Herbalism and biotechnology

Pacific yew used for its anti-cancer properties

Herbalism is the study of using plants for medicinal purposes and has dated back since the first humans arose around 100,000 to 200,000 years ago. Since then, herbs have been used by cultures across the world to treat a variety of ailments and diseases. As modern medicine has progressed, traditional practices of herbalism have been considered to be primitive and archaic. But with the rise of new technology, the invaluable information accumulated by this practice in combination with biotechnology could be used to open up new way of approaching medicine through expanding the current library of compounds to be used for pharmaceutical advancement and being able to develop new and effective treatments for complex diseases.

History of herbalism

With the 400,000 of plant species known to date, there are many metabolites derived from plants that can be applied to human biology from curing headaches to autoimmune diseases. For instance, morphine, a pain drug, comes from poppy, while paclixatxel, an anti-cancer drug, comes from pacific yew. Humans have used these properties of plants across numerous cultures and have accumulated a rich collection of data on the causes and effects of certain plants on the human body. This gave rise to the practice of herbalism, which in the past served as many cultures’ primary method of dealing with ailments. The first written records of herbalism date back to Ancient Egypt around 1,500 BC in the Papyrus Ebers where more than 800 plant medicines and their effects on the human body were documented. The Compendium of Materia Medica, written by Li Shizhen, a Chinese herbalist of the sixteenth century, contains information on 1,893 different herbs and 11,096 prescriptions, demonstrating the breadth of knowledge accumulated on herbalism. In many cultures, herbalism is often tied with spirituality. For example, in African culture, it is believed that healing is a religious act, while in the Chinese culture, vital energy (qi) and the balance between yin and yang play a crucial role in healing. Perhaps due to the lack of scientific evidence, herbalist practices has been disregarded, but it is no accident that so many cultures from across the world have chosen to treat disease through plants. Plants hold many biological solutions that can be applied to humans and paralleled with years of trial and error on behalf of herbalists to harness this information, herbalism has the potential to revolutionize modern medicine.

Modern herbalism

Currently, many of the treatments approved by the FDA are single-compounds and do not have the ability to treat complex issues such as cancer or type II diabetes. However, many of the prescriptions found in herbalism use multiple ingredients mixed in a specific ratio to be synergistic. This is known as the combinatorial effect and it is hypothesized that through multiple metabolites targeting many different sites, the simultaneous action has the potential to cure these complex diseases. For example, a treatment called Food Allergy Herbal Formula-2 (FAHF-2) is currently under development to reduce peanut allergies. Developed by Chinese scientist Xiu-Min Li, FAHF-2 was refined from an ancient traditional Chinese herbal prescription known as Wu Mei Wan, which was originally used to cure intestinal parasitic infections but shares a similar mechanism as a food allergy. It consists of nine different herbs and has shown in trial to be effective for curing food allergies. However, when these nine different herbs are used individually, the treatment is much less effective, demonstrating the power of the combinatorial effect. As many herbal prescriptions use the combinatorial effect, if this phenomenon can be analyzed and understood, many kinds of diseases could be cured with just a single prescription.

The power of herbalism has shown itself to be very promising, but perhaps in conjunction with new developments in biotechnology, it can be used to its full potential.

Developments in biotechnology

Bioinformatic algorithms

Bioinformatics is the use of computers to solve biological problems specifically within the fields of macromolecular structures, genome sequences, and the results of functional genomics experiments, where large sets of data are involved. For example, they have been used to search a database of gene expression data sets from human cells treated with various small molecules. This database allows researchers to find patterns between small molecules and their mechanisms of action and can be applied to the field of herbalism through identifying the medicinal properties of plant compounds. For instance, this technology aided in the discovery of celastrol, a compound extracted from plant called Tripterygium wilfordi commonly used in traditional traditional Chinese medicine as a leptin sensitizer used to control obesity. Gene expression signatures of lean and obese mice were compared and through analysis researchers determined that celsastrol was the top compound in the database that correlated with anti-leptin resistance. Later, celastrol was tested in mice and shown to reduce obesity and could potentially be used as a treatment for obesity in humans. This example demonstrates the power of plant metabolites and how valuable knowledge of herbalism can as new technology such as bioinformatic algorithms are employed.

Crystalline sponge method

X-ray single-crystal diffraction is often used to identify and analyze structures of compounds which is an important step to analyzing existing herbal prescriptions to develop new medications. However, this method has key restrictions which limit its use. X-ray single-crystal diffraction requires the sample to be obtained as single crystals and in larger quantities. The crystalline sponge method would allow the sample to be aqueous and also requires as little as 80 nanograms of the sample. The technology uses networked porous metal complexes which have high molecule-recognition ability that can absorb molecules from an aqueous solution and order them regularly in the crystal. This way, the molecule can be analyzed with x-ray diffraction and provides a much higher accuracy than nuclear magnetic resonance (NMR) and mass spectrometry. With this technology, researchers were able to uncover the complete stereochemistry of miyakosyne A, a scarce natural marine product. Due to the small structural difference between one methylene unit, chemical and spectroscopic methods were not precise enough to determine its exact structure, making x-ray diffraction the only viable method. A tiny crystal sponge of approximately 100 by 100 by 100 µm3 was treated with 5 mg of miyakosyne A and analyzed with x-ray diffraction. This allowed the complete structure of miyakosyne A to be revealed, making researchers hopeful for its application in a variety of its fields, including herbalism. As many organic compounds from plants must first be dried into a powder and in large quantities before analysis or analyzed through inaccurate methods such as NMR or mass spectrometry, the crystalline sponge method would greatly simplify the process of identifying compounds of interest. As a result, this would make it easier for researchers to study specific metabolites and their potential applications.

Combinatorial biosynthesis

Combinatorial biosynthesis is the use of engineered enzymes and pathways to produce different metabolites as opposed traditional chemical synthesis, which is costly, inefficient, and produces byproduct waste. So, in the context of herbalism, if a specific metabolite is scare in its herbal form, it can be produced through combinatorial synthesis to create a cheap and eco-friendly treatment. Currently, there are three major strategies for combinatorial biosynthesis: precursor-directed biosynthesis, enzyme-level modification, and pathway-level recombination.

Precursor-directed biosynthesis creates different metabolites through using different substrates through the same metabolic pathway. Because pathways are promiscuous and non-substrate specific, nonnative substrates can be integrated into the pathway to produce useful variations of metabolites. If this approach is used to manipulate the metabolic pathway of certain herbs, it could lead to new drug discovery.

The second strategy for combinatorial biosynthesis is enzyme-level modification, entailing either swapping entire domains, modules, or subunits, site-specific mutagenesis, or directed evolution. Swapping entire domains, modules, or subunits of enzymes is the classical approach of combinatorial biosynthesis and allows for the direct editing of enzymes in a specific pathway, resulting in new metabolites. Site-specific mutagenesis is the modification of individual amino acids in a sequence. Compared to the previous technique, it is less invasive, leading to higher yields of viable protein. By introducing a single mutation, the substrate specificity of the protein can change, which could improve drugs and even make natural substances found in plants more effective at treating disease. Directed evolution takes a similar approach to site-specific mutagenesis, but creates larger alterations. As a result, new metabolites can emerge with and make existing treatments even more effective.

The final strategy for combinatorial biosynthesis is pathway-level recombination. This is the editing of the pathway itself. Pathway-level recombination is performed through using biosynthetic genes from different species of organisms to create a pathways in a host organism. This technique often used to edit yeast so they can produce metabolites of interest from rare herbs or plants.

References

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