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Growing Medicines in Plants

HAP

Human Assisted Phytosynthesis


HAP – Human Assisted Phytosynthesis

HAP is the process by which a completely synthetic phytoprecursor P is added to the plant feed of a cultivated plant. The plant metabolism then acts on P creating active compound A. Compound A is psychoactive in humans or otherwise physiologically active and it can manifest its activity when the plant is either (a) consumed as food (b) steeped in hot water which is consumed as a tea or (c) smoked.

The HAPpening Community

One way to envision this endeavour is to imagine an open community of people practicing HAP that communicate around an app. A member of the community has an idea: Compound P could be added to a plant to yield active A. Either other members of the community or “the HAP company” has the compound made and it is circulated among HAP members for growing and testing. Different members will be trying on different plant species or different varieties, and will be employing different methods of consumption and analysis. Alternatively, “the HAP Company” can conduct the growing and testing efforts and offer the resulting plant feed as a product if there is a beneficial result. The HAP Company would manage the app and/or other platform used to communicate

If adopting the community-oriented approach, there are different roles to play within the HAPpening community:

  1. Intuition provider – somebody with an idea for a phytoprecursor P and an explanation of why it could become active A in planta.

  2. Experimental Molecule Provider – usually a chemist, who could provide to the community or to “the HAP company” 50 grams of the actual compound envisioned by an intuition provider.

  3. Grower – someone who has plants or seeds and practices HAP with them either for experimental molecules or for already validated plant feeds.

  4. Taster – someone who takes the plants grown by a grower and consumes them using any method of consumption for the purpose of either:

  5. Discerning whether an experimental molecule has successfully yielded an effective active compound.

  6. Reporting on his/her experience with a validated product thus adding to the data pool.

Members could play one or several roles at any given time (similar to the way members in the Airbnb community can be city hosts, hosts or travellers).



Discovery Research Approach

We want to achieve a certain result in a microgreen. We have an educated notion of what the plant metabolism might be able to do. We obtain a phytoprecursor for what it is we want the plant to make. Depending on the dosage we are looking for, let’s say for example, we add 50 grams of that precursor molecule to a 2-4 litre jerry can of fertilizer and we use that to grow our microgreen. Over the course of three weeks, we slowly pour those 2-4 litres of liquid, mostly water, some nutrients and our “secret sauce” onto a tray of seeds which will sprout and grow up to about 2 inches, after which, we eat them. We want to do that for a whole range of different greens because the variable that is changing is the enzymatic repertoire of the plant. We don’t know what plant is going to have the enzymes necessary to finish the job we want finished.

We want to go over as diverse a range of plants as we can. Probably mostly


edibles but if we want to use plants that are non-edible and then make a tea of them, that’s also possible. It is probably a good idea to try it on tobacco and then smoke it. Probably one of the good examples that I think we should consider is ketamine-containing tobacco, which would make people want to smoke less. *A mention must be made as to the special laws governing tobacco.

We “tinker botanically” and the outcome could be nothing, which is also something because a documented failure will save others from trying it again. Hopefully, if our hunch is right, every once in a while we’re going to get a beneficial result: “I added this chemical to this plant and then when I ate it or smoked it or made a tea out of it: It took me up, it took me down, it made me hallucinate, it made me sleep.”

In fact the intentionality actually has a

detrimental effect here because this is going to be looked at by two authorities: One is the patenting office when you want to take this process and turn it into intellectual property; The other is when this becomes popular and the captains of society are going to ask: “Are we okay with this at all?” If it’s peoples’ intention to get high, they won’t be okay with it. But if peoples’ intention is to have a good day then they will be okay with it. If peoples’ intention is to make amphetamine they won’t be okay with it. If peoples’ intentions are to feel good and they don’t care why they will be okay with it. In a way that is diametrically opposed to how Big Pharma moves forward today, we are looking to see that “it works” and we are less obsessive about how or why it works.

The Difference Between Pharma and HAP

Pharmacokinetics and Pharmacodynamics are two very important domains in modern pharmaceutical industry. When we consume a drug, pharmacokinetics tells us how it will disperse and at what speed, while pharmacodynamics will tell us what the drug does to our body and a bit of what our body does to the drug. Acquiring these bodies of information after manufacturing the drug creates a situation in which the manufacturer that has made the drug now knows more about it than the regulating authorities. Armed with this knowledge clinical trials phase 4 and 5 are conducted and more is learned about the drug. The practice of pharmacovigilance is an emerging trend in pharmaceutical practice and, although it is to be commended it is hard. The information collected by pharmacovigilance is collected by people who are paid to collect it. With HAP, everybody who uses the “medicine” is likely to report so as to keep their profile updated and to inform the community that they have whatever they grew.


Figure 1Crystal structure of aminotransferase AspB (NP_207418.1) from HELICOBACTER PYLORI 26695 at 2.19 A resolution

The main difference is who takes responsibility, because the difference between human assisted phytosynthesis (HAP) and prescription or OTC drugs is that the user of the

method makes a decision for herself, makes the product herself and administers it herself. She is not being told by a doctor to take something that was manufactured by a manufacturer. There is no external body involved, not in making it and not in deciding to take it. It is just the consumer and other members of the HAP community. This is a complete reversal of the paradigm because the production becomes decentralized and gets moved to the nodes. So the landscape of availability and quality become geographically sensitive. One should remember that for a large population

of HAPpers, both HAPping and allopathic medicine will be available at the same time.

Organic Chemistry and Enzyme Chemistry

Organic chemistry is the art of making soup. You have a solvent, you throw your reactants into the solvent, you warm it up, you increase the pressure or reduce the pressure (sometimes reactions are done at low temperatures), you create the conditions that make the reactants in the solvents change their chemistry in the presence of one another, under those conditions. Usually for the reaction to be effected and then to last under normal world conditions, the conditions in the reactor differ greatly from normal external conditions, which means that the temperature will be either much higher or much lower than room temperature, the pH will be either much higher or much lower than normal pH, humidity, pressure differences and the solvent environment. And that will ensure that the reaction will not reverse itself or other reactions will not continue to occur once we have removed the resulting compound from the reactor. That’s how humans do chemistry and it’s called organic chemistry.

Plants employ enzymes to do their chemical reactions. And an enzyme will effect a chemical reaction one molecule at a time. An enzyme is a functional protein. It is a name given to a piece of biological machinery (always a protein) that is always a specifically evolved catalyst for catalyzing a certain reaction.

The chemistry of bringing an amino acid into the world does occur naturally under conditions of what we call “the primeval soup”. In the conditions that prevailed in the waters of the oceans of the ancient earth where you had a lot of heat and sulphur and minerals coming out of the seabed together with lightning storms coming from the atmosphere and the water in the oceans. In this environment chemical reactions were occurring and they brought forth amino acids spontaneously. Amino acids are not enzymes. Enzymes are proteins and proteins are made of hundreds or even thousands of amino acids in a very specific sequence (a different sequence for each protein).

Organic chemistry proceeds by throwing things into the mix and hoping something happens and when something does it is recorded in the annals of chemical abstracts, which is basically an archive of over more than 100 years of chemists reporting on how they have effected a synthesis. They write: “I did this I did that, these reactants under these conditions in the environment of that solvent yielded this result…”. As soon as you have several reliable reports, all indicating the same thing, that becomes a reliable reaction, which turns into a building block of organic chemistry. The role of the solvents is to provide different environments in which things happen. All of these reactions are molecules jiggling about, and they have different geometries to the way they jiggle which in turn will change the outcome of the reaction. Enzymes on the other hand take a completely different approach. They are shaped by evolution to recognize their substrates, and attach to them in a cell. When a metabolic enzyme recognizes that it is holding its two necessary substrates it will change its shape known as “changing conformation” and thereby it will force a change to take place. The substrates are the molecules on which the enzyme acts. Really the question that we are asking is, if we want to understand how feasible HAP is, what we are really asking is how promiscuous are enzymes in certain varieties of different plants. “Promiscuous” in that sentence means, will an enzyme act on substrates that it has never seen before. For example, will an aminotransferase, when it sees a ketone group, which it replaces with an amino group, will act only on the phytoprecursor of tryptophan? Or will it also swap a ketone with an amino on say, benzopropanone, thereby biosynthesizing amphetamine? Does the enzyme look at the entire context of the molecule on which it is performing the replacement? Or does it focus only on the presence of the group being replaced (ketone in this example)? Promiscuous enzymes are enzymes that will act on substrates that they are not familiar with.


Why Should Promiscuous Enzymes Exist?

There are two evolutionary forces at work in this arena. One for promiscuity and one against. With respects to primary metabolism and the creation of primary metabolites, enzymes will tend to be specific i.e. non-promiscuous because if you change anything about the function of the enzyme primary metabolism breaks. And primary metabolism is defined as the metabolic repertoire absolutely necessary to the survival of the organism. However with respect to secondary metabolism, it actually works for the benefit of the plant to be promiscuous (this is said from an evolutionary point of view). And for secondary metabolism the promiscuity of the enzymes allows the plant, in the presence of a variety of precursors to biosynthesize a variety of different metabolites. Both of these forces for promiscuity and against promiscuity are evolutionary realities. Every plant on the planet growing in the wild, if it was to have a chance to make it in nature, has to maintain a tight ship with respects to it’s primary metabolites. That’s because the lipids have to be made for the cell membranes, the membrane bound proteins and channels must be biosynthesized, and they all have to be functional in a way that will guarantee the plants’ survival so they cannot change very much. The entire photosynthesis pathway has to be present and has to be reliable in order to turn CO2 and water and the sun’s energy into sugar. All of the sugar transport pathways must be present and must be reliable (except in parasitic plants). Because sugar must be able to get to the roots and water must be able to get to the leaves. Normally, roots cannot make sugar because they have no access to light because they are stuck underground where it is dark and leaves have no access to water because they are not in the ground. Also the signaling mechanism between the root system and the foliage system has to work to keep the two systems synchronized with each other. So for all of these systems, specificity is high because any change to them reduces the survivability of the plant. But again, this pertains to primary metabolism – the bricks and mortar of the plants living mechanisms.



You want to strictly preserve your methods when it comes down to laying bricks and mortar. You rarely want to change anything. But when it comes to decorating the house – that’s when it pays off to be creative, because changes to decoration are not mission critical. They can make the difference between a more attractive house and a less attractive one but they are not mission critical and will not make or break the ability to survive (when going back to the organism which is the metaphor of this example). That’s why secondary metabolite enzymes have an advantage by being promiscuous (or

“creative” to use the language of our metaphor). Plants are normally not lucky enough to be in a static environment. The insects and the animals, if the not the environment itself around them – are constantly changing. So it is beneficial for a plant to say, biosynthesize the pheromones of the predators of its herbivore attackers. But those pheromones keep changing and the pests keep changing. So the plant wants to, basically, change its “bag of tricks” as often as it can. “Whatever works” survives better. But when you shut off the promiscuity of that biosynthetic activity, you basically shut off development. Which guarantees that the plant will be outsmarted or outcompeted by its would-be predators, two, three or perhaps eight generations down the line.

All that said, I don’t think it is worth our while to spend too much time convincing ourselves that this is going to work, or too much time pondering whether it will work or not. The main path to discovery here is a curiosity driven, inspiration driven process. It must be planned and tried and when it leads to discoveries that actually work – we have something. So, I think it makes sense to discuss Efraim Levinson’s aromatic melons, it makes sense to talk about the metabolism of carbazemide in Israeli toxicity from Israeli vegetable irrigation – because there is literature showing that this phenomenon occurs in plants that have been watered with an external unnatural molecule which has been added to their feed. Additionally, there’s a very small body of literature, which talks about something called silent metabolism, which is the capability of plants to do things that nobody (including them) knew they could.



Those are the academic tenets, which make me think we may have a leg to stand on researching this phenomenon. But the furthest I have to get in advocating this idea, is the point where I can convince an investor to put in enough money to run enough experiments to get an outcome that is a game changer. Now, that investor should ask, and I am expecting the question of “How much money is that?” If the promiscuous enzymes are already there we’ll have to do something in the range of a thousand experiments, and we’ll get

something. We are looking for avid hippie horticulturists that find the idea of harnessing phytoenzyme chemistry in order to free us from the shackles of big pharma – enticing. I would find these people, I would ask them for their inspirations, I would have those molecules made, I would purchase a seed bank of edible microgreens, or smokables, or steepables and grow these seeds into their third week and then test. That’s the best-case scenario. Others should be discussed.

Quantities

Let’s touch on concentration of metabolites in plants. Sucrose comprises 11% of the dry weight of sugarcane. Cocaine comprises 3% of the dry weight of the coca leaf and 0.5% of the wet weight of the leaf. These concentrations are well established over many validations. If we can achieve a comparable concentration in, say, alfalfa sprouts – which are biosynthesizing a compound active at 200mg, then one would need to consume 100 grams of vegetable material – the equivalent of a small side salad, to get the full effect. Microdosing would be achieved at the consumption of 10 grams of vegetable material.

DSHEA – Dietary Supplement Health and Education Act

A public-service ad that first aired in December 1993 showed camouflaged Federal agents equipped in full Special Forces gear, including night vision and weapons converging on Mel Gibson, who says, in defense, as he holds up a supplement bottle: “Hey. Guys. Guys. It’s only vitamins.”

DSHEA is in a clash of titans with the FDA. According to DSHEA:

The term “dietary supplement” -

  • “(1) means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:

  • “(A) a vitamin;

  • “(B) a mineral;

  • “(C) an herb or other botanical;

  • “(D) an amino acid;

  • “(E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or

  • “(F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E);


So if you are feeding a chemical to a plant, and the plant is turning it into another chemical. The resulting chemical is a metabolite. Furthermore, if you then extract this metabolite the resulting chemical is both a metabolite and an extract. Now, they didn’t mean for DSHEA to be used this way because nobody thought that we could make plants make whatever we wanted them to. It didn’t occur to anybody but the law says metabolite. And until the law is changed, that’s what it says. When the law is changed and if it is ever changed. The main question that will be on everybody’s mind is the intention. If the intention of HAP is to get high, it will not wash. If the intention is to have a better day or be more productive it will.

People Who Practice HAP are HAPpier

Microdosing is not about getting high. It’s about correcting our routine. It’s about slight adjustments to our mental tendencies so as to be more in tune with the kind of life that we are expected to lead. We are not naturally evolved to put up with the amount of stress that we do. We are not naturally evolved to know the amount of people that we do, to deal with the complexities that we do. There are many things about our modern routine that did not exist when our brains and bodies evolved. They are the product of a cluster of rapid cultural changes led by technology that make our lives today very different from the lives of the ancestors that evolved us into what we are today.

Creating compounds in plants and then consuming them to alleviate chronic pain, or chronic fatigue, or chronic anxiety, or chronic writer’s block is a beneficial activity and can be patented.

Value Adding Activities

At the core of this endeavour is the experiment in which a new compound is introduced to the growing plant. If this results in failure, i.e. no desired result is detected; the failure is recorded for future reference. If it results in success we should break down the success into its components. The intuition for the phytoprecursor was the first value added. Then the chemical production of the feed molecule was the second. The third is growing the experiments, and the fourth is testing or tasting. These activities correspond precisely with the four roles mentioned a few chapters ago in “the HAPpening community”. The roles of the intuition provider, the experimental molecule provider, the grower and the taster correspond exactly to the value adding activities.




Testing For Success

There are two ways to detect if the intuition behind the phytoprecursor is being enacted by the plant. One way is to use analytical chemistry to look for the presence of our target molecule in our vegetable material. And the other way is to taste and let the human brain be the judge.

Each of these approaches has its challenges. The analytical approach must detect a single chemical on the background of 4000 others. In addition, the analytical chemist does not know exactly what he’s looking for, because if the phytoprecursor was metabolized, we do not know by which enzyme and we do not know if it was metabolized by only one enzyme or more.

The tasting approach has its challenges because the result or the precursor might be harmful. To mitigate this one can feed initially to animals and taste the plants only if the animals survive. Another approach is to follow a logarithmic scale in consumption. This floats both potential dangers and effects early, before the dosage consumed is allowed to become a dangerous one.

Market Structure

Today we have:

  1. Total world population - 7.7 Billion

  2. Buyers of Pharmaceuticals – 2.8 Billion (guesstimate)

  3. Companies with GMP certificate ~20,000

  4. Companies with Marketing Authorization - 200 (BIG PHARMA)

  5. HAPPY…?


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