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In Vitro & In Vivo

Many scientific paper refer to the way they have studie something as ‘in vitro’ or ‘in vivo’. What do these terms mean? What are the differences (with regards to research)? And what is an example of their use?

In vitro

In vitro studies are usually done with just a few cells in a controlled environment like a test tube or laboratory dish. In vitro is Latin for ‘within the glass’. This way researchers can look very specifically at only one process (and get more detailed results). Because of the relatively low costs and complexity, you can do many different experiments at low cost.

A downside is that in vitro studies may forgo the necessary complexity and ‘normal’ conditions that arise within a living organism. This is also called the absence of biokinetics: (the study of) the growth changes and movements that developing organisms undergo.

Examples of studies are those in microorganisms, cells, or biological molecules (proteins, DNA, RNA). For instance, you could study how RNA molecules bind to specific ligands (ion or molecule).

To better extrapolate from in vitro to in vivo you can do apply multiple techniques. You could increase the complexity of the in vitro system. Or you can use mathematical modelling to simulate a more complex system.

In vivo

In vivo studies are done in living organism. In vivo is Latin for ‘within the living’. An in vivo study can be done in animals (including humans), and plants. This way researchers can see the real-life effects of drugs and interventions. This could show that the effect doesn’t take place, or that other (negative) side-effects happen. The costs are higher than for in vitro, but you get a much more realistic experiment.

An example of an in vivo study is to see if the body actually absorbs the molecule or treatment. If it passes through your body without getting picked up, then modifications should maybe be made.

In vivo experiments are done in many different species. Of them the mouse is one of the best known. The roundworm c. elegans is another much used test subject. Of course in vivo experiments are also done on humans. Because each animal is different (had different metabolic processes) it doesn’t mean that something that works in vivo on one, does also work in the other.

How do they translate?

Not all experiments that yield the desired result in vitro, translate to in vivo outcomes. One reason could be that the molecule or drug is not able to reach the destination you want it to work in, for instance, because it can’t breach the blood-brain barrier.

The same caveat also applies to the difference between different animals used in in vivo experiments.

Currently, I couldn’t find useful/any data on how many studies translate from in vivo -> in vitro (yeast) -> in vitro (mouse) -> in vitro (human) (of course extra steps can be added or removed). I hope to update this part soon.

In silico studies

These tests are performed on a computer (simulation). The Latin here is the same as the English: silicon (chips). Although quite new, in silico techniques could help to find out how drugs interact with the body and with pathogens. Three ways this technique could be applied are:

  1. Bacterial sequencing techniques – sequencing bacterial DNA and RNA to identify bacteria
  2. Molecular modelling – how drugs interact with the nuclear receptors of cells
  3. Whole cell simulations – simulating how a (bacterial) cell behaves in an environment

Sources

https://mpkb.org/home/patients/assessing_literature/in_vitro_studies

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

https://www.verywellhealth.com/what-does-in-vivo-and-in-vitro-mean-2249118

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

Why I Started Long Life

I’m very curious to see if we can lead longer healthy lives. I believe that this is one of the most interesting fields out there and one where I might contribute to. Longevity research might have a disproportionately large impact on the world. This blog is my first investigation into this field. Below I spell out my reasons in more depth.

Real Solutions to a Hard Problem

As far back as our history goes, people have been searching for the Fountain of Youth. We don’t want to become old (but see the next part) and so we’ve been searching for tools to tackle diseases (symptoms) and the whole ageing process itself (causes). Now that we’ve started to understand a part of our metabolism a bit better, we might stand a chance to tackle this.

Research in the lab and in animals is promising. Some mouses live twice as long before, some genes are identified in the ageing process (by deactivating them), and some prominent scientists (notably Aubrey de Grey) predict that we have a good shot at finding robust solutions to the causes of ageing in 20 years.

I Want to Live Forever

I can’t imagine myself wanting to grow old. To have pain everywhere, to battle cancer, to be in the hospital more than outside of it. Growing old has been romanticised and many people believe that it’s even good to have an expiry date. That motivates you to live a full life, right?

Well, I think that the opposite also is true. If we were to live to 150, 600, or forever, wouldn’t we take more care of the planet? Make better life decisions? Save more for the future?

And imagine the wisdom that we might accumulate. Think of the professors that don’t need to retire, the scientists that can keep on theorising, the chess grandmasters that can keep on learning. Think of the full life you can live, the countries you can visit, the love you might experience.

One of the inspirations for this blog has been this article: The Fable of the Dragon-Tyrant by Nick Bostrom. It uses the analogy of a dragon (for death) and how the people living under the dragon are used to sacrificing their family and friends to it. But what if we were able to stop the sacrifice, to keep your loved ones alive. Also, see this video by CGP Grey that summarised the article:

Longevity is Multidisciplinary

Another reason for my interest in longevity is the reason that it brings together many different disciplines. And I think that interesting research happens at the intersection of multiple areas.

For me, it brings together artificial intelligence (e.g. DeepMind doing protein folding, learning algorithms helping with drug discovery), biology (e.g. CRISPR), entrepreneurship (the many companies that have sprung up, and a chance for me to have an impact in this field), and ethics (e.g. who will get to live forever, “The future is already here — it’s just not very evenly distributed” – William Gibson) . Of course, it brings together many other fields, people, and ideas.

Now is the Time for Me

At Queal (where I’m the co-founder and CEO), we’re at a very good point and I’ve freed up some time to think about other ideas (about a day or so as of writing this). I will use this time to start an inquiry into what we (collectively) know about ageing and what we can do. At the start, I will first try and deduce what different areas/subtopics (e.g. molecular damage, dietary influences) there are, and what the latest knowledge is there. I will also focus on finding the right sources (news/scientific) to keep up with the latest discoveries.

I hope I’ve been able to give a good overview of my reasons for starting this blog. With that being said, I will leave you with this final note:

This is Why We Die

Most of us die from ageing. For every person that dies in a car accident, 34 have died from cancer, cardiovascular disease, diabetes, and other age-related diseases. Compared to homicide (105 to 1) and conflict (357 to 1) it’s even more striking[1].

Yet we don’t focus most of our energy on preventing age-related diseases. And maybe with good reason, one day we will die (probably). But what if we could extend our healthy lifespan by 10, 20, 50 or even more years. I for one think that is a very exciting possibility.

Today is the right time to start thinking about this, or as the Chinese would say: “The best time to plant a tree was 20 years ago, the second best time is now.” To the best of my knowledge, we are now at the point where we start to understand some of the underlying processes that cause ageing.

The elixer of life is now growing on the tree of knowledge and this is my first step at learning more about this.

Why We Die

With all that being said, here are the 7 reasons/categories why we die. I’ve taken these from Aubrey de Grey (wiki), a brilliant gerontologist/connector/promoter of the fight against ageing. Here we go:

  1. Mutations – in chromosomes
    • this causes cancer due to changes in the nuclear DNA, proteins that bind to this, or molecules that contain genetic information in the eukaryotes
  2. Mutations – in mitochondria
    • this causes problems in the energy-producing parts of a cell (the mitochondria), again these are changes to the (local) DNA
  3. Junk – inside of cells
    • when the junk inside the cell is not being cleaned/digested properly neurodegenerative diseases rear their heads
  4. Junk – outside of cells
    • the same but this time outside/in-between cells, Alzheimer’s senile plaques are the most well-known example of this
  5. Cells – too few
    • some cells don’t get replaced (or too slowly) and this makes us weaker with age (Parkinson’s disease, immune system)
  6. Cells – too many
    • the dead cells that don’t divide but also are in the way (senescence), they can block space for living cells or even secrete proteins that do harm
  7. Extracellular protein crosslinks
    • cells are held together by linking proteins and when too many connections form, they lose elasticity

Which Diseases are Responsible?

If we look at it from another angle, the diseases that kill us, what is it that actually takes us out? All of them have links to the 7 systems described above, yet all in different ways, which I hope to describe in future in-depth blogs.

  1. Cardiovascular diseases (18 million, 32%)
    • A class of diseases that involve the heart or blood vessels
    • “The most important determinant of cardiovascular health is a person’s age.”[2]
    • Related terms: caloric restriction (CR), sirtuins, IGF-1, rapamycin (mTOR)
  2. Cancers (9 million, 17%)
    • A disease caused by an uncontrolled division of abnormal cells in a part of the body
    • “Ageing is the inevitable time-dependent decline in physiological organ function and is a major risk factor for cancer development. “[3]
    • Related terms: genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, decreased nutrient sensing and altered metabolism, cellular senescence and stem cell function
  3. Respiratory disease (3.5 million, 7%)
    • A type of disease that affects the lungs and other parts of the respiratory system. Includes asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumonia, and lung cancer [4]
    • “The respiratory system undergoes various anatomical, physiological and immunological changes with age. The structural changes include chest wall and thoracic spine deformities which impairs the total respiratory system compliance leading to increase work of breathing .”[5]
    • Related terms: Stiffening of the thoracic cage (7th underlying principle), lower respiratory muscle strength (especially in men),
  4. Diabetes, blood and endocrine disease (3 million, 6%)
    • A disease in which the body’s ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose in the blood
    • “Almost one-third of U.S. adults over the age of 65 years have diabetes. Approximately half of those are undiagnosed, and an additional one-third of older adults have prediabetes.”[6]
    • Related terms: impaired glucose intolerance, postprandial hyperglycemia, defects in β-cell function, metformin
  5. Lower respiratory infections (2.5 million, 4,5%)
    • Lower respiratory tract infections are any infections in the lungs or below the voice box. These include pneumonia, bronchitis, and tuberculosis
    • Viruses, bacteria, fungal infections, and mycoplasma are the main causes.
    • I guess this one is a bit of an odd one out, it’s not so much related to ageing as to health (in how strong your body is to overcome this). Also, the main burden of it is felt in subsahara Africa. [7]
  6. Dementia (2.5 million, 4,5%)
    • Dementia is a general term for a decline in mental ability severe enough to interfere with daily life. Memory loss is an example. Alzheimer’s is the most common type of dementia
    • “Epidemiological studies have shown that dementia could be avoided even at extreme old ages.” The incidence of dementia has also gone down in the last few decades. [8,9]
    • Related terms: Amyloid-beta, microglia (CD22), P. gingivalis
  7. Neonatal deaths (1.7 million, 3%)
    • The first cause on the list that is not directly related to ageing
    • Neonatal deaths are all the children that die in the first month
    • This has fallen dramatically from 140/1000 (14%) to 5/1000 (0,5%) of births [10]
  8. Diarrheal diseases (1.7 million, 3%)
    • The second cause on the list that is not directly related to ageing
    • Diarrheal diseases are a collection of diseases caused by multiple viral, bacterial, and parasitic organisms that share the common symptom of diarrhoea, defined as the passage of three or more loose or liquid stools per day
    • Especially kids and the elderly are the most at risk (thus in a way linking it to ageing, at least for the latter group)
  9. Road incidents (1.3 million, 2%)
    • Not related to ageing, and unfortunately something that hasn’t gone down over the last 10 years
    • It has gone down in some countries (e.g. Germany) where safety measures prevent deaths
    • The most vulnerable group is in the 70+ bracket (35/100.000 people)
  10. Liver disease (1.3 million, 2%)
    • Not strictly related to ageing, but damage over time may lead to liver cancer

Together this top 10 causes of death cover approximately 85% of deaths. If we remove all those not strictly related to ageing, we still have 73% of deaths that are related to ageing directly.

Other Causes?

I think this list doesn’t cover everything we think of when we image death. Two things are missing that many relate to deaths. The first is war/conflict/terrorism [11]. The second is our lifestyle.

War used to be a much more common cause of death. Until the 20th century, most countries were at war, not at peace. The peak in the last 100 years was the second world war, with 22 deaths per 100.000. Today it stands at just over 1 per 100.000.

Our lifestyle is not something to boast about. Obesity stands at 13% worldwide, and at 28% in North America and Europe [12]. And I think that this can be one of the causes/co-factors of many of the causes of death listed above. Together with air pollution, bad diets, no exercise and other lifestyle related choices, we should count ourselves lucky that we’re actually living this long.

In this post I’ve explored the causes of death and looked at the diseases that eventually tackle us. I’m optimistic that we will find solutions to most, if not all, of these in the coming decades. Our solutions should be combined with an approach in which we also make sure we do our best to keep our body healthy through diet and exercise.

To end a short analogy. Imagine yourself as a car. If you run it down, put in the wrong fuel, and eventually drive it total loss in a car accident, you would be a very irresponsible driver. If you take good care of your car, change the oil when needed, and sometimes push the peddle to the floor for just a sprint, then you might have a longer journey ahead. If then someone comes along and replaces a part of the car, or gives it a special fuel that restores the engine, you might be driving the car for a very long time to come.

Longevity Websites

In my first exploration of longevity, I’m looking at who is doing what already. Here is an (incomplete) list:

Websites/Community/Non-profit

https://www.sens.org/ – SENS Research Foundation, research, education, outreach

https://www.lifespan.io/ – Website for funding research projects, blogs, and a great Rejuvenation Roadmap

https://www.reddit.com/r/longevity/top/?t=week – Subreddit for longvity, good (read: critical) comments (sorted by new)

https://neo.life/ – Original reporting on ageing (and a bit wider), by Jane Metcalfe, found via this article on Longevity as the greatest investment

https://www.longevity.international/ – Online platform, under construction, backed by Longevity International Consortium, Biogerontology Research Foundation, Aging Analytics Agency and Deep Knowledge Life Sciences, good overviews (summary here)

Companies

http://www.gerostatealpha.com/ – Gerostate Alpha – 3 well-known researchers

https://www.calicolabs.com/ – Calico, backed by Alphabet, no products, some turnover, $1.5b research center

https://verily.com/ – Verily, backed by Alphabet, $1.8b funding, work on monitoring, interventions, precise medicine (not root causes?)

https://unitybiotechnology.com/ – Unity Biotech, developing medicines that potentially halt, slow or reverse age-associated diseases, while restoring human health. Senolytic medicines

https://www.springdisc.com/ – Spring Discovery, machine learning for ageing research, $18m+ funding

https://insilico.com/ – Insilico Medicine, artificial intelligence for drug discovery, biomarker development & ageing research

https://www.longevity.vc/ – Longevity Fund, venture capital investing in longevity research

https://www.juvenescence.ai/ – Juvenescence, drug development and artificial intelligence (AI) company focused on ageing and age-related diseases. (parent company)

Other

https://ourworldindata.org/ – Research and interactive data visualizations to understand the world’s largest problems

https://en.wikipedia.org/wiki/Outline_of_life_extension – Wikipedia overview, and here an index of related topics

https://www.ldeming.com/longevityfaq#explanation – Laura Demin (Longevity Fund) explanation of ageing research

https://www.bluezones.com/ – Based on the Blue Zones (where people live long), correlation?, and only small effect

Older / Less Active

http://aginginmotion.org/blog/ – Advancing research and treatment of sarcopenia and age-related functional decline

https://joshmitteldorf.scienceblog.com/index-to-this-blog/ – Blog by Josh Mitteldorf (started September 2012)

http://act-ad.org/ – Accelerate Cure / Treatments for Alzheimer’s Disease

https://agingportfolio.org/ – Knowledge bank on ageing research, from 2011 (not active?)

https://www.agingresearch.org/about-us/ – Aliance for aging research (founded in 1986), infographic

http://www.anti-agingfirewalls.com/ – A weblog on the sciences and practices of living healthily very long by Vince Giuliano

http://www.brainpreservation.org/ – Brain Preservation Foundation (BPF), whole brain preservation (price, mammal brain preserved)

https://www.crsociety.org/ – Caloric restriction, old forum (still active), with some good posts

http://ageing-research.blogspot.com/ – Cellular Senescence blog – last post start 2018

More Organisations

https://www.afar.org/ – American Federation for Aging Research (AFAR), business organisation (B2B)/promoter, metformin trail

https://www.asaging.org/ – American Society on Aging, business organisation (B2B), more focus on quality of life

https://www.americanagingassociation.org/ – American Aging Association, business organisation (B2B), dedicated to understanding the basic mechanisms of aging in order to enable humankind to preserve and restore functions typically lost to age-related degeneration, and to extend the healthy human lifespan, linked to AFAR

https://www.a4m.com/ – American Academy of Anti-Aging Medicine (A4M), also Metabolic Medical Institute (MMI)

https://alliancerm.org/ – Alliance for Regenerative Medicine (ARM), development of safe and effective regenerative medicines and advanced therapies worldwide

http://bsra.org.uk/ – British Society for Research on Ageing (BSRA), promotion an d funding for causes and effects of ageing

http://www.cellage.org/ – CellAge, destroy aged cells, didn’t get of the ground?

https://www.churchofperpetuallife.org/ – Church of Perpetual Life (faith in technology, interesting/old website)

http://www.rlecoalition.com/ – Coalition for Radical Life Extension, conferences on radical life extension

https://www.cohbar.com/ – CohBar is a clinical stage biotechnology company whose mission is to increase healthy lifespan by developing treatments for the underlying metabolic dysfunction driving the diseases of ageing

https://dogagingproject.org/ – Dog Aging Project, study of ageing in dogs with rapamycin as possible drug

The Hidden Girl and Other Stories

The Hidden Girl and Other Stories by Ken Liu is another great collection of stories by this awesome writer and translator.

Previously I’ve written about The Paper Menagerie and also liked many of the stories in that one.

Here the stories are more focussed on sci-fi, but there is still a lot of fantasy topics in there too.

Lots of great characters and stories. I can recommend it.

See a very good review on Goodreads (with spoilers)

Founders at Work

DRAFT – taken from Evernote 26/02/15

Startups create value
Start with a sprint, then slow down the least!
Don’t look productive (e.g. suits, business meetings), be productive instead
Founders were unsure that they were onto something big
Perseverence / determination is factor nr 1
Adaptable nr 2 – never lose sight of what the users want
Have a good co-founder
Tips: 1) write a business plan, 2) don’t expect users to change behavior too much
Learn what makes you valuable
Every time you save on part you save on complexity (queal makkelijker)
Best things came from 1) not having money, 2) not having done it before

The Life You Can Save

The Life You Can Save by Peter Singer is an awesome book that will spark your interest in doing good, help you know where to donate, and discusses honestly what objections you might have to it.

Download the book for free!

Also as an audiobook!

Here are some random notes:

“The argument that we ought to be doing more to save the lives of people living in extreme poverty presupposes that we can do it, and at a moderate cost. But can we? If so, to which organizations should we donate? It’s a question all donors should ask themselves, yet only 38% of U.S. donors do any research at all, and only 9% compare different nonprofits.”

Please visit givewell.org too compare charities!

We also have had an enormous impact. Irradication of smallpox, getting millions (if not billions) out of poverty, having few mothers and children die. See Gapminder (website) or Factfulness (book).

On the whole, we’re all giving very little. “Aid over that period was about 0.3% or 30 cents of every $100 earned.” And only a small percentage of that was going to effective charities.

“To get some perspective on this: in 2017, worldwide net official development assistance and aid was approximately $170 billion, while in the same year, consumers spent $532 billion on cosmetics.”

Of that 0.3%, much was also political and defense-related spending. E.g. “Afghanistan topped the list of recipients of U.S. aid, receiving $1.3 billionAfghanistan is undoubtedly a very poor country, but so is Ethiopia, and Ethiopia has three times as many people as Afghanistan

One big question that I want to answer myself is ‘How much should I give?

I think that giving effectively will lead to more happiness (or prevent more suffering) than much of the money I earn would bring if I spend it on myself or my immediate surroundings.

Peter Singer defines it as your ‘fair share’ and offers different views on how to approach this.

Ok, I can keep on reading the book (I have it open as a .pdf (again for free to download)) but I should be making some rules for myself.

I will put them in this post that focusses on my financial situation. Go read it here.

Some basic points:

  • Save money by not spending it on things that won’t make myself happy in the first place
    • This includes spending on coffee at the train station regularly
    • But still doing this at the start of a vacation or other irregular moments
  • Figure out how much to keep/save to live comfortably
  • And how much to save/have to pay off student debts
  • Find out how to donate most effectively (via holding?)
    • Find out if that circumvents the 10% max donation limit
    • Or that I should do that by making a contract with AMF
  • Discuss this with Lotte, but should be alright since what I intend to keep is already enough

March 2020

To Get Good, Go After The Metagame

Source: Commonplace | By: Cedric Chin

“Every sufficiently interesting game has a metagame above it. This is the game about the game. It is often called ‘the meta’.”

The same applies to life, learning to know when to play, where to play, etc. Not only being good at playing the game. Although he also highlights that we should know the underlying/actionable skills too (but then know how to go above/beyond them).

2×02 How Oculus and Libra Will Save Facebook

Source: Bots and Beers

A long-ish article about how Facebook could have a good future ahead. But it needs to change to do this.

“…if Facebook really does want to be the operating system of the virtual world—if they really want to enable the unbanked through cryptographic transactions—they have to increase the public trust by taking stances on marketing and advertising that protect users. There’s no way for them to play both sides of that coin and succeed. To transition to the future, Facebook needs to leave the past behind.”

Build a Bulletproof Notion Workspace

Source: Youtube/William Nutt (Notion.so enthusiast)

Notion is the productivity app that I’m using at the moment.

You want to do two things:

  1. Centralized information (data page)
  2. Access Points (home base)

Both will have a top-level page.

PARA: projects, resources, areas (under which first two fall), archives (inactive/completed ones)

Pff, lots of info. See the post.

Politics Without Politicians

Source: New Yorker |By: Nathan Heller

The big idea: letting people do the governing. Randomly selecting people to do a small period of legislative work. As a group you will have enough knowledge and experience. No more politics.

Coronavirus COVID-19 Global Cases by Johns Hopkins CSSE

Source: Johns Hopkins

Good dashboard for tracking Coronavirus / COVID-19

I’ve been reading more about it and listening to some podcasts (see Timeline). (Verge article, another)

Zero Trust Information

Source: Stratechery

Good article about how Google laid the foundation for remote work already 5 years ago. Then also some more info about that there is more info available (so good and bad equally), but without gatekeepers that information may flow faster.

“Again, this is not to say that everything is fine, either in terms of the coronavirus in the short term or social media and unmediated information in the medium term. There is, though, reason for optimism, and a belief that things will get better, the more quickly we embrace the idea that fewer gatekeepers and more information means innovation and good ideas in proportion to the flood of misinformation which people who grew up with the Internet are already learning to ignore.”

Follow-up blog

If AI’s So Smart, Why Can’t It Grasp Cause and Effect?

Source: Wired | By: Will Knight

AI is bad at causality, so they are building some models that might be better at it. Still early days though.

A Leaderless Struggle for Democracy

Source: Freedom House | By: Sarah Repucci

So yeah, democracy is on the decline for the past 14 years. The US and India are two large ones that are sliding down. China and the treatment of Uighurs is of course still alarming.

“The protests of 2019 have so far failed to halt the overall slide in global freedom, and without greater support and solidarity from established democracies, they are more likely to succumb to authoritarian reprisals.”

“Fierce rhetorical attacks on the press, the rule of law, and other pillars of democracy coming from American leaders, including the president himself, undermine the country’s ability to persuade other governments to defend core human rights and freedoms, and are actively exploited by dictators and demagogues.”

Contemplations on Cascades

Source: Neil Kakkar (blog)

We’ve had several names for it: snowball effect, butterfly effect, and domino effect. But, they are all examples of cascades.” and “Our desires are shaped by others. That’s Mimetic theory.”

The article explains cascades from different perspectives/examples. The interesting lens I’m reading it through is marketing, how can you start a cascade that leads to more and more people to buy.

Toby Ord on the precipice and humanity’s potential futures

Source: 80000 hours | By: Robert Wiblin, Arden Koehler and Keiran Harris

A good introduction to existential risks, first part highlights some factoids of things that happened and risks we face.

Climate and Lifestyle: policy matters

Source: Founders Pledge | By: John Halstead & Johannes Ackva

And this is the follow-up also discussed below.

“if you live in a rich country and live a typical lifestyle, then you probably emit between 5 and 20 tonnes of CO2 each year.” (NL is 9 tonnes, but

Not having kids might look like the best idea (see the graph in the first article), but ignores improvements we will make in the future (less emissions per person).

Policy taken into account, having one less child is comparable to living car-free (or getting an electric car).

” rather than constraining the climate conscious individual, the ability to affect policy through donations to effective climate charities and/or political activism offers an opportunity for outsized positive climate leverage.”

“the expected impact of your personal donations is much larger than any of the lifestyle decisions”

Butttt “it is very important to choose carefully who you donate to.

Don’t do it to offset, do it to do good. “If we only donate to offset our personal emissions and no further, then we hugely restrict our potential impact.”

Coronavirus: The Hammer and the Dance

Source: Medium / Tomas Pueyo

Good article what measures can work and why we need to do them. Herd immunity is stupid since the virus will keep mutating. Stay the fuck home.

YouTube’s Copyright System Isn’t Broken. The World’s Is.

Source: Youtube / Tom Scott

Discussion about how copyright is broken, how it works now, and how it should maybe work (and why YouTube is just an example, just following the rules, not being ‘bad’ per se themselves).

Taste for Makers

Source: Paul Graham’s blog

“For those of us who design things, these are not just theoretical questions. If there is such a thing as beauty, we need to be able to recognize it. We need good taste to make good things.”

Paul starts with arguing against ‘subjective’ taste. He argues that this isn’t true and that we can define/explore set criteria for beauty. It’s also something you can get better at (just like any other aspect of a job).

He also argues that beauty/taste is very similar across fields.

  • Good design is … simple
    • do more with less, be clear
    • simple means addressing the ‘real’/underlying idea/problem
  • … timeless
    • so good, that long after you’re gone, it’s still the standard
    • stay away from fashion
    • possibly appeal to what people in the past (say 1500) (also) liked
  • … solves the right problem
    • (my interpretation) ask the right question (to …)
  • … suggestive
    • become the background/backbone, not centerpiece
    • let users/observers/etc make their own story (about the Mona Lisa)
  • … often slightly funny
    • don’t take yourself/your design too serious
    • humour shows strength
  • … hard
    • e.g. painting faces, because we’re so good at looking at them
    • but not ‘client is a dick’ hard
  • … looks easy
    • (because you worked so hard on it)
    • because your body/brain does a large part of it on autopilot/10.000 hours of learning
    • e.g. most efficient weightlifting looks beautiful
  • … uses symmetry
    • repetition (left-right), and recursion (fractals)
    • e.g. code that loops in on itself (and is short/efficient)
  • … resembles nature
    • because nature has had a long time to think about the problem
  • … redesign
    • needs confidence to say ‘I need to try again’
    • acknowledge mistakes, iterate
  • … can copy
    • imitate, but not mindlessly
    • be creative (on top of what is already there)
  • … often strange
    • (Graham thinks it’s difficult to cultivate (only) this aspect)
    • (I guess it means staying curious and open to strange-ness)
  • … happens in chunks
    • by people working together
    • e.g. creative hubs
    • (can you do it online though?)
  • … often daring
    • outside the ‘normal’, norms
    • be where conventional wisdom and truth collide

Preserving Optionality: Preparing for the Unknown

Source: Farnam Street | By: Shane Parnish / colleagues

“Instead of focusing on becoming great at one thing, there is another, counterintuitive strategy that will get us further: preserving optionality. The more options we have, the better suited we are to deal with unpredictability and uncertainty. We can stay calm when others panic because we have choices.”

Don’t get pigeonholed into knowing only one thing. Have options, know a lot about different things. Also makes me think of the lessons in Early Retirement Extreme.

The Psychedelic Experience

I wrote a review of this book for Blossom. See a copy below:

The Psychedelic Experience by Timothy Leary, Ralph Metzner, and Richard Alpert (Ram Dassmerges the psychedelic experience with the Tibetan Book of the Dead. It’s an interesting book that tried to merge Western use of psychedelics (which originate mostly from South America) with Eastern philosophy. As Daniel Pinchbeck states in the introduction, the book can best be seen as a product of the time (the 1960s), not as a complete guide on how to approach the psychedelic experience.

Quick Take

Introduction

Daniel Pinchbeck (in 2007) has some wise words to give in the introduction: “[the book] is both a historical document and an anthropological curiosity.” The book is an early attempt at a guide, but one in which “… the Harvard psychologists grasped these chemical catalysts as the Answer, rather than approaching them, with skepticism and proper caution, as tools that, potentially containing hidden dangers, required scrupulous care.”

The mismatch between the more Shamanistic origin of psychedelics (mainly psilocybin, mescaline, and ibogaine) from North and South America, and the Eastern philosophy is what strikes Pinchbeck as misguided. It also doesn’t do ‘right’ to the original Tibetan Book of the Dead. “[the book] overlays a simplistic and moralizing psychological perspective on the subtler and more profound exegesis of an ancient spiritual science found in the original text.”

General Introduction

The introduction (by the authors) gives a short explanation of what the psychedelic experience is, “[it’s] a journey to new realms of consciousness.” They state it’s not only psychedelic drugs that allow you to have such an experience. Yoga, sensory deprivation, disciplined meditation, religious activities, or even spontaneous occurrences are also possible.

A drug is only but the key to open the mind, breaking you free from ordinary patterns and structures. Already here they highlight the effect of set and setting (terms that are often attributed to Leary). Throughout the book, there is plenty of mention of ego dissolution and breaking free of your ‘personality’ and ‘games’ that we play (or ‘game reality’).

The book is divided into the three phases of the psychedelic experience:

  1. Chikhai Bardo – complete transcendence, beyond words and space-time, pure awareness and ecstatic freedom
  2. Chönyid Bardo – external game reality, clarity, hallucinations
  3. Sidpa Bardo – return to routine game reality and the self

They state that the second phase is the longest (and is described in most detail in the rest of the book). But for someone who has a bad experience, the (struggle to) return to reality (third phase) may be the longest phase.

One good point of advice that is mentioned repeatedly is to trust the process, or in their words: “Trust your divinity, trust your brain, trust your companions. Whenever in doubt, turn off your mind, relax, float downstream.”

After the introduction, the book describes the different phases, gives practical suggestions on how to prepare for and hold a psychedelic experience, and finishes with passages from the Tibetan Book of the Dead.

First Bardo: The Period of Ego-Loss or Non-Game Ecstasy

In modern language, this chapter can be understood to describe ego loss (death) and a lowering of the activity of the Defaul Mode Network (DMN).

The authors describe two different phases of ‘the clear light’.

Second Bard: The Period of Hallucinations

This part speaks mostly about experiencing the things that happen during a psychedelic experience. It highlights that you should accept what is happening and enjoy the ride.

This chapter then dives deeper into 7 different types of visions, I would argue that this part is the most esoteric. The 7 visions are:

  1. The Source or Creator Vision
  2. The Internal Flow of Archetypal Processes
  3. The Fire-Flow of Internal Unity
  4. The Wave-Vibration Structure of External Forms
  5. The Vibratory Waves of External Forms
  6. The Retinal Circus
  7. The Magic Theatre

Note: Here (in my opinion) they strife the furthest from making reasonable claims. A direct link is made between the psychedelic experience and physics. They talk about experiencing the vibrations of the universe, your every cell being able to communicate and have ‘intelligence’, and although in a way this is true, it’s very much not so in the anthropomorphized way they describe it.

Third Bardo: The Period of Re-entry

This is the period in which someone returns to reality (the come-down) or ordinary waking life. The chapter describes ways in which difficult experiences in this phase can be avoided, recognized, and alleviated.

Signs of the third Bardo are described as follows:

  1. the feeling of supernormal perception and performance
  2. experiences of panic, torture, and persecution
  3. restless, unhappy wandering
  4. feeling stupid and full of incoherent thoughts
  5. a feeling of being dead, cut off from surrounding life, and full of misery
  6. the feeling of being oppressed or crushed
  7. grey twilight-like light suffusing everything

The chapter then continues to describe the six levels or personality types to which a person can re-enter, from saints to psychosis.

Judgment visions are also considered a possible part of this period. The authors do make a very good comment about this: “Remember that fear and guilt and persecuting, mocking figures are your own hallucinations.”

This ends the description of the Bardos and the authors advise the reader to go over the text multiple times to really capture it.

The rest of the book consists of more practical and preparatory steps about holding a session, your intention, and advice for dosages.

The final pages are devoted to instructions to give during the different Bardo phases.

All These Worlds

A good conclusion to the Bobiverse trilogy. Listened to the series in beginning 2019 and 2020 (two times total). Looking forward to more books and maybe even to write some fanfiction.

The storylines almost all conclude and the Bobs win against the Others. There are more than 500 of them, so more than enough to make new stories with and explore the Bobiverse.