Chemogenomics Staubli robot retrieves assay plates from incubators
Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families (e.g., GPCRs, nuclear receptors, kinases, proteases, etc.) with the ultimate goal of identification of novel drugs and drug targets. Typically some members of a target library have been well
characterized where both the function has been determined and compounds
that modulate the function of those targets (ligands in the case of receptors, inhibitors of enzymes, or blockers of ion channels)
have been identified. Other members of the target family may have
unknown function with no known ligands and hence are classified as orphan receptors.
By identifying screening hits that modulate the activity of the less
well characterized members of the target family, the function of these
novel targets can be elucidated. Furthermore, the hits for these targets can be used as a starting point for drug discovery.
The completion of the human genome project has provided an abundance of
potential targets for therapeutic intervention. Chemogenomics strives
to study the intersection of all possible drugs on all of these
potential targets.
A common method to construct a targeted chemical library is to
include known ligands of at least one and preferably several members of
the target family. Since a portion of ligands that were designed and
synthesized to bind to one family member will also bind to additional
family members, the compounds contained in a targeted chemical library
should collectively bind to a high percentage of the target family.
Strategy
Chemogenomics integrates target and drug discovery by using active compounds, which function as ligands, as probes to characterize proteome
functions. The interaction between a small compound and a protein
induces a phenotype. Once the phenotype is characterized, we could
associate a protein to a molecular event. Compared with genetics,
chemogenomics techniques are able to modify the function of a protein
rather than the gene. Also, chemogenomics is able to observe the
interaction as well as reversibility in real-time. For example, the
modification of a phenotype can be observed only after addition of a specific compound and can be interrupted after its withdrawal from the medium.
Currently, there are two experimental chemogenomic approaches:
forward (classical) chemogenomics and reverse chemogenomics. Forward
chemogenomics attempt to identify drug targets by searching for
molecules which give a certain phenotype on cells or animals, while
reverse chemogenomics aim to validate phenotypes by searching for
molecules that interact specifically with a given protein. Both of these approaches require a suitable collection of compounds
and an appropriate model system for screening the compounds and looking
for the parallel identification of biological targets and biologically
active compounds. The biologically active compounds that are discovered
through forward or reverse chemogenomics approaches are known as
modulators because they bind to and modulate specific molecular targets,
thus they could be used as ‘targeted therapeutics’.
Forward chemogenomics
In
forward chemogenomics, which is also known as classical chemogenomics, a
particular phenotype is studied and small compound interacting with
this function are identified. The molecular basis of this desired
phenotype is unknown. Once the modulators have been identified, they
will be used as tools to look for the protein responsible for the
phenotype. For example, a loss-of-function phenotype could be an arrest
of tumor growth. Once compounds that lead to a target phenotype have
been identified, identifying the gene and protein targets should be the
next step. The main challenge of forward chemogenomics strategy lies in designing
phenotypic assays that lead immediately from screening to target
identification.
Reverse chemogenomics
In
reverse chemogenomics, small compounds that perturb the function of an
enzyme in the context of an in vitro enzymatic test will be identified.
Once the modulators have been identified, the phenotype induced by the
molecule is analyzed in a test on cells or on whole organisms. This
method will identify or confirm the role of the enzyme in the biological
response. Reverse chemogenomics used to be virtually identical to the
target-based approaches that have been applied in drug discovery and
molecular pharmacology over the past decade. This strategy is now
enhanced by parallel screening and by the ability to perform lead
optimization on many targets that belong to one target family.
Applications
Determining mode of action
Chemogenomics has been used to identify mode of action (MOA) for traditional Chinese medicine (TCM) and Ayurveda.
Compounds contained in traditional medicines are usually more soluble
than synthetic compounds, have “privileged structures” (chemical
structures that are more frequently found to bind in different living
organisms), and have more comprehensively known safety and tolerance
factors. Therefore, this makes them especially attractive as a resource
for lead structures in when developing new molecular entities.
Databases containing chemical structures of compounds used in
alternative medicine along with their phenotypic effects, in silico
analysis may be of use to assist in determining MOA for example, by
predicting ligand targets that were relevant to known phenotypes for
traditional medicines. In a case study for TCM, the therapeutic class of ‘toning and
replenishing medicine” was evaluated. Therapeutic actions (or
phenotypes) for that class include anti-inflammatory, antioxidant,
neuroprotective, hypoglycemic activity, immunomodulatory,
antimetastatic, and hypotensive. Sodium-glucose transport proteins and PTP1B
(an insulin signaling regulator) were identified as targets which link
to the hypoglycemic phenotype suggested. The case study for Ayurveda
involved anti-cancer formulations. In this case, the target prediction
program enriched for targets directly connected to cancer progression
such as steroid-5-alpha-reductase and synergistic targets like the efflux pump P-gp. These target-phenotype links can help identify novel MOAs.
Beyond TCM and Ayurveda, chemogenomics can be applied early in
drug discovery to determine a compound's mechanism of action and take
advantage of genomic biomarkers of toxicity and efficacy for application
to Phase I and II clinical trials.
Identifying new drug targets
Chemogenomics profiling can be used to identify totally new therapeutic targets, for example new antibacterial agents. The study capitalized on the availability of an existing ligand
library for an enzyme called murD that is used in the peptidoglycan
synthesis pathway. Relying on the chemogenomics similarity principle,
the researchers mapped the murD ligand library to other members of the mur ligase family
(murC, murE, murF, murA, and murG) to identify new targets for the
known ligands. Ligands identified would be expected to be
broad-spectrum Gram-negative
inhibitors in experimental assays since peptidoglycan synthesis is
exclusive to bacteria. Structural and molecular docking studies
revealed candidate ligands for murC and murE ligases.
Identifying genes in biological pathway
Thirty years after the posttranslationally modified histidine derivative diphthamide was determined, chemogenomics was used to discover the enzyme responsible for the final step in its synthesis. Dipthamide is a posttranslationally modified histidine residue found on the translation elongation factor 2
(eEF-2). The first two steps of the biosynthesis pathway leading to
dipthine have been known, but the enzyme responsible for the amidation
of dipthine to diphthamide remained a mystery. The researchers
capitalized on Saccharomyces cerevisiae
cofitness data. Cofitness data is data representing the similarity of
growth fitness under various conditions between any two different
deletion strains. Under the assumption that strains lacking the
diphthamide synthetase gene should have high cofitness with strain
lacking other diphthamide biosynthesis genes, they identified ylr143w
as the strain with the highest cofitness to the all other strains
lacking known diphthamide biosynthesis genes. Subsequent experimental
assays confirmed that YLR143W was required for diphthamide synthesis and
was the missing diphthamide synthetase.
In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; the terms are equivalent in the literature. Larger structures such as nucleic acids and proteins, and many polysaccharides are not small molecules, although their constituent monomers (ribo- or deoxyribonucleotides, amino acids,
and monosaccharides, respectively) are often considered small
molecules. Small molecules may be used as research tools to probe biological function as well as leads in the development of new therapeutic agents. Some can inhibit a specific function of a protein or disrupt protein–protein interactions.
Pharmacology usually restricts the term "small molecule" to molecules that bind specific biological macromolecules and act as an effector, altering the activity or function of the target. Small molecules can have a variety of biological functions or applications, serving as cell signaling molecules, drugs in medicine, pesticides in farming, and in many other roles. These compounds can be natural (such as secondary metabolites) or artificial (such as antiviral drugs); they may have a beneficial effect against a disease (such as drugs) or may be detrimental (such as teratogens and carcinogens).
Molecular weight cutoff
The upper molecular-weight
limit for a small molecule is approximately 900 daltons, which allows
for the possibility to rapidly diffuse across cell membranes so that it
can reach intracellular sites of action. This molecular weight cutoff is also a necessary but insufficient condition for oral bioavailability as it allows for transcellular transport through intestinal epithelial cells. In addition to intestinal permeability, the molecule must also possess a reasonably rapid rate of dissolution into water and adequate water solubility and moderate to low first pass metabolism. A somewhat lower molecular weight cutoff of 500 daltons (as part of the "rule of five")
has been recommended for oral small molecule drug candidates based on
the observation that clinical attrition rates are significantly reduced
if the molecular weight is kept below this limit.
Most pharmaceuticals are small molecules, although some drugs can be proteins (e.g., insulin and other biologic medical products). With the exception of therapeutic antibodies, many proteins are degraded if administered orally and most often cannot cross cell membranes. Small molecules are more likely to be absorbed, although some of them are only absorbed after oral administration if given as prodrugs. One advantage that small molecule drugs (SMDs) have over "large molecule" biologics is that many small molecules can be taken orally whereas biologics generally require injection or another parenteral administration. Small molecule drugs are also typically simpler to manufacture and
cheaper for the purchaser. A downside is that not all targets are
amenable to modification with small-molecule drugs; bacteria and cancers are often resistant to their effects.
Secondary metabolites
A variety of organisms including bacteria, fungi, and plants, produce small molecule secondary metabolites also known as natural products,
which play a role in cell signaling, pigmentation and in defense
against predation. Secondary metabolites are a rich source of
biologically active compounds and hence are often used as research tools
and leads for drug discovery. Examples of secondary metabolites include:
Small-molecule anti-genomic therapeutics, or SMAT, refers to a biodefense technology that targets DNA signatures found in many biological warfare
agents. SMATs are new, broad-spectrum drugs that unify antibacterial,
antiviral and anti-malarial activities into a single therapeutic that
offers substantial cost benefits and logistic advantages for physicians
and the military.
A macromolecule is a "molecule
of high relative molecular mass, the structure of which essentially
comprises the multiple repetition of units derived, actually or
conceptually, from molecules of low relative molecular mass." Polymers are physical examples of macromolecules. Common macromolecules are biopolymers (nucleic acids, proteins, and carbohydrates). and polyolefins (polyethylene) and polyamides (nylon).
Many macromolecules are synthetic polymers (plastics, synthetic fibers, and synthetic rubber. Polyethylene is produced on a particularly large scale such that ethylene is the primary product in the chemical industry.
DNA, RNA, and proteins all consist of a repeating structure of related building blocks (nucleotides in the case of DNA and RNA, amino acids
in the case of proteins). In general, they are all unbranched polymers,
and so can be represented in the form of a string. Indeed, they can be
viewed as a string of beads, with each bead representing a single
nucleotide or amino acid monomer linked together through covalent chemical bonds into a very long chain.
In most cases, the monomers within the chain have a strong
propensity to interact with other amino acids or nucleotides. In DNA and
RNA, this can take the form of Watson–Crick base pairs (G–C and A–T or A–U), although many more complicated interactions can and do occur.
Structural features
DNA
RNA
Proteins
Encodes genetic information
Yes
Yes
No
Catalyzes biological reactions
No
Yes
Yes
Building blocks (type)
Nucleotides
Nucleotides
Amino acids
Building blocks (number)
4
4
20
Strandedness
Double
Single
Structure
Double helix
Complex
Complex
Stability to degradation
High
Variable
Variable
Repair systems
Yes
No
No
Because of the double-stranded nature of DNA, essentially all of the nucleotides take the form of Watson–Crick base pairs between nucleotides on the two complementary strands of the double helix.
In contrast, both RNA and proteins are normally single-stranded.
Therefore, they are not constrained by the regular geometry of the DNA
double helix, and so fold into complex three-dimensional shapes
dependent on their sequence. These different shapes are responsible for
many of the common properties of RNA and proteins, including the
formation of specific binding pockets, and the ability to catalyse biochemical reactions.
DNA is optimised for encoding information
DNA is an information storage macromolecule that encodes the complete set of instructions (the genome) that are required to assemble, maintain, and reproduce every living organism.
DNA and RNA are both capable of encoding genetic information,
because there are biochemical mechanisms which read the information
coded within a DNA or RNA sequence and use it to generate a specified
protein. On the other hand, the sequence information of a protein
molecule is not used by cells to functionally encode genetic
information.
DNA has three primary attributes that allow it to be far better
than RNA at encoding genetic information. First, it is normally
double-stranded, so that there are a minimum of two copies of the
information encoding each gene in every cell. Second, DNA has a much
greater stability against breakdown than does RNA, an attribute
primarily associated with the absence of the 2'-hydroxyl group within
every nucleotide of DNA. Third, highly sophisticated DNA surveillance
and repair systems are present which monitor damage to the DNA and repair
the sequence when necessary. Analogous systems have not evolved for
repairing damaged RNA molecules. Consequently, chromosomes can contain
many billions of atoms, arranged in a specific chemical structure.
Proteins are optimised for catalysis
Proteins are functional macromolecules responsible for catalysing the biochemical reactions that sustain life. Proteins carry out all functions of an organism, for example photosynthesis, neural function, vision, and movement.
The single-stranded nature of protein molecules, together with
their composition of 20 or more different amino acid building blocks,
allows them to fold in to a vast number of different three-dimensional
shapes, while providing binding pockets through which they can
specifically interact with all manner of molecules. In addition, the
chemical diversity of the different amino acids, together with different
chemical environments afforded by local 3D structure, enables many
proteins to act as enzymes,
catalyzing a wide range of specific biochemical transformations within
cells. In addition, proteins have evolved the ability to bind a wide
range of cofactors and coenzymes,
smaller molecules that can endow the protein with specific activities
beyond those associated with the polypeptide chain alone.
RNA is multifunctional
RNA is multifunctional, its primary function is to encode proteins, according to the instructions within a cell's DNA.They control and regulate many aspects of protein synthesis in eukaryotes.
RNA encodes genetic information that can be translated
into the amino acid sequence of proteins, as evidenced by the messenger
RNA molecules present within every cell, and the RNA genomes of a large
number of viruses. The single-stranded nature of RNA, together with
tendency for rapid breakdown and a lack of repair systems means that RNA
is not so well suited for the long-term storage of genetic information
as is DNA.
In addition, RNA is a single-stranded polymer that can, like
proteins, fold into a very large number of three-dimensional structures.
Some of these structures provide binding sites for other molecules and
chemically active centers that can catalyze specific chemical reactions
on those bound molecules. The limited number of different building
blocks of RNA (4 nucleotides vs >20 amino acids in proteins),
together with their lack of chemical diversity, results in catalytic RNA
(ribozymes) being generally less-effective catalysts than proteins for most biological reactions.
Lignin is a pervasive natural macromolecule. It comprises about 1/3
of the mass of trees. lignin arises by crosslinking. Related to lignin
are polyphenols, which consist of a branched structure of multiple phenolic subunits. They can perform structural roles (e.g. lignin) as well as roles as secondary metabolites involved in signalling, pigmentation and defense.
Raspberry ellagitannin, a tannin composed of core of glucose units surrounded by gallic acid esters and ellagic acid units
Carbohydrate macromolecules (polysaccharides) are formed from polymers of monosaccharides. Because monosaccharides have multiple functional groups, polysaccharides can form linear polymers (e.g. cellulose) or complex branched structures (e.g. glycogen). Polysaccharides perform numerous roles in living organisms, acting as energy stores (e.g. starch) and as structural components (e.g. chitin
in arthropods and fungi). Many carbohydrates contain modified
monosaccharide units that have had functional groups replaced or
removed.
Soft matter or soft condensed matter is a type of matter that can be deformed or structurally altered by thermal or mechanical stress which is of similar magnitude to thermal fluctuations.
Pierre-Gilles de Gennes, who has been called the "founding father of soft matter," received the Nobel Prize in Physics in 1991 for discovering that methods developed for studying order phenomena in simple systems can be generalized to the more complex cases found in soft matter, in particular, to the behaviors of liquid crystals and polymers.
History
The current understanding of soft matter grew from Albert Einstein's work on Brownian motion, understanding that a particle suspended in a fluid must have a similar thermal energy to the fluid itself (of order of kT). This work built on established research into systems that would now be considered colloids.
The crystalline optical properties of liquid crystals and their ability to flow were first described by Friedrich Reinitzer in 1888, and further characterized by Otto Lehmann in 1889. The experimental setup that Lehmann used to investigate the two melting
points of cholesteryl benzoate are still used in the research of liquid
crystals as of about 2019.
In 1920, Hermann Staudinger, recipient of the 1953 Nobel Prize in Chemistry, was the first person to suggest that polymers are formed through covalent bonds that link smaller molecules together. The idea of a macromolecule
was unheard of at the time, with the scientific consensus being that
the recorded high molecular weights of compounds like natural rubber
were instead due to particle aggregation.
The use of hydrogel in the biomedical field was pioneered in 1960 by Drahoslav Lím and Otto Wichterle. Together, they postulated that the chemical stability, ease of
deformation, and permeability of certain polymer networks in aqueous
environments would have a significant impact on medicine, and were the
inventors of the soft contact lens.
These seemingly separate fields were dramatically influenced and brought together by Pierre-Gilles de Gennes. The work of de Gennes across different forms of soft matter was key to understanding its universality, where material properties are not based on the chemistry of the underlying structure, more so on the mesoscopic structures the underlying chemistry creates. He extended the understanding of phase changes in liquid crystals, introduced the idea of reptation regarding the relaxation of polymer systems, and successfully mapped polymer behavior to that of the Ising model.
Distinctive physics
The self-assembly of individual phospholipids into colloids (Liposome and Micelle) or a membrane (bilayer sheet).
Interesting behaviors arise from soft matter in ways that cannot be predicted, or are difficult to predict, directly from its atomic or molecular constituents. Materials termed soft matter exhibit this property due to a shared propensity of these materials to self-organize
into mesoscopic physical structures. The assembly of the mesoscale
structures that form the macroscale material is governed by low
energies, and these low energy associations allow for the thermal and
mechanical deformation of the material. By way of contrast, in hard condensed matter physics it is often possible to predict the overall behavior of a material because the molecules are organized into a crystalline lattice
with no changes in the pattern at any mesoscopic scale. Unlike hard
materials, where only small distortions occur from thermal or mechanical
agitation, soft matter can undergo local rearrangements of the
microscopic building blocks.
A defining characteristic of soft matter is the mesoscopic scale of physical structures. The structures are much larger than the microscopic scale (the arrangement of atoms and molecules),
and yet are much smaller than the macroscopic (overall) scale of the
material. The properties and interactions of these mesoscopic
structures may determine the macroscopic behavior of the material. The large number of constituents forming these mesoscopic structures, and the large degrees of freedom
this causes, results in a general disorder between the large-scale
structures. This disorder leads to the loss of long-range order that is
characteristic of hard matter.
For example, the turbulentvortices that naturally occur within a flowing liquid
are much smaller than the overall quantity of liquid and yet much
larger than its individual molecules, and the emergence of these
vortices controls the overall flowing behavior of the material. Also,
the bubbles that compose a foam
are mesoscopic because they individually consist of a vast number of
molecules, and yet the foam itself consists of a great number of these
bubbles, and the overall mechanical stiffness of the foam emerges from
the combined interactions of the bubbles.
Typical bond energies in soft matter structures are of similar
scale to thermal energies. Therefore the structures are constantly
affected by thermal fluctuations and undergo Brownian motion. The ease of deformation and influence of low energy interactions regularly result in slow dynamics of the mesoscopic structures which allows some systems to remain out of equilibrium in metastable states. This characteristic can allow for recovery of initial state through an external stimulus, which is often exploited in research.
Self-assembly is an inherent characteristic of soft matter
systems. The characteristic complex behavior and hierarchical structures
arise spontaneously as a system evolves towards equilibrium. Self-assembly can be classified as static when the resulting structure is due to a free energy minimum, or dynamic when the system is caught in a metastable state. Dynamic self-assembly can be utilized in the functional design of soft materials with these metastable states through kinetic trapping.
Soft materials often exhibit both elasticity and viscous responses to external stimuli such as shear induced flow or phase transitions. However, excessive external stimuli often result in nonlinear responses. Soft matter becomes highly deformed before crack propagation, which differs significantly from the general fracture mechanics formulation. Rheology, the study of deformation under stress, is often used to investigate the bulk properties of soft matter.
Classes of soft matter
A portion of the DNA double helix, an example of a biopolymer.Host-guest complex of polyethylene glycol oligomer bound within an α-cyclodextrin
molecule; a common scaffold used in the formation of gels. The atoms
are colored such that red represents oxygen, cyan represents carbon, and
white represents hydrogen.Cartoon representation of the molecular order of crystal, liquid crystal, and liquid states.
Soft matter consists of a diverse range of interrelated systems and
can be broadly categorized into certain classes. These classes are by no
means distinct, as often there are overlaps between two or more groups.
Polymers are large molecules composed of repeating subunits whose
characteristics are governed by their environment and composition.
Polymers encompass synthetic plastics, natural fibers and rubbers, and
biological proteins. Polymer research finds applications in nanotechnology, from materials science and drug delivery to protein crystallization.
Foams consist of a liquid or solid through which a gas has been dispersed to form cavities. This structure imparts a large surface-area-to-volume ratio on the system. Foams have found applications in insulation and textiles, and are undergoing active research in the biomedical field of drug delivery and tissue engineering. Foams are also used in automotive for water and dust sealing and noise reduction.
Gels consist of non-solvent-soluble 3D polymer scaffolds, which are covalently or physically cross-linked, that have a high solvent/content ratio. Research into functionalizing gels that are sensitive to mechanical and
thermal stress, as well as solvent choice, has given rise to diverse
structures with characteristics such as shape-memory, or the ability to bind guest molecules selectively and reversibly.
Colloids are non-soluble particles suspended in a medium, such as proteins in an aqueous solution.[36]
Research into colloids is primarily focused on understanding the
organization of matter, with the large structures of colloids, relative
to individual molecules, large enough that they can be readily observed.
Liquid crystals can consist of proteins, small molecules, or
polymers, that can be manipulated to form cohesive order in a specific
direction. They exhibit liquid-like behavior in that they can flow, yet they can obtain close-to-crystal alignment. One feature of liquid crystals is their ability to spontaneously break symmetry. Liquid crystals have found significant applications in optical devices such as liquid-crystal displays (LCD).
Biological membranes consist of individual phospholipid molecules that have self-assembled into a bilayer structure due to non-covalent interactions. The localized, low energy associated with the forming of the membrane allows for the elastic deformation of the large-scale structure.
Experimental characterization
Due
to the importance of mesoscale structures in the overarching properties
of soft matter, experimental work is primarily focused on the bulk
properties of the materials. Rheology is often used to investigate the
physical changes of the material under stress. Biological systems, such as protein crystallization, are often investigated through X-ray and neutron crystallography, while nuclear magnetic resonance spectroscopy can be used in understanding the average structure and lipid mobility of membranes.
Computational
methods are often employed to model and understand soft matter systems,
as they have the ability to strictly control the composition and
environment of the structures being investigated, as well as span from
microscopic to macroscopic length scales. Computational methods are limited, however, by their suitability to the
system and must be regularly validated against experimental results to
ensure accuracy. The use of informatics
in the prediction of soft matter properties is also a growing field in
computer science thanks to the large amount of data available for soft
matter systems.
Optical microscopy can be used in the study of colloidal systems, but more advanced methods like transmission electron microscopy (TEM) and atomic force microscopy (AFM) are often used to characterize forms of soft matter due to their applicability to mapping systems at the nanoscale.These imaging techniques are not universally appropriate to all classes
of soft matter and some systems may be more suited to one kind of
analysis than another. For example, there are limited applications in
imaging hydrogels with TEM due to the processes required for imaging.
However, fluorescence microscopy can be readily applied. Liquid crystals are often probed using polarized light microscopy to determine the ordering of the material under various conditions, such as temperature or electric field.
Applications
Soft
materials are important in a wide range of technological applications,
and each soft material can often be associated with multiple
disciplines. Liquid crystals, for example, were originally discovered in
the biological sciences when the botanist and chemist Friedrich Reinitzer was investigating cholesterols. Now, however, liquid crystals have also found applications as liquid-crystal displays, liquid crystal tunable filters, and liquid crystal thermometers. Active liquid crystals are another example of soft materials, where the constituent elements in liquid crystals can self-propel.
Polymers have found diverse applications, from the natural rubber found in latex gloves to the vulcanized rubber
found in tires. Polymers encompass a large range of soft matter, with
applications in material science. An example of this is hydrogel. With
the ability to undergo shear thinning, hydrogels are well suited for the development of 3D printing. Due to their stimuli responsive behavior, 3D printing of hydrogels has
found applications in a diverse range of fields, such as soft robotics, tissue engineering, and flexible electronics. Polymers also encompass biological molecules such as proteins, where
research insights from soft matter research have been applied to better
understand topics like protein crystallization.
3D/4D printing of soft materials is evolving, focusing on various
printing techniques, material types, and their broad applications in
engineering and technology. Key printing methods are extrusion and
inkjet based printing, stereolithography, selective laser sintering,
direct ink writing, and VAT photopolymerization. A diversity in soft
materials for 3D/4D printing includes elastomers, hydrogels,
bio-inspired polymers, conductive and flexible materials,
andinkjet-based biomimetic materials for applications in biomedical
engineering, soft robotics, wearable devices, textiles, food technology,
and pharmaceuticals. Changelings and limitations prevail in design
geometric complexity,cost, resolution, material #compatibility,
scalability and regulatory concerns.
Foams can naturally occur, such as the head on a beer, or be created intentionally, such as by fire extinguishers. The physical properties available to foams have resulted in applications which can be based on their viscosity, with more rigid and self-supporting forms of foams being used as insulation or cushions, and foams that exhibit the ability to flow being used in the cosmetic industry as shampoos or makeup. Foams have also found biomedical applications in tissue engineering as scaffolds and biosensors.
Historically the problems considered in the early days of soft
matter science were those pertaining to the biological sciences. As
such, an important application of soft matter research is biophysics, with a major goal of the discipline being the reduction of the field of cell biology to the concepts of soft matter physics. Applications of soft matter characteristics are used to understand biologically relevant topics such as membrane mobility, as well as the rheology of blood.
Ecotypes
are organisms which belong to the same species but possess different
phenotypical features as a result of environmental factors such as
elevation, climate and predation. Ecotypes can be seen in wide
geographical distributions and may eventually lead to speciation.
Definition
In evolutionary ecology, an ecotype, sometimes called ecospecies, describes a genetically distinct geographic variety, population, or race within a species, which is genotypically adapted to specific environmental conditions.
Typically, though ecotypes exhibit phenotypic differences (such as in morphology or physiology) stemming from environmental heterogeneity, they are capable of interbreeding with other geographically adjacent ecotypes without loss of fertility or vigor.
Summary
An
ecotype refers to organisms which belong to the same species but have
different phenotypical characteristics as a result of their adaptations
to different habitats. Differences between these two groups is attributed to phenotypic
plasticity and are too few for them to be termed as wholly different
species. Emergence of variants of the same species may occur in the same
geographical region where different habitats provide distinct ecological
niches for these organisms. Examples of these habitats include meadows,
forests, swamps, and sand dunes. Where similar ecological conditions occur in widely separated places,
it is possible for a similar ecotype to occur in the separated
locations. An ecotype is different from a subspecies, which may exist across a number of different habitats. In animals, ecotypes owe their differing characteristics to the effects
of a very local environment which has been hypothesized to lead to
speciation through the emergence of reproductive barriers.Therefore, ecotypes have no taxonomic rank.
Terminology
Ecotypes are closely related to morphs or polymorphisms which is defined as the existence of distinct phenotypes among members of the same species. Another term closely related is genetic polymorphism;
and it is when species of the same population display variation in a
specific DNA sequence, i.e. as a result of having more than one allele
in a gene's locus. In order to be classified as such, morphs must occupy the same habitat at the same time and belong to a panmictic population (whose members can all potentially interbreed). Polymorphism are maintained in populations of species by natural selection. In fact, Begon, Townsend, and Harper assert that
There is not always clear distinction between local ecotypes and genetic polymorphisms.
The notions "form" and "ecotype" may appear to correspond to a static phenomenon, however; this is not always the case. Evolution occurs continuously both in time and space, so that ecotypes
or forms may qualify as distinct species in a few generations. Begon, Townsend, and Harper offer the following analogy:
... the origin of a species, whether allopatric or sympatric,
is a process, not an event. For the formation of a new species, like
the boiling of an egg, there is some freedom to argue about when it is
completed.
Thus ecotypes and morphs can be thought of as precursory steps of potential speciation.
Research indicates that sometimes ecotypes manifest when separated by
great geographical distances as a result of genetic drift that may lead
to significant genetic differences and hence variation. Ecotypes may also emerge from local adaptation of species occupying
small geographical scales (<1km), in such cases divergent selection
due to selective pressure as a result of differences in microhabitats
drive differentiation. Hybridization among populations may increase population gene flow and reduce the effects of natural selection.Hybridization here is defined as when different but adjacent varieties of the same species (or generally of the same taxonomic rank) interbreed, which helps overcome local selection. However other studies reveal that ecotypes may emerge even at very
small scales (of the order of 10 m), within populations, and despite
hybridization.
In ecotypes, it is common for continuous, gradual geographic
variation to impose analogous phenotypic and genetic variation, a
situation which leads to the emergence of clines. A well-known example of a cline is the skin color gradation in
indigenous human populations worldwide, which is related to latitude and
amounts of sunlight. Ecotypes may display two or more distinct and discontinuous phenotypes even within the same population. Ecological systems may have a species abundance that can be either bimodal or multimodal. Emergence of ecotypes may lead to speciation and can occur if conditions in a local environment change dramatically through space or time.
Ecotype and speciation
Just
as sunlight can appear as a dim crack in the sky before clouds part,
the coarse boundaries of ecotypes may appear as a separation of
principle[sic] component clusters before speciation.
— David
B. Lowry, Ecotypes and the controversy over stages in the formation of
new species, Biological Journal of the Linnean Society.
The birth of the term 'ecotype' originally came from early interest in understanding speciation. Darwin argued that species evolved through natural selection from variations within population which he termed as 'varieties'. Later on, through a series of experiments, Turresson studied the effect
of the environment on heritable plant variation and came up with the
term 'ecotype' to denote differences between groups occupying distinct
habitats. This, he argued, was a genotypical response of plants to habitat type
and it denotes a first step toward isolating reproductive barriers that
facilitate the emergence of 'species' via divergence and, ultimately,
genetic isolation. In his 1923 paper, Turesson states that variation among species in a
population is not random, rather, it is driven by environmental
selection pressure. For example, the maturity of Trifolium subterraneum,
a clover which was found to correlate to moisture condition; when sown
in low rainfall areas of Adelaide after a few years the population would
consist of genotypes that produced seeds early in the season (early
genotype), however in higher rainfall areas the clover population would
shift to mid-season genotypes, differences among population of Trifolium subterraneum is in response to the selective action of the habitat. These adaptive differences were hereditary and would emerge in response to specific environmental conditions. Heritable differences is a key feature in ecotypic variation. Ecotypic variation is as a result of particular environmental trends. Individuals, which are able to survive and reproduce successfully pass
on their genes to the next generation and establish a population best
adapted to the local environment. Ecotypic variation is therefore described to have a genetic base, and
are brought about by interactions between an individual's genes and the
environment. An example of ecotype formation that lead to reproductive isolation and
ultimately speciation can be found in the small sea snail periwinkle, Littorina saxatilis. It is distributes across different habitats such as lagoons, salt
marshes and rocky shores the range of distribution is from Portugal to
Novaya Zemlaya and Svalbard and from North Carolina to Greenland. The polymorphic snail species have different heritable features such as
size and shape depending on the habitat they occupy e.g. bare cliffs,
boulders and barnacle belts. Phenotypic evolution in these snails can be strongly attributed to
different ecological factors present in their habitats. For example, in
coastal regions of Sweden, Spain and UK, Littorina saxatilis possess different shell shapes in response to predation by crabs or waves surges. Predation by crabs, also called crab crushing, gives rise to snails
with wary behavior having large and thick shells which can easily
retract and avoid predation. Wave-surfs on the other hand, select for
smaller sized snails with large apertures to increase grip and bold
behavior. All this provide the basis for the emergence of different snail
ecotypes. Snail ecotypes on the basis of morphology and behavior pass
these characteristic on to their offspring.
Tundra reindeer and woodland reindeer are two ecotypes of reindeer.
The first migrate (travelling 5,000 km) annually between the two
environments in large numbers whereas the other (who are much fewer)
remain in the forest for the summer. In North America, the species Rangifer tarandus (locally known as caribou), was subdivided into five subspecies by Banfield in 1961. Caribou are classified by ecotype depending on several behavioural
factors – predominant habitat use (northern, tundra, mountain, forest,
boreal forest, forest-dwelling), spacing (dispersed or aggregated) and
migration (sedentary or migratory). For example, the subspecies Rangifer tarandus caribou is further distinguished by a number of ecotypes, including boreal woodland caribou, mountain woodland caribou, and migratory woodland caribou (such as the migratory George River Caribou Herd in the Ungava region of Quebec).
Arabis fecunda, a herb endemic to some calcareous
soils of Montana, United States, can be divided into two ecotypes. The
one "low elevation" group lives near the ground in an arid, warm
environment and has thus developed a significantly greater tolerance
against drought than the "high elevation" group. The two ecotypes are
separated by a horizontal distance of about 100 km (62 mi).
It is commonly accepted that the Tucuxi
dolphin has two ecotypes – the riverine ecotype found in some South
American rivers and the pelagic ecotype found in the South Atlantic
Ocean. In 2022, the common bottlenose dolphin (Tursiops truncatus), which had been considered to have two ecotypes in the western North Atlantic, was separated into two species by Costa et al. based on morphometric and genetic data, with the near-shore ecotype becoming Tursiops erebennus Cope, 1865, described in the nineteenth century from a specimen collected in the Delaware River.
Artemisia campestris subsp. borealis an ecotype of Artemisia campestrisThe aromatic plant Artemisia campestris
also known as the field sagewort grows in a wide range of habitats
from North America to the Atlantic coast and also in Eurasia. It has different forms arccoding to the environment where it grows. One
variety which grows on shifting dunes at Falstrebo on the coast of
Sweden has broad leaves, and white hairs while exhibiting upright
growth. Another variety that grows in Oland in calcareous rocks displays
horizontally expanded branches with no upright growth. These two
extreme types are considered different varieties. Other examples include Artemisia campestris var. borealis which occupies the west of the Cascades crest in the Olympic Mountains in Washington while Artemisia campestris var. wormskioldii grows on the east side. The Northern wormwood, var. borealis has spike like-inflorescences with leaves concentrated on the plant base and divided into long narrow lobes. Wormskiold's northern wormwood, Artemisia campestris var. wormskioldii is generally shorter and hairy with large leaves surrounding the flowers.
The Scots pine (Pinus sylvestris) has 20 different ecotypes in an area from Scotland to Siberia, all capable of interbreeding.
Ecotype distinctions can be subtle and do not always require large
distances; it has been observed that two populations of the same Helix
snail species separated by only a few hundred kilometers prefer not to
cross-mate, i.e., they reject one another as mates. This event probably
occurs during the process of courtship, which may last for hours.
