We all use the same data…

I had a money manager say something to me the other day that struck me as odd—so I thought I’d dig in a bit to see if I can rationalize his comment.   He said, “We are all using the same data” when I asked him about an opinion that I heard from someone else about the stock market over the next few months. His basic point was that the market is about valuations & fundamentals” (more) and significant deviations from intrinsic value are rare, and markets usually revert rapidly to share prices commensurate with economic fundamentals.  Therefore, if you use tried-and-true analysis of a company’s discounted cash flow to make your valuation decisions you will be fine over the long run.

I think the most important thing he said was “over the long run”.  Because some investors do have access to fundamental data (private feeds) that others don’t and if a proprietary feed is faster and gives the investor a ‘speed advantage’ in trading then that is an unfair advantage. For example, if the price of a stock goes from $100 a share to $95, and you know that and someone else doesn’t, it makes sense to sell at $100 to a buyer when the investor knows the price is now $95. If you are a high-frequency trader and you know prices are changing millions of times a day across many securities, you can make a great deal of money.

“…our system for telling investors what stocks are worth should be straightforward. Instead, we have created a two-tier system of stock-price information—a lower-quality public feed and generally higher-quality private ones.”  Commissioner Robert J. Jackson Jr. (more on Public versus Private feeds)

Some investors also have access to “alternative data” like satellite imagery to analyze information such as parking lots, web scraping to track items such as consumer preferences and geolocation data to analyze information such as consumer traffic to certain stores.  With tools like Artificial Intelligence/Machine Learning the new Quant 2.0 Wall-Street geniuses can take proprietary fundamental feeds and these new alternative datasets and do Algorithmic trading to uncover value faster than any old school hedge fund manager (example).

But at the end of the day, you don’t have access to any of these tools… So, if you can suffer through all the volatility and you trust that your money manager is on top of your portfolio’s underlying fundamentals then yes, the market can still work for you over the long run.  However, just know that many strategic investors will have made a lot more money than you, on those same investments, by leveraging better tools and quant 2.0 type talent.

…you can throw all this long term investing out the window if you have a mere $7.5 billion to invest and then Bridgewater Associates can do it for you and you will likely do very well.

While the Quant’s and AI-powered algorithms can crunch numbers and make an investment decision, they can’t offer the human touch and it has become evident to me that the human touch is an essential component to long-term investing—net: you need a coach to get you through the stress of the volatility–get a good money manager.

Footnote: and never forget that you need to respect market sentiment.

How do new blockchain/crypto business model incentives differ from old school companies like Facebook?

I recently read Chris Dixon’s article at WIRED titled “BLOCKCHAIN CAN WREST THE INTERNET FROM CORPORATIONS’ GRASP” found here https://www.wired.com/story/how-blockchain-can-wrest-the-internet-from-corporations/.

The article was a fun read but it was very high level and left me with questions about how the incentives for founders, investors, customers, and the employees change in this new world (i.e. when governance is provided by the community versus the company). For example, if you compare the company Facebook to a NewCo like a steemit.

I listed my assumptions in the table below after reading the article. It would be great for this community to help contrast the changes between models (I also posted this article on steemit and I’m spending some time learning the platform as well as the new crypto/blockchain models that have momentum).

Please comment on what is right/wrong or needs to be better articulated in the table below…

Facebook (Governance provided by the Company) NewCo’s (Governance provided by the Community)
Founders invest time and $ upfront and are rewarded by pay in $ and exit (sale or IPO) in $ of shares they own Founders invest time and $ upfront and are rewarded by pay in $ from ICO/STO and from an increase in the token price of held back tokens which are eventually sold for $

Note: Founders hold back tokens that they personally own that are valued and can be sold on an exchange for $ once vested

Change= Founders can sell tokens for $ once tokens vest versus at exit or IPO

Risk: From day 1 the company is public which comes with a great deal of overhead; Founders can also cash out once vested.

Investors buy shares or debt in company in series A, B, C etc for $ and get rewarded by increased share price (over time) which in turn is sold for $ upon exit Investors buy tokens (example: STEEM, SP or SBD) in company at any time for $ and get rewarded by increased token price or interest on debt (ex:SBD)which in turn is sold for $

Change = Investors buy tokens at any time versus shares in the company

Company provides proprietary service at no-cost and sells advertising and get rewarded with $Change = Company gives proprietary service away for free versus an old school MSFT model where proprietary software is sold for $ Company provides open-source service at no-cost and sell nothing and get no reward (other than token appreciation in the market)

Note: Company holds back tokens from market to be sold for $ and used to run company

Change = Company sells nothing

Change = Company reward is 0

Employees help company make proprietary service; sell advertising and get rewarded with $ Employees help make & sell open-source service and get rewarded with pay ($ from held back tokens); Community helps company make open-source service and gets rewarded with tokens which can be sold for $

Change=Community helps develop open-source code

Customers get proprietary service and pay with their data and get rewarded with value Customers get open-source service and pay with activity and get rewarded with value and tokens which they can sell for $

What others report:

> From TechCrunch: Tokens (versus options) can better incentivize startup employees than equity “One of the largest differences between tokens and equity is that tokens are immediately liquid, assuming that they have already been listed on an exchange.”–however, as commenters to the article point out easy liquidity for employees can be bad for a startup. It can also cause tax issues for the employees.

> From CoinDesk: The Biggest Problem for ICOs? In 2018, It Was Their Own Investors” Instead of treating individuals who make early contributions as merely financial investors, projects that are truly pursuing decentralization should recognize them as more akin to employees who receive stock options (and can actively contribute to the network from outside the organization) and adopt a philosophy of ‘compensation through the protocol’ to leverage them.” — ‘Proof of Contribution’

Georgetown Retail

This is an update to my notes from last July (found here). Update since: By the time the summer ended the city had cleaned up the graffiti and fixed several of the sidewalks—great job! However, there are still issues to discuss such as the retail vacancies.

I attended the “The Future of Georgetown” meeting on 1/15/19 hosted by the amazing Citizens of Georgetown (CAG) group and spectacular Advisory Neighborhood Commission (ANC 2E) but came away a bit disappointed with what the Georgetown Business Improvement District (BID) presented as the areas future of retail.

The BID spent 30 minutes of the presentation on why it’s so hard to have a good retail ecosystem in Georgetown (i.e. Amazon, unrealistic landlords/rents, awkward spaces in old buildings) and how many retailers are going out of business.  They also painted a picture on why it’s not as bad as it looks –even though I counted 19 vacancies when I walked down Wisconsin Ave to get to the meeting. …but what really got to me was at the end of their presentation they said that this is all part of a cycle and Georgetown’s business district will still be here when other locations fail—and that’s just not a good way to manage the area’s future (i.e. telling people to wait and have hope).  I personally don’t think this is a cycle—retail as we have known it is dying and if we don’t have a well thought out strategy for how to grow with these changes then the business district will die a slow death and Georgetown will no longer be the tourist destination or the exciting place to live that it is currently.

Don’t get me wrong, this is a wonderful community (in a remarkable city) with a beautiful waterfront and a great plan for the canal (being done by the same team that did NYC High Line)—but we need a better plan for our diminishing retail market than wait for the cycle to rebound.  This 2028 strategic plan is good and the update speaks volumes but we need to have a more thoughtful discussion about the Georgetown retail problem (everything needs to be on the table—policy, zoning, investment etc.).

I don’t disagree with anything the BID laid out in regards to our challenges (most big city retail communities are facing the same issues) but what the presentation made me think is that the ‘Free Market’ is not working for Georgetown’s retail district if online commerce is hurting it, absent/uncaring landlords are leaving spaces vacant for years and the city infrastructure is not desirable because it’s old/lacks parking & a metro—and when the free market doesn’t work policymakers need to get involved. I didn’t see any policy ‘makers’ (Jack-Ward 2, Kenyan-Chair Committee on Bus & Economic Dev) at the meeting but I may have missed them—however I would not have expected them at the meeting as the ANC had it covered very well and that is our voice to the policy makers–and they did ask for our feedback (hence this update)!

What I hear from the community is that Georgetown visitors and locals want great restaurants, art & entertainment, shopping, and experiences—but most importantly they want Georgetown to stay relevant to the world as a brand destination and a great place to live. The ANC asked for feedback and ideas:

Maybe to ensure Georgetown stays relevant we could:

  • Make it harder for landlords to leave storefronts vacant via new legislative policies (examples & risks). 
  • Create income tax abatements for commercial building rehab or new development (example from Falls Church VA).
  • Ring-fence grant funding for the types of businesses we want to attract (maybe extend this program to include M Street and understand if it worked for Wisconsin and push to increase funding).
  • Revisit zoning laws for Wisconsin Avenue (old article)
  • Invest in a metro rather than a gondola 😊 (old article)
  • Learn from others success… Just look across the river at https://nationallanding.com/

We also have an incredible resource of entrepreneurs & professors at the Georgetown MBA (ranked #19 in US) and Legal schools within the University–Maybe we could lean on them for some help…   

Just some ideas—I’ll add more as I read about other’s successes…

Wake up! You are being manipulated.

This holiday season I talked to several people with different opinions from my own. I met a young 20-year-old woman that said she would never bring kids into this world because global warming meant we have no future… I chatted at a party with a Trump supporter that was convinced tariffs were good policy.  I listened to a young person (under 18) tell me that Socialism was indeed better than Capitalism. I’m not saying any of these opinions were wrong but I did notice that NONE of them were based on a broad set of knowledge—they were all drawn from a few headlines, things they heard or opinions they created themselves based on their belief system. You might say that this has been going on since the beginning of humanity (people formulating strong opinions without a lot of facts)—but it seems much more pronounced now.  (As you will read below this might be due to me having a slight Negativity Bias.)

I get it, we are human, and we have innate flaws that allow us to be influenced –but how and why? I thought it was time to do some digging, take some notes, and begin a list of all the ways I could be manipulated so I can defend against it in the future.

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Political ads, search and social media advertising, partisan cable TV and fake news content is constantly being pushed at all of us–While product designers create products that cause addictive behavior to distribute such content.  Design engineers read books like Hooked: How to Build Habit-Forming Products to understand how to build products & services that we have to constantly check for a little boost of dopamine. In the past, this wasn’t as big of an issue because the portals for distributing content were not as widely used (as our smartphones are today) for such a large part of the day and their influence was not as personalized (more on how much just a couple tech firms knows about you found here).

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To understand how we are being manipulated we need to understand one of our many glitches–Bias.

Everyone is susceptible to some form of Bias

Response to the survey question “Do you think human activity is a significant contributing factor in changing mean global temperatures?”

The first thing I’d ask is why less than 60% of the general public believe human activities are a significant contributing factor in climate change when >95% of the scientists that study climate change for a living (PHDs) are adamant about the fact.  Think about this for a second–These specialists have studied climate for their entire professional careers, yet a large majority of people that NEVER studied the climate don’t believe them—that’s just crazy!  Are these non-believers’ lives impacted negatively by climate change policy? Are these non-believers’ drawing conclusions based on how much snow they saw in their backyard this past winter? Take this a step further—these non-believers are voters and 40% is a lot of people (more on a related subject). Reference this video about bias and climate change:

Most (if not all) people have a “bias blind spot”. Humans are less likely to detect bias in themselves than in others per published research in Management Science. The reality is that people are susceptible to all kinds of bias (defined as a mental leaning or inclination; partiality; prejudice; bent).

  • We love to agree with people that agree with us—This is called confirmation bias. To compensate we should surround ourselves with a diverse set of people that have different backgrounds and experience than your own.
  • We jump to conclusions without having a lot of information – This is called Anchoring Bias. To compensate we can draw upon tools such as the Ladder of Inference to help us make decisions.
  • We may believe that after flipping a coin 5 times and getting heads all 5 times that there is an increased likelihood that the next coin toss will be tails and the odd would be in our favor.   They are not.  This is called Positive Expectation Bias and forms the basis of gambling addictions. To compensate, we need to look at trends from a number of angles versus just chronologically.
  • We blame others when something goes wrong. Perhaps blaming the other driver for being a ‘bad driver’ in a traffic accident versus blaming the weather. This is an Attribution Bias. To compensate we need to look at others as people and use empathy versus treating them as objects (use tools like Arbinger Institutes Leadership and Self Deception framework).
  • We overlook faults or defects with a large purchase of an expensive product or service in order to justify the purchase – this is a form of cognitive bias called Buyer’s Stockholm Syndrome
  • We might despise the opposing political party.  Negative feelings towards another group form from favoritism towards one’s own group – This is called Ingroup bias and forms the basis of discrimination.
  • We fear flying more than driving even though statistically, we have a 1 in 84 chance of dying in a vehicular accident, as compared to a 1 in 5,000 chance of dying in a plane crash [other sources indicate odds as high as 1 in 20,000]) – this is called Neglecting Probability Bias.
  • We start to see our new car everywhere after we purchase it—this is called Observational Selectional Bias and it causes us to actually believe this is happening with increased frequency.
  • We often say “If it ain’t broke, don’t fix it” – This is called status-quo bias
  • We think that things are getting worse in the world not better. – This is Negativity Bias and is the basis of Steven Pinker’s book The Better Angels of Our Nature: Why Violence Has Declined.  In general, people tend to pay more attention to bad news than good.

The human brain is easily deceived, and we have to be diligent in not letting others manipulate us because of its natural bias. After all, marketing professionals have been exploiting these fundamental human flaws for years.  Here is a great article outlining how titled “How marketers use 20 cognitive biases that screw up your decisions” by Paul Marsden.

Here is a link to all bias’s (specifically cognitive bias) in which we are all susceptible.

We must constantly ask ourselves if our personal bias is making us draw conclusions without all the data… have we listened to the other side?  Do we have empathy for the people on the other side of the dialog or are they ‘objects’ to us? Are we only listening to news that confirms our personal bias?  Are we being manipulated or are we thinking about all sides of an argument? –don’t be the nitwit that doesn’t believe in global warming when >95% of all climate scientists (who spent their entire careers studying the issue) believe humans are at fault.

We are vulnerable to The Sleeper Effect

This was first identified in U.S. soldiers during World War II. Scientists measured a soldier’s opinions 5 days and 9 weeks after they were shown a movie of propaganda. They found that the difference in opinions of those who had observed the movie and those who did not watch the movie were greater 9 weeks after viewing it than 5 days. This leads us to believe that our impressions have more influence on us than rational thinking over time. Maybe this is why drug companies place disclaimers at the end of a commercial because we won’t remember them over time. Could this be why the older generation wants to Make America Great Again…

Some are vulnerable to Group Think

The brain is always looking for approval from other people and this can be perverted in all kinds of unsettling ways. Our brains prioritize ‘being liked’ over ‘being right.’ so people will go along with a crowd and engage in activities they would never pursue by themselves for the sake of fitting in.  Terrorism is a great example—it occurs when ‘group think’ morphs into ‘group polarization’. For more on this subject there is a great study in the Journal of Social and Political Psychology titled “Social Psychological Perspectives on Trump Supporters”.

Some are vulnerable to Cognitive Dissonance

Not knowing things makes humans anxious. When we are not given adequate closure, we fill in the gaps to create a cohesive whole that makes sense to us. It’s why some of us believe in heaven, astrology, or ghosts. Humans fear the unknown, and intrinsically combat this angst by supplementing our limited information with things that fit a particular paradigm. It’s why we create religions and subscribe to them to our death to give us answers to life’s complex questions.

“When a thousand people believe some made-up story for a month — that’s fake news. When a billion people believe it for a thousand years — that’s a religion,”- Yuval Noah Harari.

Most may be susceptible to some level of hypnotism

I know… this sounds farfetched but it’s not. We know the result of hypnosis is real—but we don’t understand how it works.

“Follow the Lord!” says the priest. “Defeat the Enemy!” says the politician. “Place your Order within the next Ten Minutes for Double the Benefit!” says the sales person. These are all examples of mass hypnosis—used just the same way that Stalin and Hitler practiced it. Manipulating emotions is a way to seize control over someone’s body and mind.  The more we understand our subconscious mind, the greater our ability to make rational decisions.

Hypnosis is generally regarded as an altered state of consciousness—but since consciousness isn’t understood, alterations to it such as hypnosis, meditation and psychosis aren’t very well understood either. David Spiegel M.D. does a great job explaining what is known about hypnosis in this 9 chapter lecture titled “Tranceformation: Hypnosis in Brain and Body” found on NIH.gov.

Someone can learn how susceptible they are to hypnosis here.

It may be based somewhat on intelligence

Gordon Pennycook and colleagues published a paper titled “On the reception and detection of pseudo-profound bullshit” and found that people who are more susceptible to BS score lower for verbal and fluid intelligence, are more prone to “conspiratorial ideation,” and more likely to “endorse complementary and alternative medicine.”

A person’s intelligence is not set in genetic stone—Here are some ideas on how to increase intelligence.

It may be in our genes

Bradley B. Doll, Kent E. Hutchison and Michael J. Frank published a paper in The Journal of Neuroscience titled “Dopaminergic Genes Predict Individual Differences in Susceptibility to Confirmation Bias” that suggested that variants in the genes involved in the prefrontal dopaminergic reward system predicted the degree to which study volunteers persisted in responding to a test, following previous instructions, even as evidence against the veracity of the instructions accumulated. In contrast, variants in genes associated with dopamine function in the striatum correlated with the ability to learn from actual experience.

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Conclusion: We are not flawed, we are human.  The key is to understand how our brains work and to defending against others that try to exploit our human design.

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More information:

Will the US debt eventually make the economy implode?

I just started reading Ray Dalio’s new book “Principles For Navigating BIG DEBT CRISES” and I decided to ask my money manager about his thoughts on some of the concepts in the book. My first question was what he thought about the USA’s National Debt situation and if it was going to have an impact on the future economy/stock market.  His answer, “it’s been an issue for years and if you worried about it you would have never made any returns.” He pontificated about a few other charming variables but for a guy that likes more detail, it was NOT a great answer—so let’s start digging and taking some notes. Ray’s book makes some assumptions that the reader understands these concepts so it’s good to do a review as I forgot most of what I learned in high school finance (wait, they didn’t teach finance in my high school–well, they should…).

We must start with the basics: What is credit, trust, spending power, and debt? 

Debt is money a borrower owes in the future to a lender.   Credit is the trust which allows a lender to provide money to a borrower where that borrower repays the money (and usually interest) at a later date. Credit creates both spending power and debt. The key is to use the borrowed money productively to generate enough income to pay back the debt.

What is the national debt?

The national debt of the United States is the funds that the country borrowed (via selling securities issued by federal government agencies such as the Treasury). If the federal government runs a “deficit” (spends more than it takes in) the country has to borrow to cover the delta and this increases the debt.

Who is lending the US money to cover the debt?

The current US National Debt can be found here.

You can find details here but ~28% of the debt is held by intra-governmental agencies and the rest (public debt) is held by foreign governments other governmental entities (Federal Reserve and state and local governments), mutual funds, private pension funds, holders of savings bonds and Treasury notes, banks, insurance companies, trusts, companies, and investors.

In regards to foreign ownership, in October 2018, China owned $1.14 trillion of U.S. debt,  Japan at $1.023 trillion. Why? Because, both Japan and China want to keep the value of the dollar higher than the value of their currencies to keep their exports affordable for the United States, which helps their economies grow.

What are unfunded obligations?

Note that the US published National Debt number does NOT include Medicare, Medicaid and Social Security—these are considered “unfunded obligations”.  It’s estimated that the US has between $47 Trillion and $210 Trillion of unfunded obligations (here or here).

What is GDP (Gross Domestic Product)?

GDP is a measure of the total size and output of the economy of a country in a year.

Why is the Debt-to-GDP ratio important?

A debt-to-GDP ratio under 100% simply indicates that the economy produces and sells goods and services enough to pay back debts without incurring further debt. Here is a chart that shows this % since 1900 –note that we were over 100% around the time of World War II. The current ratio is~106% and climbing.

How does the USA’s debt-to-GDP ratio compare to other countries?

You can find a chart comparing all countries here.  If you take all the countries around the world and sort them by the % highest to lowest you will see the following:

How do we stack up if you include unfunded obligations in our numerator?

So, what’s the problem?

Borrowing is OK if it allows for development. However, if the return on the loan is such that it doesn’t produce enough to repay the loan then we are essentially bankrupt.  We see above that for several recent years the US has been borrowing from its future.  How much is too much?

What happens if we default? Great article here.

What is Reserve Currency status and why does it matter?

By the end of the 20th century, the United States dollar (USD) was considered the world’s most dominant reserve currency. Most countries hold most of their reserves in USD. Why? It’s because the United States has:

  • large, liquid financial markets capable of taking huge investments
  • a reputation for safety and rule of law, so that other countries are willing to invest billions and billions of dollars in that country’s government securities
  • a willingness to run current account deficits indefinitely since that’s the counterpart of a capital account surplus.

Being a dominant reserve currency causes the country’s currency to appreciate due to foreign demand.  This then dampens growth, and it causes unemployment (US exports would be more competitive, and more people in the US would have jobs making goods for exports).

The fact that the USD is the world’s major reserve currency is one of the main reasons why it has run a current account deficit for most of the last 30 years. (known as the Triffin dilemma).

So, what are the benefits of being the country with the dominant reserve currency? From Michael Pettis in 2016it isn’t easy to list these benefits because for all the conviction that they are substantial, few analysts can identify them except very vaguely. The main benefits seem to include:

  • It lowers US government borrowing costs.
  • It allows Americans to consume beyond their means.
  • Outstanding currency notes provide seignorage benefits. 
  • The US sells economic insurance.”

Others are pointing out that the debt will cause the US to lose it’s reserve currency status and it has already started (see here).  Others refute that it will happen (more) – “the US dollar will continue to be the dominant reserve currency for the next several decades unless the US government itself decides to prevent or limit the ability of foreign central to accumulate reserves in US dollars”.

More on the subject of ‘what happens if…’ (consider source with caution given HQ in Moscow)

Other reading:

Take the following propaganda with MAJOR CAUTION GIVEN THE SOURCE but if you want to see a very negative view of the US debt situation from the RUSSIAN accounting firm Awara read “An Awara Accounting Study on US Economy 2018: Signs that the US Debt-Fueled Economy Might Actually Collapse” found here. “it is clear that the present US economic system will not survive over the coming 5 to 10 years. Massive changes in the economic model would have to be undertaken either in an organized fashion (hardly imaginable) or through a mega financial crisis.”

One of the best debates that leans toward the US debt NOT having a big impact on the future economy can be found here at a podcast that I enjoy called: Money for the rest of us

Net/Net: It’s really hard to tell when/if the US National Debt will eventually sink our economic ship and I think my money manager gave me the best advice he could as I’m sure he has no clue either…

Great info to share with your kids:

OK, back to Ray Dalio’s new book…

DMD, Going one level deeper – a personal problem…

I’ll keep these notes updated as a learn more about Duchenne Muscular Dystrophy (DMD) and the progress toward a cure.

I love Wired.  They have incredible content for people interested in STEM but after I read an article I’m often left with a feeling that I grasped the basics but I really didn’t understand the details–and I think it may be because I didn’t listen as well as I should have during high school biology.  For example, this article from August 2018 on DMD was very interesting to me because I have young relatives with the disease.  

Basically the article says the following:

  • Some King Charles Spaniels have a mutation on their X chromosomes, in a gene that codes for a muscle protein called dystrophin much like a human suffering from DMD.
  • Eric Olson from the University of Texas Southwestern Medical Center has successfully halted the progression of the disease in some of the dogs using a gene editing tool known as CRISPR but there is still a lot of work to be done (additional longer-term canine studies to test for safety) before human trials would be safe.
  • “Olson found a way to target an error-prone hot spot on exon 51, which he figured could, with a single slice, benefit approximately 13 percent of DMD patients.”
  • Olson licensed the technology and founded a startup called Exonics Therapeutics along with the CureDuchenne group (who invested $2M) and The Column Group (who invested $40M).
  • One of the challenges is figuring out how to manufacture enough viral delivery vehicles to inject CRISPR into all the muscles in the human body.

I get the basics and I should just move on but I can’t... I need to know more.  The new technology fascinates me: What is CRISPR and how does it work?  What is gene editing? What is a viral delivery vehicle?  What is dystrophin? ...but then there are also items I should understand but I don’t (items that I know I learned in high school but I’ve forgotten or never really grasped at the time): What’s a chromosome? What’s a gene?  What’s an Exon? What’s a protein and why is it important? …and how do dogs relate to humans? 

So the journey begins and it shows how I think and my limitations :-).  I know I won’t understand what Exonics does without understanding CRISPR/Cas9.  I won’t understand CRISPR/Cas9 without understanding ‘gene editing’.  I won’t understand ‘gene editing’ without understanding chromosomes & genes.  I won’t understand chromosomes & genes without understanding DNA.  I won’t understand DNA without understanding cells.   I won’t understand cells without understanding proteins. I won’t understand proteins without understanding molecules and atoms.  Hopefully, you get the point.  Most people know when to stop… me… unfortunately I need to go one step further and I constantly find myself realizing I didn’t retain much of what I learned in high school. …and then it becomes a bit of a puzzle. Some people like Sudoku… I like science. …but unfortunately, I’m not a scientist however I do have the passion (and motivation) to learn about this subject. 

Let’s start with the basic definitions (YES, high school biology)–humans only:

What’s a cell

The cell is the smallest unit of life.  The human body has >10Trillion cells.  A Cell has a membrane that contains receptors (proteins) that detect external signaling (ex. Hormones) and cytoplasm (all the stuff inside the cell like amino acids that perform functions and the nucleus).  

We have to take a detour to high school chemistry for a second: What are molecules and atoms?

An atom is the smallest unit of matter containing a nucleus (Protons, Neutrons) and electrons. The number of atoms in the human body–it’s staggering (here).

A molecule is 2 or more atoms held together by chemical bonds.  Much of the research references molecular formulas so you need to understand them. 

A molecular formula (example ‘a’) is a representation of a molecule that uses chemical symbols to indicate the types of atoms followed by subscripts to show the number of atoms of each type in the molecule. (A subscript is used only when more than one atom of a given type is present.)

The structural formula (example ‘b’) for a compound gives the same information as its molecular formula (the types and numbers of atoms in the molecule) but also shows how the atoms are connected in the molecule. The lines represent bonds that hold the atoms together. A chemical bond is an attraction between atoms or ions that holds them together in a molecule.

Example A and B are the formulae for methane as it contains one Carbon atom and four Hydrogen atoms.  Here are other examples for your reference:

A typical human cell has somewhere around 42 million protein moleculesYou can also find he number of molecules in the human body (here).

What is DNA (Deoxyribonucleic acid)?

DNA (and RNA) are nucleic acids, and, along with lipids, proteins and carbohydrates, constitute the four major macromolecules essential for all known forms of life.

Specifically, DNA is a molecule composed of two chains that coil around each other to form a double helix carrying the genetic instructions used in the growth, development, functioning, and reproduction of all known living organisms.  All the cells in a person’s body have the same DNA and the same genes. However, the difference between cells in different tissues and organs is that the “expression” of the genes differs between cells. Expression generally means that the message from the DNA is being copied and made into protein. For example, liver cells have different proteins than skin cells, even though their DNA is the same.

DNA is made up of Nucleotides (sugar, phosphates and nitrogenbases).  There are 4 types of nitrogen bases: Thymine (T), Adenine(A), Guanine (G), Cytosine(C)

“A” bonds only with “T” and “C” only bonds with “G”

What is RNA (Ribonucleic acid)? 

RNA is a molecule essential in various biological roles in coding, decoding, regulation, and expression of genes. Like DNA, RNA is assembled as a chain of nucleotides, but unlike DNA it is more often found in nature as a single-strand folded onto itself. Cellular organisms use messenger RNA (mRNA) to convey genetic information (using the nitrogenous bases of guanine, uracil, adenine, and cytosine, denoted by the letters (G, U, A, and C) that directs the synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

What is a chromosome?

A chromosome is a DNA molecule that contains part of a human’s genetic material.  A  human cell nucleus contains 23 pairs (46 total) of chromosomes (DNA molecules) which are long strands of DNA tightly wound into coils (note that sperm and egg cells contain only 23 total chromosomes). If you unwound each cells DNA it would be about 6 foot long. 

What is a gene?

gene is a sequence (section) of DNA or RNA that uses a set of rules to translate information encoded within the DNA or mRNA sequences into proteins for a molecule that has a function.

Genes are either turned ‘on’ or ‘off’ mixed among other non-coded ‘junk DNA’.

Human beings have roughly 20,500 genes, all coiled up in DNA, housed in each cell. That’s 20,500 places where the machinery of human life can be altered.

Genes are divided into sections called exons and introns (junk DNA). Exons are the sections of DNA that code for the protein and they are interspersed with introns.

The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome.

Genes can also mutate…  Although the human genome consists of 3 billion nucleotides, changes in even a single base pair can result in dramatic physiological malfunctions.  For example, sickle-cell anemia is a disease caused by the alteration of a single nucleotide in the gene for the beta chain of the hemoglobin protein (the oxygen-carrying protein that makes blood red) and that is all it takes to turn a normal hemoglobin gene into a sickle-cell hemoglobin gene. This single nucleotide change alters only one amino acid in the protein chain– the results are devastating! Beta hemoglobin is a single chain of 147 amino acids, but because of the single-base mutation, the sixth amino acid in the chain is valine, rather than glutamic acid. Note below that ‘Wild-Type’ is the normal hemoglobin. 

To understand amino acids like valine and glutamic acid you need to understand the codon table found here:

Gene Sequencing

DNA sequencing is the process of determining the order of nucleotides in DNA.  DNA molecules are incredibly long and consist of billions of nitrogen bases. In fact, if all the DNA bases of the human genome were typed as A, C, T, and G, the 3 billion letters would fill 4,000 books of 500 pages each.  The Human Genome Project was the effort to map all the human nucleotides and genes. 

The sickle-cell gene mentioned above is CLLU1 and if you were to compare the human gene sequence to that of a chimp or a macaque it would look like the following:

Tools

There are 2 common Genome Browsers (and several others).  One from Ensembl and another from the University of California Santa Cruz Genomics Institute browser.

Let’s look at an Ensembl example:


Within the chromosome you can view the detail of a region (1) and inspect the genes (2).  For example, here (3) you can see the sickle-cell anemia gene CLLU1

The sequence will provide the order of nucleotides in the gene and you can begin to see the sequence from the chimp / macaque example from above (1). 

Now, with that backdrop, we can now begin to understand the content in the Wired article.

What is CRISPR/Cas9 and gene editing? 

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) method is based on a natural system used by bacteria to protect themselves from infection by viruses.  When a bacterium detects the presence of virus DNA it produces 2 types of short RNA one of which contains a sequence that matches that of the invading virus.  These 2 RNAs form a complex with a protein enzyme called Cas9. Cas9 can cut DNA (think of Cas9 as a set of molecular scissors). When the matching sequence known as a “guide” RNA finds it matching target within the viral genome the Cas9 cuts the target DNA disabling the virus.

Cas9 can be engineered to cut any DNA sequence (not just viral DNA) at a precise location by changing the guide RNA to match the target DNA. Once inside the nucleus of the cell, the RNA-Cas9 complex will locate and lock on to a short target sequence known as the PAM (Protospacer Adjacent Motif). The Cas9 will then unzip the DNA and match it to its target RNA and if the match is complete the Cas9 will use its tiny molecular scissors to cut the DNA.  Once the CRISPR system has made the cut this new DNA can pair up with the cut ends recombining and replacing the original sequence with the new version.

Here is the basic process:

  1. Build the guide RNA (gRNA).  This guide RNA will direct the protein (Cas9) to its target DNA sequence. The guide RNA consists of a tracrRNA (a scaffold sequence necessary for Cas-binding) and a crRNA sequence (a user-defined ∼20 nucleotide spacer) that is identical to the target. The crRNA can be any ∼20 nucleotide DNA sequence, provided it meets two conditions:
    • The sequence is unique compared to the rest of the genome.
    • The target is present immediately adjacent to the Protospacer Adjacent Motif (PAM). The PAM sequence is essential for target binding, but the exact sequence depends on which Cas protein you use (check out the list of additional Cas proteins and PAM sequences).
  2. Guide RNA + CAS9. Once expressed, the Cas9 protein and the gRNA form a complex through interactions between the gRNA scaffold and surface-exposed positively-charged grooves on Cas9. Cas9 undergoes a conformational change upon gRNA binding that shifts the molecule from an inactive, non-DNA binding entity into an active DNA-binding entity. Importantly, the spacer region of the gRNA remains free to interact with target DNA.
  3. Bind. Once the Cas9-gRNA complex finds a DNA target, the seed sequence (8-10 bases at the 3′ end of the gRNA targeting sequence) will begin to bind to the target DNA. If the seed and target DNA sequences match, the gRNA will continue to bind to the target DNA in a 3′ to 5′ direction.
  4. Cut. Once Cas9 binds to the target DNA it cuts the target DNA ∼3-4 nucleotides upstream of the PAM sequence.
  5. REPAIR: (NHEJ or HDR) Once the CRISPR system has made the cut this new DNA can pair up with the cut ends recombining and replacing the original sequence with the new version.
    • The efficient but error-prone non-homologous end joining (NHEJ) pathway
    • The less efficient but high-fidelity homology-directed repair (HDR) pathway

CRISPR can also be used to target many genes at once which is helpful for complex diseases that are caused not by one single mutation but by many genes acting together.

If you want to geek out you can try CRISPR yourself by ordering a kit here.  … here is a YouTube video that shows the basics.  If you want to go very very deep on CRISPR read this PMC article.

What is Dystrophin and how is it important to Duchenne Muscular Dystrophy (DMD)?

In the study published in Science, a team led by Eric Olson at the University of Texas Southwestern Medical Center used CRISPR to successfully modify the DNA of four young dogs, reversing the molecular defect responsible for the canine version of DMD

The dystrophin gene (view it in Ensembl) is the largest in the human genome, and there are thousands of different mutations that can all result in the disease. Olson found a way to target an error-prone hot spot on exon 51 (Ensembl), which he figured could, with a single slice, benefit approximately 13 percent of DMD patients

However, a challenge is manufacturing enough viral delivery vehicles to inject CRISPR into all the muscles in the human body and it is expensive.

What is Exonics doing?

From PMC Oct 2018 Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

From ScienceMag.org Oct 2018 “We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression…” “dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. ” You can purchase the full report for $30 here.

From PMC Nov 2017 Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy

From the funding PR release Nov 2017: “Exonics has used SingleCut CRISPR to genetically repair and restore dystrophin, the key protein missing in children with Duchenne.”

From ScienceMag.org April 2017 CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice “pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing”

These folks at Exonics are heros!

Hope…

Preface: I’ve always respected well-practiced leadership principles—they were drilled into me during my time as a mid-level manager at Microsoft and I have built very strong opinions. With this background, I must say I find our President’s leadership unacceptable on many levels.  However, this set of notes is not meant to promote a conservative or a liberal position.  These notes have one goal – to find a glass-is-half-full position and to test those positions over time.

If you are wondering about my bias: I’ve always been fiscally conservative (i.e. lower taxes, reduced government spending, minimal government debt, free trade, and deregulation of the economy etc..) yet socially liberal (i.e. support universal healthcare, SMART poverty programs, investment in education, gay marriage, abortion, cannabis legalization etc..)—…and I believe good managers of resources can make both work!

Backdrop: On our family’s vacation in Europe this past summer we had dinner with the owner of a bed and breakfast where we stayed for a few days.  Over the course of a great meal, the owner edged the discussion to the current US political landscape and he made the following statement that stuck with me–“the USA is getting a long-needed enema” … “The USA’s [government] system is strong enough to handle such an invasion and this Presidents’ flaws will highlight your country’s strengths.”  I didn’t quite agree (I had a much more negative view at the time), but I’m starting to understand where he was coming from. I started to find the light recently when a good friend (HR executive and minority) said to me, “the racists were always there but it was hard to know who they were prior to this President, and now they are out in the open.”  Another friend (ex-CIA) said “I look at him [the President] much like a plumber fixing a broken overflowing toilet—I don’t care if he smells, shows his crack, or even tells racist jokes… I just want the toilet fixed and the crap cleaned up [in our government].”  I’m used to hearing people that have little underlying facts regurgitate what they have heard the night before on Fox News or MSNBC and I generally ignore them, but the friends I referenced above are highly educated people that have spent a great deal of time analyzing the US government and our political system.

So, after thinking about this quandary for a while I thought I’d write down some of the glass-is-half-full items that hopefully will come out of this President’s assault on the Executive Office to see if they stand the test of time.

Optimism is the faith that leads to achievement. Nothing can be done without hope and confidence. – Helen Keller

I’ll group these items in 5 broad categories:

1.     More people will vote and get involved in politics

It seems that the President’s misogynist tendencies are driving more women to get involved—more are voting, and more are running and winning political office.  It started the day after the President was inaugurated when millions of women worldwide took to the streets in a massive show of resistance. But since that day the President has been accused more than once of silencing women with whom he had had extramarital affairs during his administration. His liaison director in the White House Communications Office accused the President of calling her a “dog”. The President has publicly defended advisors and friends when they have been accused of domestic violence and sexual harassment at work. He continues to insult television presenters, artists, and models. He mocked Dr. Ford’s testimony at the Kavanaugh hearings and insulted a reporter during a press conference at the White House after giving her the floor to state her question and stating, “I know you’re not thinking, you never do.”. At rally’s he’s called out the negative consequences of the #metoo movement saying, “It is a very scary time for young men in America, where you can be guilty of something you may not be guilty of,”. The hope is that the President’s misogyny provides fuel for the #metoo movement, and its positive impact on women’s rights, and will drive more women to get involved in politics.  Things look hopeful because a record number of women have run and won primaries for the U.S. House, U.S. Senate, and governorships this year, according to the Center for American Women and Politics at Rutgers University, and a record number of women have also won nominations for state legislatures. (more)

It seems that the President’s well-documented racist comments are driving more minorities to vote, especially after his remarks about the white nationalist rally in Charlottesville–As of August 2018, PBS found nearly 100 examples bridging on racial discrimination. According to the African American Research Collaborative, who surveyed African-Americans immediately before the 2018 mid-term elections, “9 out of 10 African-Americans surveyed on the eve of the election said they were voting or had already voted early for a Democrat in the congressional races, up from 77 percent who said so in July”. The hope is that more minorities vote and run for office and it seems to be working since an unprecedented number of Latinos ran for office in the 2018 primaries.

And then, we can only hope that the President’s hundreds (if not thousands) of bold lies and authoritarian tendencies (admiration for dictators) will wake up those that are considered ‘supporters’ to the fact that he is highly likely mentally unstable—and it looks like this is slowly happening. The fear about these unstable characteristics are also hopefully driving more people overall to the polls–We saw this during the 2018 midterm elections which aren’t usually known for high levels of turnout. On average, roughly 40% of eligible voters cast a ballot in a midterm. At least, that was the case from 1982 until this year, when an estimated 49% of the nation’s voting-eligible population (about 116 million people) cast a ballot, according to a preliminary analysis by the U.S. Elections Project.

2.     The quality of our US Congress will go up

This is a simple point—The President had a huge effect on the 2018 midterm elections.  Our US Congress is well documented as being broken by many intellectuals that would know (more) (more) (more).  The hope is that the turnover (the two-year congressional term ending in 2018 had the third-highest rate of turnover since 1974) and the 114 women that won will take on these challenges.  Congress is also getting younger which is well needed—after all, did you watch the Mark Zuckerberg hearings? Every person under 50 was embarrassed for our Senate’s lack of understanding of the Internet.

3.     We will have less bias in our media

Millions of citizens get their information, and form their opinions, by watching cable television or reading internet media sites. The US media systematically skews reporting in a way that crosses standards of professional journalism due to strong profit-making incentives by drawing conservative OR liberal audiences for infotainment versus news and monetizes those audiences with advertisers (see the bias here).  Rupert Murdoch, the owner and executive co-chairman of 21st Century Fox (the parent of Fox News), self-identifies as a “libertarian” and exerts a strong influence over the media he owns (more on the Fox News effect here). Comcast owns NBC and the Xfinity cable system as well the MSNBC cable channel has a known liberal bias. These arguments intensified when it is revealed that both parties receive donations from these same organizations.

On February 17, 2017, our President tweeted “The FAKE NEWS media (failing @nytimes, @NBCNews, @ABC, @CBS, @CNN) is not my enemy, it is the enemy of the American People!”

The hope is that by our President calling attention to media bias (even though how he is doing it is twisted and self-serving) our citizens will recognize the undue influence of the outlets and begin to understand that they are being manipulated by one-sided propaganda.

4.     We will have a better understanding of the weaknesses in our systems

Yes, partisan elected officials should not be in charge of the election administration process… yes, money has had a very corruptive influence on our Capitalism (see Citizens United)… yes, granting 2 senators from a rural state such as Wyoming (population 580,000 ) the same representation as California (home to 39 million) makes no sense—this list goes on and on… However, this is not the issue!  The risk to democracy occurs when: “A nationalist leader gets elected by playing on public fears and anxieties, then uses the election as a hijacking tool by asserting a democratic mandate to centralize power by controlling or undermining pluralist institutions that stand in the way – a free media, an independent judiciary, a diverse civil society, civil liberties, and minority rights.  What’s left is the shell of democracy.” “He’s [our current President] labeled journalists “enemies of the people” and assaulted the mainstream media as purveyors of fake news.  He’s challenged the independence of the judiciary and smeared the integrity of judges.  He’s attacked civil society by claiming massive voter fraud, challenging the voting rights of millions of Americans, and discounting minority voters by supporting the gerrymandering of their election districts.  And he’s abused the power of the presidency by putting pressure on the FBI Director to drop an investigation of a former Trump White House official, then firing the Director for investigating whether the Trump campaign colluded with Russia to influence the Presidential election.” – HumanityInAction.ogr

If you don’t believe in the President, then believe in the system! Our Constitution divided the Government into three branches: legislative, executive, and judicial for something called checks and balances to make sure no one branch would be able to control too much power and to guard against tyranny. “If men were angels, no government would be necessary,” “In framing a government which is to be administered by men over men, the great difficulty is this: You must first enable the government to control the governed; and in the next place, oblige it to control itself.” — James Madison, The Federalist Papers

The hope is that we learn where our system is vulnerable and legislate fixes to strengthen our democracy.

5.     We will have a better understanding of the weaknesses in our society (Technology & Globalism)

Technology: Google, Facebook, and Twitter threaten our democracy by being abused and if left unchecked will continue to be used for political corruption.  These social media & search giants are beginning to understand their roles, but they are public companies that are driven by profitability and will always have their shareholders as their top priority. The hope is that we now understand these issues and take a thoughtful approach to new legislation.

Globalism has had both a positive and a negative impact.  Positive for corporations (and in turn employees) and negative for those displaced by the change.  Countries like China and India benefit where the US, UK, and EU may not—hence populism is taking hold across all those geographies.  China transformed peasant farmers into low-cost manufacturing workers, thereby reducing poverty but those jobs were at the cost of jobs in America’s Rust Belt.  India and western Europe’s $15/hour accounting, customer service, and technical skills replaced white-collar American workers earning $50+/hour.  These issues had a lot to do with the election of this President and can no longer be ignored–The hope is that we never again neglect these issues.

“All the great things are simple, and many can be expressed in a single word: freedom, justice, honor, duty, mercy, hope.” – Winston Churchill

Whether you are left or right leaning, respect our President or do not… Have hope, understand the bias and its motivations, respect others, know your facts and get involved!