Table human brain 1.3.5. Current therapies 1.3.5.1. Drug

Table of content:

Abstract

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1.     
Introduction

 

1.1.  
Stem
cells

1.1.1.     
Definition

1.1.2.     
Characteristics
and mechanism

1.1.3.     
Types
of stem cells and their sources

1.1.4.     
Induced
pluripotent stem cells

 

1.2.  
The
Human brain

1.3.  
Alzheimer’s
disease

1.3.1.     
Definition

1.3.2.     
Causes

1.3.3.     
Symptoms
and stages

1.3.4.     
Effect
of Alzheimer’s disease on the human brain

1.3.5.     
Current
therapies

1.3.5.1.           
Drug
therapies

1.3.5.2.           
Other
therapies

1.3.6.     
Recent
therapy development

1.3.6.1.           
Research
study carried out at École Polytechnique Fédérale de Lausanne (EPFL) in
Switzerland

1.3.6.2.           
Research
study conducted by the University of Southampton in the UK

 

2.     
How
to work with stem cells

3.     
Ethical
dilemmas

4.     
Laws
and regulations of stem cell usage in research

5.     
Therapies
in development >??

6.     
Current
and future stem cell therapies for the treatment of Alzheimer’s disease

6.1.  
Example
x

6.2.  
Example
y

7.     
Results

8.     
Conclusion

9.     
References

10. 
 

1.     
Introduction

 

1.1. Stem cells

 

1.1.1.     
Definition:

The creation of every human being
biologically depends on the union of the egg with the sperm, that will lead to
the early embryo stage that will introduces us to the “pool of stem cells” that
can develop into different cell types in the body, up to 200 different types of
cells to be more specific. Upon its division these cells have the possibility
to either continue as a stem cell or change into any other cell with a more
specific function in the body (e.g. brain cell).

(understanding
stem cells, the national academies)

1.1.2.     
Characteristics
and mechanism:

Three characteristics identify stem
cells:

Ø  Self-renewal.

Ø  Unspecialized;

Ø  Induce specific function (e.g. repair damaged tissues in the bone
marrow).

 (Bethesda, MD: National Institutes of Health,
U.S. Department of Health and Human Services, 2016)

The mechanism related to stem cell
self-renewal is related to the division of the cells that needs cell cycle
control. This program involves networks that balance cell-intrinsic mechanisms that
are regulated by cell-extrinsic signals from the niche. In response to changing
tissue demands, stem cells undergo changes in cell cycle status, requiring
different self-renewal programs at different stages of life.

(Mechanisms of Stem Cell Self-Renewal,Annual
Review of Cell and Developmental Biology, Vol. 25:377-406 (Volume publication
date 10 November 2009) He Shenghui, Daisuke Nakada, and Sean J. Morrison )

For the unspecialized characteristic
of stem cells, which is considered one of the crucial properties for a stem
cell, tissue-specific structures are not a precondition to grant it to behave
in a specialized function. Nonetheless specialized cells can be raised from
unspecialized stem cells (e.g. heart muscle cells, blood cells, or nerve cells).

(Bethesda, MD: National Institutes
of Health, U.S. Department of Health and Human Services, 2016)

 

1.1.3.     
Types
of stem cells and their sources:

Stem cells are introduced mainly to
be two types; somatic (adult) stem cells and embryonic stem cells. The
difference between these two types is that the somatic stem cells occur in the
body after the embryonic development stage and can give rise to certain
specialized cells only, that are responsible for the replacement of lost cells
due to injury or disease (e.g. tissues of the bone marrow, fat,
muscle, and brain). Whereas the embryonic cells, as the name suggests, are
withdrawn during the blastocyst phase of development of a 3-5-day old human
embryo and can produce all types of cells in the entire body (e.g. tissues of
the brain, bone marrow, blood, blood vessels, skeletal muscles, skin, and the
liver) and does not have a limited ability to give cell rise like the adult
stem cells as some scientists believe.

(https://www.medicalnewstoday.com/info/stem_cell)

The sources of embryonic stem cells
are mainly established from three origins, Invitro fertilization, already
existing embryos and Nuclear transfer.

Invitro fertilization and already
existing embryos are today’s most opposed sources with ethical dilemma;

Basically, IVF is a surgical procedure
when doctors try to fertilize all the eggs with sperm for reproductive purposes
but not all cells will be used due to the inability for the womb to have more
than one implanted fertilized-egg.

Meanwhile a group of people believe
that the excess blastocysts that will be produced from the IVF procedure and
will be reserved in freezers with other billions of banked cells, should be
thrown away instead of using it in experimental research and potential
therapies for life threatening and incurable diseases and viruses.

On the other hand, Somatic cell
nuclear transfer (SCNT) is a different way of generating stem cells. This
technique did not show any achievement yet, but scientists believe that soon
some potential results will be observed. SCNT is also known as “therapeutic
cloning”. To clear up* reproductive cloning includes the creation of the embryo
and implanting back into the female’s body, whereas therapeutic cloning
involves similar embryo formation but keeps the created cell in the lab.

This procedure is used for creating
an ovum with a donor nucleus, where the nucleus is removed from a healthy egg
and the egg becomes the host for a nucleus that is removed from another cell
(e.g. skin cell). The result of this transfer can be used to generate embryonic
stem cells from the produced embryo.

(understanding stem cells, the
national academies)

As mentioned previously the adult
somatic stem cells can be found within the body organs and tissues.

1.1.4.     
Induced
pluripotent stem cells:

Induced pluripotent stem cells
(iPSCs) are adult cells that have been genetically reprogrammed to an embryonic
stem cell. It is still unknown if iPSCs and embryonic stem cells differ in the
clinical approach.

According to the National Institutes
of Health in 2006, mouse iPSCs were first reported, where in late 2007 human
iPSCs were first reported.

Pluripotent stem cell
characteristics are displayed from both mouse and human iPSCs, such as expressing
stem cell markers, forming tumors containing cells from all three germ layers.
An additional mouse iPSCs is demonstrating is the ability to provide to many
different tissues when injected into mouse embryos at early developmental
stages.

Even though iPSCs research is quite
limited for the time being, it proved to be a very beneficial tool for disease
modeling and drug development, and are aspired to be used in organ
transplantation medicine. This iPSC strategy will help researchers find out how
to reprogram cells to repair damaged tissues in the human body.

(https://stemcells.nih.gov/info/basics/6.htm )

 

 

 

 

 

 

 

 

 

 

 

 

1.2. The Human brain

The human brain is one of the most
powerful organs in the body, it weighs about 1.5 kilograms and makes about 2%
of the total human body’s weight. It is the control center for the nervous
system and contains billions of nerve cells.

https://www.livescience.com/29365-human-brain.html

The human brain is divided into
three sections; The cerebrum, the cerebellum and the brain stem respectively.

The cerebrum is the biggest portion
of the human’s brain, it is in the front area of the skull and it controls the
brain’s function of remembering, problem solving, thinking, feeling and
movement. The cortex is the wrinkled surface that is found in the cerebrum and
is responsible for interpreting sensation, forming and storing memory, generate
thoughts and control the voluntary movements.

The cerebellum is in the back
section of the skull, behind the cerebrum, and commands coordination and
balance.

The brain stem is located under the
cerebrum and in front of the cerebellum; it controls the body’s automatic
functions and connects the brain to the spinal cord (e.g. breathing, digestion
etc).

A fun fact about the human brain is
that it is divided into two halves, right and left, where the right half
regulates the left side of the body’s movement and vice versa.

Since the adult brain contain
billions of neurons/nerve cells, cell signaling through small electrical
charges between the nerve cells results in memory and thought formation. The
connection of two nerve cells at the synapses trigger the release of a chemical
called a neurotransmitter; this chemical can carry signals to other cells.

 

https://www.alz.org/braintour/3_main_parts.asp

 

*insert brain different section
photo*

 

 

 

 

 

 

1.3. Alzheimer’s disease

 

1.3.1.     
Definition:

The first encounter of Alzheimer’s
disease happened in 1906 by a German psychiatrist and neuropathologist, Dr.
Alois Alzheimer who named it after him*.

The first case that confirmed
Alzheimer’s disease was that of a woman that had died of an unusual mental
illness, at the time, where Dr. Alzheimer noticed changes in her brain tissues.
She displayed memory loss, language problems, and unpredictable behavior as her
diagnostic symptoms.

(Alzheimer’s Reading Room, Jan 18,
2016)

Today Alzheimer’s is defined as a
neurological disorder that causes the death of brain cells leading to memory
loss and cognitive decline. This disease is known to be a very common form of
dementia. Keeping in mind that dementia is not a specific disease but a clinical
presentation of a disease, that generally involves memory loss. This disease is
known to get worse with time and is not an old age type of disease where it can
affect people in their 40s and 50s (early onset type) as well as 65 and older. (https://www.medicalnewstoday.com/articles/159442.php)

1.3.2.     
Causes:

While it is believed that the neuron
failure is the bigger reason for causing Alzheimer’s disease, it is still
unknown why this happens. Some scientists believe that the total brain size
shrinks with the progression of the disease.

Because it can’t be seen in a
conscious-living brain, some scientists attained a conclusion after performing
an autopsy on an Alzheimer’s affected brain; Researchers suppose that the prime
suspects related with the cause of this disease are plaques and tangles.

Beta-amyloids are protein pieces,
that are sticky in nature, which bundle together to appear in the form of plaques.
These proteins are found in the fatty membrane that surrounds the nerve cells.
This plaque bundle can lead to cell-to-cell signaling blockage at the synapses
in addition to that triggered inflammation can also occur. Plaques are mainly
found between the dying cells in the brain.

Tangles at the same time destroy
proteins transport system and are found within the brain neurons. Due to the
formation of tangles, Tau- a protein that helps the transport system track to
stay straight- will collapse leading to the disintegration of these tracks and
will disable nutrients and other essential supplies from moving causing its
eventual death.

**insert tangles photo** ( https://www.alz.org/braintour/3_main_parts.asp )  

 

1.3.3.     
Symptoms
and stages:

Each person experiences Alzheimer’s
in an individual way, depending on his/her own brain function and activity.

Symptoms might include:

·        
Memory
loss that disrupts daily life

·        
Challenges
in planning or solving problems

·        
Difficulty
completing familiar tasks at home or at work

·        
Confusion
with time or place

·        
Misplacing
things and losing the ability to retrace steps

·        
Decreased
or poor judgment

·        
Changes
in mood and personality

·        
Trouble
sleeping

·        
Stress
and depression

https://www.alz.org/10-signs-symptoms-alzheimers-dementia.asp

According to Dr. Barry Resiberg, the
7 stages of Alzheimer’s disease can by summarized by the following:

·        
Stage
1: No Impairment

·        
Stage
2: Very Mild Decline

·        
Stage
3: Mild Decline

·        
Stage
4: Moderate Decline

·        
Stage
5: Moderately Severe Decline

·        
Stage
6: Severe Decline

·        
Stage
7: Very Severe Decline

https://www.alzheimers.net/stages-of-alzheimers-disease/

 

1.3.4.     
Effect
of Alzheimer’s disease on the human brain:

The main target that Alzheimer’
disease damages in the human brain is neurons, where it messes up the activity
of neurotransmitters along with the electrical charges within the cells.

With the progress of Alzheimer’s
disease some changes happen to the human brain; firstly, dehydration of the
cortex is noticed. Next an area in the cortex – called the Hippocampus,
responsible in forming new memories, gets shrinker in size. Also, an increase
in ventricles is observed. These changes do not necessary have to happen in
order.

**insert brain change + brain
difference photo **

https://www.alz.org/braintour/3_main_parts.asp

 

1.3.5.     
Current
therapies:

Unfortunately, up till now, no known
current therapies had been discovered for the treatment of this life-changing
disease. Considering that the death of the brain cells cannot be reversed,
treatments available for Alzheimer’s are used to help patients adapt with their
sickness;

1.3.5.1.Drug therapies:

Cholinesterase inhibitors are a
class of drugs that help relief the symptoms and can slow down the development
of Alzheimer’s, it is majorly used in the treatment of dementia.  

·        
Donepezil
(Aricept)

·        
Alantamine
(Reminyl)

·        
Rivastigmine
(Exelon)

The above mentioned drugs are used
to treat mild to moderate cases of Alzheimer.

For moderate to severe Alzheimer’s
Memantine can be used.

(https://www.webmd.com/alzheimers/guide/treatment-overview#2 )

1.3.5.2.Other therapies:

This type of therapy is still
debatable, since little evidence stand with it. Few used to believe that the
antioxidant effect of vitamin E can protect nerves from damage. Others focused
on therapies that can stimulate senses like art and music by helping in memory
triggering. Supplements at some point were supported to be used for the
treatment of Alzheimer’s but were not regulated by the FDA- unlike the
medications.

( https://www.webmd.com/alzheimers/guide/alzheimers-disease-therapy-options#2 )

 

 

 

1.3.6.     
Recent
therapy development:

All the new therapies and treatments
are still undergoing clinical trials and research and it looks quite promising.

1.3.6.1. Research study carried out at École
Polytechnique Fédérale de Lausanne (EPFL) in Switzerland: (2016)

This study revealed how implanting a
capsule under the skin can help in slowing down the progression of Alzheimer’s
disease.

The researchers of this study
focused on reducing the role of beta-amyloid protein, that has the ability in
forming plaques.

The capsule that has been under
study is described as a “macroencapsulation device,” and have the
features of 27 mm in length, 12 mm in width and 1.2 mm thick. It is made up
cells that are extracted from muscle tissues and had been engineered
genetically to produce high amounts of antibodies to target beta-amyloid
proteins in the brain.

This capsule had been tested out on
mice with early Alzheimer’s disease for a duration of 39 weeks and encouraging
results were established. When this capsule reaches the brain stream antibodies
are released and an invasion to beta-amyloid proteins happens leading to an
immune system attack and plaque formation had been significantly reduced in the
presence of these antibodies.

 Keeping in mind that these genetically
engineered cells should be compatible with the patient’s body to avoid any
refusal.

(https://www.medicalnewstoday.com/articles/308104.php )

 

1.3.6.2. Research study conducted by the University of Southampton in the
UK:

Healthy people brain tissues were
compared to those with Alzheimer’s disease, both groups being the same age, in
this study. The results of this comparison showed the contrast in the number of
microglia; a cell that helps regulate immune responses like inflammation. For
people affected with Alzheimer’s microglia’s presence is much higher than
normal rates.

This study attained a conclusion
that using an oral dose CSF1 (colony stimulating factor 1 receptor) protein
inhibitor can block the excessive increase of microglia. the CSF1R inhibitor also
suggested to show fewer memory and behavioral problems.

(https://www.medicalnewstoday.com/articles/304834.php )

  

 

 

2.     
How
to work with stem cells

The usage of stem cells in therapy
and treatment can go back to as early as 1950’s, the first step to work with
stem cells is the preparation of the stem cell line through the culturing of
these cells. Stem cell lines provide a long supply of cell multiplication that will
need to be genetically altered to have the ability to turn into any specific
cell wanted. But cell differentiation is still a questionable field for
researchers.

New drug testing is currently done
on animals and then goes under human clinical trials. For stem cell research,
scientists use animals to make sure the incorporation of the cells in the
tissues occur and functions in harmony with the rest of the body without
showing any harmful consequences.

But if these new drugs can be
directly tested on human cells it would save a lot of time, money and effort
and will give the exact anticipated results.

Unfortunately, nowadays this is not
an open option.

The first stem cell therapy was done
back in 1956 for the treatment of leukemia; a bone marrow transplant was performed,
and the donor bone marrow was injected into the patient, stem cells established
themselves in the patient’s bone where the donor cells differentiated
themselves into the needed and wanted blood cells for the patient.

The only fear scientists are facing
today is the body’s rejection to the injected stem cells, that is why patients
with transplanted stem cells must take drugs to prevent their immune system
from its rejection since the immune system may see the new injected stem cells
as an invader to his or her body.

https://science.howstuffworks.com/life/cellular-microscopic/stem-cell5.htm
+ understanding stem cells, the national academies

 

 

 

 

 

 

 

 

 

3.     
Ethical
dilemmas

The biggest burden stem cell
research is bearing at the current moment is the ethical dilemma that divides
this research according to two sides; the theological view and the society
view.

It all goes back to the source of
stem cells that will be used, particularly the embryonic stem cells.

Before talking about what the
opponents of this research believe and support, some facts need to be stated concerning
the actual reality behind this study.

The embryo is only considered a
human being after 14-15 days, when monozygotic twinning is developed. Where the
main concern of this dilemma is the unfair killing and destruction of “innocent
human embryo cells” which is stopping stem cell researchers from the full
investigation in this study with many boundaries and issued raised around them.

In fertility treatments the embryo
only becomes an embryo after implanted in the women’s body, when it remains in
the dish it is still considered a cell and not a human being.

But since HESC researchers (Human
Embryonic Stem Cell) develop the embryonic stem cells from a 5-day embryo cell
and this according to the classification of human existence should not be
considered killing a human life since cell differentiation into an organism
occur only after 16 days of fertilization.

To be fair, it should also be
regarded from the opponent’s point of view, meaning the assumption of embryonic
cells being humans from the first day, brings us to a solution of having other
ways to get these cells e.g. overthrown embryos; which are the spare embryos
from fertility treatment, instead of throwing these cells away scientists
suggest using them for research. Others might suggest the continuous use of
these cells for fertilization, but these cells have a certain life span,
depending on the function they get differentiated into. Some survive for five
months while others survive up to five years. (Materials provided by
Sanford-Burnham Medical Research Institute) But in females undergoing fertility
treatment they don’t need more than 10 eggs, so it would be a waste if the
extra cells won’t be conducted for research.

https://plato.stanford.edu/entries/stem-cells/ 

On the other hand, the theological
view is on debate and will probably remain this way. In March 14, 2007 at
Harvard Divinity School, an event was conducted for the world’s three major
religions to state their opinions about the beginning of human existence; from
the Christian’s point of view humans are established from conception, which
contradicts the Muslim’s and Jewish’s ideas that believe humans are created
after the soul enters the growing baby between 40 to 120 days after conception
and 40 days after conception respectively. They also debated about the abortion
right and whether or not the embryonic cell and the aborted baby should be
treated the same way.

(Harvard Gazette: Stem cells,
through a religious lens March 22, 2007 By Alvin Powell, Harvard News Office.)

The so-called “slippery slope”
argument, sheds the light on the society’s acceptance to a certain action will
force the approval of other objectionable action, e.g. the use of embryos may
increase the social toleration of the loss of life, making it easier for the
society to accept actions involving the termination of life. For the account of
curing and treating incurable diseases, the embryo scarification cannot be
considered unacceptable for it is the same thing when we are using it for
infertility treatment which brings us back to the same point of using spare
embryos that will be wasted after their expiry date is over.

> PDF: ethical dilemma> pg1

 The problem is that everyone is so busy focusing on the rights and
the status of the embryo, they are forgetting the needs of the sick and
suffering patients.

Just like abortion and contraceptive
pills are accepted, stem cell research should be more accepted among the
society.

!! https://www.eurostemcell.org/embryonic-stem-cell-research-ethical-dilemma
>>  video!

 

 

 

 

 

 

 

 

 

 

 

 

 

 

4.     
Laws
and regulations of stem cell usage in research

https://www.aamc.org/advocacy/research/74440/embryonicstemcellresearch.html

Another controversy this research
had encountered, are the laws and regulations that limits the research. It all
started when President George W. Bush restricted federal stem cell research, in
2001, when funds can only be used for the existing 22 stem cell lines with no
further creation of other lines.

Then in 2009, President Barack Obama
expanded the late law and allowed for the creation of more stem cell lines
under a few restrictions:

·        
The cell
line was one of the 22 in existence during the Bush administration or was
created from embryos that had been discarded after in vitro fertilization
procedures.

·        
The
donors of the embryos were not paid in any way.

·        
The
donors clearly knew that the embryos would be used for research purposes prior
to giving consent.

https://science.howstuffworks.com/life/cellular-microscopic/stem-cell6.htm

 

Extraa >>

https://www.mayoclinic.org/tests-procedures/bone-marrow-transplant/in-depth/stem-cells/art-20048117?pg=2