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Table of Contents
Abstract. 2
Introduction. 3
Literature Review.. 4
Chapter 1: The Science behind this Biotechnology. 5
Chapter 2- Potential Uses
of Animal-Human Chimeras in Therapeutics. 8
Vaccinations. 8
Control disease progression. 9
Chapter 3 Potential Uses
of Animal-Human Chimeras in Surgery. 10
Chapter 4 Potential Uses
of Animal-Human Chimeras in Disease Modelling. 11
Chapter 5 Bioethics and
Alternatives. 12
References. 13
 

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Abstract

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Introduction

 

Literature Review

 

Chapter 1: The Science behind
this Biotechnology

Chimeras rely on stem cells and their ability to differentiate
into the necessary cells needed by the body. It is this feature of stem cells
that allow scientist to culture tissue samples and eventually produce
transplantable organs. The procuration of stem cells is the subject of a controversial
argument as the methodologies of some variations raises several moral and
ethical issues.

Human Embryonic Stem Cells (hESCs)

As the name suggests, this form of stem cells are derived
from human embryos. Contrary to popular belief, these cells are not obtained from
eggs fertilised inside a woman’s body; the embryos are usually donated for
research purposes by In Vitro Fertilisation Clinics, with the consent of the
donors.

The embryos are then suspended in a culture medium,
mirroring similar conditions to that of a mother’s womb, allowing the embryo to
divide into a mass of cells known as the blastocyst. The cells within the
blastocyst are usually referred to as totipotent stem cells. It is here that
the first ethical issue arises. The beginning of life is said to be conception
or fertilisation therefore this method of obtaining stem cells can be
considered as taking a life without its consent. (U.S. Department of Health and Human Services, 2016)                                                                                                                                            

Another limitation of hESCs includes carcinogenic risk when
the culture medium is altered in order to induce differentiation of stem cells
to form specialised cells such as: heart cells, lungs cells, liver cells and
nerve cells. If the wrong mix of proteins or hormones are added to the stem
cells there’s a potential risk of mutation of DNA resulting in the production
of cancerous or faulty cells.

Conversely, hESCs are more accepted in the scientific
community as the production of it can be done at lower cost with much more
efficient differentiation and the cells produced are within a suitable HLA
spectrum. 1 (Pappas, 2008)

Parthenote Stem cells

It is possible however to bypass the ethical and moral
issues that hESCs present, as these issues only arise if the cell is
post-fertilisation. Therefore, if stem cells are extracted from an unfertilised
egg, then arguably life which begins at conception or fertilisation, has not
yet begun, making the use of the stem cells less controversial. However, the
ethical implications have not been bypassed altogether, as it can still be
argued that stem cells from unfertilised eggs do still have the potential to
make a living individual. Parthenogenesis2
allows for the egg cell to be activated without the need for a sperm. Parthenogenetic
embryos will develop to the blastocyst stage and so can serve as a source of
embryonic stem cells. Parthenogenetic Embryonic Stem Cells (pESCs) have been
shown to have the properties of self-renewal and the capacity to generate cell
derivatives from the three germ layers, confirmed by contributions to chimeric
animals (Department of Animal Science, Michigan State
University, East Lansing, Michigan, USA, 2006)

Induced
Pluripotent stem cells

 

 

The process behind iPSCs was a big medical
breakthrough as it allowed somatic (body) cells to be reprogrammed into
regenerative cells. The formation of iPSCs require the donor to undergo shave
or punch biopsies, this procedure can be done under local anesthetic and is minimally invasive so the
procuration of the adult cells poses no
moral or ethical predicaments. The induction of pluripotency on adult somatic
cells via proteins, will produce genetical and immune-histocompatibility
matches thus, lowering the chance of rejection (if used for transplantation),
this also reduces the need for the patient to take immunosuppressant which can
result in a compromised immune response.

But this form of stem cells comes with its
disadvantages, as it is a new concept the cost of production is high. Therefore
this process in its current state of development is economically unviable for a
large population size. Furthermore, the mechanisms behind how the reprogramming
factors work are unknown, this presents the chances of mutagenesis3, oncogene
activation risk4, and retroviral gene
delivery5 (Pappas, 2008)

 

 

 

Chapter 2- Potential Uses of Animal-Human Chimeras
in Therapeutics

Vaccinations

As of 2015,
there are 36.7 million people living with HIV as per WHO and UNAIDS. (WHO,
2016). The field of vaccines for diseases such as Hepatitis-B and HIV
(Human Immunodeficiency Virus) have taken a heavy toll in developing countries and
have faced major failures. In the hopes of improving the current situation. Human-animal
chimeras, developed with a ‘humanized’ immune system could be useful to study infectious
diseases, including many neglected diseases. These would also serve as an
important tool for the efficient testing of new vaccine candidates to
streamline promising candidates for further trials in humans. (Bhan, et al., 2010).

Human
hematopoietic stem cells, or in layman’s terms, bone marrow cells, have the
unique capacity of engrafting, greatly expanding, and repopulating
immunodeficient mice,
with virtually all different
types of human immune cells; as shown by the image above. Humanized mouse
models are produced via
transplantation of CD34+ stem cells and/or implantation of human tissue into
immunodeficient mice. Depending on whether tissue or CD34+ cells are used and
the strain of mouse, this results in mice which have a part or a complete human
immune system. (Garcia, 2016)This xenografted6
mouse is then used as a disease model7.
This allows scientists to better understand the mechanisms behind the disease,
which results in a more efficient treatment plan for those who suffer from
Hepatitis-B.

Another disease
model being used are primates, these are considered to be the most accurate as
we share a common ancestor. Additionally, primates have the closest metabolic
conditions to humans. When this model was injected
with HIV-1 (via IV), HIV-2 (via vagina) and SIV (via rectum) the results were
advantageous as they provided useful information for vaccine and therapeutic
studies. However, the cost of producing this model is very high and raises many
moral and ethical concerns; furthermore, despite having some genetic
similarities, primates do have different cellular and molecular markers and the
time and course of infection could vary.

Chimeras are also
benefiting the treatment of Japanese encephalitis. This disease is a
type of viral brain infection that’s spread through mosquito bites, commonly
found in South-East Asia. Although there’s no cure for Japanese encephalitis,
it can be prevented through vaccination, which is usually only available
privately. (NHS, 2016).

A recently developed
vaccine, which is an animal-human chimera which is a mouse brain-derived,
inactivated JE vaccine (MBV). In order to evaluate its efficacy case controlled
studies were carried out. A randomized double-blinded study conducted in
northern Thailand, using JE MBV produced in Thailand, yielded an overall
effectiveness of 91%. Another trial in Taiwan revealed an effectiveness of
approximately 85% when two or more doses were administered. The effectiveness
of the JE vaccine in Northern Vietnam was 92.9% efficacious. (Marks, et
al., 2012).

Control disease progression

 Another therapeutic use of animal-human
chimeras is the development of drugs to aid in the treatment of known diseases.The drug called Rituximab,
is a chimeric antibody which means it contains portions of both human and mouse
antibodies mixed together. The drug was licensed in 1997 for the treatment
of NHL (Non-Hodgkin’s lymphoma)-a form of cancer which causes B-cells to mutate
and divide abnormally.

The drug
targets the CD20 receptor on B-cells as this receptor is located on the surface
of the cell and it doesn’t mutate, move inside the cell or fall off in the life
cycle of the B-cell. The drug contains the variable domain of the mouse
antibody, the portion that specifically binds CD20, along with the constant
domain of human antibody, the portion that recruits other components of the
immune system to the target-the B-cells and so after it is administered, and a large number of tumour
cells are immediately destroyed and eliminated from the body.

Rituximab
is also used to treat advanced rheumatoid arthritis and it has also been part
of anti-rejection treatments for kidney transplants (both involve B cells).

The
disadvantage only that the mouse antibody was unsuitable for direct use in
humans and clinical trial results varied, likely due to the differing sizes of
tumors between the patients,

(Speaking of
Research, 2017)

 

Chapter 3 Potential Uses of Animal-Human Chimeras
in Surgery

 

The demand for organ transplantation has rapidly increased
all over the world due to the increased incidence of vital organ failure.
However, the unavailability of adequate organs for transplantation procedures to
meet this growing demand has resulted in a major organ crisis. In 2014, 429
patients died while on the waiting list for an organ transplant- that’s up to 3
patients a day. (Knapton, 2015).

Currently,
the government plan on changing the organ donation system to an opt out system,
which hopes to promote organ donation and increase the availability of organs. The
opt-out system presumes the donor’s consent unless the individual expresses a
refusal to become a potential donor- allowing the donor to make a free choice (Abouna, 2008). As well as
increasing obtainability of organs, it also increases the likelihood of more
organs found within a suitable HLA spectrum. (Department of Health and Social
Care and Cabinet Office, 2017).

But it can be argued that this system of obtaining organs is
seen as unfair as majority of organ donors must be recently deceased (excluding
kidney donors) therefore the longevity of one person’s life is at the
cause of another’s death. (World Health Organisation, 2005)

To prevent this choice being made,
alternative solutions are being developed in order to aid the organ crisis-one
of them being animal-human chimeras. Current research on stem cells have shown
that they can differentiate into different cell types but cannot effectively
produce usable tissues and organs as a culture medium cannot replicate the
growth of an organ in a body. A recent breakthrough by the (Salk Insititute of Biological Research, 2017) shows a pig-human
chimera, which would be capable of making human organs.

The research began by creating an interspecies chimera8
consisting of a rat and mouse. They used a gene editing technology known as
CRSIPR (Clustered Regularly Interspaced Short Palindromic Repeats) to “turn
off” the gene that makes the pancreas. They then inserted rat iPSCs which
contained a pancreas gene into the mouse embryo. The result, when implanted
into surrogate mouse mothers, was a fully developed mouse with a growing rat
pancreas.

This concept was then mirrored using pigs’ embryos and human
stem cells; as pigs have similar organ sizes and developmental timescales as
humans. Although this experiment had to be halted at 4 weeks of development due
to ethical issues and the lack of consent- as the experiment was designed to
prove it was possible, not to produce a human organ-we can safely assume that,
if the development of the pig was allowed to continue, the pig would have a
whole human organ inside it.

Theoretically, this concept can then be implemented,
producing specific human organs, eliminating the wait for a human donor and
reducing the risk of organ rejection.

http://www.bbc.com/earth/story/20170104-the-birth-of-the-human-animal-chimeras

http://www.cell.com/cell/fulltext/S0092-8674(16)31752-4

https://geneticliteracyproject.org/2017/02/09/will-pig-human-chimeras-solve-organ-transplant-shortage/ 

 

 

 

 

 

Chapter 4 Potential Uses of Animal-Human Chimeras
in Disease Modelling

 

Chapter 5 Bioethics and Alternatives

Scientific research is not always accepted as they require the use of
controversial methods to obtain the necessary results. The methodologies behind
creating chimeras have ethical and moral dilemmas primarily due to the use of
animals.

There is a large emphasis on animal welfare, although the use of animals
as chimeras or in general medical research is considered very valuable as they
help the medical community to better under the effects of treatments (drugs or
otherwise) on living organisms. The
matter still finds itself to be the subject of a very heated debate; as those
opposing the use of animals – animal rights extremists and anti-vivisectionist groups-believe that animal experimentation is
unnecessary and cruel regardless of its benefits ergo the opposition want total
abolition of animal research and if the majority supports this view then there
will be severe consequences for scientific research. (Festing & Wilkinson, 2007)

On the other hand, the UK has gone further than most countries in
regards to the ethical framework by
introducing the Animals (Scientific Procedure) Act 1986 which regulates the use
of animal research. Along with this, there is more and more public awareness as
polls run by Ipsos MORI state that in 2005 64% of the population agreed with
the use of animals in research if the research objectives are important and the
animals experience minimal suffering and all alternatives are considered. (Department for Business & Freeman, 2014)

 

Another bioethical view that must be
considered is `whether we treat the chimeras as animals or human?’ this arises
as some chimeras require the altering of cognitive capacities. The chimeras are
to be used to develop a better understanding of
diseases such as Parkinson’s and Dementia which affect 850 000 people every
year (Anon., 2014)
. Unfortunately, the research is very slow due to moral views as some
people regard this form experimentation a violation of human dignity and the
order of nature as well as, the initial disagreement of using chimeras in the
first place. (Hermerén, 2015)

Opportunely, there is some support for
the use of animal-human chimeras as previous medical techniques that are widely
accepted today allow the use of porcine, bovine and equine biological heart
valves are implanted in those with cardiac valve dysfunction. Moreover, insulin
extracted from porcine pancreas is
routinely used with those with diabetes. And so, the prospect of a pig carrying
a pancreas or liver of human origin should be justifiable. (Bourret, et al., 2016)

Alternatives

 

A lesser conventional view is the alternatives to chimeras, these
methods do not require the use of animals to carry out medical research, which
hopefully, should eliminate bioethical arguments. The issue that arises with this
is the efficiency and viability of the results.

The alternatives to chimeras include cell cultures, human tissues and computer models.

Almost all cell types can be recreated in laboratory conditions and
these can be coaxed to grow into 3D structures- miniature organs. Cell cultures
have also been used to create `organs-on-chips’ which can be used to study
disease mechanisms, as well as, drug metabolism. This form biotechnology has
already managed to mimic the heart, lungs
and kidneys. The goal is to be able to this for all organ systems.

The idea is already aided in the development in the production of
vaccines, and drug testing on top of aided research in the study of cancers, sepsis and AIDS.

Human tissues can be donated by both healthy and diseased volunteers
through surgeries such as biopsies, cosmetic surgery
and transplants or via post mortem- such as brain tissue from a patient with
Multiple Sclerosis to help better understand a large variety of diseases
furthermore the tissues can make more effective models than through chimeras as
they will contain only human DNA thus providing a more relevant way of studying
human biology.

Finally, computer models can be used to create virtual experiments based
on existing information. Models of the musculoskeletal systems, heart, lungs
etc. already exist. Inopportunely, this method isn’t as effective as testing in
vivo as the concept is very theoretical. (Anon., n.d.)

 

 

 

 

 

References

Anon., 2009. HTA. Online
Available at: https://www.hta.gov.uk/policies/human-tissue-xenografts
Accessed 13 12 2017.
Anon., 2014. Dementia
UK. Online
Available at: http://www.alzheimers.org.uk/info/20025/policy_and_influencing/251/dementia_uk/2
Accessed 12 12 2017.
Anon., 2017. Online

Available at: https://bmcinthealthhumrights.biomedcentral.com/articles/10.1186/1472-698X-10-8
Anon., 2017. Online

Available at: https://speakingofresearch.com/2009/07/13/from-mouse-to-monkey-to-humans-the-story-of-rituximab/
Anon., 2017. Online

Available at: https://www.geneticliteracyproject.org/2016/08/25/chimeric-organ-transplants-science-ethics-growing-human-organs-pigs/
Anon., 2017. Online

Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743631/table/T1/
Anon., n.d. Online
Available at: http://www.sciencedirect.com/science/article/pii/S1934590907000872

Accessed 15 12 2017.
Anon., n.d. Alternatives
to animal testing. Online
Available at: https://www.crueltyfreeinternational.org/why-we-do-it/alternatives-animal-testing
Accessed 12 12 2017.
Anon., n.d. Britannica.
Online
Available at: https://www.britannica.com/topic/chimera-genetics
Accessed 15 12 2017.
Anon., n.d. Guardian.
Online
Available at: https://www.theguardian.com/science/2017/jan/26/first-human-pig-chimera-created-in-milestone-study
Accessed 15 12 2017.
Anon., n.d. Wired.
Online
Available at: https://www.wired.com/2017/01/first-human-pig-chimera-step-toward-custom-organs/

Accessed 15 12 2017.
Bhan, A., Singer, P.
A. & Daar, A. S., 2010. BMC International Health and Human Rights. 19
05.10(8).
Bourret, R. et al.,
2016. Human–animal chimeras: ethical issues about farming chimeric animals
bearing human organs. Online
Available at: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-016-0345-9
Accessed 12 12 2017.
Department for
Business, I. &. S. & Freeman, G., 2014. Public attitudes to animal
testing. Online
Available at: https://www.gov.uk/government/news/public-attitudes-to-animal-testing
Accessed 12 12 2017.
Department of Animal
Science, Michigan State University, East Lansing, Michigan, USA, 2006. Embryonic
Stem cells from Parthenotes. Online
Available at: https://www.ncbi.nlm.nih.gov/pubmed/17141033
Accessed 19 01 2018.
Festing, S. &
Wilkinson, R., 2007. The ethics of animal research. Talking Point on the
use of animals in scientific research. Online
Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2002542/#b18
Accessed 12 12 2017.
Garcia, V. J., 2016. Humanized
Mice for HIV and AIDS research. Online
Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021593/
Accessed 19 01 2018.
Hermerén, G., 2015. Development.
Online
Available at: http://dev.biologists.org/content/142/1/3#ref-4
Accessed 12 12 2017.
Holgren Lab, 2004. Molecular
Biological Sciences. Online
Available at: http://groups.molbiosci.northwestern.edu/holmgren/Glossary/Definitions/Def-O/oncogene.html
Accessed 19 01 2018.
Jin, L., 2014. Yale
Scientific. Online
Available at: http://www.yalescientific.org/2014/10/when-stem-cells-go-bad/
Accessed 15 12 2017.
Marks, F. et al.,
2012. Effectiveness of the Viet Nam Produced, Mouse Brain-Derived,
Inactivated Japanese Encephalitis Vaccine in Northern Viet Nam. Online
Available at: http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001952
Accessed 21 01 2018.
NHS, 2016. Japanese
encephalitis. Online
Available at: https://www.nhs.uk/conditions/japanese-encephalitis/prevention/
Accessed 21 01 2018.
Pappas, J. J., 2008.
Human ESC vs iPSC-pros and cons. Journal of Cardiovascular Translational
Research, 06.p. 5.
Rowland, T., 2009. Hematopoietic
Stem Cells: A Long History in Brief. Online
Available at: http://www.allthingsstemcell.com/2009/02/hematopoietic-stem-cells/
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Online
Available at: https://www.britannica.com/science/somatic-cell-nuclear-transfer
The Free Dictionary
by Farlex, n.d. Medical Dictionary. Online
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Available at: https://stemcells.nih.gov/info/basics/3.htm
Accessed 19 01 2018.
 

 

 

 

1
HLA (human leukocyte antigen) spectrum

A group of protein molecules that can provoke an
immune response. A donor’s and recipient’s HLA types should match as closely as
possible to prevent the recipient’s immune system from attacking the cells- as
the body sees this as foreign material that doesn’t belong in the body. (The Free Dictionary by Farlex, n.d.)

2 Parthenogenesis
is a reproductive mechanism that is common in lower organisms and produces a
live birth from an oocyte (egg cell) activated in the absence of sperm. (Department of
Animal Science, Michigan State University, East Lansing, Michigan, USA, 2006)

3
Mutagenesis-is a process by which the genetic information of an organism is
changed, resulting in a mutation. (The Free Dictionary by Farlex, n.d.)

4
Oncogene activation-A gene that contributes to the production of a cancer.
Oncogenes are generally mutated forms of normal cellular genes
(proto-oncogenes). A gene capable, when activated, of transforming a cell (Holgren Lab,
2004)

5

6
Xenograft- Cells, tissue or organs that are transplanted from one species to
another. Human tissue xenograft is the transplantation of human tissue into
another species. Human tissue xenografts are widely used in research in
connection with disorders, or the functioning, of the human body (Anon., 2009)

7
See page     entitled Disease modelling
for further explanation.

8
Interspecies chimeras encompass animal-human chimeras, they are essentially two
species of DNA fused into one embryo.

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