There is going to be a lot of debate over the next 2 years about healthcare and moving to a single-payer system. Democrats are talking about “Socialized Medicine”… Republicans are talking about “Free Market Healthcare”–as an example, here is a good article that articulates a good one-sided argument without many deep recommendations. …But what are the facts?
I’m building the following notes to start capturing data to help me formulate my opinion on the subject. I’ll use a “5 Whys” strategy to think through the issues.
5 Whys is an iterative interrogative technique used to explore the cause-and-effect relationships underlying a particular problem. The primary goal of the technique is to determine the root cause of a problem by repeating the question “Why?”. Each answer forms the basis of the next question. The “5” in the name derives from an anecdotal observation on the number of iterations needed to resolve the problem.
Let’s review the
The United States has the poorest population health outcomes. For example, we had the lowest life expectancy (78.8 years compared with a mean of 81.7 years).
If you compare the U.S. to the top 11 other countries in the world we are out of balance:
We know a “free market” healthcare system won’t work for a simple economic reason: Healthcare demand will always outstrip supply and this imbalance will always create a wide (and ever-widening) economic gulf. However, we don’t have a “free market” system today—we have a mix… We have a Medicare, Medicaid, VA, Fed / DoD, and Indian Health Services System… we have the so-called “free market” system primarily sponsored by employers and then we have the 10s of millions of un (or under) insured citizens…
So, what are our goals:
Wait! What about being the leading innovator in healthcare? What about driving more of the conversation away from “sick care” and really toward “health care” – that’s going to require entrepreneurism and a free market to innovate and capitalism to support… The reality is that this isn’t an easy fix… it’s quite complicated and anyone involved in the argument needs to know the details.
So what are the “5 Whys” of the healthcare debate?
The first two “Whys” are easy…
We know that the United States spend 17.8% of GDP ($9,403 per person) on healthcare when Canada, Germany, Australia, the U.K, Japan, Sweden, France, the Netherlands, Switzerland, and Denmark spend 11.5% and all have better overall outcomes (i.e. life expectancy as an example). Why?
We know from the JAMA study mentioned above the high U.S. spend is because Physicians earn more in the U.S., Administrative costs are higher in the U.S., and general prices for pharmaceuticals, procedures, and tests (example: MRI) are higher in the U.S.. Why?
Here is where it gets complicated… We need to dig into each of these:
The number of slots supported by Medicare (who pays for most residency slots) has been frozen for two decades after Congress lowered it in 1997 at the request of the American Medical Association and other doctors’ organizations.
What could policymakers do?
Fund more residency slots.
Allow Medicare to limit the slots for certain areas of specialization to control supply and demand.
End the requirement mandating that foreign doctors complete a U.S. residency program and allow them to complete an equivalent residency program in another country or allow foreign-trained doctors to practice under the supervision of a U.S.-trained doctor.
Allow nurse practitioners to perform more procedures that they are qualified to complete.
The reliance on multiple payers (Medicare, Medicaid, and many private insurers, all who each have their own set of procedures and forms for billing and collecting payment) drives up the costs. The American health system offers a lot of choice among health plans. This all causes physicians to spend on average 3 hours per week addressing billing-related matters, medical support workers spent an additional 19 hours per week on billing-related matters, and administrators spent a total of 36 hours per week on billing and collection matters. Why?
We are only at the beginning of creating interoperability and data standards for healthcare. There is a great deal that has been done and a lot on the table. It’s a very complicated issue but well understood. More here, here, here, here and here.
What could policymakers do?
Legislate strict electronic data standards (provider example) for interoperability and transparency.
Legislate standard electronic billing and collection policies.
General prices for pharmaceuticals, procedures & tests (example: MRI) are higher in the United States? Why?
Other countries negotiate with the providers and set rates that are much lower. In Canada and Britain, prices are set by the government and in Germany and Japan providers and insurers come to an agreement or the government steps in. However, in the United States health-care providers have considerable power to set prices, and so they set them high. Why?
In the U.S., health care delivery and payment are fragmented, with numerous, separate negotiations between drug manufacturers and payers and complex arrangements for various federal and state health programs (more). And, in general, the U.S. allows wider latitude for monopoly pricing of brand-name drugs than other countries are willing to accept. Why?
Two of the most profitable (and powerful) industries in the United States are the pharmaceuticals and medical device industries. (It is, however, true that Medicare and Medicaid negotiate prices on behalf of their members and purchase care at a substantial markdown from the commercial average prices.). These powerful industries have pushed back on government policymakers why try to legislate setting overall spending levels for payments to providers & drug makers because it would impair their revenue and profit growth.
Other countries may also have policies that result in new drugs and medical technologies being adopted more gradually. (more)
Other countries have more friendly legal environments to challenge the validity of patents. Why is the US different?
This article shows how numerous patent filings (“patent thickets”) are used to drive up the costs of Humira by AbbVie Inc. in the US as an example.
Create legislation to counteract patent thicket practices (note: Sen. Susan Collins of Maine has called for ways to counter such practices but there has been no policy put forward).
“How many businesses do you know that want to cut their revenue in half? That’s why the healthcare system won’t change the healthcare system.” Rick Scott – Senator from Florida
Let the federal government negotiate lower drug prices for Medicare beneficiaries. This would shift the U.S. policy toward a more centralized pricing system like that used in other high-income countries. Currently, the Veterans Health Administration and the Department of Defense are the only federal entities allowed to effectively negotiate directly with drug manufacturers; they pay prices that are roughly half of those paid at retail pharmacies. (more, more) RISK: Too much legislation may make our pharmaceutical sector less attractive to investments resulting in less innovative and effective drugs in the future.
This is a work in progress so I will add more as I research and learn.
Health care is a misnomer for our medical system–It should be called sick care. Doctors mostly make their money when we are sick. What if doctors really could prevent disease? —well they can, but you need to be prepared to do the work because disease prevention is about:
Lifestyle (what you eat, your weight and how much you exercise—covered here)
Keeping great medical records (don’t get me started on a. doctors keeping paper files, b. doctors making it difficult to get your medical records (push them) and c. electronic medical record systems having different formats for the data (more))
Documenting and understanding your genome (DNA)
This set of notes will dig into “4” – Your genome! My hope is to explain this subject in a way where you can understand how to get your genome data, view it at a high level, view the details and begin to understand the interworking’s of your genetic makeup so you understand the value of leaving your ‘sick care’ doctor behind and finding a true personalized ‘health care’ MD).
Step 1: Have your genome mapped
There are many low-cost direct-to-consumer DNA mapping sites and this linked article will explain a few options for you to consider (here is another). I personally like 23andMe ($199 USD) because it does a great job of explaining DNA to a novice and a professional, they seek FDA approval, and the site allows you to download your data.
Let’s first cover a few standard definitions to make sure we
are all on the same page:
DNA (deoxyribonucleic acid) – 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 and many viruses.
Chromosome – a DNA molecule with part
or all the genetic material (genome) of an organism. Human cells have 23 pairs
of chromosomes (22 pairs of autosomes and one pair of sex chromosomes), giving
a total of 46.
Genes – From 23andMe, “Genes are
segments of DNA that tell your body how to function and what traits to express.
People have about 22,000 genes in their genome. Most of these come in duplicate
– one copy from your mother and one from your father. Everyone has the same set
of genes, but each one can vary by a few letters (bases) between people. These
“variants” can lead to differences in the way you look, how you
respond to stimuli, and whether or not you are predisposed to certain diseases.”
Once you get your data back from one of these direct-to-consumer
genome mapping sites you will have access to their portal. I’m going to use 23andMe as the example, but
many are similar. When you get your report, you can easily go to the ‘Health’
section and see what it is reporting. It will look something like the
2: Download your raw genome data to a safe password protected and encrypted
If you are using 23andMe you can download your raw data
instructions. If you know what you
are looking for you can also dig into your raw data here (more on this later).
But what can you do with your raw genome data?
WARNING: This is where things get a bit tricky. There
are five very important things to know:
Some sites (like Promethease) list all the SNP markers (From 23andMe, “A marker is a specific location in the genome where a genetic sequence has been shown to vary between people. Markers are denoted by a unique identifier, most often an “rs number”) associated with different traits and diseases, as curated from SNPedia. Drawing any conclusion from this reporting is often frowned upon by geneticists. There is such a thing as an SNP that is strongly associated with a disease (These are typically the ones 23andme has FDA approval to report—example BRCA1/2 The individual gene mutations BRCA1 increases the risk of breast cancer. Angelina Jolie is just one of the thousands of women who chose bilateral prophylactic mastectomy to mitigate the increased risk of the BRCA1 mutation.) but most common diseases are not really affected by any given SNP.
The best analysis uses the compound effect of many SNPs with an understanding that each only contributes a small effect. This concept is called polygenic risk scoring (PRS). This allows scientists to take anyone’s genome and calculate your aggregate risk for certain diseases even if you don’t have one of the known major mutations. Polygenic Risk Scoring is the total score of all the minor gene variations that increase disease risk. This is a powerful upgrade to your doctor’s ability to predict disease in any given patient. This means doctors are no longer in the dark with only the family history to guide them. (here, here, here and here are 4 great articles on PRS)
Be careful of companies target marketing supplements or programs at gene variants –always check with a licensed medical doctor (MD) before taking any actions.
Step 3: Mapping your raw data to the SNPedia database (but heed warning #2 above)
I am going to
use the Promethease site. A report is $12, and it can directly connect
your 23andMe DNA data with the SNPedia human
genetics wiki. It also provides information on the effects of genetic variants
on Phenotypes (the
composite of the organism’s observable characteristics or traits, including its
physical form and structure; its developmental processes; its biochemical and
physiological properties; its behavior, and the products of behavior, for
example, a bird’s nest. An organism’s phenotype results from two basic factors:
the expression of an organism’s genetic code, and the influence of
environmental factors.) and the information is sourced from peer-reviewed
scientific publications. Keep in mind that the match against the SNPedia
database may be wrong, as the raw data is not held to the same quality level as
that which is part of an FDA approved report from 23andMe.
The report only takes 5 to 10 minutes to generate and you will get it via email as a zip file and via their website. It will look like the figure below where you have a search panel on the right and the data on the left. In the example below, you can see the SNP (Single Nucleotide Polymorphism) marker is rs1333049 (From 23andMe, “A marker (SNP) is a specific location in the genome where a genetic sequence has been shown to vary between people. Markers are denoted by a unique identifier, most often an “rs number”, or “rsid”.”). You will also see the Position (From 23andMe, “If you stretched out all of the DNA in a chromosome from end to end, you could count the position of each letter (A,C,T,G) relative to the first one in the sequence. This count is referred to as a genome coordinate or position. 23andMe uses the same coordinates as the National Center for Biotechnology Information (NCBI), build 37.”). You will also see the Magnitude (From SNPedia.com, “Magnitude is a subjective measure of interest varying from 0 to 10. Over time it should be adjusted up or down by the community.” The range is from 0 (you have the common genotype) to 10 (significant information).) You probably only want to review magnitude 3 and above.
If you click on the SNP marker hyperlink rs1333049 you will be
taken to the details page in the WIKI.
From the page above on the far right, you have links to many great sites including Ensembl and 23andMe’s detail pages.
Once on the 23andMe page you can also see the Variant (From 23andMe, “At any position in the genome that varies, there is more than one possible version (or variant) of the DNA sequence. For example, some people might have an A at a certain position, whereas other people might have a T.” Genetic variations, or variants, are the differences that make each person’s genome unique. DNA sequencing identifies an individual’s variants by comparing the DNA sequence of an individual to the DNA sequence of a reference genome maintained by the Genome Reference Consortium (GRC).) and Your genotype at a marker (From 23andMe, “Your genotype at a marker is the combination of variants that you have at that position on both chromosomes’ copies. For example, if you have the A on one chromosome copy and a T on the other one, your genotype is AT. Some chromosomes don’t come in pairs (i.e. the mitochondrial chromosome and, for the most part, the X and Y chromosomes in men), so your genotype can sometimes be a single letter.”)
There are several other tools out there to get information on each one of the SNP markers. One of the best is found here at NIH.gov. With this, you can search for many research articles per SNP marker.
Now that you have all that data, please reread Warning #2 above!
Step 4: Map your data to known polygenic algorithms
These sites are reported to be working with polygenic risk scores:
Keep in mind that this is a relatively new science that has been enabled by the mapping of the human genome. The research is coming out fast. As an example, Sekar Kathiresan and his colleagues at Harvard University and the Broad Institute have been focused on variations linked to coronary artery disease, atrial fibrillation (an irregular heart rate), type 2 diabetes, inflammatory bowel disease, and breast cancer. They developed an algorithm that could use all this information on a disease’s genetic variants to produce a polygenic risk score, a single number that would indicate a person’s risk of developing each disease based on their genomic data. Their algorithm identified 20 times more people at high risk of a heart attack than did the traditional method of just looking for the variant that indicates inherited high cholesterol. If more people know they’re at risk, they can go on medication or start making lifestyle changes to prevent the onset of the disease. You can get a copy of the report here or here.
As an example, here is data from Impute.me a non-profit (please donate) genetics analysis site run by independent academics since August 2015. Their design goal is to provide analysis at the cutting edge of what is currently known and possible in genetics research. A central part of their site is the creation of a guidebook for personal genome analysis. This book provides more in-depth explanations for many of the concepts involved and it’s highly recommended as a guide to accompany your analysis. (New: Updates to the site will be announced at twitter).
Let’s go into a couple interesting things
you can do with their site. Note that I am using the text below
directly from the Input.me website.
A polygenic risk score is a value that gives a summary of a large number of different SNPs – each of which contributes a little to disease risk. The higher the value, the higher the risk of developing the disease. Of course, the interpretation of this risk depends a lot on other factors as well: How heritable the disease is. How much of this heritability we can explain with known SNPs. And not least, what would the risk of disease be for you otherwise, i.e. without taking the genetic component into account. Because the polygenic risk score is only a risk-modifier, knowledge of these three other values are all required if you want to know your overall risk is, i.e. what’s the chance in percent. This calculator cannot provide that. But it can provide a view of the known genetic component of your disease risk, based on all the SNPs that we know are associated with the disease. This, we believe, makes it a better choice for complex diseases than the typical one-SNP-at-the time analysis typically seen in consumer genetics.
If you upload your 23andMe data after a couple of days you will have access to this site and a unique ID that will be good for 2 weeks.
This is a module that
can visualize the entire compendium of human disease – at each point showing
relevant genetic findings. The goal is to illustrate how to present genetic
data depending on a medical status.
Diseases, where one mutation has a strong medical effect on you are luckily rare. For the majority of people, learning from our genes is instead matter risk modifications and weak predictions. For a healthy adult, these are typically of little practical use. However, the assumption changes drastically if you are not healthy; If you are anyway being evaluated for a given disease, it may very well be useful to know if a different but medically related diagnosis has a particularly high or low risk.
For example, if a person is suffering from mental problems, but have not yet been properly evaluated for any specific diagnosis, then genetic risk information for all diseases related to mental problems may become useful knowledge. Because the information can then serve as a guiding point in that difficult challenge of first diagnosis. Similar examples can be made for virtually all areas of early medical evaluation.
It is the purpose of the module to help with this: By forcing browsing into pre-defined sets of disease-areas, the algorithm provides you only with genetic information that is relevant to.your current medical status. Nothing more, nothing less. Risk scores relevant to the medical area you are interested in will be shown. Fluke signals from irrelevant disorders will not. The details behind all information given here can be explored in the remaining modules of the site, as indicated when you click on each of colored bubbles above. As such this module can serve as an entry-way into the entire site, depending on your context and interest.
In the root of the tree, we find ‘feeling fine’, which is always a neutral color: People who feel fine don’t need to worry about their genetic risk scores. However, when selecting ‘heading to hospital’, climbing up the tree, the genetic risk scores are revealed as they become relevant. More of the thinking behind this module is explained in this short animation-video from 2017.
The overview of rare disease variants found in this module is not the most extensive single-SNP effects available online. They are shown here because they are all well-supported strong genetic effects, for a selection of rare inherited diseases where microarray analysis made sense. This was the reason these SNPs were included in the 2016-version of the 23andme health.
Especially the last part – that microarray analysis made sense – is very important when analyzing the genetics of rare disease; the microarray technology used in consumer genetics is not optimal because the really strong mutations typically are not measured on a microarray. DNA-sequencing is required to detect them. Therefore microarray analysis of rare disease effects has many problems with false negative results. There’s a lot of further details to this discussion, chapter 3.5 in this book is a good place to seek more information.
Nonetheless, the 2016-selection of microarray-measurable SNPs made by 23andme still is reasonably relevant to report, particularly for the carrier-information. For non-23andme users, this module has the additional benefit of translating the data for proprietary 23andme SNPs, with the caveat that because the SNPs are very rare they are often hard to impute.
This is a test of a systematic approach to drug-response SNPs. Most of the known drug-response-associated genetics concern liver enzymes (e.g. CYP2C19) and their break-down of drug metabolites. These are well characterized elsewhere already. The focus of this module is to integrate systematic multi-SNP profiles beyond liver enzymes and provide estimates of drug-response.
To illustrate how this works, the module shows the calculations that take place for a number of drug response predictions, both on a per-drug level and on a per-SNP level, corresponding to the first and the second table. The first table summarizes per-drug calculation whenever possible. If possible, a Z-score is calculated in the same way as also described in the complex disease module. If not, it is indicated as ‘not calculated’. In that case, it is necessary to look at the second table for comments on the individual SNPs from the input studies. The Z-score approach takes information from many SNPs, and can, therefore, be considered as more thorough, of course depending on the underlying scientific study.
Most SNPs in the genome are not actually found within a gene: They are ‘intergenic’. When talking about a gene-mutation however, as is done in popular media, most often the meaning is a SNP that alters the sequence of a gene. Because of selection pressure throughout our evolution, these are rare. Also, they are often the focus of scientific studies using DNA-sequencing technology to discover the causes of rare diseases. However, interestingly many of us actually have these ‘gene-breaking’ SNPs while nonetheless being perfectly healthy. The imputation technology used with this site gives the opportunity to identify a number of these based on just on genotyping microarray results. If you give your ID-code to this module a table of all measured missense and nonsense mutations will be presented.
Interpretation of the table can be done in many ways and unlike other modules, this does not give ‘one true answer’. One method is to search for SNPs where you have one or two copies of the non-common allele and then investigate the consequence using other resources such as dbSnp or ExAC. Note however that the definition of ‘common’ is very dependent on ethnicity: in this browser common just means the allele most often found in impute.me-users. However, it is recommended to check the ethical distribution in e.g. the 1000 genomes browser. Another help provided is the polyphen and SIFT-scores, which can give an indication of the consequence. Ultimately the goal of this is to satisfy one’s curiosity about the state of your functional genes. If you happen to find out that you carry two copies of completely deleterious mutations (nonsense mutation) but otherwise feel healthy, feel free to contact us. By being healthy, in spite of a specific broken gene, you’d be contributing to complete our view of genes and how they work.
Thousands of mutations in the BRCA1 and BRCA2 genes have been documented. 23andMe reports data for three mutations that account much of inherited breast cancer, but other possible mutations in these two genes are not included in the 23andme report. Many can only be detected by sequencing, such as from myriad genetics. However, dozens of extra possible mutations of interest can be reached with imputation analysis. The following lists your genotype for the directly measured three 23andme-SNPs as well as all other SNPs in the two genes that are either missense or nonsense. For interpretation, we recommend reading more about polyphen, sift-scores, and clinvar.
If clinvar is indicated as pathogenic and the SNP is measured in your genome and your genotype is not of the genotype indicates as normal, then this indicates a potential problem. The list is sorted according to the clinvar variable by default.
UK Bio-bank Calculator
A study of ~½ million UK residents, known as the UK biobank, has recently been published. This module allows the calculation of a genetic risk score for any of the published traits.
Now that you have all that data please reread Warning #4 above.
Step 5. Make a plan.
If you are high risk for coronary artery disease see a cardiologist. If you are at high risk for breast cancer, mental illness, eye problems etc. see a medical (MD) specialist.
…but be wary of Warning #5 above–don’t go see a “quack” and don’t self medicate!
..but also do your homework and understand if the specialist is up to date on the latest and greatest –for example, if you see a psychiatrist for ADHD make sure they are trained in epigenetics.
This holiday season I talked to several people with different opinions from my own. I met a young 20-year-old woman that said she would never bring kids into this world because global warming meant we have no future… I chatted at a party with a Trump supporter that was convinced tariffs were good policy. I listened to a young person (under 18) tell me that Socialism was indeed better than Capitalism. I’m not saying any of these opinions were wrong but I did notice that NONE of them were based on a broad set of knowledge—they were all drawn from a few headlines, things they heard or opinions they created themselves based on their belief system. You might say that this has been going on since the beginning of humanity (people formulating strong opinions without a lot of facts)—but it seems much more pronounced now. (As you will read below this might be due to me having a slight Negativity Bias.)
I get it, we are human, and we have innate flaws that allow us to be influenced –but how and why? I thought it was time to do some digging, take some notes, and begin a list of all the ways I could be manipulated so I can defend against it in the future.
Political ads, search and social media advertising, partisan cable TV and fake news content is constantly being pushed at all of us–While product designers create products that cause addictive behavior to distribute such content. Design engineers read books like Hooked: How to Build Habit-Forming Products to understand how to build products & services that we have to constantly check for a little boost of dopamine. In the past, this wasn’t as big of an issue because the portals for distributing content were not as widely used (as our smartphones are today) for such a large part of the day and their influence was not as personalized (more on how much just a couple tech firms knows about you found here).
To understand how we are being manipulated we need to understand one of our many glitches–Bias.
Everyone is susceptible to some
form of Bias
The first thing I’d ask is why less than 60% of the general public believe human activities are a significant contributing factor in climate change when >95% of the scientists that study climate change for a living (PHDs) are adamant about the fact. Think about this for a second–These specialists have studied climate for their entire professional careers, yet a large majority of people that NEVER studied the climate don’t believe them—that’s just crazy! Are these non-believers’ lives impacted negatively by climate change policy? Are these non-believers’ drawing conclusions based on how much snow they saw in their backyard this past winter? Take this a step further—these non-believers are voters and 40% is a lot of people (more on a related subject). Reference this video about bias and climate change:
Most (if not all) people have a “bias blind spot”. Humans are less likely to detect bias in themselves than in others per published research in Management Science. The reality is that people are susceptible to all kinds of bias (defined as a mental leaning or inclination; partiality; prejudice; bent).
We love to agree with people that agree with us—This is called confirmation bias. To compensate we should surround ourselves with a diverse set of people that have different backgrounds and experience than your own.
We jump to conclusions without having a lot of information – This is called Anchoring Bias. To compensate we can draw upon tools such as the Ladder of Inference to help us make decisions.
We may believe that after flipping a coin 5 times and getting heads all 5 times that there is an increased likelihood that the next coin toss will be tails and the odd would be in our favor. They are not. This is called Positive Expectation Bias and forms the basis of gambling addictions. To compensate, we need to look at trends from a number of angles versus just chronologically.
We blame others when something goes wrong. Perhaps blaming the other driver for being a ‘bad driver’ in a traffic accident versus blaming the weather. This is an Attribution Bias. To compensate we need to look at others as people and use empathy versus treating them as objects (use tools like Arbinger Institutes Leadership and Self Deception framework).
We overlook faults or defects with a large purchase of an expensive product or service in order to justify the purchase – this is a form of cognitive bias called Buyer’s Stockholm Syndrome
We might despise the opposing political party. Negative feelings towards another group form from favoritism towards one’s own group – This is called Ingroup bias and forms the basis of discrimination.
The human brain is easily deceived, and we have to be diligent in not letting others manipulate us because of its natural bias. After all, marketing professionals have been exploiting these fundamental human flaws for years. Here is a great article outlining how titled “How marketers use 20 cognitive biases that screw up your decisions” by Paul Marsden.
We must constantly ask ourselves if our personal bias is making us draw conclusions without all the data… have we listened to the other side? Do we have empathy for the people on the other side of the dialog or are they ‘objects’ to us? Are we only listening to news that confirms our personal bias? Are we being manipulated or are we thinking about all sides of an argument? –don’t be the nitwit that doesn’t believe in global warming when >95% of all climate scientists (who spent their entire careers studying the issue) believe humans are at fault.
We are vulnerable to The Sleeper Effect
This was first identified in U.S. soldiers during World War II. Scientists measured a soldier’s opinions 5 days and 9 weeks after they were shown a movie of propaganda. They found that the difference in opinions of those who had observed the movie and those who did not watch the movie were greater 9 weeks after viewing it than 5 days. This leads us to believe that our impressions have more influence on us than rational thinking over time. Maybe this is why drug companies place disclaimers at the end of a commercial because we won’t remember them over time. Could this be why the older generation wants to Make America Great Again…
Some are vulnerable to Group Think
The brain is always looking for approval from other people
and this can be perverted in all kinds of unsettling ways. Our brains prioritize
‘being liked’ over ‘being right.’ so people will go along with a crowd and
engage in activities they would never pursue by themselves for the sake of
fitting in. Terrorism is a great example—it
occurs when ‘group think’ morphs into ‘group polarization’. For more on this subject
there is a great study in the Journal of Social and Political Psychology titled
Perspectives on Trump Supporters”.
Some are vulnerable to Cognitive Dissonance
Not knowing things makes humans
anxious. When we are not given adequate closure, we fill in the gaps to create
a cohesive whole that makes sense to us. It’s why some of us believe in heaven,
astrology, or ghosts. Humans fear the unknown, and intrinsically combat this
angst by supplementing our limited information with things that fit a
particular paradigm. It’s why we create religions and subscribe to them to our
death to give us answers to life’s complex questions.
“When a thousand people believe some made-up story for a month — that’s fake news. When a billion people believe it for a thousand years — that’s a religion,”- Yuval Noah Harari.
Most may be susceptible to some level of hypnotism
I know… this sounds farfetched but it’s not. We know the result of hypnosis is real—but we don’t understand how it works.
“Follow the Lord!” says the priest. “Defeat the Enemy!” says the politician. “Place your Order within the next Ten Minutes for Double the Benefit!” says the sales person. These are all examples of mass hypnosis—used just the same way that Stalin and Hitler practiced it. Manipulating emotions is a way to seize control over someone’s body and mind. The more we understand our subconscious mind, the greater our ability to make rational decisions.
Hypnosis is generally
regarded as an altered state of consciousness—but since consciousness isn’t
understood, alterations to it such as hypnosis, meditation and psychosis aren’t
very well understood either. David Spiegel M.D. does a great job explaining what
is known about hypnosis in this 9 chapter lecture titled “Tranceformation:
Hypnosis in Brain and Body” found on NIH.gov.
Someone can learn how susceptible they are to hypnosis here.
A person’s intelligence is not set in
genetic stone—Here are some ideas on how to
It may be in our genes
Bradley B. Doll, Kent E.
Hutchison and Michael J. Frank published a paper in The Journal of Neuroscience
Genes Predict Individual Differences in Susceptibility to Confirmation Bias”
that suggested that variants in the genes involved in the prefrontal dopaminergic
reward system predicted the degree to which study volunteers persisted in
responding to a test, following previous instructions, even as evidence against
the veracity of the instructions accumulated. In contrast, variants in genes
associated with dopamine function in the striatum correlated with the ability
to learn from actual experience.
Conclusion: We are not flawed, we are human. The key is to understand how our brains work and to defending against others that try to exploit our human design.
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:
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:
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”
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.
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.
A 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 exonsand 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:
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:
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:
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).
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.
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.
Cut. Once Cas9 binds to the target DNA it cuts the target DNA ∼3-4 nucleotides upstream of the PAM sequence.
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”
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)?
There are 3 species of cannabis: Sativa, Indica, 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. Myrceneis 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:
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.
A 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 addictiveto 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 roleScientists 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.
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.
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.
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.
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.
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.
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.
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: (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.
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?
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.
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.
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.
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.
No one really dies of old age. What kills people according to the CDC (at least in the USA) are primarily diseases that have connections back to a person’s lifestyle.
Even with all our great healthcare life expectancy is lower in the USA than in many other countries. (great read at NYT)
70% of Americans take prescription drugs and more than 50% take 2 (Mayo Clinic). This is an increase from 44% in 2000.
What you eat matters—A LOT!
“Healthy eating may be best achieved with a plant-based diet, which we define as a regimen that encourages whole, plant-based foods and discourages meats, dairy products, and eggs as well as all refined and processed foods. We present a case study as an example of the potential health benefits of such a diet. Research shows that plant-based diets are cost-effective, low-risk interventions that may lower body mass index, blood pressure, HbA1C, and cholesterol levels. They may also reduce the number of medications needed to treat chronic diseases and lower ischemic heart disease mortality rates. Physicians should consider recommending a plant-based diet to all their patients, especially those with high blood pressure, diabetes, cardiovascular disease, or obesity.” – Kaiser Permanente
Among U.S. adults, more than 90 percent of type 2 diabetes, 80 percent of CAD, 70 percent of stroke, and 70 percent of colon cancer are potentially preventable by a combination of nonsmoking, avoidance of overweight, moderate physical activity, healthy diet, and moderate alcohol consumption. — Willett So, if the most common diseases that kill people “are potentially preventable” why does the US diet score so low on the international diet quality index? (summary) –the answer is ‘dopamine’. The higher in calories the food, the more dopamine is released in the brain. Read more here about dopamine…
Oxford University found that moderate obesity (BMI of 30 to 35) reduces life expectancy by about 3 years, and severe obesity (BMI of 30 to 35), can shorten a person’s life by 10 years. Here is a BMI calculator.
Only 22.9% of adults meet the Department of Health and Human Services national and state-wide exercise guidelines (18.7% of women and 27.2% of men) yet it’s been proven that exercise extends life expectancy by as much as 4.5 years. – link and Strength training (lifting weights) has been proven to extend life expectancy… Lifters have a 46 percent less risk of early death than people who don’t lift. Lifters also have a 41 percent less chance of having a cardiac-related death and a 19 percent chance of dying from cancer. –Penn State College of Medicine.