Antimalarial Artemisinin Research Articles

Efflux transporter engineering markedly improves amorphadiene production in Escherichia coli.

Metabolic engineering aims at altering cellular metabolism to produce valuable products at high yields and titers. Achieving high titers and productivity can be challenging if final products are largely accumulated intracellularly. A potential solution to this problem is to facilitate the export of these substances from cells by membrane transporters. Amorphadiene, the precursor of antimalarial drug artemisinin, is known to be secreted from Escherichia coli overexpressing the biosynthetic pathway. In order to assess the involvement of various endogenous efflux pumps in amorphadiene transport, the effects of single gene deletion of 16 known multidrug-resistant membrane efflux transporters were examined. The outer membrane protein TolC was found to be intimately involved in amorphadiene efflux. The overexpression of tolC together with ABC family transporters (macAB) or MFS family transporters (emrAB or emrKY) enhanced amorphadiene titer by more than threefold. In addition, the overexpression of transporters in the lipopolysaccharide transport system (msbA, lptD, lptCABFG) was found to improve amorphadiene production. As efflux transporters often have a wide range of substrate specificity, the multiple families of transporters were co-expressed and synergistic benefits were observed in amorphadiene production. This strategy of screening and then rationally engineering transporters can be used to improve the production of other valuable compounds in E. coli. Biotechnol. Bioeng. 2016;113: 1755-1763. © 2016 Wiley Periodicals, Inc.

Enzymes Involved in Pyrophosphate and Calcium Metabolism as Targets for Anti-scuticociliate Chemotherapy.

Inorganic pyrophosphate (PPi) is a key metabolite in cellular bioenergetics under chronic stress conditions in prokaryotes, protists and plants. Inorganic pyrophosphatases (PPases) are essential enzymes controlling the cellular concentration of PPi and mediating intracellular pH and Ca(2+) homeostasis. We report the effects of the antimalarial drugs chloroquine (CQ) and artemisinin (ART) on the invitro growth of Philasterides dicentrarchi, a scuticociliate parasite of turbot; we also evaluated the action of these drugs on soluble (sPPases) and vacuolar H+-PPases (H+-PPases). CQ and ART inhibited the invitro growth of ciliates with IC50 values of respectively 74±9μM and 80±8μM. CQ inhibits the H+ translocation (with an IC50 of 13.4±0.2μM), while ART increased translocation of H+ and acidification. However, both drugs caused a decrease in gene expression of H+-PPases. CQ significantly inhibited the enzymatic activity of sPPases, decreasing the consumption of intracellular PPi. ART inhibited intracellular accumulation of Ca(2+) induced by ATP, indicating an effect on the Ca(2+) -ATPase. The results suggest that CQ and ART deregulate enzymes associated with PPi and Ca(2+) metabolism, altering the intracellular pH homeostasis vital for parasite survival and providing a target for the development of new drugs against scuticociliatosis.

Artemisia annuaLeaf Extract Attenuates Hepatic Steatosis and Inflammation in High-Fat Diet-Fed Mice

Artemisia annua L. (AA) is a well-known source of the antimalarial drug artemisinin. AA also has an antibacterial and antioxidant activity. However, the effect of AA extract on hepatic steatosis induced by obesity is unclear. We investigated whether AA extract prevents obesity-induced insulin resistance and hepatic steatosis in high-fat diet (HFD)-fed mice. Mice were randomly divided into groups that received a normal chow diet or HFD with or without AA for 12 weeks. We found that AA extract reduced insulin resistance and hepatic steatosis in HFD-fed mice. Western blot analysis showed that HFD-induced expression of nuclear sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein in the livers was decreased by AA extract. In particular, dietary administration of AA extract decreased hepatic high-mobility group box 1 and cyclooxygenase-2 expression in HFD-fed mice. AA extract also attenuated HFD-induced collagen deposition and fibrosis-related transforming growth factor-β1 and connective tissue growth factor. These data indicate that dietary AA extract has beneficial effects on hepatic steatosis and inflammation in HFD-fed mice.

Developing Commercial Production of Semi-Synthetic Artemisinin, and of β-Farnesene, an Isoprenoid Produced by Fermentation of Brazilian Sugar

The antimalarial drug artemisinin and the specialty chemical β-farnesene are examples of natural product isoprenoids that can help solve global challenges, but whose usage has previously been limited by supply and cost impediments. This review describes the path to commercial production of these compounds utilizing fermentation of engineered yeast. Development of commercially viable yeast strains was a substantial challenge that was addressed by creation and implementation of an industrial synthetic biology pipeline. Using the engineered strains, production of β-farnesene from Brazilian sugarcane offers several environmental advantages. Among the many commercial applications of β-farnesene, its use as a feedstock for making biodegradable lubricants is highlighted. This example, along with others, highlight a powerful new suite of technologies that will become increasingly important for production of chemicals, spanning from pharmaceuticals through commodity chemicals.

ChemInform Abstract: Natural Products as Source of Therapeutics Against Parasitic Diseases

AbstractReview: 14 refs.

Study of current prescribing pattern of antimicrobial drugs in indoor cases of enteric fever in a tertiary care hospital

Background: Rational antibiotic prescription is very important to prevent antimicrobial resistance. Hence the present study was conducted to evaluate the prescribing pattern of antimicrobial drugs in indoor enteric fever patients of medicine and paediatric department of a tertiary care hospital. Methods: A retrospective study of 2 months duration was undertaken during July and August of 2015. A total number of 97 enteric fever patients’ case sheets were utilized for our study from medicine and paediatric in-patients department of a tertiary care hospital. The data was analysed and results were expressed as percentage. Results: Out of 97 enteric fever patients, 54.64% were females. 13.4% of paediatric population were suffered because of enteric fever. The incidence of enteric fever was 74.23% in 13-40 years. Most commonly prescribed antimicrobials were 3 rd generation cephalosporins and fluoroquinolones. 43.30% patients received more than one antibiotic. Antimalarials chloroquine, artemisinin derivatives and metronidazole were other drugs prescribed to enteric fever patients concurrently for associated clinical conditions. Conclusions: Interventional programme should focus on the use of rational antibiotic prescription aimed at minimizing unnecessary cost, adverse drug reactions and emergence of bacterial resistance.

Identification of Compounds with Efficacy against Malaria Parasites from Common North American Plants.

Some of the most valuable antimalarial compounds, including quinine and artemisinin, originated from plants. While these drugs have served important roles over many years for the treatment of malaria, drug resistance has become a widespread problem. Therefore, a critical need exists to identify new compounds that have efficacy against drug-resistant malaria strains. In the current study, extracts prepared from plants readily obtained from local sources were screened for activity against Plasmodium falciparum. Bioassay-guided fractionation was used to identify 18 compounds from five plant species. These compounds included eight lupane triterpenes (1-8), four kaempferol 3-O-rhamnosides (10-13), four kaempferol 3-O-glucosides (14-17), and the known compounds amentoflavone and knipholone. These compounds were tested for their efficacy against multi-drug-resistant malaria parasites and counterscreened against HeLa cells to measure their antimalarial selectivity. Most notably, one of the new lupane triterpenes (3) isolated from the supercritical extract of Buxus sempervirens, the common boxwood, showed activity against both drug-sensitive and -resistant malaria strains at a concentration that was 75-fold more selective for the drug-resistant malaria parasites as compared to HeLa cells. This study demonstrates that new antimalarial compounds with efficacy against drug-resistant strains can be identified from native and introduced plant species in the United States, which traditionally have received scant investigation compared to more heavily explored tropical and semitropical botanical resources from around the world.

Erratum to: Effects of angled-impeller rotational speed and aeration rate on production of artemisinin and cell biomass of Artemisia annua L.

Plant cell culture technology offers a promising alternative for the production of plant bioactive compounds. In this study, a 5-L mechanically agitated culture vessel with introduced aeration was employed to improve the culture conditions for higher biomass production of Artemisia annua, a source of the antimalarial compound artemisinin. The effects of impeller rotational speed and introduced aeration rate on cell biomass production were evaluated by using response surface methodology (RSM). We report the successful scale-up of A. annua cell cultures, with a growth index of 6.9, through the synergistic effects of optimized impeller rotational speed (104 rpm) and introduced aeration rate (0.07 vvm (air volume/culture volume/min)). Use of an impeller blade angle of 30° vertical slant in the 5-L culture vessel significantly increased the biomass obtained over that obtained with a 45° vertical slant angle. This information is a key to future scale-up of bioprocessing in this species.

Comparison of methods probing the intracellular redox milieu in Plasmodium falciparum

Glutathione plays a crucial role in the redox regulation of the malaria parasite Plasmodium falciparum and is linked to drug resistance mechanisms, especially in resistance against the antimalarial drug chloroquine (CQ). The determination of the glutathione-dependent redox potential was recently established in living parasites using a cytosolically expressed biosensor comprising redox-sensitive green fluorescent protein coupled to human glutaredoxin 1 (hGrx1-roGFP2). In order to further elucidate redox changes induced by antimalarial drugs and to consolidate the application spectrum of the ratiometric biosensor we systematically compared it to other methods probing thiol and redox metabolism. Among these methods were cell disruptive and non-disruptive approaches including spectrophotometric assays with Ellman’s reagent and naphthalene dicarboxyaldehyde as well as molecular probes such as ThiolTracker™ Violet and the dichlorofluorescein-based probe CM-H2DCFDA. To directly compare the methods, blood stages of the CQ-sensitive P. falciparum 3D7 strain were challenged with the oxidative agent diamide and the antimalarial drugs artemisinin and CQ for 1h, 4h, and 24h. For all conditions, dose-dependent changes in the different redox parameters could be monitored which are compared and discussed. We furthermore detected slight differences in thiol status of parasites transiently transfected with hGrx1-roGFP2 in comparison with control 3D7 cells. In conclusion, ThiolTracker™ Violet and, even more so, the hGrx1-roGFP2 probe reacted reliably and sensitively to drug induced changes in intracellular redox metabolism. These results were substantiated by classical cell disruptive methods.

In vitro and in vivo anti-malarial activity of plants from the Brazilian Amazon.

BackgroundThe anti-malarials quinine and artemisinin were isolated from traditionally used plants (Cinchona spp. and Artemisia annua, respectively). The synthetic quinoline anti-malarials (e.g. chloroquine) and semi-synthetic artemisinin derivatives (e.g. artesunate) were developed based on these natural products. Malaria is endemic to the Amazon region where Plasmodium falciparum and Plasmodium vivax drug-resistance is of concern. There is an urgent need for new anti-malarials. Traditionally used Amazonian plants may provide new treatments for drug-resistant P. vivax and P. falciparum. Herein, the in vitro and in vivo antiplasmodial activity and cytotoxicity of medicinal plant extracts were investigated.MethodsSixty-nine extracts from 11 plant species were prepared and screened for in vitro activity against P. falciparum K1 strain and for cytotoxicity against human fibroblasts and two melanoma cell lines. Median inhibitory concentrations (IC50) were established against chloroquine-resistant P. falciparum W2 clone using monoclonal anti-HRPII (histidine-rich protein II) antibodies in an enzyme-linked immunosorbent assay. Extracts were evaluated for toxicity against murine macrophages (IC50) and selectivity indices (SI) were determined. Three extracts were also evaluated orally in Plasmodium berghei-infected mice.ResultsHigh in vitro antiplasmodial activity (IC50 = 6.4–9.9 µg/mL) was observed for Andropogon leucostachyus aerial part methanol extracts, Croton cajucara red variety leaf chloroform extracts, Miconia nervosa leaf methanol extracts, and Xylopia amazonica leaf chloroform and branch ethanol extracts. Paullinia cupana branch chloroform extracts and Croton cajucara red variety leaf ethanol extracts were toxic to fibroblasts and or melanoma cells. Xylopia amazonica branch ethanol extracts and Zanthoxylum djalma-batistae branch chloroform extracts were toxic to macrophages (IC50 = 6.9 and 24.7 µg/mL, respectively). Andropogon leucostachyus extracts were the most selective (SI >28.2) and the most active in vivo (at doses of 250 mg/kg, 71 % suppression of P. berghei parasitaemia versus untreated controls).ConclusionsEthnobotanical or ethnopharmacological reports describe the anti-malarial use of these plants or the antiplasmodial activity of congeneric species. No antiplasmodial activity has been demonstrated previously for the extracts of these plants. Seven plants exhibit in vivo and or in vitro anti-malarial potential. Future work should aim to discover the anti-malarial substances present.

Nobelprize 2015 for Phytomedicine

Three scientists who developed therapies isolated from natural sources against parasitic infections have won this year’s Nobel Prize in Physiology or Medicine. William C. Campbell, a microbiologist at Drew University in Madison, New Jersey and Satoshi Ōmura, a microbiologist at Kitasato University in Japan isolated avermectins from Streptomyces bacteria and tweaked the structure of one of the most promising compounds to develop it into a drug against onchocerciasis (river blindness) — ivermectin. The second half of the nobel pize was awarded for a new plant-derived drug to Youyou Tu, a pharmacologist at the China Academy of Chinese Medical Sciences in Beijing. Tu, who won a Lasker prize in 2011, developed the antimalarial drug artemisinin in the late 1960s and 1970s. She is the first China-based scientist to win a Nobel prize in sciences. In the 1960s, the main treatments for malaria were chloroquine and quinine, but they were proving increasingly ineffective. Diseases caused by parasites such as malaria have been with humankind for millennia and constitute a major global health problem affecting the world’s poorest populations and represent a huge barrier to improving human health and wellbeing. Malaria is a mosquito-borne disease caused by single-cell parasites infecting close to 200 million individuals yearly. The parasites invade red blood cells, causing fever, and in severe cases brain damage and death. Malaria claims more than 450 000 lives, predominantly among children. So in 1967, China established a national project against malaria to discover new therapies. Tu and her team screened more than 2,000 Chinese herbal remedies to search for drugs with antimalarial activity. An extract from the wormwood plant Artemisia annua proved especially effective and by 1972, the researchers had isolated chemically pure artemisin. Artemisinin represents a new class of antimalarial agents that rapidly kill the Malaria parasites at an early stage of their development, which explains its unprecedented potency in the treatment of severe Malaria. Nowadays, artemisinin is used in all Malaria-ridden parts of the world. When used in combination therapy, it is estimated to reduce mortality from Malaria by more than 20 % overall and by more than 30 % in children. For Africa alone, this means that more than 100 000 lives are saved each year. Thus, a plant-derived new drug has provided humankind with powerful new means to combat a debilitating parasitic disease that affect hundreds of millions of people annually. The consequences in terms of improved human health and reduced suffering are immeasurable. There is increased hope that phytomedicine will deliver additional new important discoveries that transform the treatment of human diseases in the future. Prof. Dr. Dr. Andre Gessner Institute of Clinical Microbiology and Hygiene University of Regensburg Franz-Josef-Strauss-Allee 11 D-93053 Regensburg

The effect of over-expression of rate limiting enzymes on the yield of artemisinin in Artemisia annua

Medicinal plants are rich source of bioactive compounds which are important for human healthcare. The production of bioactive compounds such as artemisinin is limited in plants. Novel antimalarial drug artemisinin was obtained from leaves of Artemisia annua L. plants. The content of artemisinin in the natural plant is 0.01–1.1 % on dry weight basis. Due to its low content, the drug could not be commercialized in the global market to explore the artemisinin-based combined therapies in the world. The economic limitations of chemical synthesis is unfeasible due to its complexity and cost effectiveness. In this article, we have studied the effect of rate limiting enzymes/genes expression, HMG-Co A reductase and amorpha-4,11-diene synthase on physiochemical changes in terms of total biomass, chlorophyll, total protein, artemisinin content and yield in transgenic lines of A. annua L. plants. The shoot length (42.00 %), number of leaves (86.89 %), the number of root (39.82 %) root length (83.61 %), total biomass accumulation (100 %), total chlorophyll level (138.14 %), total protein level (73.36 %) in TR4 at in vitro level while artemisinin (93.54 %) and its yield (237.26 %) were maximum in TR5 at polyhouse conditions, followed by TR1, TR2, TR3, TR7 and TR9 as compared to non-transgenic Artemisia annua L. plants. A similar trend in leaf biomass, stem biomass and leaf:stem ratio was also recorded in polyhouse condition.

Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya.

BackgroundThe artemisinin anti-malarials are widely deployed as artemisinin-based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce.MethodsThis was a prospective cohort study of women of child-bearing age carried out in 2011–2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used.ResultsThe risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (≥6 to <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08–2.68) and HR = 1.61 (0.96–2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56–2.74) and HR = 0.73 (0.19–2.82) relative to unexposed women, and HR = 0.99 (0.12–8.33) and HR = 0.32 (0.03–3.61) relative to quinine exposure, but the numbers of quinine exposures were very small.ConclusionACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0950-6) contains supplementary material, which is available to authorized users.

The Art and Science of Traditional Medicine Part 3: The Global Impact of Traditional Medicine

It is appropriate and timely that Chinese scientist Youyou Tu was awarded half of the 2015 Nobel Prize in Physiology or Medicine in recognition of her pioneering work on the antimalarial artemisinin, extracted from Artemisia annua, an ancient herbal remedy used to treat fever. This third issue in the Art and Science of Traditional Medicine series features another time-honored herb, ginseng. Also discussed are the systems and network pharmacology of TCM, pharmacognosy and regulation of traditional medicine in Europe, and how these best practices can be applied globally, but particularly in Africa. Attention garnered by the Nobel award hopefully will generate interest in traditional medicines from other parts of the world, including the Middle East, the Indian sub-continent, and the Americas. This special supplement brought to you by the Science /AAAS Custom Publishing Office.

The Art and Science of Traditional Medicine Part 3: The Global Impact of Traditional Medicine

It is appropriate and timely that Chinese scientist Youyou Tu was awarded half of the 2015 Nobel Prize in Physiology or Medicine in recognition of her pioneering work on the antimalarial artemisinin, extracted from Artemisia annua, an ancient herbal remedy used to treat fever. This third issue in the Art and Science of Traditional Medicine series features another time-honored herb, ginseng. Also discussed are the systems and network pharmacology of TCM, pharmacognosy and regulation of traditional medicine in Europe, and how these best practices can be applied globally, but particularly in Africa. Attention garnered by the Nobel award hopefully will generate interest in traditional medicines from other parts of the world, including the Middle East, the Indian sub-continent, and the Americas. This special supplement brought to you by the Science /AAAS Custom Publishing Office.

Natural Products as Source of Therapeutics against Parasitic Diseases.

An end to suffering: Parasitic infections with protozoa and worms cause unimaginable misery, in particular in the tropics. Fortunately, natural products, such as the antimalarial artemisinin (1) and the anthelmintic avermectin (2) were discovered and developed into therapeutics. These major achievements now culminated in the 2015 Nobel Prize for Medicine.

Genetic Transformation of Artemisia carvifolia Buch with rol Genes Enhances Artemisinin Accumulation.

The potent antimalarial drug artemisinin has a high cost, since its only viable source to date is Artemisia annua (0.01–0.8% DW). There is therefore an urgent need to design new strategies to increase its production or to find alternative sources. In the current study, Artemisia carvifolia Buch was selected with the aim of detecting artemisinin and then enhancing the production of the target compound and its derivatives. These metabolites were determined by LC-MS in the shoots of A. carvifolia wild type plants at the following concentrations: artemisinin (8μg/g), artesunate (2.24μg/g), dihydroartemisinin (13.6μg/g) and artemether (12.8μg/g). Genetic transformation of A. carvifolia was carried out with Agrobacterium tumefaciens GV3101 harboring the rol B and rol C genes. Artemisinin content increased 3-7-fold in transgenics bearing the rol B gene, and 2.3-6-fold in those with the rol C gene. A similar pattern was observed for artemisinin analogues. The dynamics of artemisinin content in transgenics and wild type A.carvifolia was also correlated with the expression of genes involved in its biosynthesis. Real time qPCR analysis revealed the differential expression of genes involved in artemisinin biosynthesis, i.e. those encoding amorpha-4, 11 diene synthase (ADS), cytochrome P450 (CYP71AV1), and aldehyde dehydrogenase 1 (ALDH1), with a relatively higher transcript level found in transgenics than in the wild type plant. Also, the gene related to trichome development and sesquiterpenoid biosynthesis (TFAR1) showed an altered expression in the transgenics compared to wild type A.carvifolia, which was in accordance with the trichome density of the respective plants. The trichome index was significantly higher in the rol B and rol C gene-expressing transgenics with an increased production of artemisinin, thereby demonstrating that the rol genes are effective inducers of plant secondary metabolism.

Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library.

Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease.

ChemInform Abstract: Manganese‐Catalyzed Late‐Stage Aliphatic C—H Azidation.

We report a manganese-catalyzed aliphatic C–H azidation reaction that can efficiently convert secondary, tertiary, and benzylic C–H bonds to the corresponding azides. The method utilizes aqueous sodium azide solution as the azide source and can be performed under air. Besides its operational simplicity, the potential of this method for late-stage functionalization has been demonstrated by successful azidation of various bioactive molecules with yields up to 74%, including the important drugs pregabalin, memantine, and the antimalarial artemisinin. Azidation of celestolide with a chiral manganese salen catalyst afforded the azide product in 70% ee, representing a Mn-catalyzed enantioselective aliphatic C–H azidation reaction. Considering the versatile roles of organic azides in modern chemistry and the ubiquity of aliphatic C–H bonds in organic molecules, we envision that this Mn-azidation method will find wide application in organic synthesis, drug discovery, and chemical biology.

Responsibility and intellectual property in synthetic biology: A proposal for using Responsible Research and Innovation as a basic framework for intellectual property decisions in synthetic biology.

Synthetic biology (SynBio) is an engineering view of biotechnology that has the potential to increase the number and industrial utility of biotechnological applications by implementing engineering principles such as standardization and modularity. The boundaries between SynBio, biotechnology, and metabolic engineering are not always clear, but assessing SynBio in a wider sense—that of modeling‐based biotechnology and/or “sophisticated” metabolic engineering—we find that a significant number of applications and research articles have been generated in the past few years [1]. One of the best‐known examples is that of a synthetic pathway for producing artemisinic acid, a precursor to the antimalarial drug artemisinin, which has been engineered in yeast to produce commercially relevant concentrations of artemisinic acid. This impressive accomplishment can be easily adapted for the development of biofuels, biomaterials, new drugs, or fine chemicals [1]. > The concept of RRI has gained increasing relevance for policy in the EU and has become a cross‐cutting leitmotiv in the Horizon 2020 strategy Two of the authors of this essay (PD and MP) attended the so‐called Giant Jamboree of the international Genetically Engineered Machine (iGEM) competition in Boston, as members of the Valencia Biocampus team, and presented a project, supported by the EU‐funded SYNENERGENE initiative (http://www.synenergene.eu), on Intellectual Property (IP) in SynBio (http://2014.igem.org/Team:Valencia_Biocampus/). The project included an attempt to develop a common language for practitioners, from lawyers to scientists and engineers. Moreover, the team developed an attempt to quantify IP issues by including a “patentability index” (PI), with values ranging from 0 to 10 based on parameters including novelty, inventive step, and industrial application. An additional parameter, “responsibility” (R), was introduced in such a way that the PI can only be greater than zero when R is not zero. In other words, lack of “responsibility” could lead an otherwise‐patentable SynBio invention to fail the …