L4 - stem cell uses and ethics

• The first stem cell an organism uses:

  -fertilisation is the start of the formation of a complete human being, but this single diploid cell needs to become every cell of the body

  -this zygote will need to be able to form all the 216 different types of cell within a human body

  -we refer to this as a totipotent stem cell (meaning it can become any/all of the cells)
• Early stages of stem cell development:

  -the first cell formed by fertilisation will need to undergo cleavage to form 2 cells, and this will continue, uniformly dividing the cell into 2 new cells (mitosis)

  -this occurs without pausing for interphase so no growth occurs

  -this will ultimately result in a hollow ball of identical undifferentiated cells called a blastocyst (taking around 5 to 6 days in humans)
• Early stages of development

  
• Early stages of development:

  -the blastocyst consists of embryonic stem cells (totipotent)

  -prior to becoming a blastocyst, the cell ball is known as a morula

  -some inner cells have already lost their totipotency, and outer layer will become the placenta

  -inner layer is now pluripotent as some genes were turned off so they can’t form a placenta anymore
• Three types of stem cell in animals:

  -embryonic stem cells

  -umbilical cord stem cells

  -adult stem cells
• Embryonic stem cells:

  -these are pluripotent stem cells that can now form into other stem cells, for example forming blood stem cells or skin stem cells

  -by around 3 months they are fully specialised and lose their pluripotency
• Umbilical cord stem cells:

  -the blood that drains form the placenta and umbilical cord after birth is a rich source of pluripotent stem cells

  -if the blood is kept and stored, it could be available throughout the lifetime of the person should it be required

  -however, this level of storage would be unrealistic and expensive and there is not much evidence that this blood has been successfully used to treat any conditions
• Adult stem cells:

  -some body cells remain undifferentiated and are found amongst the differentiated cells in a tissue of organ

  –these are referred to as somatic stem cells.

  -can differentiate when needed to produce the major cell types found within that tissue or organ

  -an example is bone marrow, which contains stem cells that can form white blood cells as well as red blood cells

  -there are a limited number of adult stem cells in each different tissue and are difficult to extract

  -these are referred to as being multipotent as they can only form a limited range of differentiated cells
• Plant stem cells:

  -present in the meristematic tissue (meristems)

  -meristematic tissue is found wherever growth is occurring (roots and shoots)

  -also found between phloem and xylem tissues (vascular cambium)

  -cells in cambium differentiate into the different cells in phloem and xylem tissues so vascular tissue grows with the plant

  -stem cells in meristems remain pluripotent for the plants life
• Development of an organism:

  -the genes in stem cells from the early totipotent stem cells is a result of gene expression

  -this is achieved by the switching on and off of the transcription of certain genes

  -this is done via transcription factors and epigenetic mechanisms. it is this combination of active and silenced genes that leads to differentiation in cells
• Differences between foetal and adult haemoglobin:

  -haemoglobin exits in different forms; alpha, beta, and gamma

  -in adults each red blood cell contains 2 alpha and 2 beta

  -in a foetus there is a greater need for oxygen so they possess 2 alpha and 2 gamma

  -during development different versions of the globin genes are switched on or off, changing the levels of each in the blood over the 40 weeks of pregnancy

  -globin production of a foetus moves from the yolk sac, to the liver, to the spleen

  -by birth, the bone marrow genes have fully taken over globin production
• Foetal globin levels

  
• An example of epigenetic control:

  -the genes needed form the alpha globin form are needed throughout so these kick in around 6 weeks one the foetus starts to form (heart beat also starts)

  -the genes for gamma globin are very important during foetal development, but need to be silenced around birth (when beta globin genes need to be activated)

  -this leads to a decrease in gamma at the same time beta begins to increase
• There are several theories about epigenetic control:

  -histone acetylation activates the gamma globin gene in the foetus

  -DNA methylation is involved in silencing the foetal gamma globin just before and after birth

  -histone methylation compliments this DNA methylation

  -other transcription factors are also involved in shifting the production sites of these different globin forms
• Stem cells are cells that have the potential to become any other cell in the body when given the right environment
• Using stem cells:

  -scientists are looking for ways to use stem cells as medical treatment when the patients own cells are damaged

  -bone marrow transplants are widely used in treating certain cancers and immune system disorders (taken from close relatives to ensure tissue match)

  -further stem cells within bone marrow can differentiate into bone, fat, cartilage, fibrous tissue

  -brain stem cells discovered in the 1990s can give the potential to treat conditions like Alzheimer’s
• Why has stem cell therapy been unsuccessful:

  -very difficult to control how the cells differentiate; seen in an early case where they cured one condition but the stem cells divided uncontrollably into cancer cells or cysts

  -many work uses embryonic stem cells but, as much as this is legal in many countries, it has raised many ethical issues
• Stem cell therapy:

  -issues of embryonic stem cells have pushed us to use adult stem cells; these are successful in tissue regrowth (eg. burn treatment)

  -stem cells grown on a biodegradable mesh (raft culture). this can produce new skin quicker than a skin graft with minimal rejection risk

  -also used to help repair hearts after heart attacks

  -stem cells injected into heart have been tried experimentally with some success
• Therapeutic cloning:

  -a novel technique which is hoped to be utilised in the future to produce large quantities of human tissue
• Therapeutic cloning:

  -could be used to treat diabetes and Alzheimer’s disease if successful

  -first step is to take a cell from the patient and remove the nucleus, then inserted into enucleated ovum from a donor

  -given a mild electric shock to cause the cell to start dividing by mitosis

  -ball of cells can then be cultured and grown into different tissues or organs
• What issues could arise from therapeutic cloning:

  -grown tissues or organs can be implanted with minimal risk of rejection as they are genetically identical

  -scientists are still trying to ascertain the triggers that cause cell differentiation into the different tissue types

  -nucleus would also need to be modified to avoid any genetic mutation
• Pitfalls of stem cell therapy:

  -no one quite knows the causes of cell differentiation

  -risks that stem cells could become cancerous in the body

  -organ transplants are always risky, as rejection can be a major factor
• Rejection happens as glycoproteins are used to enable the body to identify ‘self’ and the immune system will attack anything it sees as ‘non-self’
• Benefits of stem cell therapy:

  -understanding of cell differentiation is improving so there will be a time we can fully utilise this method

  -would be a major breakthrough and may extend lifespans, even with a risk of later disease

  -could reduce the risk of rejection (a mothers immune system does attack the embryo so this concept could be used)
• Induced pluripotent stem cells:

  -adult cells that have been reprogrammed to become pluripotent again by the addition of new genes

  -do not require an embryo and can renew themselves

  -appear similar to embryonic stem cells in their behaviour and researchers managed to make them develop into brain and heart muscle cells
• Benefits of induced pluripotent stem cells:

  -stops all ethical issues involved with embryonic stem cells

  -no risk of rejection as they have been cultured from patients own tissue
• Downfalls of induced pluripotent stem cells:

  -no easy to induce pluripotency in these cells

  -getting the cells to differentiate into required cells can be even more challenging

  -can demonstrate a high tendency to become cancerous because the genes have been linked with cancer development
• Parkinson’s disease:

  -loss of nerve cells in the midbrain (substantia nigra)

  -brain can compensate for loss, not many show symptoms until 80% of dopamine producing cells remain

  -usually develops after 50 but can rarely occur before

  -strong genetic link in young Parkinson’s (less so in later life)

  -environmental factors (toxins, herbicides, pesticides) may play a part

  -7 to 10 million people globally
• The substantia nigra (damaged with Parkinson’s disease):

  -area involved in coordination of movement and dopamine production

  -axons here reach out to the frontal cortex, the brain stem and spinal cord

  -these cells die with Parkinson’s disease and motor control is gradually lost
• Parkinson’s disease symptoms:

  -tremors and shaking (starting in one hand)

  -slowness of movements and eventually movements take much longer to perform

  -rigidity and stiffness if the muscles, making it difficult to stand after sitting in a chair

  -loss of balance

  -walking difficulty

  -depression

  -some speech or breathing problems
• Parkinson’s disease cure:

  -scientists have managed to take mouse stem cells and create dopamine neurones, which when transplanted into rats with Parkinson’s disease, the cells grew and started to release dopamine correctly

  -this could be revolutionary at allowing Parkinson’s patients to regain movement of their limbs
• Alzheimer’s disease:

  -brain cells are destroyed as a result of the build up of abnormal proteins called amyloid plaques

  -currently drugs only alleviate symptoms

  -research is underway to see if stem cells could be used to replace destroyed brain cells
• Type 1 diabetes:

  -glucose sensitive insulin secreting cells of the pancreas stop making insulin, resulting in unregulated blood glucose concentration

  -can be severe and even fatal

  -insulin injections are available but type 1 patients must monitor food intake as well as blood glucose concentration regularly

  -stem cell therapy could replace these damaged cells and allow them to regain blood glucose control
• Type 1 diabetes:

  -trials with mice were successful at creating the cells and improved the quantity of insulin in the blood and reduced blood glucose levels

  -in 2014 Harvard scientists used human embryonic stem cells to develop functioning insulin producing beta cells in large enough numbers to use in patients

  -trialled experimentally with some success
• Damaged nerves:

  -when nervous tissue of the spine or brain is damaged, no cure or treatment

  -can lead to permanent paralysis

  -stem cells have been transplanted into mice and rats with spinal damage and they did regain a certain amount of movement

  -the stem cells had grown into working neural cells in the spinal tissue and partly rejoined
• Macular degeneration:

  -this condition is responsible for causing blindness in the elderly and diabetics

  -scientists are currently researching the use of stem cells in treating this disease and early results are successful
• Birth defects in model animals (such as mice) have been successfully reversed using stem cells
• Transplant organs:

  -organ transplants rely on organ availability

  -many patients die before receiving an organ due to extensive waiting lists and the issues of tissue matching

  -has been some success in producing functioning kidney cells by stem cell manipulation, so could be used for transplants for those with kidney failure

  -hope is that induced plutipotent stem cells could provide all organs needed for transplant patients globally
• Stem cell success:

  -number of successful therapies has been very small, with many still at the animal trialling phase

  -number of successful treatments is expected to increase rapidly in the next 10 years
• Major ethical issues with stem cell use fall under 4 key principles:

  -respect for autonomy

  -beneficence

  -non maleficence

  -justice