Synthetic biology for Entrepreneurs: Innovations in the Healthcare Sector
Imagine if you can have a tree that can mine gold or be resistant to any kind of virus forever. Would you be amazed by that? What would happen if I tell you that this possibility will be present sooner that you might think?
This kind of innovations can only be present thanks to a new field that will revolutionize how we behave and, probably, even what we are. It is called: Synthetic Biology.
What is Synthetic biology?
We can define synthetic biology as a new interdisciplinary area that involves applying engineering principles to biology. It aims to (re-)design and fabrication of biological components and systems that do not already exist in the natural world.
There is a difference between synthetic biology and gene editing.
Synthetic biology studies complex natural biological systems as complete systems using modelling and simulation tools, focusing on taking parts of natural biological systems, characterizing and simplifying them, and using them as components of an engineered biological system. Instead, genetic engineering is based on transferring individual genes from one microbe or cell to another. From another perspective, we can define synthetic biology as gene engineering with more functions and more variables, considering the whole cell rather than just the DNA.
Synthetic biology is linked to Systems biology. It is the computational and mathematical analysis and modelling of complex biological systems. It is a biology-based interdisciplinary field of study that focuses on complex interactions within biological systems. Its mission is to understand the larger picture — be it at the level of the organism, tissue, or cell — by putting its pieces together. It’s in stark contrast to decades of reductionist biology, which involves taking the details apart.
Synthetic biology is based on four main fields:
Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism’s complete set of DNA, including all of its genes. Suppose genetics refers to the study of individual genes and their roles in inheritance. In that case, genomics aims to collectively characterize and quantify all of an organism’s genes, their interrelations, and their influence on the organism.
Moreover, genomics focuses on interactions between loci and alleles within the genome and other interactions such as genome, epistasis, pleiotropy and heterosis.
A genome is an organism’s complete set of genetic instructions. Each genome contains all of the information needed to build that organism and allow it to grow and develop. The genome includes both the genes (the coding regions) and the non-coding DNA and mitochondrial DNA and chloroplast DNA.
Epistasis is a phenomenon in genetics in which the effect of a gene mutation is dependent on the presence or absence of mutations in one or more other genes, respectively termed modifier genes. In other words, the mutation’s effect is dependent on the genetic background in which it appears.
An example of epistasis is pigmentation in mice. The wild-type coat colour, agouti (AA), is dominant to solid-coloured fur (aa). However, a separate gene is necessary for pigment production. A mouse with a recessive c allele cannot produce pigment and is albino regardless of the allele present at locus A. Therefore, the genotypes AAcc, Aacc, and aacc all produce the same albino phenotype.
Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expressions is called a pleiotropic gene.
One of the most widely cited examples of pleiotropy in humans is phenylketonuria (PKU). A deficiency of the enzyme phenylalanine hydroxylase causes this disorder. This enzyme is necessary to convert the essential amino acid phenylalanine to tyrosine. Therefore, a defect in the single gene that codes for this enzyme results in the multiple phenotypes associated with PKU, including mental retardation, eczema, and pigment defects that make affected individuals lighter-skinned.
Heterosis refers to the phenomenon that progeny of diverse varieties of a species or crosses between species exhibit greater biomass, speed of development, and fertility than both parents. Scientists have used various models to explain heterosis, including dominance, overdominance, and pseudo-overdominance.
Transcriptomics is the study of the ‘transcriptome,’ a term whose first use, to signify an entire set of transcripts. The term transcriptome is now widely understood to mean the complete set of all the ribonucleic acid (RNA) molecules expressed in some given entity, such as a cell, tissue, or organism. In other words, it encompasses everything relating to RNAs. This includes their transcription and expression levels, functions, locations, trafficking, and degradation. It covers all types of transcripts, including messenger RNAs (mRNAs), microRNAs (miRNAs), and different kinds of long non-coding RNAs (lncRNAs).
In the human genome, about 5% of all genes get transcribed into RNA. The transcriptome consists of coding mRNA which comprises around 1–4% of its entirety and non-coding RNAs, including the rest of the genome and does not give rise to proteins. The more an organism is complex, the more the number of non-protein-coding sequences increases.
Proteomics is a fast and powerful discipline aimed at studying the whole proteome or the sum of all proteins from an organism, tissue, cell or biofluid.
Proteomics is the large-scale study of proteomes. We can define the proteome as a set of proteins produced in an organism, system, or biological context. It differs from cell to cell and changes over time. Generally, we can say that the proteome reflects the underlying transcriptome. However, many factors and the expression level of the relevant gene modulate protein activity (speed of the reaction in which the protein is involved)
Most proteomic discoveries and efforts have been mainly directed towards cancer research, drug and drug target discovery, and biomarker research.
In general, proteomics needs to investigate
- the expression of proteins
- the movement of proteins between subcellular compartments
- protein interaction
- the involvement of proteins in metabolic pathways
Metabolomics is the large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms. Collectively, these small molecules and their interactions within a biological system are known as the metabolome.
These compounds are the substrates and by-products of enzymatic reactions and directly affect the phenotype of the cell. Thus, metabolomics aims at determining a sample’s profile of these compounds at a specified time under specific environmental conditions. It best represents the molecular phenotype.
A small molecule (or metabolite) is a low molecular weight organic compound, typically involved in a biological process as a substrate or product.
Some examples of metabolites are sugars, amino acids, fatty acids, phenolic compounds and alkaloids.
If there are 4 bases and 20 amino acids, there are around 200,000 metabolites. In humans, there are approximately 3,000 endogenous or common metabolites.
Industrial Revolutions have always been relevant thanks to the union of different fields. For example, during the Fourth Industrial Revolution, you can find the cooperation between sensors, 3D printers, smart factories, IoT and much more. These innovations, by themselves, would haven’t been so relevant. In the field of synthetic biology, it is going to be the same. The time of synthetic biology is now because personal genomes, proteins and metabolites can be scrutinized affordably.
Many of those opportunities will be in the healthcare sector that can finally become 4.0.
Here are the most exciting innovations in the field:
Public health recommendations for nutrition and diet are based on averages of population data. Anyone is different in the DNA and based on that, there are differences in the response. Indeed, we should consider two main factors:
- the Genotype
- The Phenotype
Overall, the so-called omics revolution provides a solid framework for a systems-based approach to personalized nutrition research. From this point, we can consider the possibility to design a more personalised food based on randomized controlled trials, which are designed to minimize variation across study population groups, to these new opportunities. From this perspective, we need to consider the importance of variation and a way to quantify the genome–exome–phenome relationships.
The goals of personalised nutrition can also extend beyond preventing and mitigating chronic disease, improving mood, attention, endurance, weight maintenance, and well-being in general. For this perspective, the boundaries between medical treatments, illness prevention strategies, and strategies to achieve optimal health have become negligible.
William W. Li, MD, is an internationally renowned, Harvard-trained medical doctor and researcher, and is the president and co-founder of the Angiogenesis Foundation. In his studies, he focused on how food can have an impact on our health. He studies more than 70 diseases including cancer, diabetes, blindness, heart disease, and obesity.
Different macronutrients act differently on overlapping regulatory processes involved in phenotypic flexibility. For example, carbohydrates directly trigger an insulin response through rising glucose levels in circulation. On the other hand, triglycerides and fatty acids do not induce an insulin response, but insulin-dependent regulatory processes primarily govern their metabolism. Dietary protein consumed with carbohydrates can potentiate the insulin response, and individual amino acids can act as insulin secretagogues. Insulin-dependent pathways also regulate protein turnover, consisting of protein biosynthesis and amino acid degradation, which provide energy. As we can see, different processes regulate energy metabolism. This regulation prevents excess concentrations of metabolic constituents by maintaining complex machinery of metabolic flexibility distributed over many organs and functions. The lack of phenotypic flexibility can lead to pathologies or suboptimal health. There could be several problems such as insulin resistance, overnutrition or other diseases. Genetics may also contribute to the development of diseases. Insulin resistance can also cause increased accumulation of hepatic triglycerides, ultimately resulting in hepatic steatosis and fatty liver disease.
The optimal way to have personalized food is to create it by us.
In February, Ginkgo spun out Motif Ingredients developing vegan-friendly proteins that can be added to food to replace animal products like meat and cheese, with $90 million in Viking and others’ funding. And in May it acquired the genome-mining platform of Warp Drive Bio, a subsidiary of Revolution Medicines, and with it an agreement with pharmaceutical giant Roche to search for a new class of antibiotics, a deal that could be worth $160 million, plus additional royalties if Ginkgo succeeds.
You can improve taste, texture, appearance but even performance and nutritional benefits thanks to that.
Proteins are biomolecules composed of amino acids that participate in nearly all cellular activities.
Translation is the process through which proteins are synthesized and occurs in the cytoplasm,
Typically, a single set of amino acids constructs a protein. Every protein is specially equipped for its function.
The human body can create any protein from permutations of only 20 amino acids.
A protein is made from a ribbon of amino acids that folds itself up with many elaborate twists and tangles. This structure determines what it does. For example, the haemoglobin molecule comprises four heme groups surrounding a globin group, forming a tetrahedral structure. Its structure determines its function. Figuring out what proteins do is key to understanding the basic mechanisms of life, when it works and when it doesn’t.
There are seven types of proteins: antibodies, contractile proteins, enzymes, hormonal proteins, structural proteins, storage proteins, and transport proteins.
Types of Proteins
There is a total of seven different protein types under which all proteins fall. These include antibodies, contractile proteins, enzymes, hormonal proteins, structural proteins, storage proteins, and transport proteins.
Antibodies are specialized proteins whose mission is to defend the body against antigens or foreign invaders. Their ability to travel through the bloodstream enables them to be utilized by the immune system to identify and protect against bacteria, viruses, and other foreign intruders in blood. One way antibodies counteract antigens is by immobilizing them to be destroyed by white blood cells.
Contractile proteins are responsible for muscle contraction and movement. Actin and myosin are an example of these proteins. Myosin powers the tasks carried out by actin by supplying it with energy.
Enzymes are proteins that facilitate and speed up biochemical reactions. They are defined as biological catalysts. Well-known enzymes such as lactase and pepsin are essential for their roles in digestive medical conditions. Lactase, for example, is an enzyme that breaks down the sugar lactose found in milk. His deficiency causes Lactose intolerance Pepsin is a digestive enzyme that works in the stomach to break down proteins in food. The lack of this enzyme leads to Indigestion.
Other examples of digestive enzymes present in saliva: salivary amylase, salivary kallikrein, and lingual lipase all perform essential biological functions. Salivary amylase is the primary enzyme found in saliva, and it breaks down starch into sugar.
Hormonal proteins are messenger proteins that help coordinate certain bodily functions. Examples include insulin, oxytocin, and somatotropin.
Insulin regulates glucose metabolism by controlling blood-sugar concentrations in the body, oxytocin stimulates contractions during childbirth, and somatotropin is a growth hormone that incites protein production in muscle cells.
Structural proteins are fibrous and stringy; this formation supports various other proteins such as keratin, collagen, and elastin.
Keratins strengthen protective coverings such as skin, hair, quills, feathers, horns, and beaks. Collagen and elastin provide support to connective tissues like tendons and ligaments.
Storage proteins reserve amino acids for the body until ready for use. Examples of storage proteins include ovalbumin, found in egg whites, and casein, a milk-based protein. Ferritin is another protein that stores iron in the transport protein, haemoglobin.
Transport proteins are carrier proteins that move molecules from one place to another in the body. Haemoglobin is one of these and is responsible for transporting oxygen through the blood via red blood cells. Cytochromes, another type of transport protein, operate in the electron transport chain as electron carrier proteins.
A protein structure may be globular or fibrous depending on its particular role (every protein is specialized). Globular proteins are generally compact, soluble, and spherical in shape. Fibrous proteins are typically elongated and insoluble. Globular and fibrous proteins may exhibit one or more types of protein structures.
There are four structural levels of protein: primary, secondary, tertiary, and quaternary. These levels determine the shape and function of a protein. They are distinguished from one another by the degree of complexity in a polypeptide chain. The primary level is the most basic and rudimentary, while the quaternary level describes sophisticated bonding.
A single protein molecule may contain one or more of these protein structure levels and the structure and intricacy of a protein determine its function. Collagen, for example, has a super-coiled helical shape that is long, stringy, strong, and rope-like — collagen is excellent for providing support. Haemoglobin, on the other hand, is a globular protein that is folded and compact. Its spherical shape is useful for manoeuvring through blood vessels.
DeepMind is an artificial intelligence company acquired by Google, whose mission is to helps us understand the world. It has already notched up a streak of wins, showcasing AIs that have learned to play various complex games with superhuman skill, from Go and StarCraft to Atari’s entire back catalogue.
Their last release is called AlphaFold that could help researchers design new drugs and understand diseases. In the longer term, predicting protein structure will also help design synthetic proteins, such as enzymes that digest waste or produce biofuels. Researchers are also exploring ways to introduce synthetic proteins that will increase crop yields and make plants more nutritious.
Many drugs are designed by simulating their 3D molecular structure and looking for ways to slot these molecules into target proteins. The more a twin model is close to the reality, the closer the actual effects are. This example is the case for only a quarter of the roughly 20,000 human proteins that are present. Thanks to AlphaFold, we can enter into a new area of research with 15,000 untapped drug targets.
Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Liposomes, proliposomes, microspheres, gels, prodrugs, cyclodextrins are typical examples of drug delivery systems. Nanoparticles composed of biodegradable polymers can fulfil these delivery systems’ stringent requirements, such as the ability to be transferred into an aerosol, stability against forces generated during aerosolization, biocompatibility, targeting and the release of the drug.
Synthetic biology can be fundamental in this new revolution. For example, The Elani Artificial Cell Engineering Group at Imperial College is designing semi-synthetic cells that can release drugs at a precise time and place. It can be able only thanks to the complete knowledge of the manipulations of cells. These semi-synthetic cells can also work as sensors.
One example of synthetic biology’s most intriguing clinical uses comes from scientists at UK-based GlaxoSmithKline (GSK).
This company plans to use synthetic biology to create living systems that make small molecules, like aspirin, typically from chemical rather than biological processes. The main benefits are that these systems are faster and more efficient compared to the previous ones.
Their mission is to engineer biology as an improvement or replacement of traditional chemistry in our medicines’ manufacture. According to Fuerst, emeritus professor at Queensland University, this system can improve the compounds’ quality and reduce the cost. According to Mark Buswell, head of GSK’s advanced manufacturing technologies, “Using this enzyme evolution approach opens the chemical reaction space that is difficult to access with traditional chemical approaches.” The biological approach is the only way to catalyze some reactions.
Once a reaction process is engineered through the enzymes, it can be put into cells so that each cell performs like a drug-making factory.
Pharmacogenomics implies using genetic sequence and genomics information of the host (normal or diseased) or of the pathogen in patient management to enable therapy decisions. Pharmacogenomics, an essential part of personalized medicine, can impact all drug development phases, from drug discovery to clinical trials. This part also applies to a wide range of therapeutic products including bioengineered proteins, cell therapy, antisense therapy and gene therapy. Genetic factors may significantly impact a particular drug’s pharmacokinetics and pharmacodynamics, thereby influencing a drug’s sensitivity in an individual patient with a specific genotype. Pharmacogenetics has three leading roles in the pharmaceutical industry:
- it studies drug metabolism and its pharmacological effects
- it predicts genetically determined adverse reactions
- it is used for drug discovery and development.
With the synthetic biology approach, pharmacogenetic knowledge can be used to design drugs with less adverse effects and improved efficacy.
Another example of Drug discovery comes from a common bacterium called Salmonella.
At the Centers for Disease Control and Prevention reports that Salmonella infects about 1 million people every year in the United States. Scientists at Prokarium in the United Kingdom use genetically altered Salmonella to deliver vaccines. They have engineered it to retain its ability to enter the body’s immune cells, preventing it from causing diseases. The main idea is that Prokarium uses the bacteria to deliver a vaccine orally. Fjällman, the company’s CEO, says that It enters through the gut lining, is engulfed by immune cells, and then starts making the vaccine.
This technology is still in the test phase, and it has been tested in humans in the United Kingdom, the United States, and Vietnam. Besides, it has been tested as a vaccine against diarrhoea, hepatitis B, and typhoid. Potentially it can deliver any protein vaccine, and it could be an excellent example of how vaccines will look like in the future
In medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Synthetic biology provides the following advantages over conventional techniques for drug discovery and development:
- It can enable the design of cells to screen drug molecules and reduce drug discovery time and expense.
- Metabolic pathways can be more precisely regulated in synthetic organisms and manipulated by molecular tools.
- It enables the redesigning of cells to produce desirable molecules with higher efficacy and lower toxicity.
- It can help improve personalized medicine thanks to data accumulated with advances in sequencing.
- It can reduce the cost of biologicals, particularly therapeutic proteins.
- It can boost the production of synthetic therapeutic proteins.
One of the most important steps in developing a new drug is target identification and validation. Proteins, genes and RNA are examples of targets. A good target needs to be efficacious, safe, meet clinical and commercial needs and, above all, be ‘druggable’. A ‘druggable’ target has to elicit a biological response measured both in vitro and in vivo. Good target identification and validation enables increased confidence in the relationship between target and disease and allows us to explore whether target modulation will lead to mechanism-based side effects.
According to the scientific paper “Principles of early drug discovery”, data mining of available biomedical data has led to a significant increase in target identification. In this context, data mining refers to the use of a bioinformatics approach to not only help in identifying but also selecting and prioritizing potential disease targets. The available data comes from various sources but includes publications and patent information, gene expression data, proteomics data, transgenic phenotyping and compound profiling data. Identification approaches also include examining mRNA/protein levels to determine whether they are expressed in disease and if they are correlated with disease exacerbation or progression. Another powerful approach is to look for genetic associations; for example, there is a link between genetic polymorphism and the risk of disease or disease progression or is the polymorphism functional. For example, familial Alzheimer’s Disease (AD) patients commonly have mutations in the amyloid precursor protein or presenilin genes, leading to the production and deposition in the brain of increased amounts of the Abeta peptide, characteristic of AD. There are also examples of phenotypes in humans where mutations can nullify or over-activate the receptor.
An alternative approach is to use phenotypic screening to identify disease-relevant targets. One example is using a phage-display antibody library to isolate human monoclonal antibodies that bind to the surface of tumour cells. Clones were individually screened by immunostaining choosing malignant cells. The antigens recognized by those clones were isolated by immunoprecipitation and identified by mass spectroscopy.
Once researchers identify a promising compound for development, they conduct experiments to gather information on:
- How it is absorbed
- How it is distributed
- How it is metabolized
- How it is excreted.
- Its potential benefits and mechanisms of action.
- The best dosage.
- The best way to give the drug (such as by mouth or injection).
- Side effects or adverse events that can often be referred to as toxicity.
- How it affects different groups of people (such as by gender, race, or ethnicity) differently.
- How it interacts with other drugs and treatments.
- Its effectiveness as compared with similar drugs.
Synthetic biology envisages the engineering of human-made living biomachines from standardized components that can perform predefined functions in a self-controlled manner. Synthetic biology can exploit nature’s incredible diversity of existing, natural parts to construct synthetic compositions of genetic, metabolic or signalling networks with predictable and controllable properties. It can produce drugs, biomaterials and fine chemicals resulting in living pills based on engineered cells to detect and treat disease states in vivo autonomously.
Another possibility is to design biological systems from scratch and synthesize artificial biological entities not found in nature. This more knowledge-driven approach investigates the reconstruction of minimal biological systems capable of performing activities, such as self-organization, self-replication and self-sustainability.
An artificial organ is a device that we can implant or integrate into a human body to connect with living tissue to replace a natural organ, duplicate or augment a specific function or functions so the patient may return to everyday life as soon as possible. We can divide artificial organs based on the materials used.
- mechanical, made of inanimate polymers and metals;
- biomechanical, made of partially living cells
- biological, made of living cells, biodegradable polymers and metal elements.
In general, the former two classes have an expiration date. They need to e changed after a while. Instead, the biological class can totally and permanently restore defective/failed organs.
Everything starts from a single fertilized egg. After that, it becomes to duplicate and to differentiate. Different tissues combine to form organs, and various organs make us.
For a typical tissue, the cell and ECM (Extracellular matrix) are the same. In a distinct organ, the cell and ECM types are very different. An organ consists of at least two or three different cell/ECM types with specific morphological characteristics and physiological functions.
For this reason, having artificial organs may face the problem of having multiple cell types.
According to a study from Xiaohong Wang, there are two stem cell engagement strategies have been developed in our former studies.
The first one is to mix growth factors in the cell-laden polymeric hydrogels before three-dimensional (3D) printing.
The second one is to add growth factors in the culture medium after 3D printing. The later is termed as “cocktail stem cell engagement”, in which different growth factor combinations are added into the culture medium in chronological order.
In both cases, we are going to need IPS cells (Induced pluripotent stem cells) to make the artificial organ 100% biocompatible.
Biocompatible materials are called in this way because they don’t produce a toxic or immunological response when exposed to the body or bodily fluids.
We can define a typical organ manufacturing process can as follows:
- The manufacturing process is a dynamic transformation process containing the essential characteristics of life, with a series of physical, chemical or physiological properties changes.
- advance processing technologies play a crucial role in the structure, cell integration, the formation of different tissues, the maturation and the coordination of stages;
- stem cells engage for the formation of various tissues
- Natural and synthetic polymers produce a branched vascular, neural and lymphatic network with anti-suture capabilities;
- the generation of this hierarchical multi-scale network vascularizes bioartificial organ manufacture with various functions.
Just in the US, 20 people, on average, die every day from the lack of available organs for transplant. Having artificial organs can save one life every 90 minutes. It could potentially make free of pain all those who have side effects (such as pain, infection, hernia, bleeding, blood clots, wound complications) after having donated an organ.
Tissue regeneration is a part of the organism’s tissue traumatized by external forces and partially lost. Based on the remaining amount, it grows the same structure and function as the lost part. This repair process is called tissue regeneration.
This activity is due to cell turnover that differs from cell to cell. Small intestine epithelium cells, for example, change every 2–4 days and fat cells every 8 years.
This change is due to many processes such as cell duplication or stem cell.
Stem cells are cells with the potential to develop into many different types of cells in the body.
We have 3 types of stem cells:
- Embryonic stem cells
- Cord Blood stem cells
- Adult Stem Cells
Embryonic stem cells are a product of In vitro fertilization. They are made in a petri dish after that eggs are fertilized, and then they develop into blastocysts.
Cord Blood stem cells are the cells that come from umbilical cords just after a baby is born.
Adult stem cells are found in the body of an adult, and they are present in all of us. Scientists have found adult stem cells in the brain, in bone marrows, in the blood, in blood vessels, in skeletal muscles, in the skin and the liver. When there is a need to replace some cells, stem cells are the most effective way to do that.
Tissue regeneration can also come with another type of stem cell, called IPS cell discovered by Shinya Yamanaka in Japan.
Yamanaka started wondering whether he could reprogram regular adult cells, like skin cells, to become stem cell-like cells. This concept can turn cells pluripotent again. After years of painstaking research, in 2006, Yamanaka and his team discovered that proteins encoded by just four “master genes” could turn any adult cell back into a stem cell. He called these cells Induced Pluripotent Stem Cells or IPSCs.
He started with a set of 24 genes that he knew to be critical of embryonic stem cells, after having put them all together, he found a small percentage of cells turned back into stem cells. So he set about trying to figure out what was the minimal cocktail. He found that 4 genes were critical for turning stem cells back, again, in IPS cells. It was very inefficient because just the 7% of cells became stem cells with the need to wait for about 2 weeks.
At the Biological Computation Group at Microsoft, researchers study different processes to make IPSC more efficient and effective.
Stem cells are essential for our life because the more we age, the fewer stem cells we have in our body. This process is called “Stem cell Exhaustion.”
There are many examples of problems caused by ageing in the field of stem cells.
For example, Neural stem cells (NSCs) are multipotent and self-renewing cells and located primarily in the neural tissues. NSCs in humans maintain brain homeostasis, and it continuously replenishes new neurons, which are essential for cognitive functions. However, there is now strong evidence for the ageing-associated cognitive deficits, such as spatial memory deficits, and neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease),
Another example comes from Mesenchymal stem cells (MSCs). These cells are multipotent stromal cells that can differentiate into mesenchymal tissue cells such as bone cells, cartilage cells, muscle cells, and fat cells.
Ageing causes a decrease in the bone marrow MSC pool. Also, it shifts their lineage differentiation from osteoblastic differentiation to adipogenic differentiation. This shift is mainly responsible for the gradual and ageing-associated change of hematopoietic marrows to fatty marrows that contributes significantly to the aetiology of senile osteoporosis.
MSCs are also relevant because they can handle oxidative stress. During the ageing process, oxidative stress leads to hyperactivity of pro-growth pathways, such as insulin/IGF-1 and mTOR pathways. The subsequent accumulation of toxic aggregates and cellular debris ultimately leads to apoptosis, necrosis, or autophagy.
Thanks to IPS cells, we can potentially solve those problems. One question may be how can we actually make a stem cell turn into a precise type. Indeed, once a stem cell goes into your body, you can’t control how it will develop. A stem cell could potentially become a bone cell rather than a red blood cell.
GC Therapeutics Inc. (GCTx) uses synthetic biology to program patient-derived stem cells into any cell type with efficiency (up to 10X), speed (up to 100X) and scalability. It comes from the Church Lab at Harvard University.
Reinventing the DNA
Some 3.5 billion years ago, life on Earth evolved to have just four “letters” in its genetic code. These letters are the DNA bases G, C, A and T — and they spell out the instructions for making proteins in every organism on Earth.
In 2012, new research built on the Romesberg Lab’s expanded the limited “alphabet” of natural DNA. Until now all organisms use have used only the four DNA bases to code for 20 amino acids. With the addition of X and Y, an organism could code for up to 152 new amino acids. These amino acids could, potentially, become building blocks for new medicines.
In 2014 scientists at Romesberg lab created the first semi-synthetic organism and if that wasn’t enough. At that point, these new bases just needed to store bases. But just storing these bases isn’t enough. To really be useful, these bases need to be “read,” or transcribed, into RNA molecules and translated into proteins. in 2017, indeed, they created the first functional semi-synthetic organism that can reproduce its genetic material in successive offspring.
In a study published in the journal Nature, the researchers explained that their “semi-synthetic” strain of E. coli is the first to both contain the unnatural bases in its DNA and use the bases to instruct cells to make a new protein.
The protein produced in this process was a variant of green fluorescent protein, a naturally glowing marker often used in genetic experiments, which contained different unnatural amino acids incorporated at a selected site.
From these studies started Synthorx, a clinical-stage biotechnology company focused on prolonging and improving people’s lives with cancer and autoimmune disorders. Synthorx’s proprietary, first-of-its-kind Expanded Genetic Alphabet platform technology expands the genetic code by adding a new DNA base pair and is designed to create optimized biologics, referred to as Synthorins. A Synthorin in a protein optimized by incorporating novel amino acids encoded by the new DNA base pair enables site-specific modifications, which enhance the pharmacological properties of these therapeutics. The company’s lead product candidate, THOR-707, a variant of IL-2, is in development to treat solid tumours as a single agent and in combination with an immune checkpoint inhibitor.
Other researchers started with this idea and went even further with what is called Hachimoji DNA.
Hachimoji DNA (from Japanese “eight letters”) is a synthetic nucleic acid analogue that uses four synthetic nucleotides in addition to the four present in the natural nucleic acids, DNA and RNA. This leads to four allowed base pairs: two unnatural base pairs formed by the synthetic nucleobases in addition to the two regular pairs. Hachimoji bases have been demonstrated in both DNA and RNA analogues, using deoxyribose and ribose respectively as the backbone sugar.
Benefits are not just in the field of proteomics. There are many more opportunities from that.
NASA, indeed, funded this research to expand the scope of the structures that we might encounter as we search for life in the cosmos”.Quoting Lori Glaze of the Planetary Science Division of NASA, “Life detection is an increasingly important goal of NASA’s planetary science missions, and this new work [with hachimoji DNA] will help us to develop effective instruments and experiments that will expand the scope of what we look for.”
Other possibilities could also be developing clean diagnostics for human diseases, DNA digital data storage, DNA barcoding and self-assembling nanostructures.
Synthesizing new DNA
In the United Kingdom scientists at *Touchlight Genetics* developed a two-step process to synthesize DNA used in biological products. The resulting product is called “doggybone DNA” (dbDNA) because of its shape.
Lisa Caproni, group leader of research applications at Touchlight, emphasizes that this process overcomes several shortcomings of traditional DNA synthesis. For example, the method provides a ready-to-use product in which DNA does not need to be manufactured and separated from bacterial material. This process is advantageous because DNA produced in bacteria can include genetic information that encourages antibiotic resistance which is not desirable for medical treatments. According to the scientist “Some desired DNA sequences are found to be incompatible with growth in bacteria.” For example, any cell cannot produce particular types of genes that stop its growth.
Scientists can use this technology in several clinically-related applications. This process can be used both in the biomanufacturing of therapeutic DNA products and in creating a variety of biological products.
Some examples could be DNA vaccines, DNA-based gene therapy products and therapeutic antibodies and viral vectors.
Because no bacterial steps are required, large amounts of dbDNA can be made quickly, making it easier and more economical to create therapeutic products.
In this article, I have defined what Synthetic biology is and all its future implication. There will be even more possibilities being a relatively new field than that with even more information to gather. In any case, thanks to synthetic biology, our world is going to be exponentially better. Quoting Voltaire: “Work keeps at bay three great evils: boredom, vice, and need.”
Chromosome: a grouping of coiled strands of DNA, containing many genes.
DNA (deoxyribonucleic acid): a molecule found in cells of organisms that encodes genetic information.
Gene: a biological unit that codes for distinct traits or characteristics.
Genome: the complete set of genes in a cell.
Genotype: the genetic constitution of an organism.
Metabolome: complete set of low molecular weight compounds in a cell at a given time.
Phenotype: the physical appearance/observable characteristics of an organism.
Proteome: complete set of proteins in a cell at a given time.
RNA (ribonucleic acid): a molecule, derived from DNA by transcription that either carries information (messenger RNA), provides sub-cellular structure (ribosomal RNA) transports amino acids (transfer RNA), or facilitates the biochemical modification of itself or other RNA molecules.