The concept of growing plants for human health and general well-being, rather than
for consumption as food alone, is changing people’s perception of plant biotechnology
and synthetic biology. Resurrecting the long-forgotten connection between plants and
health has launched a new generation of botanical therapeutics, which include dietary
supplements, functional foods, pharmaceuticals and multi-component drug mixtures.
Technological and methodological advances have made the discovery, validation and
manufacture of high-value phytochemicals a reality, and botanical therapeutics have
come of age.
Plants are integral to human well-being. In addition to their obvious nutritional
value, for centuries they have also been used for their healing properties. Plant
parts, potions and powders have been, and continue to be, used in traditional medicine
by a number of tribes with varying degrees of success to boost vigor, as well as to
prevent and cure disease. Archaeological evidence suggests the use of plants by humans
for medicinal purposes during the Paleolithic age, with the first written evidence
dating back to the Sumerians (Sumner, 2000).
By the 21st century, the pharmaceutical industry had mostly replaced natural plant
extracts with chemically synthesized molecules to prevent and treat diseases. With
the introduction of medicine in the form of easy to consume ‘pills’, it is easy to
dissociate plants from health and thus overlook the many modern medicines which still
contain phytochemicals in their natural form or as derivatives. Until the 20th century
plant extracts were regularly screened for novel pharmaceutically active compounds,
which were then purified from the native plants. The emphasis of the pharmaceutical
industry then shifted to making these natural products synthetically, and using them
as templates for generating structural analogues as a means of obtaining new chemical
entities with desired efficacy.
The richness and diversity of novel drugs that can be discovered from plants have
also been challenged by competition from the fields of combinatorial chemistry (Pandeya
and Thakkar, 2005; Liu et al., 2017) and computational drug design (Sliwoski et al.,
2014). It can be argued that several years of bioprospecting have resulted in the
identification of the most relevant and relatively abundant plant natural compounds
with pharmaceutical value. However, it is possible that several high-value plant-derived
compounds with pharmacological activity still remain undiscovered, either because
they are produced in plants which are not easily accessible or due to a lack of advanced
methodologies (Mendelsohn and Balick, 1995; Van Wyk, 2015). All living plant species
in the world together contribute to a greater chemical diversity of bioactive compounds
than any man-made chemical library, and therefore finding novel plant molecules today
would require more sophisticated discovery approaches.
Engineered well-ness
In addition to the pharmacological relevance of plant natural products, there is a
growing trend of boosting human well-ness by incorporating plant parts and products
into daily diets in the form of functional foods and dietary supplements (Box 1).
The regular consumption of certain fruits and vegetables is suggested to reduce the
risk of chronic diseases like cancer, diabetes, heart diseases and obesity by functioning
as medicinal nutrition therapy (Martin et al., 2013). Flavonoids comprise one such
class of phytochemicals that is commonly found in fruits, vegetables and some beverages
including wine. Flavonoids are polyphenolic compounds with health-promoting biochemical
and antioxidant effects that are beneficial for nutraceutical, pharmaceutical and
cosmetic applications. This widely distributed class of plant specialized metabolites
comprises over 8000 compounds bearing a common diphenylpropane backbone; these are
found in several parts of the plant and are commonly recognized as flower pigments
(Panche et al., 2016). It is estimated that the Western population consumes 20–50
mg of these compounds in their diet daily. Tohge et al. (2017) present an overview
of the chemical diversity of flavonoids across plant species, and showcase the impact
of technical advancements in making better phytochemical inventories for plants, with
a focus on the model plant Arabidopsis and the crop plants tomato, maize, rice and
beans. The increased accessibility of whole-genome sequencing, together with reverse
genetics and molecular phenotyping, have greatly contributed to the current understanding
of flavonoid metabolic networks (Tohge et al., 2017). The data emerging from the 1001
Arabidopsis genomes project and the 1000 plants project will enrich the structure-to-function
relationships of flavonoids to benefit translational research in the future.
The advent of fast and cost-effective next-generation sequencing technologies have
revolutionized the study of genomics and molecular biology in non-model plants that
were previously deemed inaccessible. These high-throughput platforms enable us to
study the unique structural organization of genes and the regulatory mechanisms underlying
gene expression patterns, generate catalogs of specialized metabolism at the species
level, and allow evolutionary analysis of genes, enzymes and pathways across species
(Unamba et al., 2015). The increased availability of genomic sequencing data has also
shed light on the phenomenon of gene fusions in the biosynthesis of plant natural
products. Hagel and Facchini (2017) comprehensively describe the gene fusions implicated
in plant metabolism, discuss the possible mechanisms of their origin from an evolutionary
perspective, explore the impact of fusion events in metabolism, and outline the potential
uses of gene fusions in biotechnology (Hagel and Facchini, 2017).
The ever-growing technological advances in modern biotechnology today allow the precise
engineering of new traits in plants within a short time, as opposed to traditional
plant breeding. The CRISPR/Cas system allows the engineering of plants without residual
exogenous DNA, which is beneficial for USDA approval of the final product. Advances
in technologies and methodologies are revolutionizing plant engineering at several
levels. Larsen et al. (2017) present interesting new advances in the functional characterization
of transporters, proteins integral for cellular function. Using a combination of in
silico, function- and phenotype-driven screens, several plant transporters have been
identified and functionally characterized in different plant species (Larsen et al.,
2017). Although transport proteins are not primary engineering targets for trait improvement
in plants, they offer innovative engineering applications for enhancing yield and
plant performance under stress, both of which are interesting from an agricultural
perspective. In fact, next-generation sequencing data have enriched our understanding
of natural genetic diversity among plant membrane transporters, and allowed their
engineering in crop plants like wheat and rice for sustainable food production even
under severe environmental conditions (Schroeder et al., 2013).
Today’s companies
Besides trait engineering in plants with a view to augmenting human health, the production
of high-value phytochemicals using synthetic biology approaches is a reality today.
Companies like Evolva (evolva.com) and Amyris (amyris.com) take pride in using synthetic
biology strategies for solving the supply-chain issue of nature through the bulk production
of plant natural compounds in microbial organisms. There is an upsurge in biotech
startup companies like Ginkgo Bioworks (ginkgobioworks.com) that are based on engineering
microbes for customers across multiple markets. Through its foundries, this organism-engineering
company has scaled and automated the process of making all sorts of chemicals in microorganisms.
These companies primarily focus on metabolically engineering organisms to make profitable
amounts of high-demand compounds that find applications in nutrition, health and personal
care products, flavors and fragrances, and cosmetic additives. Moses et al. (2017)
provide a systematic guide for the engineering of biorefineries from unicellular chassis
using rational design principles, whilst emphasizing the choice of chassis as a key
determinant for successful engineering (Moses et al., 2017). It cannot be reiterated
enough that synthetic biology has simplified and made achievable the design and construction
of novel biological systems to screen for and produce new bioactives, food additives,
fragrances, dietary supplements, and many other high-value chemicals.
Future prospects
Plants are poised for a comeback as technological advances unravel unique properties
and applications for diverse phytochemicals, either as pharmaceuticals or nutraceuticals
to boost human health (Box 1). High-throughput sequencing technologies will generate
a torrent of data in the coming decade from several ongoing multi-species plant projects.
The affordability and ever-increasing sensitivity of these techniques has rendered
sequencing of non-model, difficult to cultivate, and slow-growing plants plausible.
Indexing species-specific phytochemical signatures will enable effective rational
bioprospecting in the future. Alongside good cataloging of phytochemicals, it is also
time to expand engineering toolkits for both plant biotechnology and synthetic biology
to include less obvious molecular targets. For instance, the engineering of exporters
in microorganisms would obviously facilitate the export of the product out of the
cell, but in addition could also circumvent feedback inhibition and compound-associated
toxicity, which in turn can increase yields and enable cost-effective downstream purification
of the product.
Box 1. Resurrecting the long-forgotten connection between plants and health
A big challenge still for phytochemical-based therapeutics is integrating the discovery
of complex biosynthetic pathways with better characterization of molecular targets
for the prevention and treatment of complex diseases. Likewise, assessing the compatibility
of multifunctional phytochemicals and complex multicomponent plant extracts for disease-specific
treatment is a challenge. However, contemplating the use of natural products in functional
medicinal foods as a means of disease prevention, rather than treatment, is highly
conceivable. As holistic approaches to prevention and treatment of sickness are increasingly
gaining popularity, convincing the consumer market to make food choices for health
benefits might be easier than currently anticipated. Plants easily represent the most
abundant renewable source of high-value compounds, as they have evolved to synthesize
a range of complex natural products efficiently. In addition, the upsurge in energy
and chemical raw material costs, together with environmental concerns of carbon dioxide
emission are detrimental to the pharmaceutical manufacturing of plant compounds. The
result of dramatic advances in metabolic engineering, synthetic biology, genomics,
proteomics, functional and molecular characterization, and pharmaceutical or nutraceutical
screening, sets the path forward for botanical therapeutics. In the future, farmers
who adapt their farming practices for the production of crops that promote health
rather than provide calories are predicted to profit, and as a result the planet could
become greener and healthier.