Plants are rich sources of medicines and drugs. This has been known since we humans started living together in communities. (Indeed, it appears that even chimpanzees chose to pick and eat specific plants as medicines). Ayurveda, Unani, Siddha, tribal medicine, Oriental medicine and Homeopathy all use plant-based compounds as medicines and tonics. The discipline of organic chemistry has specific branches such as natural products chemistry and medicinal chemistry. Practitioners here collect chosen plants and try to isolate specific molecules from them, study their specific chemical structures, check their effectiveness against chosen diseases (an area called pharmaceutical chemistry).
A given plant contains thousands of molecules and has them in varying amounts. Often, the ‘drug molecule’ one is looking for occurs in tiny amounts. It is thus not just a ‘needle in a haystack’ problem; one needs many haystacks in order to collect the target compound in a reasonable amount (say several grams) to work with. Natural products chemistry has thus been a very challenging area, and the successful practitioners are considered heroes and decorated with awards and honours. A recent example is the Chinese woman scientist, Dr. Youyou Tu, who was given the 2015 Nobel Prize in Physiology or Medicine for her back-breaking decades-long work of isolating the anti-malarial drug molecule called artemisinin from the Chinese herb Qinghao.
Once the natural products chemist isolates and determines the actual chemical structure of the drug molecule, he/she attempts to make (synthesise) it in the laboratory. This is yet another challenging and back-breaking task. Since the molecule is three-dimensional in shape, its architecture (or the spatial arrangement of atoms within) can be quite complex. To build such complex molecules in the lab is somewhat akin to the job of an architect putting together a building from bricks and mortar. (Here too, heroes are recognised. One such is the late Professor Robert Woodward of Harvard, whose decades-long successful achievement of the synthesis of several complex molecules fetched him the Nobel Prize in Chemistry in 1965). It was with this analogy in mind that the late Professor Subramania Ranganathan, an outstanding organic chemist, wrote a monograph titled: “The Art of Organic Synthesis”.
How does Qinghao make artemisinin? It involves over a dozen steps, many of them catalysed by enzymes which are protein molecules. We have been able to decipher each of these steps, and the genes involved in synthesising these enzymes in the plant cells, in fact the whole gene cluster involved in the process. Now, given this knowledge, and given the advances in genetics and genetic engineering, can we make artemisinin in the lab, using genetic engineering methods, rather than organic chemical methods? And if we were to insert this gene cluster into a microbe, say baker’s yeast, will the yeast produce artemisinin? If we can do this, we need not harvest tonnes (‘haystack’) of the herb, but brew the yeast in large cultures, and manufacture the drug in kilogram quantities!
This idea of recruiting a microbe to make artemisinin (or for that matter any molecule that a plant makes) is a true “Out of the Box” one. If we succeed, we would have made a ‘plant’ out of baker’s yeast - which has been used in homes and bakeries for the last five millennia or more! But this demands that the yeast cells contain (besides their own genome) the genetic cluster that the plant has, in order to produce the desired drug.
Idea worth pursuing
Thanks to the advances in genetics and genetic engineering, this idea is no longer foolhardy but worth pursuing; so argued Professor Jay Keasling of the University of California, Berkeley, and Dr. Neil Renninger of the company called Amyris. Aided by a grant from the Gates Foundation, their team chemically synthesised the entire gene cluster used by the herb to produce the drug, modified it to suit the yeast cells, and inserted the cluster into yeast cells. Culturing the genetically modified yeast in the laboratory, they found that they could produce artemisinin from yeast. (This landmark paper by V. Hale et al., in Am. J. Trop. Med. Hyg., 77, 198-202, 2007 is accessible free on the web). By 2013, the group had improved the method and has been able to produce as much as 25 grams of this anti-malarial medicine per litre of the culture medium.
During the last a few years, several other drugs, naturally found in plants and herbs, have been produced in yeast. The most recent is a paper by Li et al., from UC Riverside and Stanford, published in PNAS last month, where they made the anti-cancer drug noscapine (found in the opium-making poppy plant), again using yeast (www.pnas.org/cgi/doi/10.1073/pnas.1721469115). The trick is to identify the cluster of genes involved in making the molecule in the plant cells, make them in the lab, insert them in yeast, optimise the conditions and generate the molecule in yeast, the new plant ‘avatar’. Baker’s yeast (or Khmer as the Arabs call it), known for over five millennia, to leaven bread and to brew alcohol, now has another equally useful role.
dbala@lvpei.org
