Personalized Medicine for Crops? Opportunities for the Application of

Perspective pubs.acs.org/JAFC

Personalized Medicine for Crops? Opportunities for the Application of Molecular Recognition in Agriculture Emily Mastronardi,† Carlos Monreal,‡ and Maria C. DeRosa*,† †

Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada Agriculture and Agrifood Canada, 960 Carling Avenue, Neatby Building, Ottawa, Ontario K1Y 4X2, Canada

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‡

ABSTRACT: This perspective examines the detection of rhizosphere biomarkers, namely, root exudates and microbial metabolites, using molecular recognition elements, such as molecularly imprinted polymers, antibodies, and aptamers. Tracking these compounds in the rhizosphere could provide valuable insight into the status of the crop and soil in a highly localized way. The outlook and potential impact of the combination of molecular recognition and other innovations, such as nanotechnology and precision agriculture, and the comparison to advances in personalized medicine are considered. KEYWORDS: aptamers, molecularly imprinted polymers, antibodies, rhizosphere, root exudates

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INTRODUCTION The prospect of personalized medicine and the rise of point-ofcare (POC) diagnostics are two emerging themes in the field of medicine that promise to revolutionize human health. Personalized or precision medicine refers to the patientcentered tailoring of treatment. The European Union (EU) defines personalized medicine as “providing the right treatment to the right patient, at the right dose at the right time”.1 An enabler of this revolution has been the rapid growth of diagnostic and “omics” technology that can provide a molecular level understanding of disease and the unique clinical, genetic, and environmental information of each patient to allow for individual tailoring of response. The accurate and low-cost detection of biomarkers, measurable indicators of a biological state or condition (e.g., genes, proteins, and metabolites), are essential tools for accurate prognosis, dose selection, tracking of therapeutic response, and detection of adverse outcomes. In particular, POC biomarker testing can provide close to immediate information about the condition of an individual, can provide more widespread access to diagnosis, and can facilitate real-time treatment decisions, all at a modest cost and in a non-invasive or minimally invasive fashion.2 In many ways, agriculture parallels health as an area of study with similar challenges, complexities, and questions. For example, the challenge of efficient delivery of payloads, such as fertilizers, pesticides, and herbicides, mirrors that seen in drug delivery, e.g., the complex environment, the danger of offtarget effects, and thus, the need for efficient targeting, etc. It is not surprising then that technologies and other innovations that first see an incipience in medical sciences are eventually applied to analogous problems in agriculture. Nanotechnology is one example of an enabling innovation that was first applied to questions and challenges in medicine before applications in agriculture were examined.3 There are, of course, striking differences between the fields of medicine and agriculture, including the type of regulatory oversight and the level of cost and/or risk that is tolerated by stakeholders. These parallels and disparities will shape to what degree advances from one field can impact the other. © 2017 American Chemical Society

On the basis of the congruence between medicine and agriculture, could there be an agricultural equivalent to personalized medicine? Could POC-type technologies be used to better manage variable field and crop conditions and to respond to needs in real-time? Indeed, precision farming has many critical features that mirror those in personalized medicine. Precision farming is an approach to agriculture where crop management decisions are informed by data from global positioning systems, remote sensing, computer modeling of biotic and abiotic conditions, and soil properties to provide highly localized information and precisely identify the nature and location of problems.4,5 The measurement of and response to inter- and intrafield variation in soils and crops allows the farmer to make decisions that support the success of the whole farm that in many ways parallels the guiding principles of personalized medicine. In this case, the goal is to ensure that crops are growing at maximum efficiency and yield while increasing the use efficiency of inputs, such as fertilizers, pesticides, and herbicides. However, to date, the majority of these data acquired relate to macroscale factors, such as land surface temperature, soil moisture, drainage, topography, etc., rather than reporters at the molecular level. Furthermore, the “omics” revolution has also had a demonstrable effect on agriculture.6 The importance of biomarkers is being realized; for example, gene expression biomarkers as indicators of nitrogen status7 and water status8 are being studied. Similarly, a number of protein biomarkers for abiotic stress have been identified.9 In fact, “field-omics” is seeking to integrate genomic, transcriptomic, proteomic, and metabolomic data with crop science for informing crop system biology and crop management strategies.10 Nevertheless, at Special Issue: Nanotechnology Applications and Implications of Agrochemicals toward Sustainable Agriculture and Food Systems Received: Revised: Accepted: Published: 6457

July 18, 2017 September 19, 2017 October 6, 2017 October 6, 2017 DOI: 10.1021/acs.jafc.7b03295 J. Agric. Food Chem. 2018, 66, 6457−6461

Perspective

Journal of Agricultural and Food Chemistry

put metabolomic approaches, the characterization of these complex solutions has become easier.21,22 However, the cost and complexity of these approaches would make them prohibitive in terms of their use in real-time precision agriculture. For these reasons, greater attention should be paid to the development of simpler and lower cost alternatives in the form of biosensors and bioassays. Biosensors take the information from the biochemical interaction of a target molecule with a recognition or affinity element and translate it into a measurable output with a defined sensitivity; two classic examples are the electrochemical glucose meter and the lateral flow pregnancy test.23 To develop new biosensor platforms for rhizosphere biomarkers, nanoscale molecular recognition agents or affinity ligands are needed that are capable of binding the specific target of interest at low concentrations and in a complex environment. These ligands interact with their targets through shape complementarity and non-covalent interactions. Three main types of affinity ligands are described here. They are antibodies, molecularly imprinted polymers (MIPs), and aptamers (Figure 1). The most widely used and well-studied probes for molecular

present, the analyses for these biomarkers are still relatively costly and laborious, and the extraction of samples is invasive, e.g., collection of tissue from roots or shoots for analysis. Interest in non-invasive testing for phenomics is on the rise,11 but an alternative approach would be to look outside the plant itself for biomarkers. In the field, detection of these biomarkers could serve as a “POC” equivalent that could use a molecularlevel understanding of crop and field conditions to inform farm management decisions.

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BIOMARKERS IN THE RHIZOSPHERE?

The rhizosphere, the millimeters thick region of soil in the direct vicinity of plant roots, is a complex and chemical-rich environment laden with potential information about the interplay between the plant, soil, and microbial community. Root exudates, chemical compounds secreted into the rhizosphere by root cells, in addition to the metabolites excreted by the microbial communities present in the soil environment, could contain valuable biomarkers for assessing the state of the crop and soil in a very localized way.12,13 These compounds are involved in the chemical signaling that regulates many processes, including microbial and fungal colonization, deterring herbivory, and inhibiting the growth of encroaching plant species.14 For example, amino acids have been found to suppress the growth of nematodes and competing plant species, while the flavonoid quercetin has been implicated in resistance to aluminum toxicity in maize.15,16 It has been estimated that plants release between 5 and 25% of net fixed carbon into the rhizosphere in the form of exudates, ranging in complexity from organic anions to polymers.17 Notably, up to 70% of photosynthesized 13CO2 was found to be exuded by wheat roots in recent work.18 The identification, quantification, and functional understanding of these complex solutions could underlie crop yield and farm management. Current data suggest that low-molecular-weight compounds are the most diverse group of soil solution components, including sugars, amino acids, organic acids, and phenolics, while higher molecular weight compounds, such as polysaccharides and proteins, make up a larger proportion by mass.19 The soil, plant species, and nutrient availability all seem to have an impact on the quantity and type of compounds present, suggesting that these compounds could serve as indicators that could be examined as surrogates for crop status.20 For example, recent work on chemical composition analysis of soil solutions in wheat rhizospheres over the growing season were able to identify hundreds of chemical compounds distributed in 11 chemical classes.13 Although the specific function of many of these compounds is unknown, several have been implicated in mediating the positive and negative interactions affecting plant and microbe growth.13,20 Thus, the presence of key biomarkers in the rhizosphere could provide useful information on crop health and could be combined with the platform of precision agriculture to allow farmers to better monitor and respond to existing field conditions.

Figure 1. Rhizosphere biomarkers, such as root exudates and microbial metabolites, could be detected using affinity reagents, such as aptamers, antibodies, and MIPs.

recognition are antibodies, naturally occurring immune system proteins with exquisitely specific molecular recognition.24 Sometimes known as “plastic antibodies”, MIPs are alternative affinity reagents that are synthesized through the polymerization of suitable monomers in the presence of the target molecule acting as a molecular template.25 This templating yields nanoscale three-dimensional binding sites in the polymer that are size- and shape-complementary to the target molecule as well as chemically compatible to allow for specific binding. Aptamers are synthetic oligonucleotides that are capable of selective, high affinity binding to a molecular target.26 These reagents are discovered through an in vitro selection procedure known as systematic evolution of ligands by exponential enrichment (SELEX), where iterative steps of target incubation, partitioning, and amplification are used to enrich a large combinatorial oligonucleotide library in sequences with affinity for the target. The lists of biosensor and assay applications that include antibodies, MIPs, and aptamers as affinity reagents are extensive.24−28 Thus, affinity reagents for potential rhizosphere biomarkers are examined here. Because rhizosphere biomarkers encompass a wide variety of compound types, many affinity ligands already exist for these targets and could be applied directly to agricultural applications.

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AFFINITY LIGANDS AND BIOSENSORS FOR RHIZOPHERE BIOMARKERS The diversity, low concentrations, and localized presence of rhizosphere biomarkers have made their identification a challenge. With the development of sensitive mass spectrometry techniques, isotope-labeling strategies, and high-through6458

DOI: 10.1021/acs.jafc.7b03295 J. Agric. Food Chem. 2018, 66, 6457−6461

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Journal of Agricultural and Food Chemistry Table 1. Affinity Ligands Available for Select Rhizosphere Biomarkers Identified from Maize chemical class amino acids

organic acids carbohydrates

a

identified soil component

MIP

aptamer

antibody commercially available

aspartic acid29−31 glutamic acid29−31 glutamine29−31 alanine29−31 tyrosine29−31

yes32 yes33 yes35 yes37 yes38

no yes34 yes36 no yes39

isoleucine29−31 arginine30 valine30,31 histidine31 phenylalanine31 γ-aminobutyrate (GABA)29,30 malic acid29−31 benzoic acid30 fructose29−31

no yes41 yes43 yes45 yes47 yes49 yes50 yes51 yes53

glucose29−31

yes55

yes40 yes42 yes44 yes46 yes48 no no no no, but fructose 1,6-bisphosphate aptamer is reported54 no

yesa yesa yesa yesa no, however, a phosphotyrosine antibody is availablea yesb yesa yesb no yesa yesa no no, however, literature reference available52 no no

b

Available from Abcam. Available from Antibodies-Online.

Table 2. Affinity Ligands Available for Select Soil Components Identified from Wheat chemical class fatty acids flavonoids

lignin monomer/phenolics alkylbenzene sterols and tocopherols

a

identified soil component56

MIP

aptamer

antibody commercially available (yes/no)

arachidonic acid flavones luteolin kaempferide quercetin ferulic acid methylbenzene cholesterol ergosterol stigmasterol β-sitosterol α-tocopherol

no yes57 yes58 yes59 yes60 yes61 yes62 yes63 yes64 yes65 yes66 yes67

no no no no no no no no no no no no

yesa no no no yesb yesc no yesd no no no yesd

Available from Antibodies-Online. bAvailable from MyBiosource. cAvailable from Creative Diagnostics. dAvailable from LifeSpan BioSciences.

Tables 1 and 2 show a selection of existing affinity ligands that could be used directly for sensing soil components, using only corn and wheat rhizosphere biomarkers, respectively, as examples. Using affinity ligands, such as aptamers, antibodies, or MIPs, to detect rhizosphere biomarkers could provide information on plant health and development, nutrient requirements, and encroaching invasive species. For example, some root exudates are suspected indicators of the nutrient status of a plant. Carvalhais et al. examined how the composition of root exudates was affected in maize under varying nutrient deficiencies.28 Iron deficiency stimulated increased release of glutamate, glucose, ribitol, and citrate. An examination of available affinity ligands in the literature showed that an aptamer has been selected for glutamate, while MIPs for glutamate and glucose have also been developed.31,32 A phosphorus deficiency resulted in the increased release of γaminobutyric acid as well as carbohydrates: inositol, erythritol, ribitol, fructose, glucose, and arabinose. γ-Aminobutyrate-, glucose-, and fructose-binding MIPs have been developed, 47,51,53 while an antibody for γ-aminobutyrate is commercially available. On the other hand, nitrogen deficiency showed a decrease of amino acids, such as aspartate, tyrosine, and isoleucine; aptamers, MIPs, and antibodies exist for many of these amino acids.28,30,36−38

In the future, the combination of technologies of precision agriculture, such as satellite-positioning systems, geographic information systems, and remote sensing devices, with nanosensors dispersed in the soil or plant canopy capable of recognizing these biomarkers with their spatial variabilities, could help in the efficient use of water, nutrients, and agrochemicals. In the nearer term, simple biosensing platforms, such as lateral flow assays, could be developed to allow farmers access to quick spot tests to help with decision-making. To achieve this short- or long-term vision, existing affinity reagents for rhizosphere biomarkers will need to be characterized for their specificity under realistic testing scenarios in the presence of the complex chemical mixture of the soil matrix as well as their stability under varying environmental conditions. New recognition agents should be developed for key rhizosphere biomarkers as their functions are elucidated. Other affinity systems are also emerging, including nanobodies,66 recombinant antibodies,67 and affibodies,68−70 each with their own advantages and disadvantages, which could also be applied to these molecular targets. Precision farming, with the help of biosensors for rhizosphere biomarkers, could usher in a new era of “personalized medicine” for crops and crop rotations, where, to paraphrase the EU definition of personalized medicine, the right treatment (nutrient, agrochemical, etc.) is provided to the right group of 6459

DOI: 10.1021/acs.jafc.7b03295 J. Agric. Food Chem. 2018, 66, 6457−6461

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Journal of Agricultural and Food Chemistry plants, at the right dose, at the right time and spatial scale.1 Detecting biomarkers implicated in nutrient uptake could be useful in more effectively timing the application of fertilizers, while detecting specific phytotoxins could help determine appropriate pesticide application, for example. The limitations of our current knowledge of how to detect these biomarkers in the complex chemical environment of the soil as well as how to transduce this binding event into a measurable signal could be overcome by the further development of agricultural nanotechnology and bionanotechnology. This perspective focused on crop care for secure food production is based on the potential development of antibodies, aptamers, or MIPs for known rhizosphere biomarkers. A combination of a better understanding of the connection between rhizosphere biomarker composition and crop status and improved tools relying on molecular recognition to detect these biomarkers will be necessary to achieve the full potential of precision agriculture.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Maria C. DeRosa: 0000-0003-1868-6357 Notes

The authors declare no competing financial interest.

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DOI: 10.1021/acs.jafc.7b03295 J. Agric. Food Chem. 2018, 66, 6457−6461