2015 Nobel Prize highlights importance of botanical chemistry

1600 years ago, a Chinese physician wrote in a book called "Emergency Prescriptions Kept Up One's Sleeve", that soaking a plant now known as Artemisia annua  in water, and then drinking the juice, can reduce fever. This text was rediscovered in the second half of the 20th century by a then obscure Chinese pharmacologist, Tu Youyou. Ms Tu was working on a secret project to find a novel cure for malaria. She found that artemisia extract was highly efficient in combating the malaria parasite. Her work led to the development of the drug artemisinin, which is now widely used in malaria treatment in Africa.  Ms. Tu's role in the discovery of artemisinin remained hidden from the West for most of her life. But now at the age of 85, she has been recognized with the 2015 Nobel Prize in Medicine for her work

An illustration describing Ms Tu's work displayed during the press conference announcing the winners of the Nobel Medicine Prize. Linked from and The Telegraph: Nobel Prize for Chinese traditional medicine expert who developed malaria cure. Photo: AFP

This reminds us that many of our medicines have their roots in botany. The ancient Greek physician Hippocrates described a bitter substance, now known to be salicylic acid, from willow bark that could ease aches and reduce fevers. Other cultures in the ancient Middle East also used willow bark as a medicine, as did Native Americans. Centuries later, we know salicylic acid as the chemical precursor for aspirin (which is acetylsalicylic acid), and salicylic acid itself is a key ingredient in many modern anti-acne face washes.

The Pacific Yew is a conifer found primarily in the Pacific Northwest. Its thin scaly back would probably go unnoticed if not for the fact that it contains a chemical called paclitaxel, or more commonly known as the chemotherapy drug Taxol. Taxol was discovered in the mid 1960s as part of a large-scale program to identify natural products which might be used against cancer. In 1992 Taxol was approved by the FDA for use in fighting breast, ovarian and lung (and a few other) cancers.

And what would life be like without the opium poppy, the source of morphine or codeine. The medicinal (and likely recreational) uses of opium poppy have been known for thousands of years. And the increasingly legal uses of cannabinoids in western medical protocols cannot be ignored.

These are prime examples of how a deep knowledge of botanical diversity and chemistry can lead to incredibly important applications.

Unfortunately, education towards and development of expertise in these fields over the past decades were not a priority for many universities, where plant biology outside of the study of model organisms was looked down upon. At Tel Aviv University we've recognized the importance of botanical pharmacology. As Dean of the Faculty of Life Sciences, together with the Dean of the Faculty of Medicine, we have initiated a search for a botanical pharmacologist whose position will be divided between our two Faculties, between plant biology and pharmacology. Such interdisciplinary research is critical for exploiting the medicinal potential hidden in plants.

Fun with Gat

Catha edulis (gat)

Catha edulis, better known as gat or khat, is native to Yemen and the Horn of Africa.  Locals chew on the leaves, which releases small concentrations of a neuroactive alkaloid called cathinone.  This stimulates the cental nervous system, and according to gat chewers, increase endurance, gives a feeling of strength and health, suppresses hunger (which is an advantage in areas known for chronic famine) and tiredness (which is an adavantage during hard labor and long walks). Because the leaves contain so little cathinone, large qauntitites of leaves have to be cchewed to get any effect. Consequently, gat-chewing is a social experience with groups of men or women sitting around and chewing and conversing together. In Yemen gat is so popular that 40% of the county's water supply is dedicated to gat agriculture!

Hagigat in Tel Aviv

Of course western culture doesn't have time for hours of leaf chewing (or the stomachs to see people spitting out the leaves and juice, though this to me seems no different than chewing tobacco). An Israeli biochemistry student working for some shady characters isolated cathinone from gat, who then marketed it in a concentrated pill called hagigat, which loosely translates to "party gat". While initially legal, hagigat soon became abused in the local party scene, was connected to several hospitalizations due to damage to the cardiac and central nervous systems, and was added to the list of illegal drugs. 


Gat itself though is still legal in Israel and many other countries. Apparently, its difficult to abuse something that you have to chew for hours. 

The chemistry of pot

We all know that THC (Δ⁹-Tetrahydrocannabinol) is the main active ingredient of marijuana. However, you may not be aware of the high-tech research going into figuring out how pot plants make THC.

A recent paper published in the Proceedings of the National Academy of Sciences of the United States of America (affectionately known as PNAS) illustrates how some of this research is carried out.

To produce THC, cannabis employs a number of differenet enymes which work in a linear series simplified below:

hexanoyl-CoA + malonylCoA --> OA --> CBGA --> THCA --> THC

Each of the arrows is a different enzyme. A big challenge in understanding how cannabis makes THC (and maybe to be able to make it artificially) is identifying each of the enzymes. As the biochemistry behind this pathway is very complex, this has not been a simple matter.

trichomes on a Cannabis sativa leaf

The lab of Jonathan Page in Saskatchewan figures that the genes encoding these enzymes should be specifically enriched in the THC-rich trichomes, the sticky, furry things on cannabis leaves. They first identified all the genes that are expressed in these trichomes, and then, using their knowledge of enzymology, sought out particular genes that looked like a particular class of enzymes that could potentially take part in the chemistry of the first arrow. They found three candidate genes, and then put each into E.coli to make the proteins. When they added these proteins to hexanoyl-CoA and malonylCoA, the precuursors of OA, they found OA is the mixture. In other words, they identified gene encoding the enzyme for the first arrow. 


When they put this gene in yeast, the yeast started making OA. Just think of the possibilities for beer if they wold add the genes for the arrows...

Yesterday-today-and-tomorrow

Brunfelsia pauciflora (yesterday-today-and-tomorrow)

The Brunfelcia is a small shrub with beautiful pansy-like flowers. Yesterday-today-and-tomorrow is aptly named as its flowers begin life with a deep purple color which change to lavender, and finally fade away to white. While native to Brazil, this evergreen shrub has been cultivated and is used in gardens indoors and out. It also contains a neuro-active drug called "scopoletin". Animals or people who mistakenly eat this plant develop an irregular heart rate, dryness of the mouth, dilated pupils, and in rare cases, coma. In controlled dosage, this chemical can be used as a medicine.

Is Marijuana Kosher for Passover?

In the spirit of the Passover Holiday, I couldn't resist commenting on this. High Times, which since 1974 has been spreading the gospel of legalizing pot, has run an article asking the obvious question, can a person get high on Passover and still be religious?

This may not be as absurd as it seems, as the question on what is kosher for Passover, and what isn't, is taken very seriously in some circles, and can even lead to familial conflict. For example, when I was a kid, rice was verboten as it is for all Ashkenazi Jews. This is NOT because rice is a leavened product. Indeed the Talmud clearly states that rice should be eaten at Seder to commemorate sacrifices at the temple. But a few hundred years ago European rabbi's decided that rice COULD be contaminated with wheat, and this should not be eaten during Passover. This prohibition was expanded to include other grains and legumes. The overall effect on the Ashkenazi digestive system is best left not discussed.

Sephardi Jews though never adopted this extreme position, and as such their seders contain rice and a variety of foods I could only dream about. So I was totally shocked 30 years ago to find out that my wife's family eats rice on passover! Not that my wife is Sephardi, but her family had years ago adopted the customs of one of the uncles by marriage. It didn't take long until I also became a convert.

Which then leads us to the question of marijuana. Now under no condition should this be construe as a call for illegal activity (for those unfortunante places where marijuana is still considered a controlled illegal substance)! But IF one were to partake in any illegal activity, is it still kosher (for Passover that is)?

The article concludes that marijuana would fall under the classification of legumes, which means that, as always, the Sephardim get to have all the fun.

Poppies

Papaver someniferum (Opium poppy)

What would life be like without the opium poppy? No poppy seed bagels. No beautiful poppy flowers. No Dorothy falling asleep in the poppy fields in the Wizard of Oz. No morphine or codeine. The use of poppy as a pain killer is probably it's claim to fame and, when misused as in heroin, to infamy. The medicinal uses of opium poppy have been known for thousands of years. Turkey, India and surprisingly Australia, provide most of the worlds legal opium poppy. I once saw some opium poppy growing in a road divider on the way to Hadassah Hospital. Obviously it was planted for convenient use in the hospital, and not for any illicit uses.