The Long Game 65: Polygenic Embryo Screening, Cognitive Improvement, The Measure & Improve Paradox

🌒 Seeing on the Far Side of the Moon, The Dissident, North Korea, Earth’s Most Wanted Hacker, and Much More!

Hi there, it’s Mehdi Yacoubi, co-founder at Vital, and this is The Long Game Newsletter. To receive it in your inbox each week, subscribe here:

📣 We are hiring at Vital, help us build the “Strava for Health.”

In this episode, we explore:

  • Polygenic embryo screening

  • Walking

  • 13 Steps to Cognitive “Perfection”

  • Building something no one else can measure

  • The social media trap

  • The Dissident

Let’s dive in!


🥑 Health

🐣 Polygenic Embryo Screening

We talked about Polygenically Screened Babies a few weeks ago. I thought this article was a good follow-up on this critical discussion.

The author explores two papers (Carmi et al. and Visscher et al.

Here’s what the author concludes:

To summarize, several groups have now validated the risk reduction from polygenic screening (PGT-P). The methodologies are different (i.e., simulated genotypes vs studies using large numbers of adult siblings) but come to similar conclusions. 

Whether one should regard, for example, relative and absolute risk reduction in type 2 diabetes (T2D) of ~40% and ~3% (from figure above) as important or valuable is a matter of judgement. 

Studies suggest that type 2 diabetes results in an average loss of over 10 quality-adjusted life years -- i.e., more than a decade. So reducing an individual's risk of T2D by even a few percent seems significant to me. 

Now multiply that by a large factor, because selection using a genomic index (see figure) produces simultaneous risk reductions across a dozen important diseases.

Finally, polygenic predictors are improving rapidly as more genomic and health record data become available for machine learning. All of the power of modern AI technology will be applied to this data, and risk reductions from selection (PGT-P) will increase significantly over time. See this 2021 review article for more.

The medical part of risk reduction is very interesting. Still, the ethical side of things is perhaps even more interesting, and above all, should be a discussion we have in society:

Once the basic scientific results are established, one can meaningfully examine the many ethical issues surrounding embryo selection. 

My view has always been that new genomic technologies are so powerful that they should be widely understood and discussed -- by all of society, not just by scientists. 

However, to me it is clear that the potential benefits of embryo PRS screening (PGT-P) are very positive and that this technology will eventually be universally adopted. 


🌱 Wellness

🚶‍♀️ A Simple Way to Feel Better

Nothing fancy here, just walking around your neighborhood listening to a good podcast. Try it. It does wonders.


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🧠 Better Thinking

🗯 13 Steps to Cognitive “Perfection”

I discovered Bryan Johnson through this interview, and I liked his way of thinking. I already talked about him in the newsletter, and this week I read his article about seeking cognitive improvement.

Hi, my name is Bryan Johnson, and I have a problem. My brain is critically flawed. I see other people’s cognitive errors but can’t see my own. Just like you. Just like everyone else.

Inspired by Ben Franklin's quest for moral perfection, Bryan details his 13 steps for cognitive perfection. The idea is then to take one week for each of these and focus on improving it.

The quicker we can make radically improving our brains the single highest priority of the human race, the more effective we will be to work on everything else we care about.

Here are some of my favorites:

  • TEMPERANCE (“Eat not to dullness; drink not to elevation.” — Ben Franklin)

    MY GOAL: Carefully categorize thoughts; be neither too specific nor too general in assumptions or conclusions; consider specifics and notice wholeness.

  • ORDER (“Let all your things have their places; let each part of your business have its time.”- BF)

    MY GOAL: Do not be swayed by the ordering of events or memories; identify context and do not be seduced by novelty.

  • FRUGALITY (“Make no expense but to do good to others or yourself; i.e., waste nothing.” -BF)

    MY GOAL: Do not overvalue the present or that which is immediately before me; embrace ideas unfamiliar to me in space (i.e. across the world) and time (i.e. the past or the future).

  • TRANQUILLITY (“Be not disturbed at trifles, or at accidents common or unavoidable.” -BF)

    MY GOAL: Resist the lure of certainty; overcome fast or error-prone intuitions about probability through rigor, clarity, and honesty.

A good quote to re-read often:

"Delay your intuition. Don’t try to form an intuition quickly. Focus on the separate points, and when you have the full profile, then you can have an intuition.”

— Daniel Kahneman


⚡️ Startup Stuff

🛠 Building Something no One Else Can Measure

Sriram Krishnan has a great piece about building something that’s hard to measure. Often, companies fall into the trap of optimizing for what can easily be measured and end up in a problematic situation because picking the metric can distort the long-term goal.

You enter the Measure & Improve Paradox:

"If you can't measure it, you can't improve it."

— Drucker's maxim

"When a measure becomes a target, it ceases to be a good measure."

— Goodheart's law

Any large system picks a metric to goal itself on. Entire books and way-too-long Medium posts have been written on the importance of said metric - it influences everything from people’s incentives to how quickly you can optimize your business. In an organizational equivalent of Schrödinger’s cat, picking the metric itself can cause weird cultural distortion (see Goodhart’s Law).

The reason pushing big companies to pick a metric is that it’s tough to quantify things without metrics to measure and track.

Since it is near impossible to perfectly measure human behavior, most large teams/products pick a proxy metric to measure underlying behavior. For example - ‘clicks’ are a proxy for “did I read this?” and “will I buy this product sometime in the future?”, ‘time spent’ is a proxy for “did I enjoy this content?” and NPS is often a substitute for “do I love this company?”. You convert a nebulous human emotion/behavior to a quantifiable metric you can align execution on and stick on a graph and measure teams on. Engineers and data scientists can’t do anything with “this makes people feel warm and fuzzy”. They can do a lot with “this feature improves metric X by 5% week-over-week”. Figuring out the connection between the two is often the art and science of product management.

Sriram explains that this could be your chance to compete with the big tech companies as an outsider. If you try an approach that the incumbent can go after easily, you’ll have an opportunity to beat them. Of course, this is easier said than done:

But you, as an outsider, you can do better. If you can figure out this blind spot, you can build something that captures a space that the existing incumbent can’t go after easily. This is not easy and almost always needs some instinct or intuition on product/human beings/communities that is not broadly known and by its very nature, high beta.

Here are some crazy, impractical examples in this vein.

  • A social network that makes you spend less time on it and tries to get you to get outside/workout more instead to optimize for long term health. (👋 Vital 👀)

  • A niche community/behavior that has no unified online presence (and hence can’t be measured/understood easily by an outsider).

  • A supermarket with a limited catalog that only sells healthy items.

  • Having only long form pieces that demands you spend a lot of time reading it.

  • Mobile operating systems that don’t show you non-urgent notifications when you wake up or before bedtime or when you’re with family (stolen from Tristan Harris).


📚 What I Read

📱 The Social Media Trap

Social media is fundamentally changing how people think and what they allow themselves to experiment with because we are constantly watched and observed:

Building personal brands has turned us all into public relations professionals. Public companies are notoriously risk-averse. Compared to private ones, they operate on short-term horizons and face more scrutiny when they make bold bets. In practice, we now have to justify risky career moves to our friends, so it’s often easier to follow the well-worn path, do what everybody else is doing, and guarantee the approval of our peers. 

🌍 After Climate Alarmism

The war on climate denial has been won. And that’s not the only good news:

And yet, this is the face of the new world. Or it will be, if we’re lucky. While adaptation sounds like a technocratic, “just fix it” option, what is required even now seems to approach the scale of terraforming — at least until you remember that 95 percent of the earth’s surface has already been remade by human hands. These measures aren’t trivial; they aren’t a way to avoid hard choices but a last-resort attempt to square the punishing climate we are making with one we may feel comfortable living in, relatively speaking. In the century to come, which will be defined both by ghastly impacts and, one hopes, extraordinary human responses, even conditional success may require as much world-building as world-saving.

🔨 Entrepreneurship is contagious

Exposure to entrepreneurs (mostly) encourages entrepreneurship.


🎙 Podcast Episode of the Week

As I had no access to a gym (where I usually listen to music), I listened to a lot of great episodes this week:

  • Optimizing Your Inputs

    • This is an excellent episode on everything related to your information diet. Here’s a quote from the episode:
      ”And you can see that your resting heart rate spiked, you can see when you've got a good night of sleep or not. You kind of know this stuff kind of intuitively, but tracking it over time is actually very valuable. You hit what you measure. What are we optimizing today? Twitter likes. That sucks. It's funny, people say that we have nothing in common around the world. Well, every politician in the world, every celebrity is optimizing their Twitter likes, or their followers, or what have you.”

  • Daniel Schmachtenberger: Steering Civilization Away from Self-Destruction

    • This episode is, without a doubt, in the top 3 of what I listened to this year. Daniel is brilliant in understanding the trends that will shape the future, especially exponential technologies. It’s a great complimentary episode to the one just above. It also discusses how social media could optimize for better outcomes (health, wealth, learning) than they currently do (time on app, ad revenue.)

  • Yeonmi Park: North Korea

    • A poignant conversation about the atrocities happening in North Korea. If you don’t have the time for the whole discussion, I particularly recommend these two parts (1:13:35 - Diversity 1:20:55 - Political correctness.)


🍭 Brain Food

🌘 Seeing on the Far Side of the Moon

I found this piece making a case for building telescopes on the far side of the Moon to be fascinating:

Astronomy, then, faces a Catch-22. Terrestrial telescopes can be built with excellent resolution thanks to aperture synthesis, but they have to cope with atmospheric interference that limits access to certain bands, as well as radio interference from human activity. Space telescopes don’t experience atmospheric interference, but they cannot benefit from aperture synthesis to boost resolution. What we need is to develop a telescope array that can marry the benefits of both: a large synthetic aperture like Earth-based arrays that is free from atmospheric and human radio interference like space telescopes.

A telescope array on the surface of the moon is the only solution. The moon has no atmosphere. Its far side is shielded from light and radio chatter coming from Earth. The far side’s ground is stable, with little tectonic activity, an important consideration for the ultra-precise positioning needed for some wavelengths. Turning the moon into a gigantic astronomical observatory would open a floodgate of scientific discoveries. There are small telescopes on the moon today, left behind from Apollo 16 and China’s Chang’e 3 mission. A full-on terrestrial-style far-side telescope array, however, is in a different class of instrument. Putting one (or more) on the moon would have cost exorbitant sums only a few years ago, but thanks to recent advances in launch capabilities and cost-reducing competition in the new commercial space industry, it is now well worth doing—particularly if NASA leverages private-sector innovation.


🎥 What I’m Watching

☠️ The Dissident

I really enjoyed this documentary about the assassination of Jamal Khashoggi. I loved Bryan Fogel's previous documentary Icarus about the Russian doping scandal, and this one is as good. Here’s a short clip of Bryan Fogel on the Mystery Behind the Death of Jamal Khashoggi.

💻 Earth’s Most Wanted Hacker

An excellent video about one of the best hackers ever.


🔧 The Tool of the Week

📚 Read Something Great

I do my best to share the best of what I read, listen to, and watch on The Long Game. If you need an additional place to find great content, Read Something Great is a place where you’ll discover high-signal, low-noise content.


🪐 Quote I'm Pondering

When you first start to study a field, it seems like you have to memorize a zillion things. You don't. What you need is to identify the core principles – generally three to twelve of them – that govern the field. The million things you thought you had to memorize are simply various combinations of the core principles.

— John Reed


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👋 EndNote

Thanks for reading!

If you like The Long Game, please share it on social media or forward this email to someone who might enjoy it. Podcast reviews are also gratefully received. You can also “like” this newsletter by clicking the heart just below this, which helps me get visibility on Substack.

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Feel free to email me or find me on Twitter if you have any feedback or questions.

Until next week,

Mehdi Yacoubi

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