Denis Odinokov – Conquering Cross-Linking for Biomedical Longevity

In order to achieve biomedical longevity, the problem of cross-Linking of the extracellular matrix needs to be addressed. Cells are held together by special linking proteins. When too many cross-links form between cells in a tissue, the tissue can lose its elasticity and cause problems including arteriosclerosis, presbyopia and weakened skin texture. These are chemical bonds between structures that are part of the body, but not within a cell. In senescent people many of these become brittle and weak. Fixing cross-linking may prove more difficult than just removing it – as it may create a vacuum where more waste is pulled in to fill the void left behind. Though some research is being conducted, the problem deserves a lot more hands on deck – and far more funding.
Denis gives a technical explanation of why conquering cross-linking is important, and strategies for addressing this problem in this interview conducted at the Undoing Aging conference in Berlin 2019.

Introduction to Denis’ writing/research here – “The Impact of Extracellular Matrix Proteins Cross-linking on the Aging Process“.

Understanding the consequences of the formation of protein crosslinks requires more attention both from the scientific community and independent researchers who are passionate with regards to the extension of the human lifespan. By doing so, it allows us to level up the playing field where we can create and work on more serious and impactful solutions.

Also see GlycoSENSSENS proposes to further develop small-molecular drugs and enzymes to break links caused by sugar-bonding, known as advanced glycation endproducts, and other common forms of chemical linking.

 

Jim Mellon – Investing in the Age of Longevity

Interview with hugely successful investor Jim Mellon at the Undoing Aging conference in Berlin 2019!
We cover reasons why it’s a good time to invest in Anti-Aging and rejuvenation biotechnology today, the ethical reasons why we should, and effective advocacy: i.e. what one would say to a billionaire to convince them that investing in longevity medicine is a good thing to do now.
Jim raised over $150 Million for his venture Juvenescence recently!

Transcript

My name is Jim Mellon, and I’m the chairman of Juvenescence, which is a company involved in the science of longevity. It is relatively recently formed; it is about a year and a bit old, but we’ve raised a significant amount of funding – nearly $160 million now – in the last year to advance the cause of longevity science. By the end of this year, we’ll have made 18 investments. Most of them are subsidiary companies of ours, so we control those companies. We give both development and financial backing to the scientist-entrepreneurs and institutions that we collaborate with.

I am fortunate to have two partners who have broad experience in the biotech and healthcare area, in particular, Declan Doogan, who was the head of drug development at Pfizer for a long period, and then he became the CEO of Amarin, which, as you know, is a very successful biotech company with a nearly $10 billion market valuation today. About four years ago, the three of us started a company called Biohaven, which is now listed on the New York Stock Exchange and has a valuation of about $2.5 billion. The company has approval for a drug for migraine, which will be on the market in the US next year. There is a good team of veteran drug developers and business entrepreneurs who have come together to create this Juvenescence company, and we’re very, very excited about it. We’re the biggest investors in the company ourselves, on the same terms as other investors. We will take the company public in the first quarter of next year, barring market disasters, and probably on the US stock exchanges.

We’re interested in this field of longevity science and able to raise significant funding because we’ve been in biotech for quite a long period of time, together, and created a number of companies. It seemed to be a natural outgrowth of the great developments that have occurred in the last few years. The unveiling of the human genome identified aging pathways that can now be manipulated. For the first time ever, you and I are in the cohort that is able to be bioengineered to live a healthier and longer life. It is still in a very primitive stage; we’re in the internet dial-up era equivalent, but the science is advancing very quickly.

I always say that I wrote my first book on biotech seven years ago, it was called Cracking the Code, and since then, we’ve had CRISPR/Cas9, which didn’t exist seven years ago, we’ve had the cure for Hepatitis C, we’ve had artificial intelligence for the development of novel compounds. The latter of which is a key part of our strategy, as investors in In Silico Medicine, which I think you are familiar with. Then, of course, you have cancer immunotherapy, which didn’t exist seven years ago, and is now a $100 billion / year industry. So, what’s going to happen in the next seven years? We don’t know, but it’s going to be very, very good. If you want to regard it as a casino table, we’re covering all the markers that we can with the funds that we’ve raised. We hope to raise a substantial further amount on the initial public offering of the company in the first quarter of next year, and that will give us enough firepower to do five Phase 2 trials without partners so that we can get the maximum leverage on the products that we’re developing.

So far, we’ve invested in small molecules, which is the specialization of our team. For instance, we have a senolytic drug in development in that area. We’ve also invested in stem cells; we’re the largest investor in Mike West’s company, AgeX Therapeutics, which is now a public company in the US. We own about 46% of that company. Then, via Lygenesis, we’ve also got our first product going into patients in the first quarter of next year, sick patients in a phase II trial, for organ regeneration, regenerating the liver, using hepatocytes to seed lymph nodes to act as ectopic bioreactors to grow fully functioning liver tissue. The FDA has agreed to the protocol for doing that in sick patients, which is a remarkably fast path to demonstrating successful outcomes in that area. If that is successful, then we will look to regenerate other organs, in particular the thymus, which as you know is related to aging in a big way.

We’re moving very, very quickly. We’ve got great colleagues; Margaret Jackson from Pfizer is on our team. Howard Federoff, ex-Pfizer, is on our team. Annalisa Jenkins, who was head of drug development and research and development at Merck Serono, a very big drug company, is on our team. We’ve put it all together remarkably quickly, but we have experience in doing that, and so we’re full of confidence. This is a remarkable time to be alive, and I want to be alive for at least another 20 or 30 years beyond what would be considered to be my allotted life span. The same is the motivating factor for my cofounders, Declan Doogan and Greg Bailey.

Working to extend life is an ethical cause. No one can argue, successfully at least, that this isn’t a good thing to do. There are some people who say “well, it is for the haves and not for the have-nots” but that is rubbish, because, ultimately, all these drugs will become generally available, and some of them already are. Metformin, which, as you are aware, is a drug that has some anti-aging properties, costs essentially nothing. It is a generic drug. As antibiotics, ulcer drugs, and so forth were once expensive and are now very cheap, the same thing will happen to drugs for longevity. Gene therapy and stem cells are another matter, though, and they will probably be expensive things for some time to come. But, undoubtedly, the cost will come down for those as well.

The other people who argue against work on aging talk about overpopulation; if there are all these old people, will there be enough room on the planet. Well, the answer is, we’re already alive, so we’re not going to be adding to the population. You and I are already here. The big issue on population is how many children does each woman have around the world, and that figure is falling dramatically, to the point where we can see populations actually shrinking. Just as an example, if Japan doesn’t allow immigration, or doesn’t have a baby boom, its population will fall from 126 million today to 50 million by the year 2100. So both those arguments, the haves versus the have-nots, and the overpopulation concern, are nonsensical arguments. In my view, there is absolutely no reason why governments, institutions, the general population, and the voting population shouldn’t be pushing really hard to make this happen.

Regarding the aging of the existing population and how to cope with it, the main point made by Aubrey de Grey, and other eminent scientists as well, is that if you treat the top of the cascade of damage in aging, then you are going to treat the underlying diseases of aging that pharmaceutical companies are trying to address. But for those pharmaceutical companies, it is a whack-a-mole exercise, so if you get one disease and that is cured, then you’ll get another one, and they’ll have to cure that one. Ultimately, we become destabilized and we die, all of us. So, let’s try and treat aging as the central disease, and from that as the unitary disease, we’ll be treating the cascade that follows from that.

Some people say it is hubris to target aging, but I think that this is because until relatively recently, nothing worked. It has been an aspiration of human beings for millennia to find the fountain or elixir of youth, and nothing has worked. So, people are skeptical about the fact that it might be working now: why now rather than 20 years ago or 20 years in the future? But the fact is that it is now, and we need to seize the moment and rise to the challenge. We need much more funding to come into this area, and that funding will drive the science. We need many more advocates for this cause to come to the fore and tp spread the word, that this is going to be monumentally great for human beings.

In my own case, I’ve set up a charity with Andrew Scott, who wrote The 100 Year Life, and we do a Longevity Week in London. We did the first one last year, and we’re doing the next one in November of this year, to spread the word. This will have a big societal impact, on consumption, on the way in which we look at the trajectory of life, but it is also going to have a major impact on us as human beings. In the past, you’d have expected to live to about 85 or 90, the same with me, and now we’re very likely to live to 110 or 120, so let’s do it. Let’s make it happen. I think that all of us, yourself, myself, have relatives, dear friends, and acquaintances who are suffering the indignities of aging as it currently exists. We’d like to relieve that burden of suffering by extending the healthy span of life. The personal motivation is a very big factor. Here in Berlin, there are 300 or 400 people at this conference, and I imagine that all of them, beyond just the business or scientific side of things, have an altruistic motivation for this as well. More people need to do it, so get on to it!

The elevator pitch for high net worth people thinking about investing in this space is that, first of all, we’re at the front end of a huge upward curve. I said earlier on that this was like the internet dial-up phase of longevity biotech. If you’d invested in the internet in the very early days, you’d be more than a billionaire now; you’d be one of the richest people on the planet. We’re at that stage now, so the opportunity for investors is huge, but you could do both. You could invest in something like the SENS Research Foundation or the Buck Institute or one of those wonderful organizations that is trying to advance the cause, and at the same time invest in some of the companies that come out of those institutions. We’ve undertaken two joint ventures with the Buck Institute, and we’ve made a couple of investments as a result of introductions by the SENS Research Foundation, including the organ regeneration program. If you’re a sensible billionaire, you will be putting some of your funds to work in a combination of a charitable enterprise that drives the science and the businesses themselves that come out of those enterprises.

Many thanks to Leaf Science for doing the transcript!

Perhaps one of the most interesting companies in which Juvenescence has invested is Lygenesis, which is developing an approach to address liver failure by creating miniature livers to pick up the slack. Lygenesis is using a technique in which liver cells are delivered to lymph nodes, where they develop and grow into fully working liver tissue, albeit smaller than the organ they replace. If these organs are shown to perform all the functions of a working liver, they could potentially remove the need to replace damaged livers through transplants. Initial work in mice and pigs has been promising, and Lygenesis plans to move to phase 2 clinical trials in early 2020.

Judith Campisi – Senolytics for Healthy Longevity

I had the absolute privilege of interviewing Judith Campisi at the Undoing Aging conference in Berlin.  She was so sweet and kind – it was really a pleasure to spend time with her discussing senolytics, regenerative medicine, and the anti-aging movement.

 

 

 

Judith Campisi was humble, open minded, and careful not to overstate the importance of senolytics, and rejuvenation therapy in general.  Though she really is someone who has made an absolutely huge impact in anti-aging research.  I couldn’t have said it better than Reason at Fight Aging!

As one of the authors of the initial SENS position paper, published many years ago now, Judith Campisi is one of the small number of people who is able to say that she was right all along about the value of targeted removal of senescent cells, and that it would prove to be a viable approach to the treatment of aging as a medical condition. Now that the rest of the research community has been convinced of this point – the evidence from animal studies really is robust and overwhelming – the senescent cell clearance therapies known as senolytics are shaping up to be the first legitimate, real, working, widely available form of rejuvenation therapy.

“Biomimicry”, a Documentary

Biomimicry is a 20 minute long documentary film, produced by Leonardo DiCaprio (film producer, and environmentalist), on the topic of how life and biology can be the mentors for our own innovation in the world.

Janine Benyus, the founder of the Biomimicry Institute, describes how biomimicry has been applied to different problems successfully, from designing forms that capture carbon to replacing toxic solvents we use.

Benyus believes that there is much to be learned in terms of sustainability and success in innovation from the organisms that compose the history of life in our planet. Biomimicry is brought to us by Leonardo DiCaprio, Executive Producer Oliver Stanton, and directed by Leila Conners, produced by Mathew Schmid and Bryony Schwan, with Executive Producers Roee Sharon Peled and George DiCaprio.

Biomimicry, the practice of looking deeply into nature for solutions to engineering, design and other challenges, has inspired a film about it’s ground-breaking vision for creating a long-term, sustainable world. This film covers how mimicking nature solves some of our most pressing problems, from reducing carbon emissions to saving water. The film, titled “Biomimicry” features Janine Benyus, is brought to you by Leonardo DiCaprio, Executive Producers Oliver Stanton, directed by Leila Conners, produced by Mathew Schmid and Bryony Schwan, created by Tree Media with Executive Producers Roee Sharon Peled and George DiCaprio.

For more on the film: http://www.treemedia.com

Jerry Shay – The Telomere Theory of Ageing – Interview At Undoing Ageing, Berlin, 2019

“When telomeres get really short that could lead to a dna damage signal and cause cells to undergo a phenomenon called ‘replicative senescence’…where cells can secrete things that are not necessarily very good for you..”

Why is it that immune cells don’t work as well in older age?

Listen to the interview here

Jerry and his team compared a homogeneous group of centenarians in northern Italy to 80 year olds and 30 year olds – and tested their immune cells (T-Cells) for function (through RNA sequencing) – what was observed was all the young people clustered apart from most of the old people clustered.. but the centenarians didn’t cluster in any one spot.  It was found that the centenarians clustered along side the younger cohorts had better telomere length.

Out of 7 billion people on earth, there is only about ~ half a million centenarians – most of them are frail – though the ones with longer telomeres and more robust T-Cell physiology seem to be quite different to the frail centenarians.   What usually happens is when telomeres wear down the DNA in the cell gets damaged, triggering a DNA damage response. From this, Jerry and his team made a jump in logic – maybe there are genes (i.e. telomere [telomere expression genes?]) that when the telomeres are long these genes are repressed, and when the telomeres short the genes get activated – circumventing the need for a DNA damage response.  What is interesting is that they found genes that are really close to the telomere genes (cytokines – inflammatory gene responses – TNF Alpha, Ennalucan 1 etc) – are being activated in humans – a process called ‘Telomere Looping’. As we grow and develop our telomeres get longer, and at a certain length they start silencing certain inflammation genes, then as we age some of these genes get activated – this is sometimes referred to as the ‘Telomere Clock’.  Centenarians who are healthy maintain longer telomeres and don’t have these inflammation genes activated.

 

During early fetal development (12-18 weeks) telomerase gets silenced – it’s always been thought that this was to stop early onset of cancer – but Dr Shay asked, ‘why is it that all newborns have about the same length of telomeres?’ – and it’s not just in humans, it’s in other animals like whales, elephants, and many large long-lived mammal – this doesn’t occur in smaller mammals like mice, rats or rabbits.   The concept is that when the telomere is long enough, it loops over and silences its own gene, which stays silent until we are older (and in need of it again to help prevent cancer).

This Telomere Looping probably evolved as part of Antagonistic Pleiotropy – where things that may have a protection or advantage early in life may have unpredicted negative consequences later in life. This is what telomerase is for – we as humans need it in very early development, as do large long-lived mammals, and  a mechanism to shut it off – then at a later older age it can be activated again to fight against cancer.

 

There is a fair amount of evidence for accumulated damage as hallmarks for ageing – can we take a damage repair approach to rejuvenation medicine?

Telomere spectrum disorders or telomeropathies – human diseases of telomere disfunction – diseases like idiopathic pulmonary fibrosis in adults and dyskeratosis congenita in young children who are born with reduced amounts of telomeres and telomerase – they get age related diseases very early in life.  Can they be treated? Perhaps through gene therapy or by transiently elongating their telomeres. But can this be applied for the general population too?  People don’t lose their telomeres at the same rate – we know it’s possible for people to keep their telomeres long for 100 years or more – it’s just not yet known how.  It could be luck, likely it has a lot to do with genetics.

 

Ageing is complex – no one theory is going to explain everything about ageing – the telomere hypothesis of ageing perhaps makes up for about on average 5% or 10% of aging – though understanding it enough might give people an extra 10% of healthy life.   Eventually it will be all about personalised medicine – with genotyping we will be able to say you have about a 50% chance of bone marrow failure when you’re 80 years old – then if so you may be a candidate for bone marrow rejuvenation.

What is possible in the next 10 years?

 

Inflammation is highly central to causing age related disease.  Chronic inflammation can lead to a whole spectrum of diseases. The big difference between the subtle low grade inflammation that we have drugs for – like TNF blockers (like Humira and Enbrel) which subtly reduce inflammation – people can go into remission from many diseases after taking this.

There are about 40 million people on Metformin in the USA – which may help reduce the consequences of ageing – this and other drugs like it are safe drugs – if we can find further safe drugs to reduce inflammation etc this could go a long way – Aspirin perhaps (it’s complicated) – but it doesn’t take much to get a big bang out of a little intervention – the key to all this is safety – we don’t want to do any harm – so metformin and Asprin have been proven to be safe over time – now we need to learn how to repurpose those to specifically address the ageing problem.

 

Historically we have more or less ignored the fundamental problem of ageing and targeted specific diseases – but by the time you are diagnosed, it’s difficult to treat the disease – by the time you have been diagnosed with cancer, it’s likely so far advanced that it’s difficult to stop the eventual outcomes.   The concept of intervening in the ticking clock of ageing is becoming more popular now. If we can intervene early in the process we may be able to mitigate downstream diseases.

Jerry has been working on what they call a ‘Telomerase Mediated Inhibitor’ (see more about telomerase meditation here) – “it shows amazing efficacy in reducing tumor burden and improving immune cell function at the same time – it gets rid of the bad immune cells in the micro environment, and guess what?  the tumors disappear – so I think there’s ways to take advantage of the new knowledge of ageing research and apply it to diseases – but I think it’s going to be a while before we think about prevention.”

Unfortunately in the USA, and really globally “people want to have their problems their lifestyles the way they want them, and when something goes wrong, they want the doctor to come and and give them a pill to fix the problem instead of taking personal responsibility and saying that what we should be doing is preventing it in the first place.”  We all know that prevention is important, though most don’t want to practise prevention over the long haul.

 

The goal of all this not necessarily to live longer, but to live healthier – we now know that the costs associated with intervening with the pathologies associated with ageing is enormous.  Someone said that the 25% of medicare costs in the USA is in treating people that are on dialysis – that’s huge. If we could compress the number of years of end of life morbidities into a smaller window, it would pay for itself over and over again.   So the goal is to increase healthspan and reduce the long period of chronic diseases associated with ageing. We don’t want this to be a selected subgroup who have access to future regenerative medicine – there are many people in the world without resources or access at this time – we hope that will change.

Jerry’s goal is to take some of the discovered bio-markers of both healthy and less healthy older people – and test them out on larger population numbers – though it’s very difficult to get the funding one needs to conduct large population studies.

The Ghost in the Quantum Turing Machine – Scott Aaronson

Interview on whether machines can be conscious with Scott Aaronson, theoretical computer scientist and David J. Bruton Jr. Centennial Professor of Computer Science at the University of Texas at Austin. His primary areas of research are quantum computing and computational complexity theory.
Scott blogged about this and other segments of our interview – his blog is very popular and has way more comments than this one does – check it out.

Check out interview segment “The Winding Road to Quantum Supremacy” with Scott Aaronson – covering progress in quantum computation, whether there are things that quantum computers could do that classical computers can’t etc..

Transcript

Adam Ford: In ‘Could a Quantum Computer have Subjective Experience?‘ you speculate where the process has to fully participate in the arrow of time to be conscious and this points to decoherence. If pressed, how might you try to formalize this?

Scott Aaronson: So yeah so I did write this kind of crazy essay five or six years ago that was called “The Ghost in the Quantum Turing Machine“, where I tried to explore a position that seemed to me to be mysteriously under-explored! And all of the debates about ‘could a machine be conscious?’ and we want to be thoroughgoing materialists right? There’s no magical ghost that defies the laws of physics; the brains or physical systems that obey the laws physics
just like any others.
But there is at least one very interesting difference between a brain and any digital computer that’s ever been built – and that is that the state of a brain is not obviously copyable; that is not obviously knowable to an outside person well enough to predict what a person will do in the future, without having to scan the person’s brain so invasively that you would kill them okay. And so there is a sort of privacy or opacity if you like to a brain that there is not to a piece of code running on a digital computer.
And so there are all sorts of classic philosophical conundrums that play on that difference. For example suppose that a human-level AI does eventually become possible and we have simulated people who were running a inside of our computers – well if I were to murder such a person in the sense of deleting their file is that okay as long as I kept the backup somewhere? As long as I can just restore them from backup? Or what if I’m running two exact copies of the program on two computers next to each other – is that instantiating two consciousnesses? Or is it really just one consciousness? Because there’s nothing to distinguish the one from the other?
So could I blackmail an AI to do what I wanted by saying even if I don’t have access to you as an AI, I’m gonna say if you don’t give me a million dollars then I’m just going to – since I have your code – I’m gonna create a million copies of your of the code and torture them? And – if you think about it – you are almost certain to be one of those copies because there’s far more of them than there are of you, and they’re all identical!
So yeah so there’s all these puzzles that philosophers have wondered about for generations about: the nature of identity, how does identity persist across time, can it be duplicated across space, and somehow in a world with copy-able AIs they would all become much more real!
And so one one point of view that you could take is that: well if I can predict exactly what someone is going to do right – and I don’t mean you know just saying as a philosophical matter that I could predict your actions if I were a Laplace demon and I knew the complete state of the universe right, because I don’t in fact know the complete state of the universe okay – but imagine that I could do that as an actual practical matter – I could build an actual machine that would perfectly predict down to the last detail every thing you would do before you had done it.
Okay well then in what sense do I still have to respect your personhood? I mean I could just say I have unmasked you as a machine; I mean my simulation has every bit as much right to personhood as you do at this point right – or maybe they’re just two different instantiations of the same thing.
So another possibility, you could say, is that maybe what we like to think of is consciousness only resides in those physical systems that for whatever reason are uncopyable – that if you try to make a perfect copy then you know you would ultimately run into what we call the no-cloning theorem in quantum mechanics that says that: you cannot copy the exact physical state of a an unknown system for quantum mechanical reasons. And so this would suggest of you where kind of personal identity is very much bound up with the flow of time; with things that happen that are evanescent; that can never happen again exactly the same way because the world will never reach exactly the same configuration.
A related puzzle concerns well: what if I took your conscious or took an AI and I ran it on a reversible computer? Now some people believe that any appropriate simulation brings about consciousness – which is a position that you can take. But now what if I ran the simulation backwards – as I can always do on a reversible computer? What if I ran the simulation, I computed it and then I uncomputed it? Now have I caused nothing to have happened? Or did I cause one forward consciousness, and then one backward consciousness – whatever that means? Did it have a different character from the forward consciousness?
But we know a whole class of phenomena that in practice can only ever happen in one direction in time – and these are thermodynamic phenomena right; these are phenomena that create waste heat; create entropy; that may take these little small microscopic unknowable degrees of freedom and then amplify them to macroscopic scale. And in principle there was macroscopic records could could get could become microscopic again. Like if I make a measurement of a quantum state at least according to the let’s say many-worlds quantum mechanics in principle that measurement could always be undone. And yet in practice we never see those things happen – for the same for basically the same reasons why we never see an egg spontaneously unscramble itself, or why we why we never see a shattered glass leap up to the table and reassemble itself right, namely these would represent vastly improbable decreases of entropy okay. And so the speculation was that maybe this sort of irreversibility in this increase of entropy that we see in all the ordinary physical processes and in particular in our own brains, maybe that’s important to consciousness?
Right uh or what we like to think of as free will – I mean we certainly don’t have an example to say that it isn’t – but you know the truth of the matter is I don’t know I mean I set out all the thoughts that I had about it in this essay five years ago and then having written it I decided that I had enough of metaphysics, it made my head hurt too much, and I was going to go back to the better defined questions in math and science.

Adam Ford: In ‘Is Information Physical?’ you note that if a system crosses a Swartzschild Bound it collapses into a black-hole – do you think this could be used to put an upper-bound on the amount of consciousness in any given physical system?

Scott Aaronson: Well so I can decompose your question a little bit. So there is what quantum gravity considerations let you do, it is believed today, is put a universal bound on how much computation can be going on in a physical system of a given size, and also how many bits can be stored there. And I the bounds are precise enough that I can just tell you what they are. So it appears that a physical system you know, that’s let’s say surrounded by a sphere of a given surface area, can store at most about 10 to the 69 bits, or rather 10 to the 69 qubits per square meter of surface area of the enclosing boundary. And it has a similar limit on how many computational steps it can do over it’s it’s whole history.
So now I think your question kind of reduces to the question: Can we upper-bound how much consciousness there is in a physical system – whatever that means – in terms of how much computation is going on in it; or in terms of how many bits are there? And that’s a little hard for me to think about because I don’t know what we mean by amount of consciousness right? Like am I ten times more conscious than a frog? Am I a hundred times more conscious? I don’t know – I mean some of the time I feel less conscious than a frog right.
But I am sympathetic to the idea that: there is some minimum of computational interestingness in any system that we would like to talk about as being conscious. So there is this ancient speculation of panpsychism, that would say that every electron, every atom is conscious – and do me that’s fine – you can speculate that if you want. We know nothing to rule it out; there were no physical laws attached to consciousness that would tell us that it’s impossible. The question is just what does it buy you to suppose that? What does it explain? And in the case of the electron I’m not sure that it explains anything!
Now you could say does it even explain anything to suppose that we’re conscious? But and maybe at least not for anyone beyond ourselves. You could say there’s this ancient conundrum that we each know that we’re conscious presumably by our own subjective experience and as far as we know everyone else might be an automaton – which if you really think about that consistently it could lead you to become a solipsist. So Allen Turing in his famous 1950 paper that proposed the Turing test had this wonderful remark about it – which was something like – ‘A’ is liable to think that ‘A’ thinks while ‘B’ does not, while ‘B’ is liable to think ‘B’ thinks but ‘A’ does not. But in practice it is customary to adopt the polite convention that everyone thinks. So it was a very British way of putting it to me right. We adopt the polite convention that solipsism is false; that people who can, or any entities let’s say, that can exhibit complex behaviors or goal-directed intelligent behaviors that are like ours are probably conscious like we are. And that’s a criterion that would apply to other people it would not apply to electrons (I don’t think), and it’s plausible that there is some bare minimum of computation in any entity to which that criterion would apply.

Adam Ford: Sabine Hossenfelder – I forget her name now – {Sabine Hossenfelder yes} – she had a scathing review of panpsychism recently, did you read that?

Scott Aaronson: If it was very recent then I probably didn’t read it – I mean I did read an excerpt where she was saying that like Panpsychism – is what she’s saying that it’s experimentally ruled out? If she was saying that I don’t agree with that – know I don’t even see how you would experimentally rule out such a thing; I mean you’re free to postulate as much consciousness as you want on the head of a pin – I would just say well it’s not if it doesn’t have
an empirical consequence; if it’s not affecting the world; if it’s not affecting the behavior of that head of a pin, in a way that you can detect – then Occam’s razor just itches to slice it out from our description of the world – always that’s the way that I would put it personally.\
So I put a detailed critique of integrated information theory (IIT), which is Giulio Tononi’s proposed theory of consciousness on my blog, and my critique was basically: so Tononi know comes up with a specific numerical measure that he calls ‘Phi’ and he claims that a system should be regarded as conscious if and only if the Phi is large. Now the actual definition of Phi has changed over time – it’s changed from one paper to another, and it’s not always clear how to apply it and there are many technical objections that could be raised against this criterion. But you know what I respect about IIT is that at least it sticks its neck out right. It proposes this very clear criterion, you know are we always much clearer than competing accounts do right – to tell you this is which physical systems you should regard as conscious and which not.
Now the danger of sticking your neck out is that it can get cut off right – and indeed I think that IIT is not only falsifiable but falsified, because as soon as this criterion is written down (what the point I was making is that) it is easy to construct physical systems that have enormous values of Phi – much much larger then a human has – that I don’t think anyone would really want to regard as intelligent let alone conscious or even very interesting.
And so my examples show that basically Phi is large if and only if your system has a lot of interconnection – if it’s very hard to decompose into two components that interact with each other only weakly – and so you have a high degree of information integration. And so my the point of my counter examples was to try to say well this cannot possibly be the sole relevant criterion, because a standard error correcting code as is used for example on every compact disc also has an enormous amount of information integration – but should we therefore say that you know ‘every error correcting code that gets implemented in some piece of electronics is conscious?’, and even more than that like a giant grid of logic gates just sitting there doing nothing would have a very large value of Phi – and we can multiply examples like that.
And so Tononi then posted a big response to my critique and his response was basically: well you’re just relying on intuition; you’re just saying oh well yeah these systems are not a conscious because my intuition says that they aren’t – but .. that’s parochial right – why should you expect a theory of consciousness to accord with your intuition and he just then just went ahead and said yes the error correcting code is consciouss, yes the giant grid of XOR gates is conscious – and if they have a thousand times larger value of Phi than a brain, then there are a thousand times more conscious than a human is. So you know the way I described it was he didn’t just bite the bullet he just devoured like a bullet sandwich with mustard. Which was not what I was expecting but now the critique that I’m saying that ‘any scientific theory has to accord with intuition’ – I think that is completely mistaken; I think that’s really a mischaracterization of what I think right.
I mean I’ll be the very first to tell you that science has overturned common sense intuition over and over and over right. I mean like for example temperature feels like an intrinsic quality of a of a material; it doesn’t feel like it has anything to do with motion with the atoms jiggling around at a certain speed – okay but we now know that it does. But when scientists first arrived at that modern conception of temperature in the eighteen hundreds, what was essential was that at least you know that new criterion agreed with the old criterion that fire is hotter than ice right – so at least in the cases where we knew what we meant by hot or cold – the new definition agreed with the old definition. And then the new definition went further to tell us many counterintuitive things that we didn’t know before right – but at least that it reproduced the way in which we were using words previously okay.
Even when Copernicus and Galileo where he discovered that the earth is orbiting the Sun right, the new theory was able to account for our observation that we were not flying off the earth – it said that’s exactly what you would expect to have happened even in the in ?Anakin? because of these new principles of inertia and so on okay.
But if a theory of consciousness says that this giant blank wall or this grid is highly highly conscious just sitting there doing nothing – whereas even a simulated person or an AI that passes the Turing test would not be conscious if it’s organized in such a way that it happens to have a low value of Phi – I say okay the burden is on you to prove to me that this Phi notion that you have defined has anything whatsoever to do with what I was calling consciousness you haven’t even shown me any cases where they agree with each other where I should therefore extrapolate to the hard cases; the ones where I lack an intuition – like at what point is an embryo conscious? or when is an AI conscious? I mean it’s like the theory seems to have gotten wrong the only things that it could have possibly gotten right, and so then at that point I think there is nothing to compel a skeptic to say that this particular quantity Phi has anything to do with consciousness.

Cognitive Biases & In-Group Convergences with Joscha Bach

True & false vs right & wrong – People converge their views to set of rights and wrongs relative to in-group biases in their peer group.
As a survival mechanism, convergence in groups is sometimes more healthy than being right – so one should optimize for convergence sometimes even at the cost of getting stuff wrong – so humans probably have an evolutionary propensity to favor convergence over truth.
However by optimizing for convergence may result in the group mind being more stupid than the smartest people in the group.

 

 
Joscha highlights the controversy of Yonatan Zunger being fired for sending out an email about biological differences between men and women effecting abilities as engineers – where Zunger’s arguments may be correct – now regardless of what the facts are about how biological differences effect differences in ability between men & women, google fired him because they thought supporting these arguments would make for a worse social environment.

This sort of thing leads to an interesting difference in discourse, where:
* ‘nerds’ tend to focus on ‘content‘, on imparting ideas and facts where everyone can judge these autonomously and form their own opinions – in view that in order to craft the best solutions we need to have the best facts
* most people the purpose of communication is ‘coordination‘ between individuals and groups (society, nations etc) – where the value on a ‘fact’ is it’s effect on the coordination between people

So is Google’s response to the memo controversy about getting the facts right, or about how Google at this point should be organised?

What’s also really interesting is that different types of people read this ‘memo’ very differently – making it very difficult to form agreement about the content of this memo – how can one agree on whats valuable about communication – whether it’s more about imparting ideas and facts or whether it’s more about coordination?

More recently there has been a lot of talk about #FakeNews – where it’s very difficult to get people to agree to things that are not in their own interests – and including, as Joshca points out, the idea that truth matters.

Joscha Bach, Ph.D. is an AI researcher who worked and published about cognitive architectures, mental representation, emotion, social modeling, and multi-agent systems. He earned his Ph.D. in cognitive science from the University of Osnabrück, Germany, and has built computational models of motivated decision making, perception, categorization, and concept-formation. He is especially interested in the philosophy of AI and in the augmentation of the human mind.

Discussion points:
– In-group convergence: thinking in true & false vs right & wrong
– The group mind may be more stupid than the smartest individuals in the group

Physicalism & Materialism – John Wilkins

Materialism was a pre-socratic view that for something to be real it has to be matter – physical stuff made of atoms (which at the time were considered hard like billiard balls – fundametal parts of reality).  The reason these days the term physicalism is used is because it can describe things that aren’t matter – like forces, or aren’t observable matter – like dark matter, or energy or fields, or spacetime etc..  Physicalism is the idea that all that exist can be described in the language of some ‘ideal’ physics – we may never know what this ideal physics is, though people think that it is something close to our current physics (as we can make very accurate predictions with our current physics).

If magic, telepathy or angels were real, there would be a physics that could describe them – they’d have patterns and properties that would be describable and explainable.  A physicist would likely think that even the mind operates according to physical rules.  Being a physicalist according to John means you think everything is governed by rules, physical rules – and that there is an ideal language that can be used to describe all this.

Note John is also a deontologist.  Perhaps there should exist an ideal language that can fully describe ethics – does this mean that ideally there is no need for utilitarianism?  I’ll leave that question for another post.

Interview with John Wilkins on Materialism & Physicalism.

Here are some blog posts about physicalism by John Wilkins:

Is physicalism an impoverished metaphysics?

Every so often, we read about some philosopher or other form of public intellectual who makes the claim that a physicalist ontology – a world view in which only things that can be described in terms of physics are said to exist – is impoverished. That is, there are things whereof science cannot know, &c. A recent example is that made by Thomas Nagel [nicely eviscerated here by the physicist Sean Carroll], whose fame in philosophy rests with an influential 1974 paper that there is something like being a bat that no amount of physics, physiology or other objective science could account for.

Recent, Nagel has argued that the evolutionary view called (historically misleadingly) neo-Darwinism, is “almost certainly” false. One of the reasons is that “materialism” (which Nagel should know is an antiquated world view replaced by physicalism defined above; there are many non-material things in physics, not least fields of various kinds) does not permit a full account of consciousness; the subjective facts of being a particular individual organism. Another is that the chance that life would emerge from a lifeless universe is staggeringly unlikely. How this is calculated is somewhat mysterious, given that at best we only have (dare I say it?) subjective estimates anyway, but there it is.

But Nagel is not alone. Various nonreligious (apparently) thinkers have made similar assertions, although some, like Frank Jackson, who proposed the Knowledge Argument, have since backed down. What is it that physicalism must account for that these disputants and objectors say it cannot?

It almost entirely consists of consciousness, intentions, intelligence or some similar mental property which is entirely inexplicable by “reductionist” physicalism. [Reductionism is a term of abuse that means – so far as I can tell – solely that the person who makes such an accusation does not like the thing or persons being accused.] And that raises our question: is physicalism lacking something?

I bet you are dying to know more… you’ll just have to follow the link…
See more at Evolving Thoughts>>

Is Physicalism Coherent?

In my last post I argued that physicalism cannot be rejected simply because people assert there are nonphysical objects which are beyond specification. Some are, however, specifiable, and one commentator has identified the obvious ones: abstract objects like the rules of chess or numbers. I have dealt with these before in my “Pizza reductionism” post, which I invite you to go read.

Done? OK, then; let us proceed.

It is often asserted that there are obviously things that are not physical, such as ideas, numbers, concepts, etc., quite apart from qualia, I once sat with a distinguished philosopher, who I respect greatly and so shall not name, when he asserted that we can construct natural classifications because we can deal first with the natural numbers. I asked him “In what sense are numbers natural objects?”, meaning, why should we think numbers are entities in the natural world. He admitted that the question had not occurred to him (I doubt that – he is rather smart), but that it was simply an axiom of his philosophy. I do not think such abstract objects are natural.

This applies to anything that is “informational”, including all semantic entities like meanings, symbols, lexical objects, and so on. They only “exist” as functional modalities in our thoughts and language. I have also argued this before: information does not “exist”; it is a function of how we process signals. Mathematics is not a domain, it is a language, and the reason it works is because the bits that seriously do not work are not explored far[*] – not all of it has to work in a physical or natural sense, but much of it has to, or else it becomes a simple game that we would not play so much.

So the question of the incoherence of physicalism is based on the assumption (which runs contrary to physicalism, and is thus question begging) that abstract objects are natural things. I don’t believe they are, and I certainly do not think that a thought, or concept, for example, which can be had by many minds and is therefore supposed to be located in none of them (and thus transcendental), really is nonphysical. That is another case of nouning language. The thought “that is red” exists, for a physicalist, in all the heads that meet the functional social criteria for ascriptions of red. It exists nowhere else – it just is all those cognitive and social behaviours in biological heads…

Yes, I know, it’s a real page turner…
See more at Evolving Thoughts>>

In philosophy, physicalism is the ontological thesis that “everything is physical”, that there is “nothing over and above” the physical, or that everything supervenes on the physical. Physicalism is a form of ontological monism—a “one substance” view of the nature of reality as opposed to a “two-substance” (dualism) or “many-substance” (pluralism) view. Both the definition of physical and the meaning of physicalism have been debated. Physicalism is closely related to materialism. Physicalism grew out of materialism with the success of the physical sciences in explaining observed phenomena. The terms are often used interchangeably, although they are sometimes distinguished, for example on the basis of physics describing more than just matter (including energy and physical law). Common arguments against physicalism include both the philosophical zombie argument and the multiple observers argument, that the existence of a physical being may imply zero or more distinct conscious entities. “When I lost my belief in religion I had to decide what I needed to accept as a bare minimum. I decided that I needed to believe in the physical world. I never found the slightest reason to accept the existence of anything else. To this day I am a physicalist only because I never found the need to be anything else. The principle of parsimony suggests that one should not believe in more than one needs to. Even if it does make you feel comfortable.”

 

Let’s get physicalism!

See John Wilkin’s Blog ‘Evolving Thoughts

#philsci #philosophy #science #physics

Science, Mindfulness & the Urgency of Reducing Suffering – Christof Koch

In this interview with Christof Koch, he shares some deeply felt ideas about the urgency of reducing suffering (with some caveats), his experience with mindfulness – explaining what it was like to visit the Dali Lama for a week, as well as a heart felt experience of his family dog ‘Nosey’ dying in his arms, and how that moved him to become a vegetarian. He also discusses the bias of human exceptionalism, the horrors of factory farming of non-human animals, as well as a consequentialist view on animal testing.
Christof Koch is an American neuroscientist best known for his work on the neural bases of consciousness.

Christof Koch is the President and Chief Scientific Officer of the Allen Institute for Brain Science in Seattle. From 1986 until 2013, he was a professor at the California Institute of Technology. http://www.klab.caltech.edu/koch/

Towards the Abolition of Suffering Through Science

An online panel focusing on reducing suffering & paradise engineering through the lens of science.

Panelists: Andrés Gómez Emilsson, David Pearce, Brian Tomasik and Mike Johnson

Note, consider skipping to to 10:19 to bypass some audio problems in the beginning!!


Topics

Andrés Gómez Emilsson: Qualia computing (how to use consciousness for information processing, and why that has ethical implications)

  • How do we know consciousness is causally efficacious? Because we are conscious and evolution can only recruit systems/properties when they do something (and they do it better than the available alternatives).
  • What is consciousness’ purpose on animals?  (Information processing).
  • What is consciousness’ comparative advantage?  (Phenomenal binding).
  • Why does this matter for suffering reduction? Suffering has functional properties that play a role in the inclusive fitness of organisms. If we figure out exactly what role they play (by reverse-engineering the computational properties of consciousness), we can substitute them by equally (or better) functioning non-conscious or positive hedonic-tone analogues.
  • What is the focus of Qualia Computing? (it focuses on basic fundamental questions and simple experimental paradigms to get at them (e.g. computational properties of visual qualia via psychedelic psychophysics)).

Brian Tomasik:

  • Space colonization “Colonization of space seems likely to increase suffering by creating (literally) astronomically more minds than exist on Earth, so we should push for policies that would make a colonization wave more humane, such as not propagating wild-animal suffering to other planets or in virtual worlds.”
  • AGI safety “It looks likely that artificial general intelligence (AGI) will be developed in the coming decades or centuries, and its initial conditions and control structures may make an enormous impact to the dynamics, values, and character of life in the cosmos.”,
  • Animals and insects “Because most wild animals die, often painfully, shortly after birth, it’s plausible that suffering dominates happiness in nature. This is especially plausible if we extend moral considerations to smaller creatures like the ~1019 insects on Earth, whose collective neural mass outweighs that of humanity by several orders of magnitude.”

Mike Johnson:

  • If we successfully “reverse-engineer” the patterns for pain and pleasure, what does ‘responsible disclosure’ look like? Potential benefits and potential for abuse both seem significant.
  • If we agree that valence is a pattern in a dataset, what’s a good approach to defining the dataset, and what’s a good heuristic for finding the pattern?
  • What order of magnitude is the theoretical potential of mood enhancement? E.g., 2x vs 10x vs 10^10x
  • What are your expectations of the distribution of suffering in the world? What proportion happens in nature vs within the boundaries of civilization? What are counter-intuitive sources of suffering? Do we know about ~90% of suffering on the earth, or ~.001%?
  • Valence Research, The Mystery of Pain & Pleasure.
  • Why is it such an exciting time round about now to be doing valence research?  Are we at a sweet spot in history with this regard?  What is hindering valence research? (examples of muddled thinking, cultural barriers etc?)
  • How do we use the available science to improve the QALY? GiveDirectly has used change in cortisol levels to measure effectiveness, and the EU (what’s EU stand for?) evidently does something similar involving cattle. It seems like a lot of the pieces for a more biologically-grounded QALY- and maybe a SQALY (Species and Quality-Adjusted Life-Year)- are available, someone just needs to put them together. I suspect this one of the lowest-hanging highest-leverage research fruits.

David Pearce: The ultimate scope of our moral responsibilities. Assume for a moment that our main or overriding goal should be to minimise and ideally abolish involuntary suffering. I typically assume that (a) only biological minds suffer and (b) we are probably alone within our cosmological horizon. If so, then our responsibility is “only” to phase out the biology of involuntary suffering here on Earth and make sure it doesn’t spread or propagate outside our solar system. But Brian, for instance, has quite a different metaphysics of mind, most famously that digital characters in video games can suffer (now only a little – but in future perhaps a lot). The ramifications here for abolitionist bioethics are far-reaching.

 

Other:
– Valence research, Qualia computing (how to use consciousness for information processing, and why that has ethical implications),  animal suffering, insect suffering, developing an ethical Nozick’s Experience Machine, long term paradise engineering, complexity and valence
– Effective Altruism/Cause prioritization and suffering reduction – People’s practical recommendations for the best projects that suffering reducers can work on (including where to donate, what research topics to prioritize, what messages to spread). – So cause prioritization applied directly to the abolition of suffering?
– what are the best projects people can work on to reduce suffering? and what to work on first? (including where to donate, what research topics to prioritize, what messages to spread)
– If we successfully “reverse-engineer” the patterns for pain and pleasure, what does ‘responsible disclosure’ look like? Potential benefits and potential for abuse both seem significant
– If we agree that valence is a pattern in a dataset, what’s a good approach to defining the dataset, and what’s a good heuristic for finding the pattern?
– What order of magnitude is the theoretical potential of mood enhancement? E.g., 2x vs 10x vs 10^10x

Panelists

David Pearce: http://hedweb.com/
Mike Johnson: http://opentheory.net/
Andrés Gómez Emilsson: http://qualiacomputing.com/
Brain Tomasik: http://reducing-suffering.org/

 

#hedweb ‪#EffectiveAltruism ‪#HedonisticImperative ‪#AbolitionistProject

The event was hosted on the 10th of August 2015, Venue: The Internet

Towards the Abolition of Suffering Through Science was hosted by Adam Ford for Science, Technology and the Future.

Towards the Abolition of Suffering Through Science

Towards the Abolition of Suffering Through Science