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!

Potholes…

Warning: This is a long article so if you have ingested cannabis recently you may not make it through to the end. 😉 Come back after you sustain for at least 24 hours.  Reference: “Attention, memory and learning are impaired among heavy marijuana users, even after users discontinued its use for at least 24 hours”- “The Residual Cognitive Effects of Heavy Marijuana Use in College Students,” Pope, HG Jr., Yurgelun-Todd, D., Biological Psychiatry Laboratory, McLean Hospital, Belmont, MA

I put these notes together because the topic of cannabis is coming up at holiday parties and in discussions with friends and family.  I personally want to be knowledgeable on the subject because we live in Washington DC where cannabis use has been decriminalized.  I walk in the morning each day and see many people openly using it as I stroll along the waterfront–I have no issue with this, but I do take issue with users NOT having all the information about the impact of cannabis on their health (especially people under 25–more below).  I also think that there is a lot of confirmation bias occurring as I discuss the subject with others.

Let’s start with the confirmation bias by reviewing something similar from 1991 when 60 Minutes ran a story about the potential benefits Americans could potentially get from drinking more red wine.  Morley Safer stated that “the (French) farmers have been eating a very high-fat diet, it seems, and yet they don’t get heart disease,” “the explanation of the paradox, may lie in this inviting glass” – and demand for red wine spiked!  –what did I do?  I loaded up on red wine.   Yet the American Heart Association reported that many of red wine’s benefits, including antioxidants and HDL, can be obtained through other fruits and vegetables and no “direct comparison trials” had been conducted “to determine the specific effect of wine or other alcohol on the risk of developing heart disease or stroke.”  Why do I bring this up? Simply to help you understand ‘confirmation bias’– the tendency to search for, interpret, favor, and recall information in a way that confirms one’s preexisting beliefs or hypotheses.  People tend to interpret ambiguous evidence as supporting their existing position.  The effect is stronger for emotionally charged issues (politics, alcohol, and weed) and for deeply entrenched beliefs especially if you are personally involved.  I believe this same thing is happening with cannabis and many people are ignoring the issues and, more importantly, the ‘known’ unknowns!

So what facts do most people know… what facts may they not know… and what is currently unknown (or what do we know that we don’t know–the ‘known’ unknowns)?

Let’s review the facts that most people DO know

The main psychoactive part of cannabis is tetrahydrocannabinol (THC), a chemical compound known as a cannabinoid, which is one of 483 known compounds in the plant, including at least 65 other known cannabinoids (but there might be up to 113). Cannabidiol (CBD) is the second most referred to cannabinoid.  CBD is generally known as the cannabinoid that does not have intoxicating effects like those caused by THC and may have an opposing effect on disordered thinking and anxiety produced by THC.  

There are 3 species of cannabis: SativaIndica, and Ruderalis. Sativa is widely accepted as being indigenous to Central Asia, Indica may have originated from the Hindu Kush mountain range and Ruderalis is native to central and Eastern Europe and Russia. Indica strains generally provide a sense of deep body relaxation. Sativa strains tend to provide a more energizing experience and the effects of Ruderalis are minimized by its naturally low concentrations of THC.  Note that how Indica & Sativa make users feel has not been scientifically proven. Ruderalis is attractive to breeders because of its auto-flowering trait.  When medical cannabis dispensaries promote their products, they will report both the amount of THC/CBD and the strain I=Indica, S=Sativa and H=Hybrid of the 2 other strains. Usually, they will also report the symptoms and conditions as seen in the figure.

Beyond cannabinoids, cannabis also contains “Terpenes” the fragrant oils that give cannabis its aromatic diversity (berries, fuel, Lavender etc.). These oils are secreted in the flower’s sticky resin glands. Terpenes are by no means unique to cannabis; they can be found in many other herbs, fruits, and plants as well. Like cannabinoids, terpenes bind to receptors in the brain and give rise to various effects. Different harvests may demonstrate dramatically different terpenoid profiles due to variances in growing and curing techniques. Myrcene is the most abundant terpene in cannabis, which is where it’s mostly found in nature. It can make up as much as 65% of total terpene profile in some strains. Limonene is the second most abundant terpene in all cannabis strains, but not all strains necessarily have it. Linalool is the most responsible for the recognizable cannabis smell with its spicy and floral notes. Caryophyllene has a spicy and peppery note. Alpha-pinene and Beta-pinene smell like pine trees. Alpha-bisabolol has a pleasant floral aroma. … and there are many more Eucalyptol, Trans-nerolido, Humulene, Delta 3 Carene, Camphene, Borneol, Terpineol, Valencene, and Geraniol.

As of November 2018, 33 states and the District of Columbia have broadly legalized cannabis for recreational (The District of Columbia, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington) or medical use under certain circumstances.

Many state politicians are moving to legalize cannabis because:

  • Their constituents (funders and voters) are pushing for it (62% of voters want Cannabis legalized)
  • The tax revenues are sorely needed by the state governments (Study: Legal cannabis could generate more than $132 billion in federal tax revenue and  1 million jobs)
  • There are too many people incarcerated for cannabis possession costing taxpayers a fortune (Stats: Number of people arrested in the USA for a cannabis law violation in 2017: 659,700; Number of those charged with cannabis law violations who were arrested for possession only: 599,282 (90.8%); Cost’s taxpayer ~$15.9 Billion/year).
  • Having a safe source of cannabis that’s not contaminated with pesticides or laced potentially with other drugs will save lives.

Several medical benefits have been proven:

  • In June 2018, the food and Drug Administration (FDA) approved the use of a medication containing cannabidiol (CBD) to treat two rare, severe, and specific types of epilepsy — called Lennox-Gastaut syndrome and Dravet syndrome — that are difficult to control with other types of medication. This CBD-based drug is known as Epidiolex. A study published in 2017 found that the use of CBD resulted in far fewer seizures among children with Dravet syndrome, compared with a placebo.
  • Evidence suggests that oral cannabinoids are effective against nausea and vomiting caused by chemotherapy, and some small studies have found that smoked cannabis may also help to alleviate these symptoms.
  • Evidence to date suggests that cannabis could help to treat some mental health conditions. Its authors found some evidence supporting the use of cannabis to relieve depression and post-traumatic stress disorder symptoms. That being said, they caution that cannabis is not an appropriate treatment for some other mental health conditions, such as bipolar disorder and psychosis.
  • Another comprehensive review of the evidence, published last year in the journal Clinical Psychology Review, revealed that using cannabis may help people with alcohol or opioid dependencies to fight their addictions. But this finding may be contentious; the National Academies of Sciences review suggests that cannabis use actually drives increased risk for abuse, and becoming dependent on, other substances.
  • review from the National Academies of Sciences, Engineering, and Medicine assessed more than 10,000 scientific studies on the medical benefits and adverse effects of cannabis. One area that the report looked closely at was the use of medical cannabis to treat chronic pain.

A lot of people with “Doctor” in their titles say there is “evidence” that cannabis has a lot of positive medical benefits.   Websites are reporting benefits such as weight loss, prevent diabetes, fight cancer, treat autism, heal broken bones, treat ADHD, slow Alzheimer’s disease, treat STDs, help OCD, improve skin, replace viagra, lower blood pressure etc…  I’m not saying these items are not true–they are just NOT proven like Safer’s red wine story above.

And finally, many people are medicating, self-medicating or just enjoying cannabis.  (USA: 22.2 million, International: 158.8 million)

What most people DON’T know?

There has NOT been a lot of research—Why? We know a lot about how alcohol impacts the body because researchers have been doing studies for years (more).  But we don’t know more about the impact of cannabis on the body primarily because the U.S. Drug Enforcement Administration (DEA) considers cannabis a Schedule I drug, the same as heroin, LSD, and ecstasy, and likely to be abused and lacking in medical value. Because of that, researchers need a special license to study it.   Hopefully, this turns around soon given Sen. Chuck Grassley (R-IA), a longtime ardent cannabis legalization opponent, is stepping down as chair of the Senate Judiciary Committee potentially paving a path forward for cannabis legislation in the 116th Congress and Sen. Lindsey Graham (R-SC) is taking over.  Graham is significantly more open-minded about medical cannabis and other common-sense reform measures than the current chairman is. Grassley refused to let any cannabis bills come to a vote as Judiciary chairman, Graham has cosponsored of legislation to protect legal medical states from federal interference, supported the reschedule of cannabis and supported the removal of cannabidiol (CBD) from the list of federally banned substances.

How cannabis impacts the brain. Cannabis acts on the body’s endocannabinoid system. Great video here. A great scientific description of cannabinoids here and here. We have cannabinoid receptors all over the brain and endocannabinoids are released naturally by the body to perform certain functions. For example, the hypothalamus releases them to stimulate appetite.  Guess what?  THC (tetrahydrocannabinol) also binds to these receptors—ever hear of the ‘munchies’?  The cannabinoid receptors are special receptors within the endocannabinoid system in the brain. The cannabinoid THC molecule activates particular cannabinoid receptors. These receptors, called CB1 and CB2 (there may be many others found in the future), work like a lock and key when flooded with cannabinoids after a user ingests cannabis.  CB1 receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus and the striatum. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brainstem responsible for respiratory and cardiovascular functions (likely why you can’t overdose easily on cannabis). CB1 is also found in the human anterior eye and retina. CB2 receptors are predominantly found in the immune system or immune-derived cells with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.  Cannabinoid receptors are activated by three major groups of ligands (a molecule that binds to another molecule) endocannabinoids, produced from within the body, synthetic cannabinoids (such as HU-210),  and plant cannabinoids (such as CBD & THC).

There are potentially big negative impacts

  • Cannabis can be addictive to some people  The ‘dependence’ scenario is known as a Cannabis Use Disorder. The definition is that you’ve become dependent on it psychologically, or physiologically. About 9% of cannabis users become addicted to it. Cannabis Use Disorder in school often causes a dramatic drop in grades, truancy, and reduced interest in sports and other school activities. In adults, this disorder often is associated with work impairment, unemployment, lower income, welfare dependence, and impaired social functioning. Higher executive functioning is impaired in Cannabis Use Disorder which contributes to school and work impairment. This disorder also significantly decreases motivation at school or work. There is an increased risk of accidents while driving, at sports or at work.
  • Overdose is not likely but you can end up in the hospital… Cannabis is not in the same category as opioids that cause respiratory depression and stop breathing but it can cause hyperemesis (continuous vomiting) and increase a user’s blood pressure significantly. It can cause a user to feel paranoid and get acute psychosis and a small percentage of people may develop a long-term illness but much more research is needed.
  • It has a bigger impact on a young persons (under 25) brain. Jodi Gilman published research on 18-to-25-year-olds that showed differences in the brain’s reward system between users and non-users.  Gilman has also concluded (research) there is evidence that cannabis use, especially when initiated at a young age, (perhaps due to the effects of delta-9- tetrahydrocannabinol on cannabinoid (CB1) receptors in the brain) may be associated with worse verbal memory and altered neural development. Gilman is also reported that young adults with early-onset cannabis use had learning weaknesses and delayed recall.
  • Chronic bronchitis. There is substantial evidence of an association between long-term cannabis smoking and an increase in the frequency of episodes of chronic bronchitis. (see NASEM report referenced below)
  • Vehicle crashes. There is substantial evidence of an association between smoking cannabis and an increased risk of motor vehicle crashes. (see NASEM report referenced below)
  • Low birth rate. There is substantial evidence of an association between maternal cannabis smoking and low birth weight. (see NASEM report referenced below)
  • Schizophrenia and other psychoses. There is substantial evidence of an association between smoking cannabis and developing schizophrenia and other psychoses. The most frequent users are at the highest risk. (see NASEM report referenced below)

What is yet to be known?

We don’t fully understand the endocannabinoid system and how it is involved in certain functions (like psychosis, schizophrenia, and anxiety).  We don’t know why the response to cannabis varies so much across people. For example, some people report getting paranoid when they use cannabis and others report that it helps with anxiety.  Why?  We do know that some people have imbalances in their endocannabinoid system (under/overproduction of natural cannabinoids) in certain conditions but we don’t know exactly why.

We don’t understand what makes one user feel one way or another.  Just saying Indica is relaxing and Sativa is a stimulant is not accurate and has never been scientifically proven.  Many researchers believe that the different and diverse effects of cannabis are derived not from the genus, but from the Cannabinoids and Terpenoids produced by the plant as it grows as well as the user’s specific endocannabinoid system at the time of use.

We don’t know how to dose cannabis or how best to ingest the drug. We don’t know the appropriate doses for an individual’s physiology, or how best to take it (smoke it or use an edible).  Most medical cannabis prescriptions just get users into the dispensary but don’t say exactly what to buy and how much to take–try that at the CVS pharmacy…

We don’t know if cannabis impacts a users’ short-term memory, mood control, attention, and motivation. We know cannabis affects the hippocampus (the part of the brain that stores memories) and empirical evidence show that it may impact the ability to recall and retain information in the short term and it makes it hard to remember things, but this research is just starting.

We don’t know a lot about the impact of cannabis on the young brain. The brain is more susceptible to permanent effects of drugs if you’re younger (under 25) but in regard to cannabis is it how early it started, how frequently it’s used, the higher the dose and how bad is the impact? Unknown…  According to Krista Lisdahl, an associate professor of psychology and director of the Brain Imaging and Neuropsychology Lab at the University of Wisconsin at Milwaukee–In studies of those chronic, heavy users, “we see cannabis users have slower processing speed, worse memory and learning scores on certain tests, poorer sustained attention,”. There are also links to depression and sleep problems in some of those users, and some heavy users show brain changes linked to poorer emotional control or memory. These changes have been particularly observed in people who began using cannabis before ages 16 or 17. (more here).

We don’t know how genes play a role Scientists have identified genes that increase susceptibility, but there may be others and we are just at the beginning of understanding that.     

We know very little about the interaction of cannabis with other drugs. The Mayo Clinic lists the following ‘possible’ drug interactions: Alcohol, Anticoagulants and anti-platelet drugs, herbs and supplements. CNS depressants, Protease inhibitors, Selective serotonin reuptake inhibitors… However very little is known.

We don’t know much about each of the cannabinoids (see appendix). Per Ryan Vandrey, an associate professor of psychiatry who researches cannabis at Johns Hopkins Medicine “We know a lot about THC and we’re starting to learn about CBD”  “Out of about 400 [compounds] we know a decent amount about two.” The unknowns about what various cannabinoids do and how they interact with each other create plenty of questions about the best ways to use medical cannabis. That means there’s a lot to learn about which compounds might contribute to psychoactive effects and which might potentially have medical uses.

The National Academies of Sciences, Engineering, and Medicine (NASEM) has released a thorough report that answers what claims are well-grounded and what claims are not. The report is based on more than 10,700 abstracts of papers published in peer-reviewed journals since 1999. Download here.

These notes are not about legalization—in fact, legalization is good (especially at the federal level) if it allows scientists to better understand cannabis and its impact on the brain.  These notes are about understanding what is known and what is unknown so you can make a reasonable decision on your own personal use now that cannabis is being decriminalized across the country. You don’t want to be one of those people that said—no one told me that smoking tobacco caused cancer.  Especially when scientists suspected it as far back as 1898.  Remember science blunted the power of the tobacco industry and prevented nearly 800,000 cancer deaths in the United States between 1975 and 2000. 

Please keep in mind that there are a number of moving parts in the cannabis equation.  There are the cannabis cannabinoids (science has only really studied 2 out of the >100 that may exist), the cannabis terpenes (>100 most not studied in regards to impact on health), how the cannabis is ingested (smoked, edible), how much cannabis is ingested (mg), your cannabinoid receptors (we know of 2 but think there are more), your endocannabinoid system (not well understood by science yet it is believed to regulate and balance things like nerve functions, stress recovery, inflammation levels, immune function, energy intake and storage, cell life and the circulatory system), and your specific DNA–not to mention interaction with other things you have taken.  So don’t say “people have been smoking it for 100’s of years”, “I like to get high and it’s not having an impact on me”, “It’s healthier than drinking” without understanding that you are getting involved with a very complex drug that is not well understood.

If you are going to use cannabis know your facts and stay up on the science or risk being one of the “No one told me cannabis caused…” of the future.

Stay up to date on cannabis research by leveraging the NIH.gov site.

  

  

  

Appendix 1: Here is a list of the most well known cannabinoids:

Cannabichromenes
        Cannabichromene (CBC) – non-psychoactive and does not affect the psychoactivity of THC. CBC has shown antitumor effects in breast cancer xenoplants in mice. More common in tropical cannabis varieties.
        Cannabichromenic acid (CBCA)
        Cannabichromevarin (CBCV)
        Cannabichromevarinic acid (CBCVA)
Cannabicyclols
        Cannabicyclol (CBL)
        Cannabicyclolic acid (CBLA)
        Cannabicyclovarin (CBLV)
Cannabidiols
        Cannabidiol (CBD) – CBD does not have intoxicating effects like those caused by THC, and may have an opposing effect on disordered thinking and anxiety produced by THC. Cannabidiol has very low affinity for the cannabinoid CB1 and CB2 receptors but is said to act as an indirect antagonist (blocks or dampens a biological response) of these receptors. At the same time, it may potentiate the effects of THC by increasing CB1 receptor density or through another CB1 receptor-related mechanism.
        Cannabidiol monomethylether (CBDM)
        Cannabidiolic acid (CBDA)
        Cannabidiorcol (CBD-C1)
        Cannabidivarin (CBDV) – usually a minor constituent of the cannabinoid profile, enhanced levels of CBDV have been reported in feral cannabis plants from the northwest Himalayas, and in hashish from Nepal.
        Cannabidivarinic acid (CBDVA)
Cannabielsoins
        Cannabielsoic acid B (CBEA-B)
        Cannabielsoin (CBE)
        Cannabielsoin acid A (CBEA-A)
Cannabigerols
        Cannabigerol (CBG) – is non-psychoactive but still contributes to the overall effects of Cannabis. CBG has been shown to promote apoptosis in cancer cells and inhibit tumor growth in mice. It acts as an α2-adrenergic receptor agonist, 5-HT1A receptor antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.
        Cannabigerol monomethylether (CBGM)
        Cannabigerolic acid (CBGA)
        Cannabigerolic acid monomethylether (CBGAM)
        Cannabigerovarin (CBGV)
        Cannabigerovarinic acid (CBGVA)
Cannabinols and cannabinodiols
        Cannabinodiol (CBND)
        Cannabinodivarin (CBVD)
        Cannabinol (CBN) – the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB2 receptor is higher than for the CB1 receptor.
        Cannabinol methylether (CBNM)
        Cannabinol-C2 (CBN-C2)
        Cannabinol-C4 (CBN-C4)
        Cannabinolic acid (CBNA)
        Cannabiorcool (CBN-C1)
        Cannabivarin (CBV)
Cannabitriols
        10-Ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol
        8,9-Dihydroxy-delta-6a-tetrahydrocannabinol
        Cannabitriol (CBT)
        Cannabitriolvarin (CBTV)
Delta-8-tetrahydrocannabinols
        Delta-8-tetrahydrocannabinol (Δ8-THC) – The principal psychoactive constituent of cannabis
        Delta-8-tetrahydrocannabinolic acid (Δ8-THCA)
Delta-9-tetrahydrocannabinols
        Delta-9-tetrahydrocannabinol (THC)
        Delta-9-tetrahydrocannabinol-C4 (THC-C4)
        Delta-9-tetrahydrocannabinolic acid A (THCA-A)
        Delta-9-tetrahydrocannabinolic acid B (THCA-B)
        Delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4)
        Delta-9-tetrahydrocannabiorcol (THC-C1)
        Delta-9-tetrahydrocannabiorcolic acid (THCA-C1)
        Delta-9-tetrahydrocannabivarin (THCV) – prevalent in certain central Asian and southern African strains of Cannabis. It is an antagonist of THC at CB1 receptors and lessens the psychoactive effects of THC.
        Delta-9-tetrahydrocannabivarinic acid (THCVA)
Miscellaneous cannabinoids
        10-Oxo-delta-6a-tetrahydrocannabinol (OTHC)
        Cannabichromanon (CBCF)
        Cannabifuran (CBF)
        Cannabiglendol
        Cannabiripsol (CBR)
        Cannbicitran (CBT)
        Dehydrocannabifuran (DCBF)
        Delta-9-cis-tetrahydrocannabinol (cis-THC)
        Tryhydroxy-delta-9-tetrahydrocannabinol (triOH-THC)
        3,4,5,6-Tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol

Your First 30 Days As CEO

Congratulations!  You have been brought in by investors to repair or scale a struggling tech company.  The investors still believe in the company and need an experienced operator to right the ship.

The investors likely brought you in because either the company is shrinking or not growing (see Figure 1 for likely scenarios) and the investors have decided the problem was leadership. Or, perhaps the outgoing CEO was tired or didn’t have the skills for the next level of growth.

Figure 1: Turnaround Scenarios

Regardless, you now have the job so you better have done your homework before accepting the role.  You hopefully understand the financial situation, why the CEO departed, individual board members’ views of the company’s opportunity/risks/expectations and the ownership (cap table).  You should have also fully digested all available news, analyst research, competitive positioning, and GlassDoor feedback. Oh, and find the date of the next board meeting. After all, you do report to them.

Figure 2

Your job is to lead the company, find growth, scale the organization (In figure 2–move the company from A to B) and do a stupendous job communicating to all the stakeholders.

You need a 30-day plan.

But Be Careful.  You must learn quickly, but you don’t want to bring down the entire organization doing busy work as you come up to speed.  Be respectful of people’s time and leverage the finance team as much as possible versus customer-facing employees.  Realize that you are an unknown to the ecosystem; all people know about you is what is online. In other words, they will have judged you before they have ever met you.   Be careful not to undermine your new management team by going a couple levels down in the organization without their consent, and be careful not to engage in speculative discussions (spitballing half-baked ‘what if’ ideas) that could easily be misunderstood.  And above all else, in the first 30 days, provide no directives unless you are forced to, and then only move forward with the thoughtful involvement of your team.

Note: McKinsey wrote a great article about the time between accepting the CEO role and starting the job.  You can find it here.

First Step: Broadly communicate your vision of a better company

Help the employees understand why you took the job and your approach. It’s too early for specific plans however you should convey the values that you will use as a framework for making future decisions. Be clear about your management style so everyone is not wasting energy trying to figure out how to please you.

Here is an example of Dara Khosrowshahi’s first message to employees at UBER.

Second Step: Get your team together

Face to face is best (because you want to take a temperature of the team dynamic) but if you are geographically dispersed then make the best of it.  Go around the room (or call) and ask the team to speak to the following in 5 minutes or less:

  • Introduce themselves (how long they have been at the company and something personal like what they enjoy doing in their free time).
  • The top 3 things they must get done in the next 30 days and who on the leadership team they are working with on the task- no detailed explanation for each or discussion (only clarifications if necessary).
  • Something they want to know about you.

You should go last and provide as many answers to their ‘something to know about you’ questions as possible and then explain how you will proceed with your next 30 days of learning.   Your goal is to get introduced to the team dynamics, understand some of the cultural norms and help lay some groundwork so they understand how you think and what the next few weeks are going to look like.  You might also find that there are a couple of surprises hidden in the team’s top 3 priorities that you need to understand more clearly in a 1-on-1 discussion.

Third Step: Schedule 1-on-1’s

Start collecting data ASAP. Start with your management team, then meet with as many individual sales representatives as possible as they will have the best understanding of the market, then meet a minimum of 10 customers and partners (see the ‘be careful’ section above…).   Try to get a true idea of the culture –not just what you read on https://glassdoor.com.  The culture is made up of all the stories employees, customers and partners talk about when you’re not around–so it takes time to understand.

Be consistent with the questions you ask–Here are some suggestions:

The remaining steps are in no particular order.  Your goal is to get enough information to begin to understand the culture, the people, the customers, the partners, the issues, the opportunities, and the risks.

— “Once the information is in the 40 to 70 range, go with your gut.” – Colin Powell

Finance: Dig into the financials and the KPIs

Go over all the standard financials (Income statement, balance sheet, P&L, budget, forecast etc.) in detail looking for anything that does not meet the standard KPIs. 

  • For Software as a Service (SaaS) businesses leverage all the well-known metrics and KPI’s (CAC, LTV, MRR, Churn etc..)–you can find all the metrics and KPIs here.  Specifically look for any KPI’s that are out of range such as a low LTV to CAC ratio (LTV should be >3x CAC) or when months to recover CAC < 12….  Great site for deep dive on SaaS financials here.
  • For traditional businesses leverage old school KPI’s found here.

Finance: Go deep on expenses

Review 20% of the expenses that make up 80% of the spend.   Tag each expense with its corresponding revenue impact and its significance as best you can… With an immature team, this may be difficult but give it a go.

Then chart out the expenses and prioritize quadrant’s A and B so you know what the team can cut if they either needed to invest in something more important OR had to ensure a minimum of 2 months of working capital available for payroll.

Finance/Sales: Go deep on current contracts

Look at the 20% of the contracts that equate to 80% of the revenues.  Dig into as many as possible and look at their profitability, % of business, terms, risks, upside and most important their significance to the company.

Chart the contracts out so you can visually see how they map to the organization.

Contracts in Quadrant A you should understand the issues and determine if there is any way to renegotiate.  Quadrant B – How can we get the cost down ‘per account’? Quadrant C – How can we get the cost down ‘overall’.  Quadrant D – Ask: How do we do more of these?

Finance: Go deep on AR and AP

Accounts Receivables (AR) and Accounts Payables (AP) – You want to ensure you understand any large outstanding receivables or payables that are behind and could impact near-term cash flow.

Finance: Break up the P&L

Break out the natural categories of a P&L and look into the company’s performance per sector, per vertical, per product/service.   If professional services are sold break out into separate P&L (more).  You need to understand where the company is financially strong and where they are struggling. 

Finance: Budget vs. Actuals

You need to figure out the budget process and how well the team has done. Are they always behind budget? are they always exceeding? Or are they on target?  Each result tells you something different.

Finance: Understand banking, legal, accounting, tax and insurance relationships

These third parties should be consultants to the company–you need to gauge if they are being used in this way.

Sales: Do a pipeline review

…of each appropriate segment (example: Enterprise versus Small & Medium Business (SMB))

For the Enterprise segment you want to figure out how well the team understands their customers’ business, the competition, how tight of a solution sales process exists and to get a general sense of the potential of the organization.

Try to review the top 80% of the revenue opportunity by account representative.  If possible also look at history (closes since start) to see how well they have done for the company and what types of discounts are being applied.  Comparing that history to the current velocity/deal revenue is also key.

Dig into the deal dynamics and see if the team understands (Pain) i.e. what is making the customer buy? (Power) How well does the rep know the person empowered to write a check?  If the deal is 40% or higher do they have a written commitment in email? (Vision) How well the rep knows how our solution would fix the problem and by when. (Value) Does the rep know how much our solution would this save (or make) the customer? (Control) What are the next steps w/dates? …and if the company is using Solution Selling read a few of the ‘Sponsor Letters’ & ‘Evaluation Plans

For the SMB segment, look more at velocity and the process surrounding the business.  Compare the rep history to the pipeline.  Spot check a few of the bigger deals.  Understand the link between marketing and the SMB sales team–are there any gaps (example: when a prospect fills out a form how long before an action).  Understand the automation, the CRM and all the tools surrounding the process.

For channel deals you want to understand the registration process (if one exists) and how well the channel opportunities are managed and if there is ever any negative competition between the channel and the sales teams.  Compare the history to the current deals and stack rank the top partners to ensure you know who they are and setup exec to exec meetings as soon as possible.

Sales: Pipeline Post Mortem

Identify why we are losing/winning and find the trends… Understand customer churn. Understand the number of deals (and revenues) we lost in the past 12 months and why.  Understand who (competitor) we are losing to (or winning against) consistently.

Marketing: Conduct a simple Customer, Employee, and Partner anonymous satisfaction survey

Have your marketing team pull together 3 quick surveys using Google Survey or another tool like SurveyMonkey.  Add your own personalized message to each of the outgoing messages introducing yourself.

If the company already does these surveys that is a great sign.  If so, there is no reason repeat these surveys just dig into the feedback AND also understand how the feedback is incorporated into leadership/management strategy, product planning and HR/Sales/Marketing/Support process changes.

Marketing: Marketing Review (Product, Place, Promotion, and Price)

It will take time to learn how well your marketing team is managing the website, the social networking presence, event marketing, landing pages, and paid advertising. However, it is always eye-opening to find the gaps in the data (“we don’t track that…”).

Find out how traffic is getting to your website and what is it costing the company:

Understand the social networking activity:

Understand how much events are costing the company and how the team is tracking success:

Understand Google/Bing ad spend and ROI:

Understand what landing pages are the most successful and why:

Sales/Product/Marketing: Understand the market

Understanding the Total Addressable Market (TAM) is key to any business.

Here is an example of how one group measured how many companies in the USA were potential targets (dark blue) based on employee count and vertical industry–just using US Census data.

Sales/Product/Marketing: Understand the competition

Read everything you can about your competitors.  If you can afford Gartner research buy it…  You need know your enemy.

Know your strengths and weaknesses: if you know the enemy and know yourself, you need not fear the result of a hundred battles. –Sun Tzu “The Art of War”

Product: Product Review

Learn as much about the product(s) as you can… Take training, use the product(s), read any patents etc… There is no need to be an expert, but you should understand the nuances of what your customers are purchasing, complaining about and why.

You need to also understand the product development and DevOps processes as they currently exist (high level).  What tools (Atlassian, Jenkins, Kubernetes, Docker etc…), what hosting providers (AWS, Azure, Google etc..), what languages (C, golang, etc..), what third-party services are integrated into the solution (CRM, Database, OpenSource projects etc..).

Assuming the team leverages Agile (if not, you need to dig into why) you should understand the sprint cycle (1 week, 2 weeks etc.), burndown, and velocity.  Does the team use LEAN startup practices such as the MVP concept?

You should understand how well the team is performing Agile (how long are standups, are they documented, how retrospectives are done, does the team use business value points). You should also get a view on how well the team is doing continuous delivery and if they are measuring items such as ‘Commit to Deploy’ metrics.  It’s important to also understand how the team manages with defects and bugs.

Finally, if some of the team is offshore, or part of a third party, it’s important to dig into how well those groups are integrated into the teams to get a sense of productivity.

Product: Review Product Backlog with Product Owner

Now that you understand the product, go deep on what the Product team is working on and why.  Try to get insight on how well the plan correlates to the market needs. If the team is using Story (Business) Value points validate these with what you are learning from the rest of the team and from customers (If not, then clearly understand how they are prioritizing the market needs as this is SUPER critical for success).

Support/Product/Sales: Review Customer Support Issues

Customer support excellence can be the key to customer renewals, product backlog prioritization and upsell/cross-sell sales if used appropriately. Dig into the issues, the timeliness and quality of resolution and understand how those issues are used in the organization.

“Your most unhappy customers are your greatest source of learning.”  — Bill Gates

Human Resources: Understand Employee Performance and Rewards

Your Human Resources team should be able to provide you a list of roles in the company and their compensation bands and then a list of employees for each role with their date of last performance review (and rating)–if not, you have more work to do…   You’re looking for how mature the HR processes are… How people are rewarded… Are you paying market rates… and most importantly turnover rates.

Human Resources: Understand Recruiting

Hiring qualified employees is hard and hiring the best is difficult.  Hiring the best is going to be key to future performance gains.  How well is your team set up to hire the best?

Human Resources: Understand HR Policies and Procedures

Review the employee handbook and all policies and procedures.  Some examples: Logical access policies, Incident response plan, disaster recovery plan.  If the organization is SOC 2 certified review the audits.

All Teams: Understand the risks

Risk management is something that must be done continually.  Doing it well can be the key to success if you need to make a quick pivot in the future.  If the team is not doing this already you need to add it to your 60 to 90 days list.

You: Report card

After 30 days you’ve learned a great deal and hopefully formed some opinions about the people, processes, and product(s).   It’s a good idea to record it all on a report card–not to be shared but to refer back to periodically and reflect.  Write down why you rated each group the way you did as it will be helpful to use this as you continue your journey.

Now it’s time to lead! You and your team now have to determine what actions are required to grow the business.

Reference the figure below–You’ve likely been brought into the company in the ‘production stage’ either in A (the company has not achieved Product-Market Fit and is surviving on Professional Services revenues or Other People’s Money) or in B (the company has reached Product Market Fit and it’s time to tune the organization for growth).   Likely it’s going to be somewhere in between, however, the key is to now have a good idea on where to focus your energy for the next 60 days because you can’t do everything (A. Innovation management and Product/Program management or B. Leadership and Sales/Marketing management).

–“People… Process… Product…” — The Profit

It’s easy to be overwhelmed at this point–the business is going to start coming at you fast.  Customers, prospects, managers, partners, analysts, board members, bankers, attorneys etc… will all want a piece of your time.   The issues at hand will require time… Scheduled event and meetings will require your time.  Your job–not to become reactive to the demands on your time (remember the ‘Big Rocks’ story from Stephen Covey?)–project manage your schedule to where you continually reprioritize the demands on your time and STAY PROACTIVE.  Remember, you have a job to do and that is to ignite growth in a company that has not been growing–that means doing something different and if you become reactive to these demands you will become part of the problem. I’d recommend 2 actions now–Schedule a leadership team offsite and get into the right frame of mind by re-reading that old book on your shelf called The Five Dysfunctions of a Team.  You’re also going to feel like diving right in and starting to provide guidance and poking harder at the items you rated low in your report card–just recognize how disempowering this may seem to the team.   You have to get your hands dirty–that’s required but at this point in your journey, you need to lead vs. manage. The next 60 days are going to be difficult.  You may need to tighten up the people, processes, and temperament of your leadership team.  You and the team will need to determine what to prioritize and de-prioritize… and then change management comes with its own cultural challenges.

A preliminary view of the next 60 days in the role…

  • Communicate with the board – As you develop your boardroom relationships, you must view the directors as neither friends nor confidants, but as bosses who hold you personally accountable for the success of the company. By actively investing in director knowledge and relationships—through one-on-one contacts, e-mail updates of corporate progress, and distribution of background material, for example—the best CEOs turn board meetings into participatory discussions rather than show-and-tell sessions by management. A new CEO who is open with—and creates the opportunity to collaborate with—their directors will be more likely to garner support from these bosses. – HBR 
  • Help your managers understand your expectations in regards to ‘leadership’.  If Management is about systems, processes, policies and resources and Leadership is about vision, inspiration, values, and people then the basic premise is that ‘Leaders deal with management shortfalls’. Basically, leadership is required when the systems & process do not work…. Leadership is required when the policies are not applicable or do not exist… Leadership is required when there are not enough resources to accomplish the task… (more)

“You are entirely responsible. It all comes down to you.” Extreme Ownership

  • Begin to introduce your team to strategic planning (if necessary)

You will quickly begin to understand how well the troops understand what the company’s Vision and Mission are and if it means anything to them (example: Microsoft’s Vision/Mission is “We believe in what people make possible. Our mission is to empower every person and every organization on the planet to achieve more.”). You will also quickly find out how well the teams know the goals they are trying to achieve, their strategy for achieving the goals, and how they are measuring success toward those goals.  If you find gaps up and down the chain it may be time to do a bit of work on your strategic plan.

  • Begin to introduce your team to innovation planning (if necessary) — Perhaps leverage Blue Ocean Strategy

If you find that the company is competing head to head with others and losing share it may be time to look at creating uncontested market space that can create new demand or break the value-cost tradeoff.

  • Depending on where your team scores on the report card it may be time to begin to introduce a new way to approach the business.  Here are some of my favorite tools:
  • Introduce your team to SCRUM (not just the product team)
 

Good luck, I can’t wait to see you ringing the NASDAQ bell someday soon!

Other articles you may find of value:

  • AN ACTION PLAN FOR NEW CEOS DURING THE FIRST 100 DAYS (here)
  • Now you’re in charge: the first 100 days (here)
  • Five Myths of a CEO’s First 100 Days (here
  • Assuming Leadership: The First 100 Days (here)

Where are the bloody entrepreneurs?

For many years’ scientists have researched Parabiosis (transfusing young blood into aging animals) to bring stem cells throughout the body back to life, helping to heal damage, replace cells, and increase organ function. 

Medical overview found here.

Many interesting findings resulted from the research such as:

  • 2005: Thomas Rando’s (Stanford University) research showed that older tissue seemed to contain the same amount of stem cells as younger tissue. Rando swapped the blood of young and old mice. After five weeks, Rando found an astonishing reversal: The younger mice had started aging, their stem cells lagging and their muscles dragging. The older mice, however, were hyped up on new cells that made their livers youthful, their hearts stronger, and practically reversed aging.
  • 2013: Amy Wagers and Richard Lee found that a protein from the blood of young mice can reverse the symptoms of heart failure in older mice. They showed that the protein GDF 11 appeared to act on skeletal muscle stem cells and enhance muscle repair. (this study disagrees)
  • 2014: Researchers found that higher levels of the hormone oxytocin in young blood stimulate muscle growth. Factors in the blood also seem to stimulate stem cells in many organs to start dividing again. This in effect, brings stem cells throughout the body back to life, helping to heal damage, replace cells, and increase organ function.
  • 2014: Saul Villeda, Tony Wyss-Coray and their team found that exposing an old mouse to young blood can decrease apparent brain age. The effects were seen not only at the molecular level, but also in the structures of the brain, and in several measures of learning and memory. In this case, the effects were controlled by a specific protein in the brain known as Creb (cyclic AMP response binding element), although the stimulating factor in the blood was not identified.
  • 2016: Irina Conboy’s research team used a blood exchange technique between old and young mice, without surgically joining them. When they received old blood, the muscle strength of young mice decreased, and the growth of their brain cells slowed down. A protein known as B2M (beta-2-macroglobulin) may be involved in this process, although it does not appear to be elevated with age-possibly acted on by another signal from the older blood.
  • 2017: Hanadie Yousef at Stanford University identified a protein called VCAM1 that increases with age and causes signs of aging when injected into young mice.
  • 2017: (study) A protein in the brain, Tet2, declines with age, but mice whose brains have been given a boost of Tet2 are able to grow new brain cells and they improve at mouse-learning tasks.  Such a boost in Tet2 can be provided by the presence of young blood because in these experiments, old mice who are joined to young mice in a parabiosis have an increase in Tet2 in their brain.

So, if it works in mice, what about humans? This is a little trickier because of the lack of research, risks and, regulatory challenges that we will get into, but 2 companies are pioneers in the field:

  • Alkahest (http://www.alkahest.com ) – Tony Wyss-Coray (board member), a neurobiologist studying Alzheimer’s disease at Stanford University has done research where plasma from young donors (aged 18-30) was transfused into patients with dementia (results of a trial).  Alkahest announced in 2016 that it had used human teen blood, injected it into old mouse blood, and remarkably reversed aging. From tired, slow, and decrepit, the elderly mice suddenly had sharp memories, renewed cognition, and were exercising with the vigor of youth. “Wyss-Coray’s lab analyzed many of the 700 protein factors circulating in the blood to determine how such factors could affect stem cell function over time. They found that they could determine a person’s relative age by analyzing these factors.” (more).
  • Ambrosia Plasma (https://www.ambrosiaplasma.com) – Jesse Karmazin’s company Ambrosia is transfusing plasma from people aged 16-25 into people aged 35-92. They found that those who had been treated with young blood had lower levels of several proteins known to be involved in disease, namely carcinoembryonic antigens (which increase in cancer patients) and amyloid (which forms plaques in the brain in Alzheimer’s disease patients). Ambrosia transfuses plasma into patients for a ~8k price (here). Video (here)–From the video you can glean that this takes ~2 hours and they have found after 1 treatment a 20% reduction in amyloid (a starch like protein that is deposited in the liver, kidneys, spleen, or other tissues in certain disease) + lower cholesterol and lower inflammation biomarkers.  That being said, an update posted here reported that “…none of the results so far are either large enough or extensive enough to definitively be something other than the placebo effect, chance, or other items such as a patient making lifestyle changes”.

Beyond Wyss-Coray and Karmazin there are several others doing incredible research in this area.   Here are just a few and their referenced papers:

  • Conboy IM, Conboy MJ, Wagers AJ, et al. (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760-764.
  • Brack AS, Conboy MJ, Roy S, et al. (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 317:807-810.
  • Villeda SA, Luo J, Mosher KI, et al. (2011) The aging systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90-94.
  • Vileda SA, Wyss-Coray T (2013) The circulatory systemic environment as a modulator of neurogenesis in brain aging. Autoimmunity Reviews 12:674-677
  • Villeda SA, Plambeck KE, Middeldorp J, et al. (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine 20:659-663.
  • Smith LK, et al. (2015) Beta-2 microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nature Medicine 8:9320937
  • Kanya Honoki, (2017) Preventing aging with stem cell rejuvenation: Feasible or infeasible? NIH
  • Castellano JM, et al. (2017) Human umbilical plasma proteins revitalize hippocampal function in aged mice. Nature 544:488–492

So, if there is both proof and pioneers pushing the envelope why is not more being done given the importance of the subject? Basically, it comes down to the science is still not well understood however what is not apparent is why there seem to be very little dollars available for research.

You would also think that there would be more entrepreneurs pushing into this area given that it’s a classic marketplace problem that is well understood.   Find and pay young 20 somethings to donate blood/plasma (they need money) and then find wealthy 70 somethings to purchase the blood/plasma transfusions.   The lack of interest may be due to the risks such as:

  • Complications: Blood transfusions are generally considered safe, but there is some risk of complications. Mild complications and rarely severe ones can occur during the transfusion or several days or more after. Reactions include:
    • Allergic reaction – which might cause hives and itching, and fever.
    • Infections – Blood banks screen donors and test donated blood to reduce the risk of transfusion-related infections, so infections, such as HIV or hepatitis B or C, are extremely rare.
    • Acute immune hemolytic reaction – Your immune system attacks the transfused red blood cells because the donor blood type is not a good match. The attacked cells release a substance into your blood that harms your kidneys.
    • Delayed hemolytic reaction – Similar to an acute immune hemolytic reaction, this reaction occurs more slowly. It can take one to four weeks to notice a decrease in red blood cell levels.
    • Graft-versus-host disease – In this condition, transfused white blood cells attack your bone marrow. Usually fatal, it’s more likely to affect people with severely weakened immune systems, such as those being treated for leukemia or lymphoma.
  • Mortality: A Canadian study published in the July 11 JAMA Internal Medicine found an elevated risk of mortality from blood donated from young (17-20) and female donors–About an 8% increased risk of death from any cause.
  • Disease: Irina Conboy, a neurologist at the University of California, Berkeley and who’s research is mentioned above, says that frequently exposing older people to foreign plasma may be unsafe because hyperactivation of their immune systems could lead to autoimmune or inflammatory disease. (more)
  • Cancer: Higher stem cell replication rates also bear the risk of cancer. (more)

After all, most tech entrepreneurs don’t want to be responsible for hurting anyone (i.e. Silicon Valley’s ‘do good’ mantra).

The second reason entrepreneurs probably don’t push into this area is due to the PR backlash.  Mario Macis, an economist at the Johns Hopkins Carey Business School who has studied incentives for blood donation said: “Even though it’s legal, it’s still considered not totally moral or ethical to pay cash to blood donors.” It’s like handing out blood money and the FDA worries that paying donors would jeopardize the safety of the blood supply. If money were on the line, donors may lie about their health or their risky behaviors.   Here is just one of many examples that Ambrosia Plasma has had to endure since its founding: (example).  Several countries such as Australia, France, the UK, Japan, and New Zealand all have made compensation for blood donation illegal (more).

The third reason entrepreneurs may not be interested in this space is the fact that advertising is prohibited.   A spokeswoman for the Food and Drug Administration says the agency “regulates the collection and manufacture of blood and blood components to help protect the health of the blood donor and to ensure the safety, purity, and potency of the blood product.” While it’s not approved specifically for anti-aging treatments, like other drugs, it can be prescribed for so-called off-label uses as long as there are no advertising or efficacy claims involved.

Ambrosia Plasma purchases their plasma but to do this at scale a company would need to create their own blood bank (that adheres to the WHO guidelines), hire a knowledgeable physician (plasma is a prescription drug) several nurses and a research staff. Link to how to start a blood bank and the associated business plan. To get such a startup off the ground would require several million dollars and as noted above much more risk than most venture capitalists would care to accept.

After looking into the subject for some time I am left to wonder 2 things.  1.  Why isn’t more government/corporate research money going into such an important subject? and 2. What if matching the age of the donor and the end recipient is super important? Could we be currently harming young people that receive blood from an older donor?

Is cryptocurrency here for good?

<These notes assume you understand Bitcoin, Public/Private & Permissioned/Permissionless & federated blockchains, consensus concepts, side chains, ICO/STO, stable-coins, utility/app-payment/security tokens and smart contracts.  If you don’t please review the following notes (1) and (2).>

It’s hard to argue that the cryptocurrency world is not here to stay when you see…

  • Tech luminaries (Andreessen, Dixon) come out and say “[Crypto tokens] will soon be seen as a breakthrough in the design and development of open networks, combining the societal benefits of open protocols with the financial and architectural benefits of proprietary networks.” I listen and want to participate. (more)
  • a crypto-market cap of $194 Billion dollars (8/14/2018)
  • big finance (Goldman Sachs, JPMorgan, Morgan Stanley, HSBC, Citigroup, Barclays, Credit Suisse, Deutsche Bank, UBS, Fidelity Investments, BlackRock) getting on board (more).
  • countries (To date Senegal, Tunisia, Marshall Islands, Venezuela and many others testing the concept more) and central banks (Caribbean) issuing or considering their own cryptocurrencies.
  • regulators stepping in (more and more)
  • Intercontinental Exchange (ICE) and Starbucks getting involved (Bakkt)
  • Coinbase having more users than Charles Schwab (more) – “Charles Schwab reported 10.6 million active brokerage accounts for October, in contrast with 11.7 million users in October for Coinbase, the leading U.S. platform for buying and selling bitcoin.”

…but this market it difficult (complex tech + complex economics + the science of network effects) with many overlapping layers (Coins such as Bitcoin & Ether, Stable-coins, Utility tokens, Security tokens etc..) and too many speculators (Tim Draper).

Putting private permissioned blockchains aside for the moment (this will be a follow-on note) I tried below to outline all the basic arguments for and against cryptocurrencies such at Bitcoin & Ether AS WELL AS the tokens that rely on the success of currencies such as Bitcoin & Ether.  I will eventually use this as a rough way to determine if this is a fad or a true economic tidal wave…

  • Pro #1: A cryptocurrency such as Bitcoin or Ether is a more effective/efficient currency than FIAT (it’s scarce (Bitcoin has 21M ceiling yet fiat is easily printed), easily divisible, durable (a ledger entry that exists on computers around the world versus fiat that slowly loses value due to inflation over time), fungible, recognizable, can’t be counterfeited, highly portable (without a need for a bank), permissionless (versus fiat where you need permission to send dollars to some nations like Russia), decentralized (versus fiat that is controlled centrally) and most importantly programmable (which fiat is not)).
    • Con: Speed: Public permissionless blockchain networks are slow and currently do not scale to yield transaction throughput on the scale of Visa (1700 tps)—Bitcoin is ~7 tps and Eth is ~10 tps (more)
    • Con: Proof of Work Consensus systems use enormous resources: Public permissionless blockchain networks (especially those that use PoW consensus) require enormous resources (bandwidth, memory, and CPU). The ledger is shared and maintained by every node of the network. To be a node in the network, one needs to download the whole ledger/blockchain and keep it on their system. Distributing a ledger potentially consumes over a hundred times the energy of single databases. Scaling up from relatively niche use could be impossible.  Also, for cryptocurrencies that using proof of work (mining) as their consensus mechanism–If the market value of the reward for mining drops below the cost of mining, then miners will stop mining, and nobody will process transactions.
      • Rebuttal: Proof of Stake consensus systems and Layer 2 solutions
        • Con-Rebuttal: Proof of Stake may be more expensive than Proof of Work—see this.
    • Con: Cryptocurrencies are not a “stable” store of value. They operate less like a “currency” and more like a “stock” whose price fluctuates. What % of today’s BTC is being used to purchase services? Less than 1%?  With crypto there is no certainty of its future value–in order to be money, you need to be able to price products & contracts in it… but none of these things can be done with crypto when its price is so volatile. Artificial scarcity is essential to cryptocurrency’s value but works against making it a viable medium of exchange.  Why would you buy a soda with Bitcoin if one day it’s $1, the next $5, and the day after that $10?
      • Rebuttal: In economics, something has value if it checks the following two boxes: scarcity and utility. Scarcity means that something has a finite supply. In the case of bitcoin, the cryptocurrency has a set cap of 21 million bitcoins. Cryptocurrency’s utility lies in the fact that no government, bank or single person has control over it hence it can’t be toppled by corruption at the top.  Gold has underlying utility value in applications such as semiconductors and jewelry. Real estate has underlying value for building, farming, and mining, among others.  Cryptoassets have an enormous amount of potential underlying utility value, promising to disrupt just about everything, including payments, record keeping, legal contracts and many other industries.
        • Con-Rebuttal: Crypto is not scarce–it can be forked off. There are 1500 current currencies and new ones every day.   Maybe the network is scarce today much like MySpace was many years ago, but bigger/better networks will constantly be created.  Yet there is only 1 gold.
      • Rebuttal: Volatility is currently high, but volatility is what happens when a market is trying to figure out what the price should be–it will eventually flatten out. Stability is earned with time. The volatility issue is self-correcting.
    • Con: Deflation is bad. Bitcoin caps out at 21 million total BTC in circulation; Litecoin at 84 million LTC. These fixed supply mechanisms give them deflationary characteristics over the long term.
      • Rebuttal: Ethereum (ETH) chose to uncap the total supply of their coins and opt for long-term, pre-determined issuance schedules. No-cap cryptocurrencies are thus inflationary in nature. The risk with inflationary crypto assets is that new, future coins entering the market will reduce the value of existing coins by increasing the supply relative to demand.
      • Rebuttal: A crypto asset with deflationary characteristics could theoretically be a better store of value because existing coins are protected from future supply-based dilution.
    • Con: Cryptocurrency is not ‘required’ for anything other than ransomware payments or illicit dark-web purchases! With fiat—governments require it for citizens to pay taxes.  Who requires crypto?  Without the requirement of use you will never know the demand (i.e. supply/demand) hence you will never have a stable price given speculators currently drive the demand not use of the currency.
      • Rebuttal: Crypto may not be required but is a necessity in the developing world (more)
    • Con: Country-specific monetary policy is required for a stable society, to offer benefits (Social Security, Medicaid, Medicare) to its population and to finance wars
      • Rebuttal: Cryptocurrency and monetary policy are not mutually exclusive. (more, more, more)

So, this might be where ‘stablecoins’ get interesting and bypass most of the issues outlined above…  

    • Con: Credit and cryptocurrencies play poorly together.
      • Rebuttal: Cryptocurrency and credit are not mutually exclusive as seen with the announcement of Bakkt.
        • ConRebuttal: “it’s also a double-edged sword because it’s likely the beginning of Wall Street creating financial claims to bitcoin out of thin air (and not backed by actual bitcoins), which could offset some of Bitcoin’s algorithmically-enforced scarcity.”-Caitlin Long
    • Con: Fragmentation: like Linux, many cryptocurrencies are open-source causing new currencies to appear quickly. There are 1500 current currencies and new ones every day.
      • Rebuttal: The network is the value not the currency/code.
        • Con-Rebuttal: Maybe the network is scarce today much like MySpace was many years ago, but bigger/better networks will constantly be created.
    • Con: Lost keys: Cryptocurrency stored in a public permissionless blockchain can be lost forever if someone loses their key. Hence, most people won’t want to maintain their own private keys, and if you don’t maintain your own private keys, cryptocurrencies are essentially no different from fiat money held in banks.
    • Con: Quantum computing: The entire blockchain assumes that hash problems take a constant time to solve. If someone can solve a hash problem even slightly faster, then the whole blockchain system fails to work.
      • Rebuttal: This is fear-mongering-any potential security risks are solvable (more and more and more)

 

Maybe there is enough value in the Pros below to bypass all the Cons above…

 

  • Pro #2: A coin such as Bitcoin or Ether can be used for low-cost international money transfers: The current system is a multibillion-dollar industry that exploits immigrants with fees (Western Union skimming a %). With cryptocurrency, the transfer fees are negligible, and the transfer times are near-instant.
  • Pro #3: A coin such as Bitcoin or Ether can minimize government intervention: Allows citizens to not have their capital tracked by governments as a means of control in the case of 1) Seizure resistance by badly acting governments and 2) Ease of transport of currencies across international boundaries (cryptocurrencies allow you to cross a border with literally a billion dollars in your pocket)
    • Con: Won’t pass regulatory scrutiny: Governments won’t tolerate the loss of monetary control. The US government specifically is not going to allow wide-scale movement of money within the United States in which it can’t identify the sources and uses.  Governments also won’t tolerate illegal commerce (especially if used for terrorism).   Eventually, societal pressure to regulate cryptocurrency will increase as more fraud (example: market manipulation) is discovered. Most people want strong governments, and strong governments want to control their own currencies.  Net: Governments can make the use of cryptocurrency illegal (much like what the Saudi’s did with Bitcoin more).
    • Con: Requires Pro #1
  • Pro #4: A token based on a coin can be a better way to fund an open source network to allow it to compete with a proprietary network (Facebook, Google, Amazon, Microsoft, Apple, Netflix etc.). A token can 1. fund the operating expenses required to host the network (Bitcoin and Ethereum have tens of thousands of servers around the world that run their networks) 2. provide shared computing resources (including databases, compute, and file storage) 3. incent network participants (developers, users of the network and investors)
    • Con: Requires Pro #1
  • Pro #5: A cryptocurrency (coin or token based on a coin) can provide for the ability to sell digital goods: For example Music & Photography
    • Con: Requires Pro #1
  • Pro #6: A token (based on a coin) can be used to replace the need for a central bank:
    • Con: Well-run central banks succeed in stabilizing the domestic value of their sovereign currency by adjusting the supply of the means of payment in line with transaction demand.
    • Con: Requires Pro #1
    • Con: Bank of International Settlement’s very negative view

 

 

Want to live longer—get skinny and find some young blood!

As I age I get more interested in the science of longevity.   However, like blockchain there are more lies than there are truths and the internet is filled with the promotion of quackery.   There are however several areas of promising research.   As I build my research I will keep these notes updated on the subject.

1.      Parabiosis-Replacing old blood with young blood

 

Several years ago, researchers found that there were compounds in the blood of young mice that could awaken old stem cells and rejuvenate aging tissue in old mice.   The researchers focused on a protein called GDF11 and found that it revived stem cells in old muscles, making old mice stronger and increasing their endurance.  It also looked like the blood of young mice altered the brains of old mice with new neurons in the hippocampus (a region of the brain that is crucial for forming memories) and also spurred the growth of blood vessels in the brain.  Researchers also found that by injecting GDF11 alone into mice had an impact, although the change was not as large as that from parabiosis.

Later research found that the enzyme Tet2 (ten eleven translocation methylcytosine dioxygenase 2), a known regulator of gene activity linked to several age-related diseases, was responsible for the enhanced cognitive functions in the adult mouse brains.  It seems that some circulating factor in the blood was able to change the level of Tet2 in the brain.

There is still a lot of research required given some caution that waking up stem cells might also lead to them multiplying uncontrollably.

More: http://www.frontlinegenomics.com/opinion/23471/young-blood-magic-or-medicine/

2.      Caloric Restriction

Undernutrition without malnutrition has been found to be one of the most successful approaches to life extension in laboratory settings. Researchers have been able to extend the mean and maximum lifespan of laboratory rats by 40% or more.  It is theorized that the longevity extension has to do with an activation of survival mechanisms that have been evolutionarily conserved to protect an organism from stress. A small human study of 60 healthy seniors receiving an average of 1500 kcal/day for a period of 3 years found significantly lowered rates of hospital admissions and a numerically lowered death rate than an equal number of control volunteers.

The downside of caloric restriction in senior citizens relates to decreases in muscle mass, strength, aerobic capacity and bone mineral density.

http://www.lifeextension.com/Protocols/Lifestyle-Longevity/Caloric-Restriction/Page-01

3.      Gene Therapy

Mitochondria serve a variety of critical functions within the cell including supplying cellular energy, cell signaling (communication process that governs basic activities of cells and coordinates all cell actions) and metabolism (conversion of food/fuel to energy to run cellular processes, the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some carbohydrates, and the elimination of nitrogenous wastes.). However, a mild disruption of the mitochondrial function has been shown to increase lifespan.   It is theorized that by manipulating insulin metabolism (such as through the development of calorie restriction mimetic drugs) may modestly slow down aging.  This has to do with two hormone receptors–the receptors for insulin and IGF-1 (these receptors signal the uptake of energy and growth).  Drosophila melanogaster3 (a mutation in the gene that encodes the insulin/IGF-1 receptor) results in higher longevity.

https://steemit.com/science/@ertwro/genetics-of-anti-aging

4.      Drug: Rapamycin, an immunosuppressant and anti-cancer drug

The Navartis drug Rapamycin has been shown to extend lifespan in mice.  The drug is a biological agent discovered in the soil on Easter Island.

https://www.age.mpg.de/healthy-ageing/research-stories/rapamycin-the-first-drug-to-extend-lifespan-from-yeast-to-mammals/

5.      Drug: Metformin

Metformin is an old generic diabetes drug known for its blood sugar lowering properties and for being quite safe and has been found to stall the aging process in animal studies.

https://www.newsweek.com/2015/12/25/diabetes-drug-could-be-anti-aging-miracle-404370.html

6. Drug: RAD001 and BEZ235, cancer drugs

RAD001 is used to fight cancer and prevent rejection in organ transplant patients. The other, known as BEZ235, was developed as a cancer drug. Both drugs, known as TORC1 inhibitors, affect a crucial cellular pathway that plays a role in the immune system and other biological functions. Similar drugs were previously linked to extending the lifespans of lab animals.

https://www.npr.org/sections/health-shots/2018/07/11/627875888/possible-anti-aging-drugs-boost-elderly-immune-systems 

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