Slow translation of Tropical Africa’s wealth in medicinal plants into the clinic: Current biomolecular infrastructural capacity and gaps in sub-Saharan universities

Tropical Africa has one of the world’s largest endowments in medicinal plant diversity. However, this potential has not been translated into pure drugs of proven efficacy and safety synonymous with modern pharmaceuticals. The basis for the slow translation of Tropical Africa’s medicinal plant wealth into value-added medicines acceptable in the doctor’s clinic is not clear. In this work, we sought to understand the patterns of research on African medicinal plants in general, and the capacity of subSaharan universities to conduct value-building research on plant-derived medicines in particular, using an extensive online search. A near-exponential growth in number of publications over the period 2000 to 2015 was found. However, most of the primary literature is on preliminary pharmacological assays and ethnobotany/ethnopharmacology. Only 6% of the publications are on advanced investigations such as isolation, structure elucidation and semi-synthetic optimization of natural compounds, structural studies of drug targets, ligand binding studies and cell biological assays, yet they are fundamental to progression of lead compounds into useful drugs. Assessment of the current biomolecular infrastructure in 25 sub-Saharan universities found severe shortage of essential equipment in many of them. Only 64, 68, 36 and 68% of the sampled universities have high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatographymass spectrometry (LC-MS), and nuclear magnetic resonance (NMR) equipment, respectively. East, Central and West Africa are particularly deficient in most of the key equipment, and some available are non-functional. The purchase cost of most biomolecular research equipment is between USD 30,000 and USD 500,000. Further analysis shows that the cost of establishing comprehensive biomolecular research infrastructure in at least one university per sub-Saharan nation is negligible relative to their gross domestic products (GDPs). Thus, even with the current economic resources, sub-Saharan African countries would upgrade biomolecular research capabilities in their leading universities without disrupting other economic priorities.


INTRODUCTION
Pure pharmaceuticals containing one and sometimes 2 to 4 active molecular entities of proven clinical efficacy and safety are the backbone of allopathic medicine (modern health care).Before the advent of allopathic medicine, humans relied wholly on natural products (plants, animals, and minerals) to manage ailments via culturally and geographically unique traditional medicine (TM) systems.Records of plant use in TM date to the early civilizations of mankind in Mesopotamia (around 2600 BC) and Egypt (Gurib-Fakim, 2006).And yet, despite the adoption of allopathic medical practice as the primary healing tool throughout the globe over the last two centuries, the medical role of natural products has barely declined.Firstly, over 50% of approved active molecular entities in modern pharmaceuticals have natural origin (Gurib-Fakim, 2006;Pan et al., 2013).Furthermore, at least 25% of active molecular entities in clinical use today have some affiliation to higher plants either as direct metabolites or as semi-synthetic derivatives of plant metabolites (Gurib-Fakim, 2006).Secondly, about 80% of the world's population still use TM for health care, the vast majority being in the resource limited countries of Africa and Asia (Ekor, 2014;Gurib-Fakim, 2006;WHO, 2002).Unfortunately, TM heavily relies on crude herbal extracts whose quality, efficacy and safety have not been scientifically validated (Ekor, 2014;WHO, 2002), hence desired therapeutic outcomes are not guaranteed.
Though, the 1980s and 1990s saw dramatic improvements in chemical synthesis capabilities with the advent of combinatorial synthesis (Seneci and Miertus, 2000), the success of drug discovery via de novo combinatorial chemistry has been mute.Despite being used by drug developers, 70% of the time over the last 30 years, de novo combinatorial chemistry has yielded only one Food and Drug Administration (FDA)-approved drug, the renal anticancer agent sorafenib (Newman and Cragg, 2012).In fact, of all the small molecule drugs approved by the FDA over the 30 years between 1981 and 2010, more (50%) were of natural original compared to 30% from purely synthetic sources (Newman and Cragg, 2012).In some disease categories such as microbial infections, about 70% of drugs approved over those 30 years are either natural products or associated with them (Newman and Cragg, 2012).Thus, drug development from natural products retains tremendous success and should be exploited to solve recalcitrant disease challenges.
The WHO African region, which comprises Tropical Africa and Algeria, has the highest burden of disease and worst health indicators in the world.The total burden of disease for the WHO African region is 74,000 disability adjusted life years (DALYs) per 100,000 population compared to 50,354 for East Mediterranean, 40,341 for South East Asia, 34,759 for Europe and 28,720 for the Americas (WHO, 2015).Furthermore, the life expectancy in the WHO African region is least in the world at 58 compared to the global average of 71; adult mortality rate is 306 per 1,000 population relative to a global average of 152; and 1,039 deaths occur per 100,000 population compared to a global average of 789 (WHO, 2015).A large proportion of morbidity and mortality in the WHO Africa region is due to communicable diseases which are either unique to tropical Africa or disproportionately affect the region more than others, for example, malaria and the 13 neglected tropical diseases (NTDs) (Feasey et al., 2010;WHO, 2015).Over 90% of the 584,000 annual deaths from malaria occur in Tropical Africa (WHO, 2015).The NTDs, a group of 13 severely debilitating infectious diseases unique to the world's poorest in the tropics, and are not commercially attractive for drug development by leading commercial pharmaceutical innovators due to the low market value of the affected population causes another 534,000 deaths per year (Hotez et al., 2007), most of which are in Tropical Africa.Where available, drugs for treatment of NTDs often have major drawbacks which hinder clinical outcomes.For example, drugs for the treatment of human American trypanosomiasis (Chaga's disease), human African trypanosomiasis (sleeping sickness) and visceral leishmaniasis, the three NTDs associated with most fatalities and disability either have inadequate efficacy or are severely toxic (Hotez et al., 2007(Hotez et al., , 2016)).There are also a few drug choices for many infectious diseases, which limits treatment options and threatens public health in the face of unprecedented rise in resistance to existing antimicrobial drugs (WHO, 2014).Thus, Tropical Africa needs an elevated role in drug development for its enormous infectious disease burden to be prioritized.Tropical Africa has about 45,000 medicinal plant species, arguably the most endowed in the world, but this potential has not been translated into pure drugs for modern health care (Mahomoodally, 2013), a trend which ought to be reversed.For this to be realized, the individual active principles from Tropical African plants ought to be isolated and structurally characterized, then investigated biochemically, pharmacologically and toxicologically for biological activity and mechanism of action, and where necessary chemically modified to optimize biological activity.University research is the bedrock of technological innovation.Not only do universities supply industrial innovators with skilled workforce and new knowledge to solve hitherto recalcitrant problems, they also feed the commercial industry with many discoveries for further development, as well as provide consultant expertise to the commercial industry (Elg, 2014;Zucker et al., 2002).Many prominent technology firms in the Western hemisphere owe their creation to universitybased discoveries (NSF, 2010;Zucker et al., 2002).
Hence, the capacity of Tropical African universities to conduct rigorous biomolecular research on phytomedicines *Corresponding author.E-mail: kambaf2000@yahoo.com.Tel: 00256 783 342793.
Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License is fundamental to commercialization of the region's rich diversity in medicinal flora.In this work, we sought to understand the extent to which this is happening in sub-Saharan African universities by assessing the magnitude and patterns of scientific output on African medicinal plants, the prevailing biomolecular infrastructural capacity at African universities, and the financial investments needed to build robust biomolecular research facilities for plant-based drug discovery and development in the region's universities.

METHODOLOGY
A desk search and review of information on the subjects of African medicinal plants and biomolecular research infrastructure was done in the four months of April, May, June and July, 2016.

Assessing magnitude and patterns of research on African medicinal plants
Insights into patterns of plant-based medicines research in Africa over the period 2000 to 2015 were obtained through analysis of search outputs in Google Scholar using the theme "Africa: medicinal plants".First, a gross search regardless of year of publication was carried out to establish the distribution of literature by nature of research; that is, whether it is ethnobotanical/ethnopharmacological report, whether it is preliminary pharmacological investigation, whether it is isolation and biomolecular characterization, and whether it regards medicinal plant conservation and in vitro propagation.Out of 178,000 search results (web pages), only the first 98 were downloadable from the Google Scholar server.Each webpage carries ten titles; hence, 980 publications were retrievable for analysis.Abstracts of all the 980 accessible publications were downloaded and reviewed to establish both the nature of research and the type of literature (original research articles or reviews/books).Secondary literature (reviews and text books) was excluded from analysis.The nature of research published in the original research articles (primary literature) was analyzed using a pie chart.
On the other hand, the search outputs from Google Scholar were filtered by year of publication, for example, 2015 to 2015, to give the approximate number of publications by year over the period covered by the study.Trend analysis of the magnitude of research output by year over the period covered by the study was then done using linear plots."research core facilities at X university" and "core research laboratories at X university", where X is the name of the university.
For the university websites, online material for the Departments of Chemistry, Biomedical Sciences (biochemistry, microbiology, molecular biology, cell biology, genetics, pharmacology, biophysics) and Pharmaceutical Sciences was thoroughly reviewed for information on research equipment.Data was summarized into bar charts showing both the micro and gross prevalence of instruments across sub-Saharan Africa, as well as into tables.This work assumed that classical organic synthesis capabilities which are essential for structural optimization of natural products are compulsory for any university chemistry department.Hence, equipment for organic synthesis was excluded from the survey.Biomolecular instruments included in the survey are shown in Table 1.

Assessing the financial investments required to build desired biomolecular research infrastructure
An extensive online search in www.google.com was done for purchase costs of each key equipment in the months of April and May 2016, using the general search themes "cost of X", "cost of X instrument", "purchase price of X", "purchase price of instrument X", "price of X", and "price of instrument X".For example, "cost of HPLC instrument", "cost of HPLC system", "cost of HPLC system with autosampler", "cost of NMR spectrometers", "cost of 800 MHz NMR spectrometer", etc.To ensure reliability of information obtained, informal blog posts such as conversational exchanges (comments and responses) on a subject were excluded from the study.Data from the following sources was retained: university websites, published literature (all types of journal articles and textbooks), marketing information, and online articles.Data was summarized into tables showing the source of information (authors and websites).

Patterns of plants-based medicines research in Tropical Africa
A custom search by year of publication shows a steadyto-exponential increase in number of publications over the last 16 years (Figure 1).
The number of annual reports on African medicinal plants increased from about 24,300 in the year 2000 to about 144,000 in 2015.On the other hand, a gross

HPLC
High resolution separation of molecules from herbal extracts; preliminary identification of small molecules occasionally.

GC-MS
Separation and identification of volatile molecules via molecular mass

LC-MS
Separation and identification of nonvolatile small molecules via molecular mass; assessment of drug metabolism; identification of non-covalent complexes of small molecules with biomacromolecules; proteomic analysis of drug effects.
FTIR/IR Identification of functional groups in molecules following high resolution separation of herbal extracts by chromatography.

NMR
Atomic structure determination of bioactive molecules isolated from herbs; atomic structure determination of drug targets; elucidation of atomic interactions between bioactive molecules and biomacromolecules; elucidation of binding affinity (potency) of bioactive molecules to biomacromolecules; elucidation of kinetics and dynamics of lead-target interactions.

XRD
Atomic structure determination of bioactive molecules isolated from herbal extracts; atomic structure determination of drug targets; elucidation of atomic interactions between bioactive molecules and their biomacromolecular targets.

CD
Determination of secondary structure of drug targets for bioactive molecules; preliminary studies of interactions between leads and biomacromolecular targets.

DSC
Elucidating the effect of small molecule binding on the thermal stability of biomacromolecular targets; indirect determination of binding affinity.

FS
Determination of affinity and free energy of interaction between bioactive small molecules isolated from plant extracts and host biomacromolecular targets.The bioactive molecule is typically ligated to a fluorescent dye such as fluorescein.

ITC
Elucidation of the affinity, enthalpy and free energy of interaction between small bioactive molecules and biomacromolecular targets.

SPR
Elucidation of the affinity, free energy, and kinetics of interaction between small bioactive molecules and biomacromolecular targets.search regardless of year of publication yielded 178,000 results (pages) or 1,780,000 publications on African medicinal plants in July 2016.Analysis of all the downloadable results (98 search results or 980 publications) for scientific content and type of report showed that 834 (85%) were primary literature while the rest were secondary literature (reviews and books).Of the primary literature, about 46 and 42% were preliminary pharmacological research and ethnobotany/ ethnopharmacology, respectively (Figure 2).Primary reports on in-depth studies such as isolation of pure pharmacologically active principles, structure elucidation, structure modification and biomolecular targets, among other endeavours needed to develop medicinal plant potential into pure, efficacious and safe drugs were very few.By and large, the voyage to translate Africa's enormous wealth in medicinal plant potential into therapeutics acceptable in the doctor's clinic is far from the desired destination.

Status of biomolecular scientific infrastructure in Tropical African universities
Translation of traditional medicinal use of a plant (ethnopharmacology) into the production of distinct active molecular entities of clinically sufficient efficacy and safety encompasses a number of scientific investigations.Among these are bioassay guided isolation of specific bioactive compounds from crude extracts, identification and structure determination of the isolated bioactive compounds, identification of biomolecular targets for the lead compounds, optimization of lead compound efficacy and/or toxicity through structural modification where necessary, preformulation studies, preclinical studies and clinical development (clinical trials).Such scientific rigor requires the availability of adequate scientific infrastructure, both physical (space and equipment) and technical (skilled human resources).
We sought to understand whether sub-Saharan African universities have adequate laboratory capabilities to undertake the advanced biomolecular investigations needed to translate its abundant medicinal plant endowment into clinically approved medicines.Out of 25 universities assessed, 16 were from the East-Central-West African cluster while 9 were from South African cluster.Our investigations revealed a mixed situation in which universities in the East, Central and West African cluster generally have large inadequacies in biomolecular research equipment whereas most in the South African cluster (South Africa, Botswana, Lesotho, Namibia, Swaziland) are reasonably endowed with such infrastructure (Figure 3).

Availability of instruments for plant metabolite isolation, purification, and characterization
Besides the classical thin layer chromatography (TLC) for routine analysis of crude natural products, advanced chromatographic techniques (HPLC and GC) are necessary to attain both higher resolution of crude mixtures and richer information content.Additionally, mass spectrometry and infrared spectrometers are needed for preliminary identification of different components of the mixture via their molecular masses and infrared fingerprints, respectively (Dias et al., 2012).
For better performance, high resolution chromatographic tools are now typically coupled with molecular identification tools to form hyphenated platforms, the most common being the gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and LC-MS/MS spectrometers.In our survey of 25 leading sub-Saharan universities, 16 (64%) have HPLC and 17 (68%) have GC-MS, but only 9 (36%) have LC-MS capabilities (Figure 3).Thus, many sub-Saharan Africa universities lack essential analytical equipment for drug discovery from plants.
When universities in the South African cluster (South Africa, Botswana, Lesotho, Namibia, and Swaziland) are excluded from analysis, the situation gets worse, with only 56, 63, 25, 63 and 56% of the 16 universities sampled from East-Central-West African cluster apparently having HPLC, GC-MS, LC-MS, infrared (IR)/Fourier transform infrared (FTIR), and NMR facilities, respectively (Figure 3).Worse still, reports indicate that some of these facilities are either broken or only intermittently operational due to poor servicing and maintenance.For example, a 2011 assessment of the University of Addis Ababa found the HPLC, GC and GC-MS facilities to be non-functional (Stenback et al., 2011); a 2014 assessment of lab capabilities at the University of Rwanda found the GC-MS instruments (two) out of service (Umereweneza, 2014); and a 2014 report on Mozambique's University Edouardo Mondlane indicated that not much of the equipment in its lab facilities are functional (Gupta et al., 2014).
As key instruments in organic structural elucidation, NMR spectrometers are essential in natural product development, but they are apparently lacking in 32% of the universities surveyed (Figure 3).Most of the universities lacking NMR capabilities are in the East-West-Central African cluster (Figure 3).Among universities with NMR capabilities, those in the South African cluster have the best infrastructure, with five out of eight universities having at least two instruments (Table 2).Most of these NMR spectrometers are low field (less or equal to 500 MHz).Nonetheless, low field magnetic strength is sufficient to elucidate the atomic structure of small molecules such as medicinal phytochemicals (Skinner and Laurence, 2008).

Availability of instruments for biochemical and biophysical characterization of drug targets and target-drug interactions
Biochemical and biophysical studies are critical in understanding the interaction of ligand (drug) and biological target (typically proteins and nucleic acids) in terms of interatomic and surface interactions and the thermodynamics and kinetics of binding.
For the thermodynamics and kinetics of ligand binding, equipment for fluorescence spectroscopy, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and recombinant protein production and engineering ought to be readily available to researchers (Cooper, 2002;Eftink, 1997;Velazquez-Campoy and Freire, 2006).For enzyme reactions, stopped flow instruments (SFI) and MS are prime tools for studies of reaction kinetics, intermediates and products (Bothner et al., 2000;Chance, 2004).For optimizing the affinity of lead compounds for their targets and for elucidating the atoms involved in target-ligand contacts (mechanism of binding), 3-dimensional atomic structures of target macromolecules, both in apo and ligand-bound state are required.X-ray crystallography and multidimensional solution NMR spectroscopy are the primary tools for atomic structure determination of proteins and nucleic acids which are the main drug targets (Skinner and Laurence, 2008;Souza et al., 2000).However, cry-electron microscopy is increasingly gaining ground as a biomolecular structure determination technique for large macromolecular complexes which can be visualized by an electron microscope (Milne et al., 2013).As of May 23rd 2016, out of 110,448 protein structures in the protein data bank (pdb), 99,437 were solved by XRD, 10,004 by NMR spectroscopy, and 745 by cryo-electron microscopy.To maximize chances of success in structure studies (protein/nucleic crystallization, X-ray diffraction, and NMR data collection), preliminary characterization of protein secondary structure and thermal stability is often necessary.Circular dichroism (CD) spectrometers are the primary tool for secondary structure profiling (Greenfield, 2006) while any two amongst CD spectrometers, thermally controlled UV/visible spectrophotometers, fluorescence spectrometers, and differential scanning calorimeters (DSC) are needed for thermal stability testing (Bruylants et al., 2005;Ramsay and Eftink, 1994).
Out of the 25 universities sampled for this review, only five (20%) had fluorescence spectrometers, one (4%) had an isothermal titration calorimeter (ITC), and none had a surface plasmon resonance (SPR) spectrometer (Figure 3).Furthermore, only two universities (8%) had stopped flow systems for enzyme kinetic assays.Hence, the capacity to establish and optimize binding affinities and enzyme inhibition constants for small molecule drug candidates is severely deficient.The capacity to produce recombinant protein for biochemical and biophysical studies is also highly deficient as only 3 (12%) of surveyed universities seemed to have the cycle DNA sequencers necessary for validation of successful cloning of target inserts into recombinant expression vectors.
As regards equipment for 3D structural studies, only 8 (40%) have single crystal XRD facilities, of which seven are from the South African cluster (Figure 3).Also, only 5 (20%) universities have the high field NMR facilities required for macromolecular structural and dynamics studies (Table 2).It is worth noting that though powerful in resolving the atomic detail of molecules, the sensitivity of NMR spectroscopy is low and a much higher concentration (at least 1 mM) of the analyte is required to get sufficient signal at low magnetic field compared to high field (Kwan et al., 2011).Unfortunately, many proteins are prone to aggregation and precipitation during concentration (Golovanov et al., 2004;Graslund et al., 2008;Pusey et al., 2005) and attainable monodisperse concentrations are commonly below 1 mM and undetectable above noise by low field NMR systems.Attaining sufficient NMR signal for proteins larger than 10 kDa is difficult at low field (Yu, 1999).Thus, more powerful high field NMR facilities are necessary for molecular investigations of the interactions between medicinal active molecular entities and their drug targets at atomic resolution.All the five high field NMR facilities available in the 25 sampled universities are also at the low end of high field magnetic capabilities, hence can only handle highly soluble small proteins at best.Finally, only one university (4%) had a CD spectrometer, hence capabilities for protein secondary structure determination are largely lacking.Thus, a huge gap in capabilities for structural studies of drug targets and target-ligand interactions exists in sub-Saharan universities, a situation which limits the capacity of their scientists to optimize plantderived drug leads into entities with more desirable attributes for clinical use.

Availability of instruments for cellular and molecular profiling of drug action
In drug development, cell biological studies are necessary to understand the organelles, cells, tissues and organs in which each lead compound accumulates as these could be the targets of drug action or the metabolic sites for the drug.Besides, cell biological studies provide information on the effect of drug candidates on cellular integrity and function.Most drug targets are either enzymes or cellular receptors whose perturbation modulates the downstream outcomes of their normal biological function.Depending on their cellular function, perturbation of protein function can modulate the cellular levels of any of the core biological macromolecules (proteins, carbohydrates, lipids, and nucleic acids).Drug action may also alter cell shape and cell populations with specificity dependent on the cellular targets.Besides, cells may be transformed from normal to immortal or tumorigenic cells.Understanding of these effects is necessary before a drug candidate can advance into clinical development.Thus, in order for Tropical Africa to turn its plant medicinal potential into clinically acceptable drugs, instrumental capabilities to decipher the molecular and cellular effects of medicinal phytochemicals are essential.Core equipment for this purpose includes mass spectrometers, next generation DNA sequencers, flow cytometers, fluorescence-and confocal microscopes, and electron microscopes.
Mass spectrometers, particularly the LC-MS, and LC-MS/MS are essential for proteomic profiling of target cells and organisms to assess drug effect on gene expression (Aebersold and Mann, 2003;Geoghegan and Kelly, 2005).Because modulation of gene expression by drugs could also occur at the level of transcription, next generation DNA sequencers are needed for transcriptome profiling of target specimen before and after drug exposure (Goldman and Domschke, 2014).For both pharmacological and toxicological studies of candidate drugs, assessing the effects on cell population, size, morphology and function is often necessary, making flow cytometers a necessity in drug development (Sklar et al., 2007).On the other hand, knowledge of the tissues and cells targeted and/or affected by a given drug, and the effects of the drug on tissue, cell and organelle architecture is necessary for comprehensive understanding of drug pharmacodynamics and metabolism.Deciphering such information typically involves high resolution biological imaging techniques such as conventional and confocal fluorescence microscopy (Lichtman and Conchello, 2005); Jonkman and Brown, 2015) and electron microscopy (Bogner et al., 2007;Milne et al., 2013;Stadtlander, 2007).
As shown earlier, the capacity for LC-MS and LC-MS/MS which are the primary tools for proteomic analysis is far from adequate in sub-Saharan African universities, with only 9 (36%) having the facilities (Figure 3).Secondly, only 4 (16%), 2 (8%), 1 (4%), 10 (40%) and 6 (24%) universities have facilities for biomolecular flow cytometry, fluorescence microscopy (FM), confocal microscopy (CM) and electron microscopy (EM) respectively (Figure 3).Thus, the capacity for tissue, cellular and subcellular evaluation of the pharmacodynamic and pharmacokinetic profiles of lead molecules is highly compromised.

Availability of instruments for genetic engineering of natural products
Utilizing natural sources for production of plant derived medicines is disadvantageous for two reasons.Firstly, extracting active principles from plants involves destruction of plants and sometimes whole plants, which is a threat to the environment.Secondly, being secondary metabolites, the concentrations of active principles in plants is often too low to sustain commercial production (Pan et al., 2013), thus necessitating alternative systems for synthesis of the active pharmaceutical ingredient (API).Unfortunately, many of the natural metabolites are products of complicated biosynthetic pathways with complex structures and many chiral centres, which makes organic synthesis often difficult, expensive and/or commercially untenable (Newman and Cragg, 2012;Phillipson, 1994;Salim et al., 2008).As a result, genetic engineering of plants to raise metabolite yields, producing plant metabolites in tissue/cell culture, and hijacking the robust biosynthetic machinery of microbes to produce plant metabolites have gained prominence in phytomedicine drug development (Pan et al., 2013;Tripathi and Tripathi, 2003).Such gene manipulations require DNA synthesis facilities to generate the oligonucleotides required for DNA manipulation procedures and DNA sequencing facilities for validating DNA cloning, transformation and mutagenesis.Out of the 25 universities surveyed, only 1 (4%) apparently has DNA synthesis facilities (data not shown) and only 3 (12%) had DNA sequencing facilities (Figure 3).None of the 16 universities from the East-Central-West African cluster had these facilities.Thus, there is a big infrastructural gap for medicinal plant biotechnology in sub-Saharan Africa universities.

Financial investments required to uplift the biomolecular research infrastructure of sub-Saharan Africa universities
Scientific discovery not only solves society's problems, it also creates jobs and new businesses and has been fundamental to human growth and the continued economic dominance of the developed west.Besides the direct returns of scientific discoveries to the patent and product license holders, significant positive returns on public investments in basic biomedical research have been demonstrated in the United States (US) (Toole, 2012).Critically, publically funded basic research is fundamental to the establishment and sustainability of a vibrant private research and development (R and D) industry.For example, over 70% of patents from the private industry in the United States (US) cite publically funded basic science (Narin et al., 1997).Thus, there is sufficient evidence that investment in scientific infrastructure and human resources carries real benefits to national economies.
The sub-Saharan Africa region is dominated by low income countries and the world's poorest economies (World Bank, 2015).With meager resources and We compiled the approximate purchase costs of biomolecular equipment critical to advanced research in phytomedicines via an extensive online search of information on costs of each equipment.While some equipment such as the most powerful NMR spectrometers (800 to 1000 MHz) and the electron microscopes require at least one million USD, most of the other equipment can be acquired for between USD 30,000 and USD 500,000 (Tables 3 and 4).
Operational and maintenance costs of large biomolecular equipment range between 10 and 30% of the purchase cost per annum (Busch, 2002;NRC, 2005).The practice in the developed west is that operational and maintenance costs of expensive research equipment are met centrally and partly financed through user fees.A simple sum shows that for only USD 3.2 million, each university could be able to purchase five NMR spectrometers (one of 300 MHz, one of 400 MHz, one of 500 MHz, one of 600 MHz, and one of 700 MHz), yet one low field instrument for small molecule studies (say 500 MHz) and one high field instrument for macromolecular studies (say 700 MHz) can service most of the NMR needs of natural product development.Similarly, simple arithmetic shows that for only USD 4 to 5 million, each university could be able to purchase each of the other biomolecular instruments listed in Figure 3.In essence, the biomolecular research infrastructure of sub-Saharan Africa universities could be comprehensively upgraded for barely USD 10 million.Among the 25 countries covered by the survey, Lesotho has the lowest GDP at USD 2.2 billion dollars (World Bank, 2014).Clearly, despite low economic status, the cost of establishing robust biomolecular research infrastructure is negligible relative to the GDPs of sub-Saharan African countries.
According to the World Bank, sub-Saharan Africa spends only 0.5% of its GDP on research and development (R and D), far less than high income countries which commit 2.4% of the same to R and D (World Bank, 2016).Thus, sub-Saharan Africa retains large resource capacity to raise its investment in research and with political good will, the procurement, operation and maintenance of most core biomolecular research equipment is within reach of its member countries.For the East-Central-West African cluster which is most deficient in contemporary biomolecular research infrastructure, communal investments by regional economic blocs such as the East African Community (EAC), the Economic Community of West African States, and the South African Development Co-operation (SADC) would minimize per capita cost to individual universities and nations, as well as boost facility consumption.

Conclusions
The last fifteen years have witnessed an exponential increase in the annual number of publications on African medicinal plants.However, most of the primary literature is on preliminary activity assays and traditional use by African communities (ethnobotany/ethnopharmacology).Publications on in-depth chemical, biochemical, biophysical and cell biology studies of African medicinal plants are severely underrepresented amongst primary literature.Essentially, not much effort is being dedicated to advanced biomolecular research on native medicinal plants in sub-Saharan Africa universities.Worse still, the infrastructural capacity to conduct advanced biomolecular investigations is lacking in most of the universities, with severe deficiency in East, Central and West Africa.In comparison to developed countries, sub-Saharan African countries spend much less of their GDP on research and development, which perhaps explains the huge infrastructural gap and low value addition to their natural medicinal endowment.Sub-Saharan Africa countries ought to raise their financial commitments to research and development.An increase in research expenditure to Two categories of flow cytometers: a) affordable ones in the price range USD 30,000 -100,000 suitable for individual researchers; b) top of the range instruments costing USD 500,000 -1,300,000 suitable for central core facilities. 2 Many platforms lie between the cheapest (Ion Torrent's PGM, USD 80,000) and most expensive (Illumina's HiSeq X, USD 1,000,000). 3Refurbished TEMs available for USD 125,000 -1,400,000 at Technical Sales Solutions (http://www.technicalsalessolutions.com). 4The prices indicated are for refurbished ones.
even half of the proportion spent on research by high income countries would both equip at least one of each nation's top universities with essential biomolecular equipment and fund many innovation and discovery projects.This work relied on online availability of information about each university's biomolecular research equipment.Thus, information not available online may have been missed, though this was minimized by diversifying the online data sources used in the study.Secondly, the study excluded sub-Saharan universities whose information is not in English, most of which are in the Central-West African cluster.Thirdly, physical verification of research infrastructure was not done; hence, future work is needed to ascertain the operational status of the equipment in sub-Saharan universities.Fourthly, there are more biomolecular equipment than this report could accommodate, hence smaller, inexpensive equipment were excluded from the survey.

Figure 1 .
Figure 1.Trend in annual volume of publications on African medicinal plants over the period 2000 to 2015.

Figure 2 .
Figure 2. Distribution of primary literature on African medicinal plants by scientific content.

Figure 3 .
Figure 3. Biomolecular instrumental capabilities in 25 Sub-Saharan Africa universities disaggregated into the East-Central-West African cluster (n = 16) and the South African cluster (n = 9).

Table 1 .
Roles of different biomolecular instruments in plants-based drug development.
Elucidation of the enzyme inhibitory potency of bioactive molecules, and hence the potency of lead natural products; metabolism of bioactive molecules.

Table 3 .
Approximate costs of NMR spectrometers versus magnetic field strength.

Table 4 .
Approximate costs of essential biomolecular instruments for natural products research and development: other core instruments.