', 'a person lacking professional skill, layman', later 'unskilled', 'ignorant', derived from the adjective ἴδιος idios 'personal' (not public, not shared). In Latin, idiota was borrowed in the meaning 'uneducated', 'ignorant', 'common',[5] and in Late Latin came to mean 'crude, illiterate, ignorant'. In French, it kept the meaning of 'illiterate', 'ignorant', and added the meaning 'stupid' in the 13th century. In English, it added the meaning 'mentally deficient' in the 14th century.

> The word shit appears to have originally been a euphemism for defecation in Pre-Germanic, as the Proto-Indo-European root *sḱeyd-, from which it was derived, meant 'to cut off'.

> In the 20th century, where the old euphemisms lavatory (a place where one washes) or toilet (a place where one dresses[20]) had grown from widespread usage (e.g., in the United States) to being synonymous with the crude act they sought to deflect, they were sometimes replaced with bathroom (a place where one bathes), washroom (a place where one washes), or restroom (a place where one rests)

You're conflating morphology with the cult-like zealotry against the four olds.

> Don't use dictionaries that change the definitions of words for political means.

I never thought I’d come across a sincere call for banning all dictionaries, but… well I never thought it, it doesn’t make me surprised.

There are plenty of dictionaries that don't manipulate you 1984 style. I don't recall calling for any bannings, either.

“There are plenty of dictionaries that don't manipulate you 1984 style.”

Yes, such as every major one.

Dictionaries are prescriptive. People use different words or use them in different ways over time and dictionaries update to reflect that. The only difference is how fast they update.

There's a difference between changing a definition to match popular use and changing a definition to support a false narrative.

Dictionaries are extremely expensive to run and rarely turn a profit. Are you surprised the "major ones" will lie straight to your face and intentionally warp your perspective of the world?

This is a thorough misunderstanding of how dictionaries work. There is no all-powerful movement (composed of people who don’t want to work…?) dictating language changes.

People update usage over time and dictionaries reflect that. It’s extremely common and not just a modern effect.

It’s just a property of human language and it occurs in every language.

Your belief stems from a nativity of the power systems and how they operate. Ideological zealots do try to dictate changes all the time. Look at history and understand the reason behind China and the replacement of the four olds. Look at what happened behind the scenes during the replacement of the Russian Tsars. Look at critical theory as a framework for gaining power.

Now understand some simple fundamental realities. Dictionaries have always been expensive and almost never turned a profit in history. They were created as loss leaders for name recognition, passion projects by eccentrics, heavily subsidized by fundraising or (most often) a combination of the three. They are subject to corruption through funding, through people, and through the will of their parent company.

Merriam-Webster should be focusing on language and it's use. Not subtly accusing Kyle Rittenhouse of fake crying during trial. It's corrupted at the personally level at the very least. Not to mention their cozy relationship with Google.

Oxford, like most universities, has had biased hiring policies since my parents were children. Today, it's filled with the out of touch, weak and over-socialized. They have received a mountain of criticism regarding their "woke score" hiring policies, "woke" additions to their dictionary and many other issues.

It's unfortunate that you and others trust such biased sources. Like being "the dictionary" gives it some sort of official authority on the way you can communicate.

Oh no! Someone must tell pharma companies because extended release pills have "retard" plastered all over their boxes! How offensive!

try this one: https://merriam-webster.com/dictionary/retard

Personally i prefer: https://en.wiktionary.org/wiki/retard

> it's kinda retarded (literal meaning of the word) how slowly progress is made.

Well the way to say that without redundance, parenthetical, and the sibling tree about whether or not it's offensive is 'it's kinda depressing/<emotion> how retarded the progress has been' (or similar).

> I felt good! The next step was in sight: a test of the drug in humans, to see if we actually saw the blood levels of cyclosporine that I expected we would. We had contracted with a CRO in the Netherlands and were raising the $1+ million needed to actually carry out the test when – pop! – the biotech markets imploded. Suddenly, investors literally stopped returning my (and everyone else’s) emails.

That sounds like a Phase 1 trial for safety in human volunteers. If the plan was to sell the IP to or partner with a major Pharma, maybe this could work. But the IP situation may not be that clear-cut with a drug repurposing, especially given this:

> This is still a tall order for a guy whose background was, again, science blogger. But things went surprisingly ok, all things considered. I linked up with an excellent corporate attorney and patent attorney, both of whom agreed to let me use their services on a pay later basis. ...

You really can't do this on the cheap.

People in tech (or even science broadly) trying to get into the drug industry frankly have no clue about what it actually takes to get a drug approved for humans in the US. Hundreds of millions are table stakes. The bar is higher than just about any other industry for new product introduction, even for a repurposing.

Even if the bear market had stayed in hibernation for another year or two, the fundamental problem is that human drug approval is a massive resource drain that requires very deep pockets and an ironclad IP position.

Failure (after massive expenditure) should be considered the base case.

So maybe people should try different markets?

What would be a clever approach to make a drug viable/revenue creating?

Well yes. But the pay off for a "blockbuster" (or two) more than makes up for all the aggregated losses. Hence why the massive pharma companies still exist, operate and, generally post massive profits YoY. You can easily absorb multiple $x-hundred million losses when your blockbusters are happily pulling in $5bn a year, YoY for 5+ years (with minimal expenditure). Years ago, somebody very senior at JnJ told me how the company really wasn't a pharma company at all, it was actually a focused, strategic accounting business.

They weigh up all their current & future pipeline almost daily in terms of risk/reward monetary values. I'm not really sure I feel a great desire to shed a tear for big pharma. They always seem to do alright when their results get posted at the end of each financial year. I've wrestled with the debate as to whether human medicine development/discovery is best done in this environment for a long time. And, I still haven't decided. Competition is good/healthy, but financial drive seems to be trumping the human/healing element more than ever.

In the last decade, it feels like they've spun most of the risks out to the small biotech startups, who they'll all get into a bidding war over once a potential product shows a vague shred of promise/monetary value. I'm not discounting the fact that the hills aren't littered with the hundreds of corpses of failed "promising" new biotechs/drugs they pumped hundreds of millions into for absolutely no return at all. I'm just not convinced the whole ecosystem is the best long-term strategy for human health. I guess that's what I'm really trying to say.

Be careful with your survivorship bias.

Plenty of large pharma companies have effectively disappeared over the last few decades - typically because the "big bets" failed and they got swallowed up by some larger player who wants to add to their portfolio.

Add in all the biotechs that spend tens or hundreds of millions on R&D and get $0 in the end, biotech is far from an "easy" business.

Damn I thought he'd be working on like, cat Ecstasy or something.

Getting Ecstasy to market involves fewer regulatory hurdles than even drugs for animals. It just so happens to be illegal in most countries.

I thought he'd be doing "this drug is for cats" wink wink and then people use it, but in retrospect a judge would see right through that.

I wonder if it would be significantly cheaper to go through regulatory approvals for a drug in another country, to the point where it would be worthwhile to relocate the company?

That's called 'catnip' :)

Given that it was on HN, I imagined someone working through various strains of catnip to optimize their cats' high through some complicated ML-guided process.

8/10 cats showed a preference for microdosing psychedelics

Easier regulatory environments. Not only do you not need to talk to the FDA before testing your drug in animals, cats are way less likely to sue you if they get sick from your drug. Of course, we’d still do our best to make sure they didn’t, but it’s less likely to sink the entire company if they do.

I thought this is paraphrased, but this is lifted straight from the article. This is so incredibly wrong I simply couldn't get past this statement.

I think this company is not understanding the role that animals have in millennial households.

The company which is betting the farm on cat owners spending money to treat their suffering cats doesn't know their market?

On the basis of what evidence.

Out of context, it sounds awful.

But having read the whole article, he doesn't seem like a monster at all. If it works as planned it'll really help some cats.

Is it? It seems like it's just acknowledging a objectively true reality. In the US getting sued for failed human medical intervention is common and costly. Courts (and juries I'm sure) don't look on animal lives with the same value as they do human lives. You might have a different value system, but the article isn't talking about your moral system, it's talking about objective reality.

I think the person you're replying to is using the term 'wrong' morally.

But, like they said, it's talking about the legal reality and not the moral reality. I find it hard to see how that could be either factually or morally wrong.

Correct, that comment was italicized to show that it was lifted straight from the article

How we got to our current state of medicine is horrifying, but the alternative is more grim.

There is no clean arrival for good, safe, effective medicine. A little gallows humor isn't hurting anyone.

Unfortunately, the reality of trying to cure animals is that sometimes you accidentally hurt animals. That's also the reality of trying to cure humans.

This is the exact same issue vets face when they perform surgery on your cat, and it's the exact same issue that surgeons face when they perform surgery on you. The difference is that vets don't have to pay tons of money for malpractice insurance in case they get sued by the owner, which is one of the big reasons why veterinary surgery is so much cheaper (i.e. affordable to ordinary people) than human surgery.

>veterinary surgery is so much cheaper (i.e. affordable to ordinary people) than human surgery....

..."in the USA". At a guess, I'd say it's the complete opposite in Europe with it's pesky human healthcare systems.

To be fair, human surgery also costs a lot in Europe. It's just not paid by the patient. It's not healthcare in itself that is free but health insurance.

It also costs less.

How many European doctors make more than $500k / year ? The average orthopedic makes roughly that (https://www.kaptest.com/study/mcat/doctor-salaries-by-specia...)

And that's a huge problem. All our doctors (Eastern EU here) are leaving for UK, US, or richer western EU countries. To resolve that, we have a law that requires newly graduate doctors to stay and work here for a long time (10 years here IIRC), which is rightly seen as a serious issue wrt. their personal freedom. That pushes people away from pursuing medical degrees.

It's cheaper, but that has its price too.

> All our doctors (Eastern EU here) are leaving for UK, US, or richer western EU countries

To be fair. That's true of educated people in general, not just doctors.

I can't fully agree. I think the situation is much better than it used to be and is improving, for example IT workers are not universally leaving anymore, a lot of them now stay and there are many foreign people coming here! There is now an exciting startup sector too, and the international corporations are finally building IT hubs here. But it keeps getting worse in the medical sector because of that law and because it's not paid well enough given the long hours and stress.

Nowadays, older doctors (those who have served their 10 years) are moving from insurance-based to cash-based treatment because they demand much more than the "pricing tables" dictate - so there's a lot of doctors around you, but you can't go to them because the "public" insurance can be used only where they accept it, they never give you cash. The prices are very similar to US hospital quotes - in absolutes, not PPP. Meanwhile, we still have the "public" healthcare providers (these are corporations, but usually wholly or partially owned by political entities), but the quality is getting worse, they are unable to keep it stable, much less improve - not surprising since they rely on essentially forced labor.

I've actually paid less for a private X-ray (in the UK) than it cost for my cat at the vet. Vetinary drugs are also often more expensive than their human equivalents.

I suspect scale may be a factor here.

And that's how our dog died in 25 days from a painkiller that the protocol is to check for liver function after 30 days...

I suppose this sentence is meant to be a little tongue in cheek, but a few of us at least do not find it funny.

I can see why you found that upsetting.

Still: our society (rationally) does not devote the same resources to drug development for animals as it does for humans. And even protocols, dosing regimens, etc, for humans are not perfect. And even when the ideal protocol is chosen, some people still have a bad outcome by being an outlier.

Medicine is very imperfect; veterinary medicine is worse.

My cat got bartonella which caused this condition and had to have all his teeth removed. Prior to the surgery he was in absolute misery, and the only treatment was steroids that did little and aren't meant for longtime use. The surgery was several thousand dollars, out of reach for a lot of families. An effective treatment for this condition would be great!

US I imagine ? It’s a few hundreds here.

curious, how is your cat doing post-surgery? I imagine it required a significant dietary change

Strangely enough it didn't, he still eats dry cat food and just crunches it with his gums a little. He is totally fine now aside from sometimes looking a little derpy with his gums

"The surgery was several thousand dollars, out of reach for a lot of families."

Wouldn't pet health insurance cover it?

Pet health insurance isn't an expected value positive sort of thing. There are often annual maxima as low as a couple thousand dollars.

This guy didn't do a lot of research when he picked chronic spontaneous urticaria as the target human indication. There already is an effective biologic, omalizumab, that works on the majority of patients and has no side effects (source: I have CSU/pressure urticaria). Cyclosporine is a heavy duty immunosuppressant with side effects that are worse than hives, imo, so I'm not sure what the target market would be. Personally I'd rather not take the risks of being seriously immunosuppressed, even if it meant getting hives. And, it was the drug my immunologist wanted me to try next if the biologic didn't work, so it's already being prescribed off label.

> I linked up with an excellent corporate attorney and patent attorney, both of whom agreed to let me use their services on a pay later basis.

I'm curious about this "pay later" arrangement - does it simply mean they'll invoice you on 30 day terms, or something else?

The corporate attorney agreed not to require me to pay any of their invoices until I closed a seed round, while the patent attorney let me pay their invoices a full year after I received them. These sorts of arrangements are common with attorneys who work with startups.

Just wanted to leave a plea for someone, anyone, to please start working on FeLV and FIV vaccines. Cats normally live 16 years. FeLV/FIV takes them at age 2 or 3. It happened to both of mine.

Not only is it common, but it's often assumed that it'll happen. It seems almost lucky when cats don't get it.

If an epidemic like that were affecting humans, a trillion dollars would be spent to fight it. But since it's cats, we just stay silent.

I wish there were more commercial incentive. I don't know how there would be, but I hope one day there will be.

Not to detract from your point, but HIV is exactly that disease and a lot of money has been spent to treat it with considerable success.

Which is to say you're correct but it's not a hypothetical.

Lost two little friends because of that ;(

> If an epidemic like that were affecting humans, a trillion dollars would be spent to fight it.

Only if it affected rich western countries. Poor fuckers of all ages from around equator are decimated daily and comparatively very little was done and its not great even now. Very easy and cheap to minimize exposure (ie mosquito nets), and completely reachable to eradicate for for maybe 70-80% of affected population. But I guess dying african/asian kid half around the world doesn't stir enough emotions these days.

I’m sorry to hear both your cats passed away at age 2-3. Can I ask whether the cats were infected with FeLV or FIV? FIV cats can often live a relatively long life (~10 years) if kept indoors. Whereas the median lifespan for a FeLV positive cat is 3 years from the date of diagnosis.

FeLV has a vaccine. Also I guess it’s regional, here not that many cases. Also have personally seen multiple cats live well past 10 with FIV, with no treatment as they are none. 2-3 years seems super short from what I’ve seen so I wouldn’t blame FIV only. (I am an European vet)

Every university vet-med program in the country probably has people working on FeLV. You can Google for this: ["university" "veterinary medicine" "felv" "lab"].

If this was published on Medium, I would have highlighted this paragraph: "On the human side, the FDA mostly considers their responsibility to be to stop unsafe or ineffective drugs from entering the marketplace, and believes that allowing safe and effective drugs to enter the marketplace is a secondary goal."

That makes perfect sense if you know the history of the FDA!

PBS has a great documentary on it. https://www.pbs.org/video/dr-harvey-wiley-father-pure-food-s...

Good. They're the only thing standing between the public and people who would run mass experiments daily for money.

Yes, they have to do this. The cost of a few bad drug approvals that cause large-scale loss of confidence in the pharma industry would be devastating- including consequential effects on good medications.

> Yes, they have to do this.

We can imagine lots of alternatives to what the FDA currently does - a partial approval pipeline immediately comes to mind in which the degree to which a drug is approved is commensurate to our confidence in the safety/efficacy of the drug. A different system could have different levels of approval on efficacy and safety. A different system could attempt to maximize lives saved (or utility years) and would look very different yet.

There are a lot of different approaches that could be taken that would definitely be more effective in the short term and I too wish we could take the most effective and logical approach. The problem is people are not always logical, especially on a large scale.

A proposal like you mentioned puts a lot of trust in the general public to be capable of making informed decisions based on detailed approval levels and risk profiles and not react to negative outcomes or side effects by blaming the FDA, pharmaceutical science, or the medical field.

It feels like putting that kind of complication into something as important and life affecting as pharmaceuticals is just asking for trouble when we live in a world where the grades for maple syrup needed to be simplified and large numbers of people think the President has direct control of gas prices.

Especially in the age of social media, it only takes a small increase in the number of people reacting illogically and lashing out to snowball, create loud counter narratives, and threaten the view of the FDA as a trusted authority and its ability to provide strong oversight. The result being increasing numbers of people harmed because they chose to avoid care or seek out sham alternative treatments.

We can already see these issues cropping up with regard to things like vaccines where factors like COVID vaccines being rolled out under early approval (an unfortunately necessary special case) has hurt public perception of the FDA.

The unhappy fact is that any approach that does not take into account the need to protect people from themselves, make efforts to minimize bad PR, and ensure the FDA appears as completely as possible to never make mistakes will result in an erosion of trust and even worse outcomes in the long term.

There's an enormous amount of literature and commentary out there about the tendency for federal regulators in general, and the FDA especially, to minimize "Type I" error (approving drugs that are unsafe/ineffective) with the negative consequence of making more "Type II" errors (not approving drugs that are safe and effective).

Yep. Not the same in most of EU where proof of efficiency is most often required. Which also explains why some people need to go to the US for treatment

A concern with using cyclosporine for neurodegeneration may be that it causes progressive kidney damage and high blood pressure with long term usage. We use it a lot for many immunologically mediated skin diseases however almost always plan to change after a year to an alternative for this reason.

Regarding chronic idiopathic urticaria - cyclosporine was used in the past but now in the UK omalizumab is licensed for this and generally is more safe and effective.

I have a quasi-thought experiment for fellow HN readers.

If you found out one of the stray cats at unofficial “cat shelter” tested positive for FeLV and the person who runs the “cat shelter” seems oblivious to it, would you consider unethical to let the person continue run it? The FeLV virus is likely to spread among all the cats and result in a short life of suffering and illness.

So is this a variation on the trolley problem or something ?

How many cats are we talking about ?

Not really. I guess it’s about disruption of the person’s lifestyle and he/her liking for cats vs the actual welfare of the cats - how having good intentions alone is often insufficient. I would put the current number of cats at 10, plus other future cats.

If you can't get them to vaccinate the other cats, then yes

@OP you should reach out to my local University and its Atlantic Veterinary College (AVC) here in PEI, Canada.

https://www.upei.ca/avc/research

Do you have any connections there, by any chance? Always looking to talk to more vets.

No I don't sorry. My cousin is a philosophy professor there not in the veterinary section. But I could ask around.

Good luck Mr Escopurr

Just from the headline I thought something similar - developing something around catnip or valerian, which is kind of an interesting idea but probably already done.

Gee whiz this is a great chemical, let's find something it's good for and perhaps we'll be able to make money on it someday...

Seems like a really long diversion from the original goals, doesn't it? "People have problem A and i want to test solution X for effectiveness" was the first principle, right? Now it sounds a lot like "we bought tons of this crap now we've gotta push it somehow"

That's the real world for you. Sometimes companies end up seeing success after long diversions from real goals, because the world throws obstacles at them that require them to adapt.

Seems like the alternative here is to do nothing, so finding a productive but realistic path forward is a better alternative. I think it's clearly wrong to call running studies in animals "pushing it" on anyone.

Yea, isn't that how Viagra came about - "Well it doesn't the blood vessels quite like we wanted, but .... well it does this!"

And Rogaine. It was also created to treat High BP as a powerful vasodilator. Turns out it made you hairy too. Maybe we should spend all of our R&D pursuing High BP -- who knows what other ailments we'll cure!

I mentioned this before in HN, will mention again. There is definitely something about vasodilation and hair growth/mobility, especially when it comes to in-grown facial hair.

If you have in-grown hairs, take Viagra once and they'll start coming out in a few hours on their own or with minimal mechanical force. The effect continues for a day or two so I am sure even the secondary metabolites might be somewhat active in inducing this effect.

Trying to cure a disease that gives cats such bad mouth sores that they sometimes can't even drink water isn't exactly "pushing crap".

We're trying to make it to profitability so we can get to the point where we can test the solution in humans who have neurodegeneration. When you're dealing with incredibly complex regulatory environments and millions of dollars in development costs, it's not always easy to make it from point A to point B. That's the point of this post.

Shocker how one needs to find resources to actually do things, huh?

god this article sounds like a writing prompt.

"im making drugs for cats!" I shreik in my underwear as the FBI raids my derelict RV full of cat clozapine and TV dinner trays.

"im making drugs for cats" I calmly explain as i wheel a teetering trolly full of drain cleaner and paint thinner toward my car.

"im making drugs...for cats?" I shake my head as the prospect of tenure track seems to fade away.

Certainly works for GPT-3 as a writing prompt:

'"im making drugs...for cats?" I shake my head as the prospect of tenure track seems to fade away.

"No, I'm not making drugs for cats."

"I'm not sure what you're trying to say."

"I'm trying to say that I'm not going to be a tenure-track professor."

"Oh."

I'm not sure what else to say. I know that I should be upset, or at least disappointed. But I'm not. I'm relieved.

I've been on the tenure track for six years, and I'm tired. I'm tired of the politics, the infighting, the backstabbing. I'm tired of the constant pressure to publish, to get grants, to bring in money. I'm tired of having to choose between my research and my teaching. I'm tired of feeling like I'm never good enough.

I'm not sure what I'm going to do next, but I know that I'm done with the tenure track. And that's OK.

"So, what are you going to do?"

"I'm not sure yet. But I'm open to suggestions."

"Well, you could always make drugs for cats."

I shake my head and laugh. "No, I don't think that's quite what I'm looking for."

But who knows? Maybe making drugs for cats is exactly what I need.

"In all seriousness, though, I wish you the best of luck in whatever you decide to do."

"Thank you. I appreciate that."

And with that, I walk away from the tenure track, and into the unknown.

Who knows what the future holds? But for now, I'm OK with not knowing.

I'm not sure what the future holds, but I'm open to whatever comes my way.

And that, to me, is the most exciting part.

(This story was originally published on The Professor Is In blog. It has been republished here with the author's permission.)'

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