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Genomics, gene therapy and stem cells

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Genomics in healthcare

As briefly touched upon in the introduction to this chapter, genomics (the study of genomes) is emerging as a key scientific field in terms of addressing disease and learning more about health. Within healthcare, genomics has the potential, and has already begun, to support risk prediction, prevention, diagnosis, treatment in terms of drug choice and dosage, and prognosis.

Genomic medicine started in the areas of oncology, pharmacology, rare and undiagnosed diseases and infectious disease.

Risk prediction is employed by studying associations between certain diseases and the presence of specific genes preferentially in that patient population. Sometimes, especially for rare disease that tend to have a single genetic root, it's possible to know the mechanism by which that mutation causes a disease. However, other times this isn't elucidated and all we can work with is the knowledge that, for whatever reason as of yet unknown, the association stands. It gives a patient a percentage increased lifetime likelihood of developing a certain disease.

One example are the BRCA1 and BRCA2 alleles whose protein products are involved in DNA repair in cells, acting as tumour suppression genes. Different variations of these genes have been linked to a 20-60% increased risk of breast and ovarian cancer. 

Prevention can then take place by paying close attention, just by being aware of the increased risk, or in some cases, preventative interventions such as taking certain drugs or elective surgeries. In pharmacology, knowledge of increased risk of side effects from certain drugs can inform patients to avoid them or take an alternative drug. This ties in with treatment, and a patient's option to take a drug they will personally have a better response to, or at a better tailored dose. For example, fast metabolism of a drug may mean they will have to take it more frequently as their body is breaking it down more quickly.

Prognosis is about knowing the likely outcome of a condition. This can connect back to the drugs taken and response to those, or refer to how a disease might develop. For example, in the case of some disease there are multiple variations in genes with different outcomes. This could be in terms of the likelihood of getting a disease, as well as in terms of disease severity and progression.

Gene delivery in gene therapy

Delivering DNA into cells for various purposes can be achieved via viruses which naturally can infect certain cells, as well as gene guns (biolistics) for plants.

Gene therapy involves inserting a functional gene into a patient who lacks it, or needs supplementary support, such as in muscular dystrophy. This works for conditions which are caused by a single faulty gene rather than multiple genes. The vector used to deliver the gene is a harmless virus. Once the new DNA is taken up in the cell nucleus, the gene is expressed like any other gene.

One problem associated with gene therapy is the immune reaction the body has to the virus. This may cause inflammation and other potentially serious side effects. Another issue is that of maintaining the effects of the healthy gene inserted into target cells. If these are recycled quickly or don't pass on the new gene to their offspring cells, then the therapeutic effect stops there, and the case is that multiple rounds of gene therapy must be administered.

A limitation specific to muscular dystrophy is that a full gene coding for dystrophin must be delivered in the virus. This is quite large, and it is difficult to fit it inside. Research is taking place to solve this.

Conditions currently treated with gene therapy include: cystic fibrosis, haemophilia, Parkinson's disease, muscular dystrophy, sickle cell anaemia among many others. One particular drug in gene therapy, Glybera, is famous for being the most expensive drug in the world at $1.6 million per patient.

Using stem cells for replacing damaged tissues and organs

Alongside gene therapy, another promising approach to maintaining health is stem cell therapy. Gene therapy relies on existing cells carrying out functions differently. Stem cell therapy aims to be able to replace some of these cells altogether.

Stem cells are the precursor cells to all the specialised cells: muscle, nervous, skin, etc. Therefore, the cultivation of stem cells can produce specialised cells under specific conditions.


The embryos of mammals possess totipotent stem cells which upon differentiation and development into the adult organism do not occur again. The adults only have multipotent stem cells which have a limited range of cells they can change into. Using totipotent cells from embryos poses ethical issues because the embryo is destroyed in the process. Additionally, a source of disposable embryos must exist to provide the source for these cells.

Adult plants, on the other hand, retain many totipotent stem cells and that's how you can actually grow a whole plant in vitro from just a cut fragment of any part of the plant. The conditions can even dictate which organ will develop!

Therapeutic Potential

The benefits of being able to grow any kind of cell from a stem cell (totipotent or multipotent) are vast. Replacing damaged tissue in heart failure and cancer is one example (bone marrow transplant are already happening). Genetic disorders such as Type I diabetes could also be addressed by stem cell therapy in the near future. Deafness, blindness and infertility are also on the list of conditions that could be treated by stem cell therapy.

The same signals known as protein transcription factors which enable differentiation in organisms can be used artificially in the lab to grow and differentiate different types of cell.

The transcription factors dictate which proteins get made from the DNA, which in turn determine the structure and function of the cell. In this manner, already differentiated cells like fibroblast cells (whose function is synthesising the cell extracellular matrix) can be coaxed into reverting to a stem cell-like state and then be used to differentiate again into a different type of cell such as a neurone. The new stem cells made this way are known as induced pluripotent stem cells (iPSC). They do not pose the issues that embryonic stem cells pose, because the source of cells is not an embryo.

Limitations of using stem cells for replacing damaged tissues and organs include delivery, integration into existing tissue, compatibility with host tissue, and sourcing and production.

Using a patient's own cells gets around the issue of compatibility and rejection, but raises challenges in terms of extracting the cells and growing them and differentiating them for the target tissue type. The balance of transplanted cells versus present tissue in a patient is an issue. Introducing few therapeutic cells causes little disturbance to the tissue, but may overpower the new cells and simply reprogram them into cells similar to the diseased cells. Introducing too many new cells can be traumatic to existing tissue, similar to surgery or implantation of synthetic devices or structures.

Questions around cell proliferation are also important if the tissue or organ seeking replacement is large or spread out, or deep into tissue. Sourcing and production (including scalability) are also limiting because growing and differentiating stem cells for certain tissue types can take a long time (many months for nerve cells), and can use up large amounts of biological materials. Some of these materials (used as food for the cells; no, they do not grow by magic) are sourced from slaughtered animals e.g. blood of calves, various other chemicals and proteins collected as a byproduct of the animal industry.

In terms of using stem cells for organ transplants, the issue is one of the extracellular matrix of organs. This is the solid, shape-giving structures made of collagen for example, that cells grow in. Hearts have had their cells (red) removed, and the scaffold used to populate with new stem cells, which spread throughout the heart successfully. There are many synthetic, bio-compatible materials being tested in combination with stem cells to make muscle, bone or skin tissues, as well as livers, kidneys, hearts, etc.

The issue is one of making the cells adhere to the artificial scaffold and proliferate in a way that leads to the normal development of organ function. 3D printing and other methods are used to create these scaffolds, sometimes at the same time as seeding them with stem cells.

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