Food and Drug Administration (FDA)-approved indications for the use of marketed botulinum neurotoxins products [1].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"}]},book:{item:{type:"book",id:"5067",leadTitle:null,fullTitle:"Insecticides Resistance",title:"Insecticides Resistance",subtitle:null,reviewType:"peer-reviewed",abstract:"This book contains 20 chapters, which are divided into 5 sections. Section 1 covers different aspects of insecticide resistance of selected economically important plant insect pests, whereas section 2 includes chapters about the importance, development and insecticide resistance management in controlling malaria vectors. Section 3 is dedicated to some general questions in insecticide resistance, while the main topic of section 4 is biochemical approaches of insecticide resistance mechanisms. Section 5 covers ecologically acceptable approaches for overcoming insecticide resistance, such are the use of mycoinsecticides, and understanding the role of some plant chemical compounds, which are important in interactions between plants, their pests and biological control agents.",isbn:"978-953-51-2258-6",printIsbn:null,pdfIsbn:"978-953-51-4208-9",doi:"10.5772/60478",price:139,priceEur:155,priceUsd:179,slug:"insecticides-resistance",numberOfPages:450,isOpenForSubmission:!1,isInWos:1,hash:"e0c89a15887b47c513a572364c7d9336",bookSignature:"Stanislav Trdan",publishedDate:"March 2nd 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5067.jpg",numberOfDownloads:29740,numberOfWosCitations:44,numberOfCrossrefCitations:43,numberOfDimensionsCitations:93,hasAltmetrics:0,numberOfTotalCitations:180,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 19th 2015",dateEndSecondStepPublish:"April 9th 2015",dateEndThirdStepPublish:"July 14th 2015",dateEndFourthStepPublish:"October 12th 2015",dateEndFifthStepPublish:"November 11th 2015",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8",editedByType:"Edited by",kuFlag:!1,editors:[{id:"78285",title:"Prof.",name:"Stanislav",middleName:null,surname:"Trdan",slug:"stanislav-trdan",fullName:"Stanislav Trdan",profilePictureURL:"https://mts.intechopen.com/storage/users/78285/images/3405_n.jpg",biography:"Prof. Stanislav Trdan, head of the Chair of Phytomedicine, Agricultural Engineering, Crop Production, Pasture and Grassland Management (Dept. of Agronomy, Biotechnical Faculty, University of Ljubljana, Slovenia), obtained his BSc, MSc and PhD (agricultural entomology) from the University of Ljubljana. Since 2006, he has been the president of the Plant Protection Society of Slovenia; since 2008, he has been an associate professor of plant protection. He is a member of many international and national research societies. He has organised two international symposia and (co)organised four national conferences in the field of plant protection. He has attended almost 30 international and 20 national conferences, workshops and seminars. Until now, he was a leader of four national scientific projects and a member of many national and international project groups. Dr. Trdan has published more than 100 scientific papers, and he or the members of his research group have given approximately 90 presentations at symposia. He was the supervisor of four PhD theses, six MSc theses and approximately 70 undergraduate theses. He was a reviewer of more than 50 scientific papers from the field of agricultural entomology or plant protection. 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The topics cover the physical growth and physiological and genetic alterations in plants, particularly under environmental stress conditions. The storyline of this book starts from the plant community, followed by cellular and ultrastructural phenomenes occurring within the plant in its interaction with the environment, and ends with elucidation of chloroplast's DNAs, their transfer to the nucleus, and the genetic engineering technology applicable for plant adaptation to changing environmental conditions. This book is aimed at attracting the attention of students, teachers, as well as scientists who have a similar focus of study or interest. 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Her scientific works focuses on Plant Physiology, particularly in Plant Cells Growth and Development and Cells/Tissue Cultures for their secondary metabolites, as well as Genetic basis of plant tolerance to abiotic stresses. She got her doctorate degree from The University of Montpellier II in France in 1987 and took a postdoctoral research program in Plant Biotechnology Laboratory which is chaired by Prof Dr Ralf Reski in Albert-Ludwig University of Freiburg, during 2002-2004. Her works were related with the functional genes of plant tolerance to abiotic stresses. She published several peer-reviewed articles in international journals, and is frequently invited to review many publication manuscripts and research proposals. In 2017, she successfully published one chapter on Alkaloids in Plant Cell Cultures, which is part of the book entitled “Alkaloids-Alternatives in Synthesis, Modifications and Application” by InTechOpen. 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Several other products are available for use in other countries, in particular in the Asian markets, and new formulations and products are underdevelopment [2]. By 2022, it is expected that the market size for botulinum products will reach $6.6 billion, driven by the expansion of their therapeutic uses and also the appetite for non-invasive aesthetic applications [3].
\nAround 200 years ago (between 1817 and 1822), a German medical officer, Justinus Kerner, published a series of papers to provide the first accurate and complete description of the symptoms of food-borne botulism, which led to the discovery of BoNT as the causative agent and the prediction by Kerner of its potential clinical utility [4]. This fascinating class of proteins present a modular molecular architecture with distinct binding, translocation and enzymatic domains. The different structural and functional domains can be regarded as ‘building blocks’ and have facilitated a number of engineering approaches aimed, amongst other purposes, at extending the therapeutic applications of BoNTs to other cell types beyond their natural target of the neuromuscular junction [5].
\nThe aim of this chapter is to (1) provide an overview of the current clinical uses and a historical perspective of botulinum neurotoxin discovery, the disease it causes and the threats and opportunities that it poses and (2) present the current understanding of the structure-function of the toxin and its application in the development of new therapeutics.
\nBoNT products are neuromuscular blocking agents which exert their effect through inhibition of acetylcholine release. BoNTs are amongst the most tissue-selective drugs known in clinical pharmacology and are characterised by high potency, high specificity and long duration of action of around 3–6 months following a single injection [6]. These characteristics have made BoNTs highly successful and effective therapeutic agents for the management of several chronic and debilitating diseases of neuronal hyperactivity. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, BoNTs are recognised to also inhibit release of neurotransmitters from autonomic nerve terminals, for example, in glands (e.g. in hyperhidrosis), and nociceptive neurons in pain states [6, 7].
\nCurrently, there are four formulations of BoNTs approved by the US Food and Drug Administration (FDA) for several clinical applications (see Table 1). Cervical dystonia, also known as spasmodic torticollis (disorder characterised by involuntary contractions of neck and upper shoulder muscles resulting in abnormal postures and/or movement of the neck, shoulder and head and that may be associated with neck pain), is the only condition for which all four formulations are approved. Other neurological conditions include spasticity (disorder characterised by tight or stiff muscles and an inability to control those muscles), with approved formulations both for adult and paediatric populations, migraine and blepharospasm (dystonia that can cause disabling eye closure). Other non-neurological therapeutic FDA-approved uses are strabismus (eye misalignment), overactive bladder, urinary incontinence and hyperhidrosis (excessive sweating).
\nFDA-approved indication | \nTreatment population | \nAbobotulinumtoxinA (Dysport®) | \nIncobotulinumtoxinA (Xeomin®) | \nOnabotulinumtoxinA (Botox®) | \nRimabotulinumtoxinB (Myobloc®) | \n
---|---|---|---|---|---|
Cervical dystonia | \nAdult | \nApproved | \nApproved | \nApproved | \nApproved | \n
Upper limb spasticity | \nAdult | \nApproved | \nApproved | \nApproved | \nna | \n
Lower limb spasticity | \nAdult | \nna | \nna | \nApproved | \nna | \n
Lower limb spasticity | \nChildren ≥ 2 years of age | \nApproved | \nna | \nna | \nna | \n
Migraine | \nAdult | \nna | \nna | \nApproved | \nna | \n
Blepharospasm | \n≥12 years of age | \nna | \nApproved | \nApproved | \nna | \n
Strabismus | \n≥ 12 years of age | \nna | \nna | \nApproved | \nna | \n
Glabellar lines | \nAdult | \nApproved | \nApproved | \nApproved | \nna | \n
Overactive bladder | \nAdult | \nna | \nna | \nApproved | \nna | \n
Urinary incontinence | \nAdult | \nna | \nna | \nApproved | \nna | \n
Hyperhidrosis | \nAdult | \nna | \nna | \nApproved | \nna | \n
Food and Drug Administration (FDA)-approved indications for the use of marketed botulinum neurotoxins products [1].
na = indication not FDA-approved.
Historically, BoNT products have been considered as a single pharmacological class [8]. However, the existing BoNT products vary in the identity and amount of toxin present, their formulations, the manufacturing processes and the potency methods used to determine the strength of the products [9, 10]. As a result, the different products are not considered to be interchangeable, and their respective clinical efficacy and safety are unique to each specific product [11].
\nIn 2016, the American Academy of Neurology (AAN) published updated guidelines for the clinical use of BoNT [12]. The 2016 AAN recommendations for BoNT use, based on evidence from clinical trials, do not fully match the FDA-approved indications or AAN’s previous guidelines from 2008, which is a reflection of the expanding uses of BoNTs [8]. Multiple clinical trials are being conducted to investigate the efficacy and safety of BoNTs for various clinical conditions and, in addition, pilot studies are being conducted to test the efficacy of BoNTs for new indications [9, 13, 14]. A summary of not approved new indications for which botulinum toxins are under investigation is presented in Table 2.
\nAchalasia | \nDysphonia | \nNeuromyotonia | \nRhinorrhoea and/or rhinitis | \n
Alopecia | \nEndometriosis | \nNystagmus | \nSialorrhea | \n
Anal fissure | \nEsophageal spasm | \nObesity | \nSpasmodic dysphonia | \n
Anismus | \nExotropia, esotropia, entropion | \nOrbital atrophy | \nStiff person syndrome | \n
Atrial flutter | \nEyelid-opening apraxia | \nOscillopsia | \nStuttering | \n
Autonomic dysreflexia | \nFacial flushing | \nOsteoarthritis | \nSynkinesis | \n
Benign prostatic hyperplasia | \nFecal incontinence | \nSome forms of pain | \nTemporomandibular joint syndrome | \n
Bruxism | \nFrey’s syndrome | \nPalatal myoclonus | \nTennis elbow | \n
Carpal tunnel syndrome | \nGastroparesis | \nParatonia | \nTension headache | \n
Cleft lip repair | \nGustatory sweating | \nPeyronie’s syndrome | \nTetanus | \n
Club foot | \nHemifacial spasm | \nPiriformis syndrome | \nTremor | \n
Constipation | \nHyperlacrimation | \nPlantar fasciitis | \nTrigeminal neuralgia | \n
Cystitis | \nLateral epicondylalgia | \nProtective ptosis | \nVaginismus | \n
Depression | \nMyofascial pain | \nPsoriasis | \nVentricular arrhythmias | \n
Diabetic polyneuropathy | \nMyokymia | \nRestless leg syndrome | \nVocal tics | \n
The use of BoNTs has been extended to aesthetic applications for the reduction of facial lines. According to recent statistics, BoNT injections are now the most popular of all cosmetic procedures worldwide, both surgical and non-surgical [15], and, in the US, more than 6.6 million injections were performed in 2014 alone for aesthetic reasons [16]. There are currently three BoNT products approved by the FDA for use in glabellar lines (wrinkles that appear between the eyebrows): abobotulinumtoxinA (Dysport®, Ipsen as the marketing authorisation holder with Galderma as distributor in the aesthetic indication), incobotulinumtoxinA (Xeomin®/Bocouture®, Merz) and onabotulinumtoxinA (Botox®/Vistabel®, Allergan) (see Table 1). The facial aesthetic uses of BoNTs are extensive, mainly not approved and under investigation, and patient satisfaction with treatment is very high, with significant improvement in patient-reported outcomes. Rhytides (skin wrinkles) regions for treatment include forehead, brow, region between the eyebrows, around the eyes (crow’s feet) and nose (bunny lines), smile (gummy smile), upper lip, corners of the mouth, jaw, chin and neck area [16, 17].
\nDespite intense use of BoNTs in clinical practice, approval and labelling guidance does not exist to address key questions such as where BoNTs fit amongst various treatment options for a given condition, recommendations of one product over another for a given indication or clinical differences in potency and duration of action (see Refs. [8, 18]).
\nBotulism is a rare but potentially fatal disease caused by BoNT intoxication. Botulism is characterised by a descending flaccid paralysis with symptoms of cranial nerve dysfunction such as diplopia (double vision), dysphagia (difficulty in swallowing), pupillary dilation and ptosis (drooping eyelids), progressing to respiratory failure and, in rare occasions if not provided with suitable intensive care and life support, ultimately death. Fever and altered mental status are absent. The diagnosis of botulism is largely clinical and is confirmed by laboratory tests, sometimes including the detection of BoNTs in contaminated materials, food or bodily waste [19]. Botulism in humans is classified according to the route of entry of the toxin: food-borne botulism occurs after the ingestion of BoNT-contaminated food that contains the preformed toxin; infant botulism is the result of bacteria colonising the immature gastrointestinal tract of infants which then produce and release the toxin in situ; wound botulism results from spore contamination into the tissue and is mostly associated with injection drug abuse; and iatrogenic botulism can occur as a result of excessive BoNT use either for therapeutic or cosmetic use [20]. Inhalation botulism is also a possibility, if the toxin were to enter through the respiratory tract. However, inhalation botulism is rare and does not occur naturally [21].
\nA stable number of cases of botulism have been reported in Europe (i.e. European Economic Area, comprised of 31 countries) in recent years. During the period 2007–2014, an average of 115 cases per year of confirmed botulism occurred, and 5% of those were fatal [22]. A very similar numbers in the US were reported by the Centres for Disease Control and Prevention (CDC) for the same period (2007–2014), with an average of 143 confirmed cases per year, with 2% of those being fatal. According to the CDC, the most numerous cases were of infant botulism, but wound and food-borne botulisms were also presented yearly, plus a minor percentage of cases of unknown aetiology [23].
\nThere is currently no approved pharmacological treatment for BoNT intoxication in humans, and recent efforts have focussed on the development of (1) vaccines from partially purified toxins, (2) use of specific antitoxin antibodies and (3) small molecule inhibitors [20, 24]. Once an outbreak occurs, medical treatment includes treatment with the botulin heptavalent antitoxin and consideration of admission to an intensive care unit with mechanical ventilation until recovery. Botulism is not contagious, and standard precautions are sufficient for infection control [19].
\nBotulism also occurs in animals and begins with the growth of the BoNT-producing bacteria in decaying carcasses followed by the release of the toxin into the environment. Both toxin and bacteria can spread via transmission of BoNT-insensitive animals such as maggots and other invertebrates that are consumed by healthy BoNT-sensitive animals, which eventually die and allow the growth of the bacteria and the subsequent production of the toxin to self-amplify the cycle [20].
\nPartly due to the fact that no effective treatment is available for BoNT intoxication in humans and the perceived ease in which it could be used in a bioterror attack, BoNT is classified as a potential bioterrorism weapon by the US CDC. BoNT belongs to the category A, the highest level of concern regarding public health and need of preparedness. Only five other agents are classified as category A agents, those being anthrax (Bacillus anthracis), bubonic plague (Yersinia pestis), smallpox (Variola major), tularemia (Francisella tularensis) and arenaviruses causing viral hemorrhagic fevers [19]. A contentious paper from 2005 regarding ease of BoNT intoxication through cow’s milk destined for human consumption calculated if would take only 4 g of BoNT, e.g. roughly equivalent to 1 teaspoon of granulated sugar, to poison over 400,000 people [25]. The publication of that research opened a public safety debate within the scientific community regarding BoNT dual-use research [26], which was reopened when the allegedly new BoNT/H type was originally reported [27]. However, it should be noted that BoNTs are much more toxic (in the range of 100–1000 times) when injected than when administered orally; and delivery by aerosols is considered inefficient [20].
\nBoNT/A is the most potent toxin known to man, with a reported estimated human lethal dose of 1.3–2.1 ng/kg intravenously or intramuscularly and 10–13 ng/kg when inhaled [4]. Not surprisingly, its effects have been known throughout history long before the molecular identity of the toxin was elucidated. Botulism-like symptoms were known by ancient Greeks and Egyptians, and the Byzantine emperor Leo IV (886–911 AD) banned ‘blood sausage’ as it caused a fatal illness. It was not until around a thousand years later that following a number of sausage poisoning outbreaks in Germany the first accurate and complete description of the symptoms of food-borne botulism was described between 1817 and 1822 by J. Kerner. The extracted causative agent was named ‘sausage poison’ and was believed to be a ‘fatty acid’. Later, a German physician named Muller referred to the sausage poisoning as botulism from the Latin name for sausage, ‘botulus’ [4, 28].
\nThe first isolation of the bacteria responsible for producing the toxic agent causing botulism was performed by the Belgian professor Emile Pierre van Ermengem and was termed Bacillus botulinus. Its name was changed to Clostridium botulinum when the aerobic Bacillus genus was separated from the anaerobic Clostridium genus [29]. To date, six different BoNT-producing bacterial groups are known; all have been taxonomically classified as clostridia. These clostridia produce seven different serotypes of botulinum toxin, termed BoNT/A to BoNT/G. BoNT/A, BoNT/B and BoNT/F were discovered following incidences of food-borne botulism, reminiscent of the original ‘sausage poisoning’, whereas BoNT/C, BoNT/D and BoNT/E were discovered following incidences of botulism in animals [27] (see Figure 1). BoNT/G, discovered in 1970, was reported in a sample extracted from soil, and to date there has not been reported cases of botulism caused by BoNT/G in the wild affecting either humans or animals [30]. A possible eighth type, initially termed BoNT/H was reported in 2013, but later reclassified as a BoNT/FA hybrid [31].
\nTimeline of the discovery of the seven botulinum toxin types. For context, also depicted are the dates of the first accurate description of botulism and the first use of botulinum toxins as therapeutic agent. A proposed eighth type was initially reported in 2013, now classified as an F/A hybrid toxin. For details see Refs. [2, 27, 28].
Despite Kerner suggesting the potential of BoNT as a therapeutic agent in conditions of muscular hypercontraction and glandular hypersecretion, it was not until around 150 years later that the first clinical application was made. In 1981, Dr. Alan B. Scott at what was formerly known as the Smith-Kettlewell Institute of Visual Science, San Francisco, California, USA, used BoNT/A for the treatment of strabismus as an alternative to surgical intervention. The original name of the drug was Oculinum®, and its rights were later acquired by Allergan Inc., which changed the name of the drug to Botox®.
\nUpon the first description of the botulism symptoms (see above), the initial hypothesis was that botulism was caused by a toxin produced by a single bacterial organism, as is the case for the closely related toxin tetanus toxin and its producing bacteria Clostridium tetani [32]. However, it soon became apparent that different types of toxin and different producing bacteria existed for BoNT [29].
\nIn 1910–1919, serological methods were introduced for categorisation of the toxin-producing bacteria and for the toxins themselves, that are still in use today [33]. Biochemical and molecular techniques have complemented those initial classifications and have confirmed the presence of multiple species of BoNT-producing clostridia and multiple species of BoNT proteins. BoNT-producing bacteria are Gram-positive, anaerobic, spore-forming and rod-shaped organisms and are commonly found in any soil or water environment. The seven distinct serotypes differ by 37–70% in amino acid sequence [34]. Early observations pointed to a level of intratypic serological diversity that led to variants within serotypes to be called sub(sero)types and a proposal that new subtypes would differ by 2.6% at the protein sequence level. However, this rule is not consistently applied today throughout all the subtypes [35]. It is considered that 41 individual toxins exist and the various toxin subtypes are given a letter designation for the toxin serotype followed by a sequential number in order of discovery, e.g. BoNT/A1 and BoNT/E11. Only 4 serotypes currently present subserotypes, namely BoNT/A (8 subtypes), BoNT/B (8 subtypes), BoNT/E (12 subtypes) and BoNT/F (7 subtypes) (see Figure 2). Interestingly, BoNT/C and BoNT/D occur naturally as well as hybrid toxins, termed BoNT/CD and BoNT/DC. A third naturally occurring hybrid, BoNT/FA, was initially proposed as the new serotype BoNT/H following its discovery in 2013 but later reclassified as a hybrid toxin [36].
\nPhylogenetic tree depicting the relationship of the 41 known botulinum neurotoxins. Individual FASTA files were accessed through the NCBI portal (NIH, USA), and the protein alignment and phylogram were constructed using the online software Clustal Omega (EMBL-EBI, Germany).
Current classification of BoNT-producing clostridia is according to group designation based on metabolic biochemical criteria (see Table 3). The metabolic groups represent distinct species of Clostridium botulinum (Groups I to III) and Clostridium argentinense (Group IV), and these species include non-toxigenic as well as neurotoxigenic members. In addition, Clostridium baratii and Clostridium butyricum are also known to produce BoNTs (Groups V and VI). To add to the confusion, some Clostridium botulinum strains do not produce BoNT, in particular if subcultured repeatedly in the laboratory; and some additional toxins are produced by the neurotoxigenic Clostridium botulinum, such as C2 toxin, C3 exoenzyme and botulinolysin. However, no alternative nomenclature for this group of organisms has been accepted [32].
\nClostridial bacteria | \nGroup | \nBoNT serotype(s) produced | \nMixture of serotype(s) produced by a single strain | \nNontoxinogenic bacteria belonging to the same group | \n
---|---|---|---|---|
Clostridium botulinum | \nI | \nA, B, F | \nA(B), A(B′), Ab, Af, Ba, Bf, Bf/a | \nClostridium sporogenes | \n
Clostridium botulinum | \nII | \nB, E, F | \n– | \nClostridium taeniosporum | \n
Clostridium botulinum | \nIII | \nC, D, CD hybrids DC hybrids | \n– | \nClostridium novyi | \n
Clostridium argentinense | \nIV | \nG | \n– | \nClostridium argentinense Clostridium subterminale Clostridium hastiforme | \n
Clostridium baratii | \nV | \nF | \n– | \nClostridium baratii | \n
Clostridium butyricum | \nVI | \nE | \n– | \nClostridium butyricum | \n
Clostridial strains in different groups can produce the same toxin (e.g. Groups I, II and V produce BoNT/F), and bivalent toxin combinations within the same strain have been identified. When more than one toxin is produced by a single strain, such as Ba or Bf, the capital letter designates the toxin produced in greater amounts. If a gene is present but not expressed, it is denoted between brackets, for example, A(B); and if a gene is present but truncated, it will have an apostrophe to indicate this fact, such as A(B′). This diversity in BoNT-producing bacterial strains is the result of toxin gene associations with transposases such as insertion sequence elements, recombinases, the acquisition of plasmids or infection by phage [37], within and between the groups and species. Groups IV–VI have the toxin genes located in the chromosome, considered less mobile, whereas Group III has the toxin genes in highly mobile elements such as plasmids and bacteriophages. Groups I and II have a mixture of chromosome and plasmid localisation [38]. A recent genetic study of C. botulinum strains causing human botulism in France showed that the genetic diversity of the BoNT-producing organism appeared as a result of multiple and independent genetic rearrangements and not from a single evolutionary lineage [39].
\nAll seven BoNT serotype toxins are released from the producing bacteria as large protein complexes with a number of neurotoxin-associated proteins (NAPs) to become highly potent oral toxins, often ingested in contaminated foods [38, 40]. The NAPs are encoded together with the bont gene in one of two different gene clusters, the hemagglutinin (HA) cluster or the orfX cluster. Both clusters encode the nontoxic non-hemagglutinin (NTNHA) protein, which assembles with BoNT to form the smaller of the progenitor toxin complexes. BoNT/A, BoNT/B, BoNT/C and BoNT/D complexes contain HA, whereas BoNT/E and BoNT/F complexes do not contain HA. The components of the BoNT complex vary with neurotoxin serotypes and the Clostridium strain producing them. BoNTs are produced in three progenitor forms: M (medium), L (large) and LL (extralarge) complex. The M form consists of the neurotoxin (of 150 KDa) with NTNHA and has a total weight of ~ 300 KDa. The L and LL complexes consist of several HA proteins besides the BoNT and NTNHA, and its molecular weight is ~ 500 KDa for the L form and ~ 900 KDa for the LL form. The function of the proteins encoded in the orfX genes remains unknown [41]. NAPs are known to protect BoNTs against the proteases of the gastrointestinal tract and the acidic conditions of the stomach and to facilitate the intestinal trans-epithelial delivery to the toxin into the lymphoid and general circulation [38]. The role of NAPs in the producing bacteria is not known. Recently, it has been proposed that the primary role of NAPs and in particular that of NTNHA is to protect BoNTs from damage in the decaying biological material where the toxin is mostly produced in the wild [20].
\nUntil recently, BoNTs were believed to be produced exclusively by clostridia organisms. In 2015, the first homologue of BoNTs was described within the genome of the rice fermentation bacteria Weissella oryzae SG25 [42]. Bioinformatic analysis of the genomic sequences of W. oryzae SG25 revealed one gene with a very similar structure to BoNTs, whereas a second gene showed partial similarity with the BoNT-associated NTNH proteins [42]. Recombinant expression of the BoNT-like protein revealed that it shares similarities with BoNT/B regarding its targeting profile and it is also expected to block neurotransmitter release. The new BoNT-like protein showed no serological cross-reactivity with the seven known BoNT serotypes, and it was dubbed BoNT/Wo by the authors [43].
\nBoNTs are zinc metalloproteases consisting of three major domains. Produced as a single polypeptide of 150 KDa, BoNTs require activation by cleavage of the polypeptide post-translationally resulting in the so termed heavy chain, of ~ 100 KDa, and a light chain (LC), of ~ 50 KDa, held together by a disulphide bridge between the two chains [44]. Functionally, the light chain hosts the metalloprotease domain, and the heavy chain comprises both the binding domain (HC) and the translocation domain (HN). The producing bacteria in Groups I, III and IV (see Table 3) are proteolytic strains and will release the cleaved active product, whereas the products of the other producing bacteria are believed to be activated by proteases of the intoxicated organism [38].
\nThe neuromuscular junction is the natural target of BoNTs, and intoxication follows an intricate multistep mechanism [20, 45], in which the toxin-associated proteins of the progenitor toxin complex play a crucial role. For an overview of the routes of entry and mechanism of action of the toxin, see Figure 3.
\nMode of action of botulinum toxins; for details in each step, see Refs. [20, 45].
Unintentional BoNT entry into the organism occurs mainly through ingestion of contaminated foods leading to food-borne botulism (see above) or through wounds [20]. Alternatively, and in particular in cases of infant botulism, the producing bacteria can colonise the immature gastrointestinal tract and produce the exotoxin in situ. The progenitor complex allows BoNTs to effectively cross the intestinal trans-epithelial barrier and reach the lymphoid and general blood circulation. Under neutral and alkaline environments, such as in the bloodstream, the complex dissociates and the naked toxin is able to target neuromuscular junctions [46]. In clinical applications, the toxin is delivered locally to the site of action. BoNT entering the body undergoes a relatively short distribution phase which sees the toxin selectively targeting peripheral nerve endings, and an elimination phase that comprises both (1) an interneuronal metabolism following cellular entry and (2) systemic metabolism and elimination which are assumed to be through the liver [47].
\nUpon reaching the neuromuscular junction, BoNTs are able to specifically target nerve terminals using their Hc-binding domain and internalise through endocytosis. Once in the acidic environment of the endosome, the BoNT HN domain translocates the LC domain into the cytosol, allowing the Zn+2 metalloprotease enzyme to cleave target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. SNARE proteins constitute an essential part of the machinery for neurotransmitter release in eukaryotic cells, and once their function is compromised by BoNTs, release of acetylcholine in the neuromuscular junction is prevented [19].
\nAlthough all serotypes, and even the most recently described BoNT-like protein BoNT/Wo [43], share a multidomain structure, crystallographic data has revealed that the molecular arrangement in the 3D space varies. BoNT/A and BoNT/B present an ‘open butterfly’ structure, whereas BoNT/E has a ‘closed butterfly’ organisation when viewed taking the HN translocation domain as a sagittal axis [48, 49]. In Figure 4, three different representations illustrate the organisation of BoNT/A and BoNT/E. This differential 3D topology has been credited to confer particular characteristics to BoNT serotypes, such as a faster way of entry for BoNT/E compared to BoNT/A [50].
\nStructural and functional domains of (A) BoNT/A (PDB 3BTA) and (B) BoNT/E (PDB 3FFZ). Hc = binding domain, HN = translocation domain, LC = light chain protease domain. Upper panels: ribbon diagram of the respective crystal structures. Middle panels: diagram depicting the three-dimensional organisation of the domains within the structure. Lower panels: simplified two-dimensional block diagram in which the HN and LC can be seen being connected by a conserved disulphide bridge. Structural image created from crystallographic using the MOE software (Molecular Operating Environment 2013.08; Chemical Computing Group Inc., Montreal, Canada).
BoNTs belong to the family of AB exotoxins, consisting of an ‘A’ toxic domain and a ‘B’ binding domain. AB toxins such as cholera toxin, lethal factor from Escherichia coli and Shiga toxin use gangliosides as their cellular receptors; whereas anthrax toxin and ricin have protein receptors identified as their targets [51].
\nIn the case of BoNTs, a dual receptor theory was postulated [52]. This dual-binding anchorage is credited for the high affinity and specificity by which BoNTs target neurons. All serotypes share a similar binding site for the interaction with the oligosaccharide portion of a polysialoganglioside. For BoNT/A, BoNT/B, BoNT/E, BoNT/F and BoNT/G, the conserved ganglioside-binding site SXWY has been reported, whereas BoNT/C, BoNT/D and BoNT/DC have analogous sites for ganglioside binding at a similar position [53]. A second, non-conserved binding site that binds a protein receptor has been identified in several BoNTs [54]. BoNT/A, BoNT/E and BoNT/F bind the family of synaptic vesicle protein SV2, whereas BoNT/B, BoNT/D and BoNT/G recognise a short peptide sequence in the luminal domain of the family of synaptic vesicle protein synaptotagmin. A protein receptor has not yet been identified for BoNT/C, which uses a dual ganglioside mechanism [55]. A second protein receptor has been identified for BoNT/A, namely, FGFR3 [56]. Crystal structures of the HC domains in complex with their receptors, where available, have contributed a major advance in the understanding of BoNT-cell interactions.
\nRecently, glycan motifs in both gangliosides [53] and protein receptors [57, 58] have emerged as key players in the targeting of BoNTs to the neuronal membranes, albeit glycosylation is not required for binding for all BoNTs [38].
\nNeuronal internalisation triggers the translocation of the LC domain to the cytosol, separating it from the HN and HC domains and thus allowing it to cleave the cytosolic target SNARE proteins. In neurons in vitro, internalisation of BoNT/A and translocation of the LC into the cytosol occur rapidly, with estimates either side of ~ 60 minutes [59]. Following entry into the synaptic vesicle, the proton pumping action of the v-ATPase present on the synaptic vesicle membrane, responsible for the loading of neurotransmitters into the vesicle, will acidify the organelle and produce the necessary environment for the LC to translocate. Treatments that inhibit internalisation, synaptic vesicle recycling, or acidification also inhibit BoNT action [60].
\nOf the various steps of the cellular mechanism of intoxication, membrane translocation for the LC is least understood at the molecular level, and several models have been suggested [48]. The first model proposes that upon acidification of the lumen of the synaptic vesicle, HN penetrates the membrane and forms an ion channel assisting a partially unfolded LC to pass through it. This model has been revised and a new proposed mechanism includes binding of the toxin domains to the luminal membrane of the synaptic vesicle, and following acidification both HN and a partly unfolded LC will destabilise and penetrate the membrane. LC will move to the cytosolic side, refold and be released upon reduction of the disulphide bond. At the same time, segments of the HN insert in the membrane and assemble an ion channel. The main difference between these models is that in the first model, channel formation by HN is an early event and translocates LC, whereas in the second model, the channel formed by HN occurs as a consequence of the LC translocation. In both models, the reduction of the disulphide bond is essential to free the LC at the end of the translocation step, and the enzyme thioredoxin and its regenerating enzyme thioredoxin reductase have been identified as the cellular system responsible for the reduction of the disulphide bridge [61]. Following translocation, another key protein recently identified is Hsp 90, which may act as a chaperone assisting the refolding of the LC once in the cytosol [62].
\nDifferent models have been proposed for the mechanism by which BoNT domains approach the membrane, which may have physiological consequences. BoNT/E is thought to owe its rapid translocation to its ‘closed butterfly’ three-dimensional structure in which the Hc and LC are in close proximity [50], whereas BoNT/A and BoNT/B, which in principle share the ‘open butterfly’ configuration, would approach the membrane differently [63].
\nThe LC domain is a metalloprotease that cleaves SNARE proteins within the nerve terminal cytosol, resulting in the inhibition of the acetylcholine release which causes a reversible neuroparalysis [44].
\nSNARE proteins are membrane-associated proteins and comprise a large family of proteins that are responsible for the binding and fusion of vesicles to membranes. In humans, there are 38 different types of SNARE proteins [64]. SNARE proteins that mediate the exocytosis of neurotransmitter vesicles with the plasma membrane of neurons are the target substrates of BoNTs [65]. In addition to inhibiting neurotransmitter release, SNARE cleavage by BoNT also affects trafficking of proteins, for example, TRPV1 and TRPA1 receptors to the neuronal surface [66]. BoNT/A, BoNT/C and BoNT/E target SNAP-25, whereas BoNT/B, BoNT/D, BoNT/F and BoNT/G target VAMP1, VAMP2 and VAMP3 proteins. BoNT/C is unique amongst BoNTs in targeting two different SNARE types, as it targets syntaxin 1 and syntaxin 2 besides also targeting SNAP-25. Hydrolysis of the SNARE proteins occurs at a unique cleavage site specific to each BoNT [35].
\nNo additional target substrates have been reported for BoNTs beyond SNARE proteins. This may be due to the extensive interaction that BoNTs make with the target proteins, including the cleavage site, which may be responsible for the exclusive specificities to SNARE isoforms in a species-specific manner [48].
\nThe length of BoNT-induced intoxication may depend on (1) how long the cleaved SNARE proteins remain in the cytosol and the ability of the cleaved SNARE proteins to maintain the block to exocytosis, (2) how long the BoNT protease remains in place to cleave newly synthesised SNARE proteins, (3) the rate at which the neuron is able to replenish uncleaved SNARE proteins relative to ongoing cleavage, and (4) the ability of the presynaptic terminal to remodel in order to overcome the temporary paralysis. There is preclinical evidence for all these hypotheses [67]. The ubiquitination pathway has been proposed as a main mechanism responsible for degradation of the LC in the cytosol, thus terminating BoNT activity [68].
\nDespite intense activity in recent years towards understanding the basic mechanism of action (MOA) of BoNTs, currently known structure-activity relationships of the four BoNT functions (binding, internalisation, translocation and SNARE cleavage at the nerve terminals of the neuromuscular junction) within three domains (Hc, HN, and LC) are not fully understood. Current gaps in basic understanding include molecular details of the specificity of the binding of each BoNT to neurons, entry into the nerve terminal and translocation of the LC, the correlation between SNARE cleavage and neuroparalysis and the length of BoNT-induced neuroparalysis. For example, it is known that the length of paralysis varies with BoNT type, dose, animal species and type of nerve terminal (from 3 to 4 months for skeletal nerve terminals to 12–15 months for autonomic cholinergic nerve terminals) [54, 69]. Furthermore, there are emerging functions that do not fall within the canonical intoxication pathway.
\nRegarding discrete functions of BoNT domains, there is increasing evidence that, in addition to their individual functions, each domain influences the other to work in concert to achieve BoNT intoxication. For example, the binding domain is not necessary for cell entry or LC translocation, but it determines the pH threshold for HN channel formation during the translocation step [70].
\nEntry of BoNTs has also been reported independent of synaptic vesicle recycling [71]; and retrograde transport within non-acidifying organelles, a characteristic of the related tetanus toxin, has been described for BoNT/A and BoNT/E [72]. Effects of BoNT in the central nervous system, such as in pain states, have also been reported, indicating actions beyond the neuromuscular junction that would involve retrograde transport of the toxin [73].
\nFurthermore, BoNTs, and in particular BoNT/A, are known to exert further actions unrelated to the cleavage of SNAP-25, at doses/concentrations that prevent SNAP-25-mediated neurotransmitter release. These activities include (1) increasing the proteosomal degradation of the protein RhoB in arachidonic-mediated neuroexocytosis, (2) induction of neuritogenesis, (3) reduction of cellular proliferation and (4) effects on gene expression, both in in vivo and in vitro settings [74]. The significance of these findings is not yet fully understood, but opens exciting opportunities to expand the use of BoNTs beyond their classical SNARE-cleaving MOA.
\nThe four FDA-approved formulations in the market for BoNT products are manufactured starting with the fermentation of the respective C. botulinum [1]. As a result, the manufacturing processes come with their own challenges, namely, (1) the anaerobic requirements mean that oxygen must be excluded from the first stages of the production system as the C. botulinum are obligate anaerobes, (2) the production of the toxin progresses from the first stages of growth, so health and safety measures are paramount throughout the manufacturing process, (3) sporulation of the bacteria can occur at low levels during the growth stages, but particularly when the bacterial life cycle ends and the bacteria die, and (4) the nutritional growth requirements of C. botulinum are not known in detail, which results in complex growth media adding extra degrees of complexity [75]. Recombinant production of BoNTs in non-obligate anaerobes and non-sporulating organisms, already widely used in the research setting (e.g. Ref. [76]), will simplify the manufacturing process enormously, as well as facilitate molecular engineering approaches that are state of the art in the protein field.
\nOne aspect that is still contentious about the current BoNT drug products is the presence/absence of the ancillary non-toxic associated proteins (NAPs). In particular, it is not clear what role these proteins, which are critical to protect the toxin during entry through the gastrointestinal tract, are playing when the toxin is injected, as is the case for the current therapeutic and aesthetic uses. AbobotulinumtoxinA (Dysport®) and onabotulinumtoxinA (Botox®) present a complex of BoNT plus non-toxic associated proteins (NAPs), whereas incobotulinumtoxinA (Xeomin®) does not have NAPs present in its formulation [11]. RimabotulinumtoxinB (Myobloc®) is also a neurotoxin complex in which the BoNT is associated with hemagglutinin and non-hemagglutinin proteins [1].
\nRegarding distant spread, the FDA prompted an inclusion of a black box warning for all FDA-approved BoNT products, as follows: ‘The effect of all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening and there have been reports of death’ [1]. Ancillary proteins are not likely to play a role in distant spread since studies show that there were no differences in product diffusion when the same dose was injected with the same technique [15].
\nTriggering of immune responses by BoNT use, and possibly triggering non-responsiveness to treatment, is a controversial topic since, despite dissociation from the toxin NAPs, HA and NTNHA proteins form part of the protein load of the injection [77]. Following meta-analysis of clinical incidence of neutralising antibody immunogenicity is often revealed as a very minor issue with low, single-digit percent occurrence with the current main products [78]. Differences have been seen with an older product (which exhibited higher incidence of neutralising antibodies), dosing frequency and cumulative dose [79].
\nNew products, produced using different manufacturing processes and with different final formulations, may help address the above issues and indeed as well for the existing natural products, which have not changed formulation or manufacturing process significantly in the last 20 years [75]. Alternative new products include Nabota® (Daewoong Pharmaceutical Co., Korea), which consists of BoNT/A obtained following a special purification process, and RT002 (Revance Therapeutics Inc., USA), which is an injectable formulation of BoNT/A containing a polycationic excipient developed to limit diffusion of the toxin into adjacent tissues and to be longer acting than the current BoNT products, amongst others [2, 9]. The use of hydrogels and liposomes, for example, in treatments for bladder or gastric disorders, has also been reported as novel BoNT formulations being investigated [80]. Liquid formulations for BoNT/A products, already in the market for BoNT/B, are actively being pursued, and their use would preclude the need of reconstitution of the products [75].
\nGiven the natural diversity of BoNTs, with 7 serotypes and over 40 individual subtype proteins, it is surprising that the leading marketed products are restricted to only two serotypes, BoNT/A and BoNT/B. So far, anecdotal use of BoNT/C and BoNT/F was reported few years ago [81]. The current landscape of new therapeutics include, for example, the potential use of the short-acting BoNT/E1 as reported in WO2014068317 [82], the use of a BoNT/B toxin with increased binding affinity for its human cognate receptor synaptotagmin II as reported in WO2013180799 [83] as well as BoNT/A3 (WO2013049139 [84]). In particular, serotype BoNT/A2 has been extensively studied in Japan as an alternative BoNT/A with differentiated biology [85, 86].
\nMolecular engineering approaches facilitate the harnessing of inherent characteristics present in the already diverse natural BoNTs [87] but also allowing the introduction of new properties. When considering engineering approaches, all three BoNT domains offer exciting opportunities; for a recent review, see Ref. [5]. Firstly, engineering of the Hc domain could facilitate (1) alternative receptor targets to modify specificity, (2) allow immune epitope modification and (3) add/modify receptor-binding motifs and related structural regions to modify affinity. Secondly, engineering the HN domain could modulate cargo capacity and pH dependency of translocation of cargo. Finally, LC engineering could provide (1) substrate specificity, (2) desired intracellular localisation, (3) modification of immune epitopes and (4) modification/manipulation of self-proteolysis and degradative pathways.
\nAn example of such engineering approaches is targeted secretion inhibitors (TSI), in which the Hc domain of BoNT is substituted by an alternative cellular targeting domain (e.g. see WO2006059093 [88]), which will be discussed in the next section.
\nNatural BoNT toxins target neuronal terminals, and their duration of action is often measured in months. These characteristics have made them very successful therapeutic and aesthetic agents (see Section 1 above), but it also limits their use to their specific target cells. Given that SNARE proteins underpin a universal mechanism of secretion in eukaryotic cells, an engineering approach that would lead to cleaved SNARE proteins in a wide range of (hypersecreting) cells would provide novel and exciting therapeutic opportunities. In TSI, the Hc-binding domain of BoNTs is substituted by an alternative cell-binding moiety, and the resulting proteins are not neurotoxins but a new class of biopharmaceuticals [89].
\nThe basis for the TSI platform development is a functional fragment from BoNTs comprising the LC and HN domain, termed LHN. LHN proteins are proteolytically cleaved during activation, and the two domains remain connected by a disulphide bridge, as is the case in the parental BoNTs. LHN/A, LHN/B, LHN/C and LHN/D are amenable to recombinant expression in E. coli and have all been described as functionally active, resembling the respective parental toxin [90, 91]. Examples of TSI include those where the targeting domain is comprised of wheat germ agglutinin, nerve growth factor, an epidermal growth factor receptor (EGFR) targeting ligand or a growth hormone-releasing hormone receptor (GHRHR) targeting ligand. These TSI have shown that it is possible to achieve internalisation of the active BoNT LC contained in their structure into non-neuronal cells otherwise resistant to the parental BoNT [92, 93, 94].
\nThe structures of LHN/D and a GHRHR-targeted TSI/D, SXN101959, are shown in Figure 5. When compared with BoNT structures depicted in Figure 3, it is seen that the BoNT Hc domain is absent in the LHN structure and, in the case of the TSI a new targeting moiety takes the place of Hc. Often, the new targeting moiety is considerably smaller than the original Hc domain of the parental BoNT. That poses its own challenges regarding ligand accessibility, and so linkers and spacers are frequently used. Furthermore, in the case of this GHRHR ligand, a free N-terminus of the peptide is required for optimal activation of the GHRHR receptor [95], which has prompted the position of the ligand to be at the N-terminal end of HN when compared to the Hc (located at the C-terminal of HN in the natural structure). Functionally, this TSI has been shown to exert a powerful and reversible inhibitory action on the endocrine growth hormone and insulin-like growth factor-I axis [96].
\nStructural and functional domains of LHN/D and a GHRHR-targeted TSI/D. (A) Crystallographic data of LHN/D (PDB 5BQN). (B) Crystallographic data for the GHRH-targeted TSI/D (PDB 5BQM) in which the targeting domain has been added using molecular modelling for illustration purposes. The ribbon to the right of the LC and HN domains corresponds to the GHRHR ligand plus the spacer, as illustrated in (C). (C) Simplified block diagrams of the structures presented in (A) and (B), respectively. The HN and LC domains in both structures can be seen being connected by a conserved disulphide bridge. Structural images created using the MOE software (Molecular Operating Environment 2013.08; Chemical Computing Group Inc., Montreal, Canada).
Little is known about TSI intracellular trafficking, and it is generally assumed that the BoNT four-step MOA (binding, internalisation, translocation and SNARE cleavage) will apply. A study using a GHRHR-targeted TSI/D reported an intracellular, punctate, immune-staining pattern indicative of the presence of the TSI in endosomes [97]. In a recent paper, internalisation of an EGFR-targeted TSI/A and BoNT/A was assessed in the same cellular system [98]. The EGFR-targeted TSI/A partially internalised in an intracellular compartment consistent with endosomes, whereas BoNT/A did so in a different compartment consistent with synaptic vesicle recycling. Both proteins were able to cleave the cytosolic SNARE protein target SNAP-25. The study confirmed that BoNT domains are a versatile tool to extend the pharmacological effect of BoNTs beyond the natural target of the neuromuscular junction.
\nIn addition to the delivery of SNARE cleaving activity into non-neuronal cells, TSI can also be used to provide alternative targeting to neurons with improved neuronal selectivity. One such example is neuronal targeting via the nociceptin receptor, which reached Phase II clinical trials for post-herpetic neuralgia and overactive bladder (WO2006059093) [88, 99].
\nBoNTs are key therapeutic agents with a seemingly ever-increasing list of new applications. The fascinating modular molecular architecture and natural diversity of BoNTs is the base for future therapeutics, being developed using recombinant technologies, new formulations and engineered new pharmacological properties.
\nEF is an employee of Ipsen Bioinnovation Ltd. I thank Dr. S.M. Liu for the structural illustrations in Figures 4 and 5 and Dr. J. Krupp and Dr. M.S.J. Elliott for their comments on the manuscript. I thank Dr. K.A. Foster and Dr. J.A. Chaddock for their contributions to the BoNT and TSI field.
\nAAN | American Academy of Neurology |
BoNT | Botulinum neurotoxin |
CDC | Centres for Disease Control and Prevention, US |
EGF | Epidermal growth factor |
EMA | European Medicines Agency |
FDA | Food and Drug Administration, US |
GHRHR | Growth hormone-releasing hormone receptor |
HA | Hemagglutinin |
Hc | BoNT-binding domain |
HN | BoNT translocation domain |
LC | BoNT enzymatic domain |
MOA | Mode of action |
NAPs | Neurotoxin-associated proteins |
NTNHA | Nontoxic non-hemagglutinin protein |
SNARE | Soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins |
TSI | Targeted secretion inhibitors |
Since the end of the Cold War and the dissolution of the former Union of Soviet Socialist Republic (USSR) in 1991, Africa as a region has undergone a major structural transformation in social, political, demographic, and economic spheres. In political sphere, the region has gone from a one-party state governance to a multiparty democratic system ([1], p. 300). In social sphere, social governance is slowly but steadily being shared by the rising civil society and the NGOs that have now become copartners at addressing and debating social, economic, and political challenges in Africa. In demographic sphere, the region has seen a twofold increase in its population growth in the last quarter century. And finally, as regards to the economic sphere, whether voluntarily or involuntarily, since the 1990s, Africa has become a full participant in the economic and commercial globalization spurred by the West and led by the United States. And because of the abovementioned structural transformation of the continent, the region has nonetheless grown economically and registered stellar economic numbers in the last decades or so. That is, through the decade of the 2000s to the year 2013, for instance, the global boom in commodity prices propelled natural resources and oil- and gas-exporting African countries to register incredible economic growth and empower Africa into the twenty-first-century global economy [2]. As a result, Africa as a region is now a full member of the world economy and a coveted actor in the international economic arena.
However, despite the impressive recorded economic growth mainly by the energy and commodity-exporting African countries as stated above, as a region, Africa is still facing serious local and transnational challenges such as youth unemployment, climate change threats, rapid population growth, undernourishment, domestic terrorism, drug trafficking, maritime piracy, protracted political crises and low-intensity short-lived wars, and conflict-induced famines like the one we are witnessing in South Sudan today. Consequently, those challenges stand in the way against Africa’s pursuit to achieve food security and eradicate hunger.1 Therefore, if these above-cited challenges are not properly addressed and seriously tackled by the African political leadership, it is probably fair to say that achieving food security and meeting nutrition needs and targets as established by the Millennium Development Goals (MDGs) (2000–2015) and Sustainable Development Goals (SDGs) (2015–2030) will simply be another elusive quest for Africa among many other policy objectives and goals. In addition, if that happens to be so, the continent will unfortunately continue to languish behind other regions of the world in socioeconomic and human developments.2 And consequently, it will be nowhere near attaining the SDG goals and targets just as it failed to meet the past MDG goals and targets. As a case in point, despite its modest registered economic growth and well-intentioned international policy initiatives such as the cited MDGs and SDGs aimed at fighting hunger and overcoming nutrition deficits [4] among many other human and development policy objectives, only few African countries managed to meet the MDGs 1c [5]. With that being said, this chapter sets out to present the state of Africa’s food insecurity and nutrition deficits and addresses the potential impacts of the above-cited challenges, widely regarded today as the real barriers against successful eradication of food hunger and achieving food security in sub-Saharan Africa.
In this chapter, we use the definition of food security as stated by the United Nations Food and Agriculture Organization (UNFAO). The FAO’s definition is our guiding principle and upon which our analysis of Africa’s food security challenges is based. The FAO defines food security as “When all people, at all times, have physical, social and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life [6].” Nonetheless, achieving food security however requires that:
Sufficient quantities of appropriate foods are consistently available.
Individuals have adequate incomes or other resources to purchase or barter for food.
Food is properly processed and stored.
Individuals have sound knowledge of nutrition and child care that they put to good use and have access to adequate health and sanitation services [7].
To begin with, it is worth pointing out from the onset that food insecurity is a multidimensional problem. It is a problem that is linked to healthcare, conflicts, policies, politics, leadership, strategic vision, trade and economic interests, agricultural production, food system, global food industry trade politics, and the environment (mother nature). As an example, in the sphere of healthcare, one can see a direct link between food insecurity, malnutrition, and a global pandemic like the HIV/AIDS. That is to say, if a member of a given family, for instance, is affected by the AIDS epidemic, the family of that patient will automatically lose a breadwinner and financial income generator. That is, the person affected by the disease will no longer be able to engage in any remunerative physical activity whether for themselves or for a third party in order to earn a living. Consequently, he or she will financially no longer contribute to his or her family well-being since they will not be able to generate any income whatsoever. And if and when that situation were to occur, the family of the patient in question would begin to eat less. The body of the affected person will by then have become vulnerable and weak to engage in any remunerative activity. As a result, food insecurity will then have set in, and poverty trap will have taken over and affected everyone within that family.
At the time of writing this chapter, Africa’s state of food insecurity relative to other regions of the world, except for West Asia, is troubling and non-promising. Hence, understanding and accepting this reality should be of a concern for all Africans regardless of their socioeconomic and political status. That is to say, this said reality should be of a concern for the African political leadership, the mayors of mega African cities,3 the NGOs, the civil society, the media, the farmers, the business community, the youth, the academia, the churches, the mosques and other faith-based organizations, and the consumer organizations alike. And according to the FAO 2015 State of Food Insecurity in the World IN BRIEF, Africa scores poorly in all indicators regarding food security and nutrition targets. For example, in 2015, only 18 out of 54 African countries have reached the MDG 1C hunger target (Millennium Development Goals 1C).
Furthermore, two of the many reasons why food security keeps evading millions of Africans are the never-ending conflicts and incessant political instability on the continent. Often, in many sub-Saharan African countries, foods are available and plentiful but not accessible to everyone. Poor families, for example, disproportionately pay the brunt of conflicts and wars. Farmers cannot bring their staple crops to the markets because of the lack of security even if and when they wanted to do so. Put it simply, conflicts disrupt markets and affect development policies that are put in place to assist the neediest of the population. And as a consequence of conflicts and wars, food prices rise, and poor families and their children can no longer have access to healthy and balanced dietary foods (utilization). Conflicts make food production drop since no one will risk their lives to work in the fields and bring foods to the markets while killings are raging. In the Central African Republic, for instance, the short-lived war of 2013 and its aftermath caused a drastic reduction in food production (availability) and engendered the rise of food commodity prices (accessibility). In fact, poor families and anyone else who could not have access to the foods in the markets were simply forced to live in subsistence. Consequently, thousands of Central Africans became nutrition-challenged because whatever was available for them to eat was obviously not meeting their nutrition needs and targets. Furthermore, widespread insecurity across the entire country made it more difficult to import foods from the neighboring countries or even receive foods from aid donors and the international community (stability) for that matter. As a result, food insecurity, and in many instances, the lack of foods thereof, became the daily reality of untold Central African families. And additionally, this added existential threat exacerbated an already desperate and deteriorating economic condition caused by years of protracted conflicts and political and economic mismanagement [9].
There are a lot of reasons as to why Africa and sub-Saharan Africa in particular is suffering from food insecurity and failing to meet its nutrition needs and targets. Though it is true that one cannot put their fingers at one specific reason as for why food shortages, insecurity, and prevalence of malnutrition uninterruptedly afflict sub-Saharan Africa, one can however identify a number of failed internal economic policy tools and international policy prescriptions as the culprit or underlying causes of systemic food insecurity in Africa. That is to say, on the internal front, for example, fewer among many reasons as for why food insecurity has been chronic in many African countries are the following: (1) the never-ending political instability and crises; (2) the short or long protracted civil conflicts and wars; (3) the endemic, persistent, and institutional corruption; (4) the misdirected economic policies and mismanagement; (5) the lack of committed political leadership; (6) the sheer neglect towards the farmers; and (7) the lack of clear financial and economic investment into the agricultural sector. On the external front, however, economic policy prescriptions mainly written and formulated by the World Bank (WB) and the International Monetary Fund (IMF) in the 1970s, 1980s, and the latter part of the 1990s directed at the African countries made an already difficult economic situation worse. This is because the architects of the alluded policies advised sub-Saharan African governments and leaders to cut aid and slash subsidies to their farmers. The economic policy rationale was that African countries should pull the plug under their parastatals (government-owned enterprises) and let the markets take care of everything. In addition, respective African governments were told that Africa should privatize and liberalize their economic policies in order to align them with the prevailing international trade, investment, and economic principles. Those economic recipes were said to modernize Africa and speed up its incorporation into the liberal-based global market economy. Consequently, because of those policy prescriptions, African farmers lost income supports from their respective governments, and millions of low-income African families became victims of food insecurity and nutrition deficits. In essence, the IMF and the World Bank, and to a certain extent the US Treasury Department promoting and owning the so-called Washington Consensus, should be held responsible for those failed policies. For, they were the ones that devised, concocted, and directed them. As a matter of fact, they actively promoted or better said imposed them upon weak and hopeless African governments. And in turn, hapless African leaders implemented the said policies without truly understanding their future potential consequences on the farmers and their societies at large ([10], pp. 369–370).
So, with the benefit of hindsight today, one can say that those structural adjustment programs (SAPs) as they were known then, and devised by the above-cited international institutions and encouraged by the US Treasury Department, contributed to the demise of many farmers in Africa. They exacerbated the food insecurity and the existing precarious economic plights of millions of African families. And with the passing years, it has now become clear to any astute observer of the recent history of the social and economic development of Africa that African leaders of that time were not wise enough to reject and outrightly oppose those policies [9]. Actually, in fairness, many of them heartily and readily adopted the said policies and imposed them on their beleaguered poor populations. In fact, soon after they did so, many African countries began to import foods in huge quantity. And unfortunately, this situation has now lingered for decades. And honestly, as of today, there is no end in sight as to when the recurring food shortages and massive food imports in sub-Sahara Africa will either abate, subside, or end altogether. And for that, African countries constantly face food shortages now despite all the good and well-intentioned policies of the international community, the African Union, and African countries themselves intended to address rampant food insecurity, eradicate hunger, and bring food security to millions of low-income African families. So, as a consequence of all that, sub-Saharan Africa today is heavily dependent on food imports than at any time in its history. And as a result of that, it is sadly subjecting millions of its populations to the mercy of foreigners, commodity speculators, foreign exchange fluctuations, food aid giving nations, and the geopolitics of global food trade [11]. In actuality, this is the state of Africa’s food security today. And as a matter of fact, when one looks back at the genesis of this episode, one can say without a doubt that this unfortunate situation could have easily been avoided. That is to say, had the African political leadership shown true leadership, heavily invested in agricultural sector and adopted economic nationalist policies, the early food production crisis, and insecurity beginning in the early 1970s would have been dealt with more effectively. Indeed, past African governments could have substantially invested in food production, assisted the small farmers with more aid and subsidies, and created policy resilience that would have saved thousands of African lives and farmers. And this may have possibly transformed and modernized the entire African food production system. In short, had the political leaders displayed true political courage to undertake such policies as stated, and shown true care for their respective populations, the concerns about the potential socioeconomic catastrophe of the rapid population growth in Africa will not have been as alarming and challenging to us as they seem today. To say the least, Africa suffers from food insecurity today and has been suffering from it for so long simply because of the utter failure and lack of vision, political courage, and sound economic policies of the African leaders and economic decision-makers of all political and ideological stripes on the Continent.
In 1990, Africa’s population was 635 million people. And, in 2018, the population of Africa stood at 1.2 billion people (see Figure 1 below). However, except for the oil exporting African countries (see Table 1), sub-Saharan Africa has, on average, grown a meager 1.1% GDP in the last quarter century [15]. Now, considering Africa’s demographic explosion in the last two decades, this underperforming GDP per capita growth is not sustainable for its long-term economic transformation. And clearly it will not help it either to meet the needs of millions of its young people that are reaching working age and expected to enter the labor market [16] in great numbers every year till the year 2030. This somber forecast is in addition to the fact that Africa’s population is projected to double by 2050 (see Figure 2 and New African March 2019 Guest Commentary by Peter Estlin, the Lord Mayor of London). Therefore, these serious challenges and threats are to be factored into any discussion about Africa’s long-term economic transformation. That is to say, every social, political, and economic actor in Africa should seriously ponder upon them and properly address these threats and challenges. As the youngest continent, Africa has tremendous challenges ahead of it. At the same time, it also has great opportunity to unlock its economic potential that will benefit hundreds of millions of its peoples. However, this can only be done if African political leadership and economic decision-makers unselfishly invest into the youth and give it access to quality health and education and skills of the twenty-first century. And assuming that that warning is heeded, a vibrant, healthy, and educated young population will undoubtedly take upon itself to resolve the issues of food insecurity and nutrition deficits, among many other challenges. As a matter of fact, a great number of economic experts and development economists agree with this economic proposition. They claim that quality health and education are the only engines of economic development that will help unleash the African potential, create inclusive prosperity for all, and economically transform the continent. (For further comments on the subject, see New African March 2019 Guest Commentary by Bill and Melinda Gates).
Evolution of Africa’s population 1960–2019 (Source: [12]).
Africa’s population forecast 2020–2050 (Source: [12]).
Furthermore, Africa’s political leadership, youth, and civil society shall all understand that without some sort of family planning, albeit a voluntary one, the rapid unplanned population growth will never make Africa be food and nutrition secure. Therefore, understanding this reality, and taking also into account the cultural and religious sensitivities of several African communities, Africa’s political leadership, and faith-based organizations of all denominations, should not have any problems investing in women, youth, and young girls. That is to say, in doing so, they will be able to properly educate mothers and future mothers and common people about the consequences of food insecurity and nutrition deficits on the future of their well-being and for Africa as a whole. That’s because an uncontrolled rapid population growth, alongside the climate change threats and its effects, will be a formidable challenge for Africa to overcome if African people are not implicated in seeking solutions for their problems and challenges themselves. In our view, not adopting this policy approach will render the search for Africa’s meaningful economic transformation unattainable just as many other unfulfilled African economic dreams (beginning since the years of its political independence in the 1950s, 1960s, and 1970s). The said contemplated family planning could also be managed through community programs, school programs, and after church and mosque services programs. And by devising such social program plans, educating people in major cities and the rural areas to understand what is truly at stake, and encouraging them to participate into the programs, it will be safe to say that Africans will take upon themselves the transformation of their agricultural production and adopt policies that will help them achieve food security on their own. And as such, they will be able to meet their nutrition needs and targets in line with their burgeoning population growths.
Climate change debates pit true believers of climate change against those that oppose it. They also confront those who are skeptical of its existence or outwardly deny it against those who are fervent believers in it. However, the debates about whether climate change exists or not are beyond the intended purpose of this chapter. In it, we base our analysis on the existence of the climate change threats and its effects as an added challenge to Africa’s existing agriculture commodities’ production, food security, and nutrition needs and targets. In fact, as of today, changes in rainfall, soil quality, weather patterns, and precipitations in many regions of Africa have become the drivers for the food challenges and insecurity in all regions of the continent. And as a result of all that, climate change threats, effects, and stress are now the multiplier for the multitude of the daily challenges that Africans face. Furthermore, it is worth recalling that many countries in the world recognize today that climate change impacts on the temperature, precipitation, and droughts on a given community adversely affect the food security of that community. And consequently, many members of the said affected community are forced to leave and migrate to other communities. That is so because adverse or abrupt climate conditions and threats stress an entire community. And more often than not, they push their younger members to mass migrate. In addition, negative effects of the climate change event like floods and droughts destroy the agricultural production capacity and inputs of the impacted community. So, as an example, communities that have experienced events like droughts and floods whether in the Sahel, the Lake Chad Basin, or East African region [17] have all seen themselves abandoning their homes and villages and moving to neighboring communities or urban cities where they have no adequate resources to help themselves cope with their new surroundings and adapt to their new-found challenges. Many members of the said displaced communities become victims of food insecurity themselves. That is because by abandoning their villages and towns and moving to the new ones, they compete for scarce resources such as water and other daily living amenities in order to survive. Moreover, their sheer presence in their new hometowns or cities swells the pockets of the already established urban poor and makes life more miserable for themselves and everyone else. In short, climate change impacts and its effects have become existential threats to vulnerable communities. And one of the visible effects of climate change today is that climate change impacts turn members of the climate-impacted communities into climate refugees within their new adopted communities.
According to the Fund for Peace, in 2017, the three most fragile states in the world were in Africa. Those states were the Central African Republic (CAR), South Sudan, and Somalia [18]. And each one of them has now become fragile because of the protracted crises that have kept it unstable since the 1960s. In the case of the Central African Republic, the years of the trouble started in the 1960s. In the case of Somalia, the disintegration of its state apparatus and the advent of its successive social, political, and economic challenges came after the fall of the regime of Siad Barre in 1991. In the case of South Sudan, the country has been in political turmoil, standoff, low-intensity warfare since it gained its independence from the Republic of the Sudan in 2011. However, it is worth noting that those three cited-above countries are not the only fragile countries in Africa. There are many other African countries that are also fragile and politically unstable because of the protracted conflicts and never-ending political crises. This is in addition to other crippling challenges such as governance deficiencies, corruption, decades-long underperforming economies, weak institutions, flagrant human rights violations, and living resources scarcity that have kept them from creating an inclusive and shared prosperity for millions of their citizens.4 Indeed, food insecurity and nutritional deficits and the lack of quality health and education are the direct results of the said never-ending challenges that Africa as a whole confronts ever since it gained its political independence from the former colonial powers.
In effect, the persistent lack of peace and security in many sub-Saharan African countries today, coupled with the never-ending political instabilities and crises, is mainly the underlying reasons why African countries seem incapable of tackling and overcoming existential challenges and threats such as food shortages and insecurity and widespread malnutrition on their own. As a case in point, since 2010, a number of civil wars and political crises have broken out in several African countries from Algeria all the way to Kenya. In addition, newer political instabilities and short-lived civil wars have also occurred or unfolded in places like the Lake Chad Basin, Nigeria (Boko Haram), Libya (the bloody ousting of Muammar Kaddafi and the ensuing civil war), Egypt, Tunisia, the Central African Republic (CAR), Kenya, Cameroon, Mali, Burkina Faso, Burundi, South Sudan, Algeria, and Sudan as of late [20]. Moreover, countries such the Democratic Republic of the Congo (DRC), Sudan, and Somalia where decades-long conflicts have weakened and rendered their respective governments inept and unable to assume the administration of their territorial security and come up with sound national economic management policies, transnational threats such as terrorism, mass migration, pandemics such as Ebola and HIV/AIDS, and maritime piracy consume and divert their meager state resources away. Because of all that, their depleted resources are never sufficient to help them successfully fight institutional corruptions, rein into drug trafficking, curb hunger and other social woes, and effectively run their day-to-day administrative affairs. And as a result of the said overwhelming challenges, food insecurity and nutrition challenges currently affect and threaten the lives of millions of South Sudanese, Central Africans, Somali, Nigerians, and million more Africans today. For further illustration of how many African countries are afflicted and overwhelmed by conflicts and protracted crises, and why food security challenges have become existential threats not just to one or two countries in Africa, see Cases of countries affected by food insecurity and acute malnutrition stemming from protracted conflicts, crises, and political unrests and Table 2.
African countries in protracted crises, conflicts, and fragile situations (Source: Data extracted and compiled from [21]).
Nigeria. This country has been grappling with severe security threats from Boko Haram and ISIS West Africa (ISIS-WA). Consequently, these threats have caused massive internal displacement of the population in the northeast region of the country and made thousands of Nigerians domestic refugees. In addition to the displaced Nigerian citizens, thousands more refugees from Niger, Cameroon, Chad, and the Central African Republic have flocked into the region, and consequently swelled the overrun refugee camps and made matters worse for everyone involved in the camps. As a result, they all have become victims of food and nutrition insecurity.
South Sudan. Due to the clashes between the South Sudanese Government and armed opposition groups, millions of South Sudanese have become the largest displaced population in their own country and been made refugees in the neighboring countries. As a consequence, this situation has created a severe case of food insecurity and malnutrition challenges in South Sudan today.
Somalia. This country is another case in Africa where protracted conflicts since 1991 have made it impossible for the Somali population at large to escape from poverty, misery, and the never-ending threats and real cases of food insecurity and chronic malnutrition that have for years affected both the youth and general Somali population.
The Central African Republic. This country is the latest case of food insecurity and widespread malnutrition in Africa. This has been the case since the short-lived Civil War of 2013 and the ensuing political unrest, rebellion, and ongoing sectarian aggressions between the Christian and Muslim communities.
The international community heretofore understood as international institutions; private sector; multinational and transnational corporations (MNCs and TNCs); civil society; private foundations such as the Bill & Melinda Gates Foundation, the Clinton Foundation, and NGOs; leading nations such as the United States, China, India, Russia, and Brazil; the Global South; the European Union (EU); and celebrities like George Clooney, Angelina Jolie, Madonna, Bono, and many others are all stakeholders in food security and hunger debates. However, the United Nations (UN) system has thus far been the leading multilateral institutional voice that addresses and shapes the policy debates and proposes policy prescriptions for the food insecurity and malnutrition challenges that Africa and other regions of the world face.
Within the United Nations system, however, the Food and Agriculture Organization (FAO) which was established as an intergovernmental body is the organization mandated to address the agricultural issues such as food security, nutrition, and malnutrition challenges of its member countries. And as an intergovernmental body, the FAO was formed to promote the “common welfare by furthering separate and collective action for the purpose of raising levels of nutrition and standards of living of the peoples under their respective jurisdictions; securing improvements in the efficiency of the production and distribution of all food and agricultural products; bettering the conditions of rural populations; and thus contributing towards an expanding world economy and ensuring humanity’s freedom from hunger [22].”
Though the FAO has had the mandate to tackle agricultural issues and concerns of its member countries, from its inception, the governments of its member countries were primarily the major actors that formulated and addressed the issues of agriculture within the United Nations’ system. However, since the end of the Cold War, other actors and stakeholders such as the NGOs, CSOs, and a multitude of transnational corporations have also become relevant actors in policy formulations addressing hunger, food issues, and nutrition security governance in Africa. This has especially been so since the establishment of the MDGs covering the year 2000–2015 and the SDGs in place from 2015 to 2030. Nevertheless, this proliferation of stakeholders and actors in food security governance that is now being shared among the UN agencies and the private sector, civil society, NGOs, and the concerned governments has led to an increase in collaboration and partnerships among all the stakeholders that address and formulate policies dealing with the food and nutrition challenges in Africa today. As an example, transnational corporations such as Unilever have now jumped into global threats issues such as world hunger and food security and malnutrition challenges. This is becoming common in corporate governance because leading global corporations have now realized that those aforementioned issues are global threats in nature and no longer local per se. And therefore, they affect everyone and every country in this age of economic, political, technological, and cultural globalization [23]. Furthermore, corporations such as Unilever and many others like it have also understood that addressing those issues as a company or private sector is actually adhering to social corporate responsibility which is increasingly aligned with the interests of a business in this globalized and interdependent world. In fact, this new social-business approach has become the new modus operandi of socially responsible companies everywhere in the world today. In other words, it’s good business to be a global corporate citizen. In effect, big corporations and brand-name companies now understand that consumers want them to also be social citizens while pursuing their economic and business profits and interests [24]. And as a response to all these new developments, in 2013, the FAO published its new strategic framework with a new focus on “governance, creation of enabling environments, and policy support in member countries is the direct outcome of its adaptation and repositioning process.” This new framework was conceived to officially help the FAO collaborate and share policy spaces with other actors and stakeholders in food and nutrition security governance in Africa [25] and anywhere else for that matter.
Africa’s responses to the food security challenges can at best be summarized as ineffective and inefficient thus far, to say the least. However, since the advent of the new millennium and the food crisis of 2007–2008, there has been a somewhat sincere and renewed commitment by the African leaders, the African Union, the Regional Economic Communities, the national governments, civil society, private sector, and all the stakeholders in Africa in support of food security. This new-found engagement in food security challenges is aimed at supporting agricultural production, replacing the prevalence of undernourishment, eradicating hunger, achieving food security, and meeting nutrition needs and targets. This has been so since the 2008 food price hikes and the subsequent social unrest and disturbances that took place in several African capitals and shook the sitting governments of that time. As a result of those vivid developments, the national security implications of food and nutrition insecurity were in plain view for all to see. In addition, the increased awareness of climate change threats and the rising awareness of the unforeseeable consequences of the rapid population growth on the food production system and on the stability of the state made African leaders take note and entice them to initiate various national policies to support food and nutrition security. Soon thereafter, as a result of those political events, several respective African governments devised new policy strategies in line with their national economic policies in support to food production, transformation, and security. For example, countries like Ghana, Nigeria, and Kenya partner more now with the private sector and the civil society in administering and managing their food systems. They basically have shifted their schemes towards private-public partnerships and involved wider private sector(s) in their food production and transformation policies. In contrast, countries like Ethiopia, South Africa, Angola, and Mali have integrated more of their food policy programs in recent years as well. That is, they have aligned them with their national economic strategies to support their food production, combat their food shortages, and replace their prevalent malnutrition. Nevertheless, what remains to be accomplished to date is the transformation of the said renewed political commitments into concrete policy actions such as (1) a visible and sustainable high-level leadership and effective governance, (2) an increase in public-private partnerships (PPPs) and shared co-leadership in fighting against hunger and food insecurity, (3) a supportive and enabling environment by the sitting governments and their decision-makers, and (4) a comprehensive and clear policy approach with all stakeholders involved in support of food production and security. Furthermore, at the continental and regional levels, it is worth highlighting also that the leading voices in formulating policies to combat food insecurity and curb the nutrition challenges in recent decades have been the African Union Commission (AUC), the NEPAD, and the Regional Economic Communities (RECs) such as ECOWAS in West Africa and ECCAS in Central Africa.
The current state of food security and widespread malnutrition in Africa is not as ideal as Africans would like it to be. That is to say, as of today, a good number of African countries are food deficit and insecure. This has been so because food insecurity and widespread malnutrition as stated in this chapter are a multidimensional problem. Challenges that are directly tied to healthcare, misdirected policies and politics, trade and economic interests, weak institutions, failed leadership, and many other variables make it hard and difficult for many African countries to achieve food security. In addition to the internal causes previously discussed as of why a good number of sub-Saharan African countries are not food secure, the chapter also highlighted that there are also external reasons as for why sub-Saharan African countries have been struggling to secure foods for their respective populations and meet their nutrition needs and targets. The chief among those external reasons as discussed and analyzed were economic policy prescriptions that the World Bank and the IMF prescribed for Africa in the 1970s, 1980s, and the latter part of the 1990s. The said policies were devised to help Africa align its economic development policies and strategies with the market-based liberal principles and practices. And as previously explained, the economic conditions of those countries later showed that those policy prescriptions did not provide the intended and expected economic results. Instead, they worsened the food insecurity in Africa. That’s because by advising and encouraging African governments to cut their aid, subsidies, and assistance to their farmers in the name of the market-based principles, food insecurity in sub-Saharan Africa worsened dramatically. Moreover, the chapter also acknowledged that, save the commodities and natural resources exporting African countries, the economic growth of the majority of African countries has not performed as expected either. That is, the GDP growth rates of many sub-Saharan African countries have not kept pace with their rapid respective population growths, especially the rapid urban population growth that many African countries have experienced in recent years. In addition to the mentioned economic policy challenges, new challenges such as climate change and its effects and the internal displacements and migrations pushed many sub-Saharan African countries to depend more on food imports and foreign aid. Consequently, in actuality, many of them are unable to feed their populations today, and food insecurity and malnutrition have become the daily staple of millions of their citizens. Last but not least, the food price hikes of 2008 and their direct political consequences thereof, namely, riots and protests in many African cities, also exposed in plain view the economic policy failures of the African countries to the whole world to see. The rioting and protests showed how inept and incompetent many African leaders had for years been in failing to provide food security to their low-income and respective vulnerable citizens. Also, one of the visible consequences of the failure of African leaders in food security management has thus far been the continuous rise of import food bills in Africa year after year [26, 27, 28, 29, 30, 31, 32, 33, 34], while agriculture dependence has remained high. In sum, the combined reasons as analyzed above are the real reasons why sub-Saharan African countries have for years seemed unable to eradicate hunger, achieve food security, and meet nutrition targets and needs for their people(s). In essence, this is fundamentally why African countries struggled to meet the MDGs targets (2000–2015) despite the assistance and resources granted to them by the international community. With that in mind, if recent history is any indication, sub-Saharan African countries are going to struggle again in order to meet a few targets of the SDGs (2015–2030). In summary, hopefully African leaders will prove their skeptics and all of us wrong this time around.
The diagnostics of Africa’s food security and malnutrition challenges has been thoroughly examined in this chapter. The international community, the African Union and respective African governments and anyone else interested in the issues of food insecurity, climate change threats, and protracted conflicts and wars in Africa have all launched policies against food insecurity in Africa. However, in order for Africa as a whole to achieve food security and lower its dependence on food imports and aid, African political leaders and economic decision-makers will have to surmount in true sense each one of the challenges mentioned in this chapter. For as those challenges are extensively analyzed in this chapter, they have been shown to be the real culprit of Africa’s never ending socioeconomic and political problems. For decades now, they have been the challenges that have crippled Africa and hijacked the well-being and welfare of its citizens. Below are the specific policy proposals that if implemented could contribute to help overcome the challenges of food insecurity and nutrition deficits and many other challenges that have kept Africa for years from meaningful economic transformations beneficial for all its citizens.
African political leadership and economic decision-makers should strive to formulate economic development strategies that are inclusive and people-centered rather than elites and upper middle-class cosmopolitan-driven. That is to say, Africa needs inclusive shared prosperity and constructive policies focused on Africa’s youth and women and solely addressed against the challenges of a population set to double by the year 2050. Employment and job creation policies ought to also be the top priority beyond anything else for the African political leadership. Those are the real challenges that Africa will be facing in the next coming decades.
African political leadership and economic decision-makers should make agriculture a strategic sector and provide African farmers with all kinds of assistance and aid regardless of how unpopular they may appear to the international community and economic experts, and how contrary they may be when evaluated against the market-based principles and policies. In addition, credit and insurance schemes for farmers should also be part of any economic development policy and strategy in any sub-Saharan African country if food security were to ever be achieved. Instituting smart credit and insurance schemes for farmers will inevitably help create robust financial resilience that will protect them from market uncertainty and shocks and keep them focused on food production. Furthermore, civil society organizations, producer organizations, and wider private sector alike should also be allowed to participate in and be part of any policy scheme devised to support food production, combat food insecurity, and curb nutrition deficits.
African political leadership and economic decision-makers should institute and establish social protection programs or food safety net in the likes of cash transfer programs whose objectives should solely be to promote food security and nutrition and provide quality healthcare and education for the youth and women in particular whether in urban centers or in the rural areas. The programs should also serve against food price shocks for low-income citizens that are vulnerable to the market prices’ volatility. Distribution programs and food banks in every neighborhood, town, and city across sub-Saharan Africa should also be established and aggressively promoted while implicating Africans of higher economic and financial means in the programs. The unscathed and seemingly unconcerned wealthy African families should also be invited to co-own the schemes and programs since they are resource-blessed and better off than the majority of their fellow citizens. That is to say, whatever incentive in the likes of tax break or any other financial schemes that may be attractive to them should be on the table for them to consider. Simply put, well-to-do Africans should be reminded of the famous African solidarity and the responsibility that comes with it in assisting their less-blessed brethren.
African political leadership and economic decision-makers should make all kinds of efforts to increase investment in food production and processing and physical transportation infrastructure that will connect rural areas with the growing urban centers where food demands are concentrated. Modern food storage facilities should also be built around major cities and link them to the four geographical corners of the back country. And this can be achieved only if food transportation networks within the country and across the immediate subregions are modernized and resourced.
African political leadership and economic decision-makers should understand once for all that without a sustained political stability and zero tolerance of any sort of institutional or personal (family-induced) corruption, agricultural production and food relief efforts that are badly needed to combat hunger, decisively tackle food insecurity, and achieve the nutrition needs and targets in Africa will never be possible. Peace therefore should be at the center of any national policy and be made the highest priority if Africa does not want to forever be dependent on the good will of foreigners, continuously import foods, and forever beg for development aid and largesse.
JEL Code: N57, Q1, Q5, F63
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\\n\\nAs a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 118,000 international scientists and researchers.
\n\nThe Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
\n\nOAPF Publishing Options
\n\n*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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