Student 2: C+SusakENG3010July 5, 2015

Literature Review

Introduction

Over 6 million people in the U.S. are affected by blindness and visual imparities,

out of the 6 million, 20% cannot currently be cured (National Federation of the Blind).

Within all the research done, it has been accepted that once the functioning eye

disconnects from its nerves, they cannot be fully reconnected (An End to Blindness).

Once the retina has disconnected from the optic nerve, eyes will begin to degenerate due

to limited stimulation (Curing Blindness: Vision Quest). For patients 65 years or older,

once degeneration occurs, it can only be slowed down, but not cured. Degeneration is

caused by disconnects between rods/cones and the nerves in the eye.

Stem cells are undifferentiated somatic cells found in cord cells and embryos.

They serve as cells, which haven’t been specialized to a specific part of the body, so in

turn they can become any type of cell. In the human body they serve as an automatic

maintenance to repair body functions (Bauman). Under controlled conditions, stem cells

can be manipulated with proteins to behave in specific ways. Stem cells also adapt the

behavior of cells around them to fit into their location (Bauman). If we can get stem cells

to behave as we want within the eye we have the ability to create regeneration of vision.

During development, stem cells are controlled by they embryo in order to form in the

correct order so the goal would be to monitor that behavior and figuring out how to apply

it to the eye. While trying to gain a better understanding of how this works in embryos,

1

the question is, how can we control these stem cells in order to regenerate lost visual

tissue in the eye?

Retinal Degeneration

Retinal degeneration falls into 3 major categories; rod-degeneration, rod/cone-

degeneration, and debris based degeneration (Jayakody, Cordero, Ali, Pearson). Although

the different types vary in intensity and form, they are all majorly caused by old age.

During this time, the photoreceptor of the eye (rods and cones), which serves to convert

light to neurons, slowly begin to disconnect from the retina, loosing their connection

from the nerves (Jayakody et. al). When the connection is lost, the impulses of light

cannot travel to the occipital lobe where they are converted to what we see (Jayakody et.

al).

The degeneration is also seen in the embryo stages. This is brought on by genetic

mutations or trauma to the baby during fetal stages. Any sort of genetic mutation is

caused through homeobox genes, in turn by understanding how those genes cause

malformations, we can better understand how to reverse it (Hill, Favor, Hogan, Ton,

Saundars, Hanson, pg.522). In cases like this, two major scenarios take place. One form

of the degeneration can be that the eyes simply don’t form, although the retinal nerve will

still be in place, the retina will have not formed. Parts of the eye will be in their correct

places, but there will be a loss of connection from the photoreceptors and the nerve,

similar to the degeneration due to old age.

Current Work In Stem Cells For Retina Regeneration

In research done, researchers have seen successful results when using stem cells

based procedures. When working with chick embryos, researchers implanted genetically

2

formed replacements into the degenerated eye and saw results of regained vision

(Coulombre, Coulombre). They replaced the neural retina of the chicks at different times

post-degeneration and they saw that when replaced immediately, the vision was

corrected, but anything replaced after a 4-day period would not form because there was a

loss of stem cells in order to reform attachments in the nerves (Coulombre et. al). Many

methods were tested in response to the differences caused by the time period of the

implantation. One alternative method tested was doing it in steps, so removing the old

eye one day and implanting the new eye the next day, but nothing yielded results like

implanting everything in one day (Coulombre et. al).

Acting in a more straightforward pattern, researchers have also attempted to plant

stem cells directly into the eye to follow the path it takes to reform the eye (Tropepe,

Coles, Chiasson, Horsford, Elia, McInnes, Van Der Kooy). When doing this they saw

that the stem cells would reform, but sight would not be restored because the stem cells,

although adapting to the cells around them, would not behave as normal retinal cells

(Tropepe et. al). This showed potential in the path of understanding how we can reform

damaged cells, but function remains the issue.

Farrar, Ward, Palfi, Chadderton, and Kenna believe that by understanding the

modular abilities within the optical nerve, they can gain control over functions of the eye

as well as understand how to reverse vision loss done through optic nerve damage. When

referring to modular strengths, it refers to the singular separations of the optic nerve

attaching to each rod or cone (Farrar et. al).

Adler talks extensively about the use of stem cells in both cloning and attachment

of an eye for repair of vision loss. By using stem cells to clone an alternative eye, you can

3

create the identical eye without any damage (Adler) and implant it using knowledge on

optic modules (Farrar et. al)

Stem Cell Work In Other Fields

Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS) studies

In patients with Parkinson’s disease, they face degeneration in a specific strain of

neural cells. Researchers feared that replicating the behavior of these cells would be

difficult because not only are the details of the cells still unknown, but they are adult cells

which meant getting stem cells to behave as adult cells could take time (Lindvall, Kokaia,

Serrano). When implanted into the degenerative part of the brain, the potential of stem

cells was seen in that they immediately began to replace the dead neural cells. Although

this process was not enough to fully eliminate degeneration, it slowed down the

progression of the disease enough for us to monitor how the cells behave in highly

differentiated parts of the body (Lindvall et. al). Understanding how these stem cells

behave in the nerves of the body is vital in the possible application to the retina. Because

the retina is such a sensitive part of the body, by applying the studies to other parts of the

body first helps us get a better understanding of stem cells before direct application to the

retina.

With ALS and MS being central nervous system diseases, we see that stem cells

are not limited in application when discussing nerves, which is one of the overarching

issues in vision loss. This allows for anticipation of nerve recovery in the eye. Comparing

this to the previous study done by Coulomre and Coulombre, there is overlap in the

application of stem cells in order to regain nerve function. Through out rat based studies

there has been visible improvements made in damaged nerve cells throughout the body

4

(Kniery, DeHart, Brown, Salgar). If researchers can combine the strength of stem cells

within the eye (Coulombre et. al) with a better understanding of modules from the optic

nerve (Farrar et. al), it will create a better overall understanding of the eye in order to

expand the methods of research on the retina.

Cancer Cell Studies

Cancerous stem cells allow us to see the pit falls of stem cell use in the human

body. In studied tumors, a similar characteristic seen surrounding the mass is an

abundance of stem cells that continue to divide and grow on the tumor. When studied

these cells show a lack of control via the body and DNA (Jordan, Guzman, Noble). The

cells behave individual of the body. By studying these stem cells, researchers are able to

produce their counterparts, stem cells engineered to control cancer cells by applying

control proteins to the cells to inhibit growth (Jordan et. al). Not only does this treatment

allow us to control cancer cells, but also it allows researchers to cater their control over

cells to get them to behave in the way they want through using proteins and gene markers

on cells, which can be applied to retinal cells (Seneviratne, Ma, Tan, Kwon, Muhammad,

Melham, Defrances, Zarnagar). When applying proteins and gene markers on cells, you

are deciding which kinds of proteins the cells will produce and it will behave in the way

the proteins dictate it too.

The gene markers on cells can also be used to reverse malformations and

degeneration in cancer cells (Seneviratne et. al). Using this feature of stem cells in the

eye gives more freedom for experimentation. The next step for studies would be to

understand how gene markers work on retinal cells.

5

Conclusion; Combining Our Knowledge

Central nervous system stem cells therapies have showed that stem cell

manipulation is possible in order to reverse years of damage. We see that stem cells aptly

behave in accordance with their surrounding not matter how specialized. In primarily

neural regions of the body, each individual cells placement in not as direct because the

connections forming are from all sides. Due to the broad placement of cells within the

eye we see that when stem cells are used directly in the eye, they will form all the correct

parts of the eye, but there in no control over their directed function so they wont do the

correct task.

Cancer cell have proven the capability of designing very specific cells made to

work in their own ways inside the body. By using this in stem cells, we have the

capabilities to create replicas of the eye outside of the human body through genetic

modification. Through research, we can create a better understanding of how the retina

works to capture messages and convey them to the optic nerve through single modules.

By combining the knowledge we have on stem cells and the eyes, we have the power to

ask the question; can researchers use the power of stem cells along with gene markers

and proteins to create reversal of blindness and visual impairments?

6

Works Cited

Kniery, Kevin, et al. "Stem cell and novel biologic therapies to enhance functional recovery in vascular composite allotransplantation (TRAN1P. 922)." The Journal of Immunology 194.1 Supplement (2015): 140-4.

Seneviratne, Danushka, et al. "Genomic instability causes HGF gene activation in colon cancer cells, promoting their resistance to necroptosis." Gastroenterology 148.1 (2015): 181-191.

Farrar, Gwyneth Jane, et al. "Gene Therapy for Dominantly Inherited Retinal Degeneration." Gene-and Cell-Based Treatment Strategies for the Eye. Springer Berlin Heidelberg, 2015. 43-60.

Baumann, Kim. "Stem cells: Human primordial germ cells in a dish." Nature Reviews Molecular Cell Biology (2015).

Lindvall, Olle, Zaal Kokaia, and Alberto Martinez-Serrano. "Stem Cell Therapy for Human Neurodegenerative Disorders–how to Make It Work." Nat Med Nature Medicine 10.7 (2004): n. pag. Web.

Tropepe, V. "Retinal Stem Cells in the Adult Mammalian Eye." Science 287.5460 (2000): 2032-036. Web.

Jayakody, Sujatha A., Anai Gonzalez-Cordero, Robin R. Ali, and Rachael A. Pearson. "Cellular Strategies for Retinal Repair by Photoreceptor Replacement." Progress in Retinal and Eye Research 46 (2015): 31-66. Web.

"Treating Blindness and Vision Loss - Restoring Eyesight - AARP." AARP. N.p., n.d. Web. 16 July 2015. <http://www.aarp.org/health/conditions-treatments/info-2015/treating-blindness-vision-loss.html>.

Ton, Carl CT, Grady F. Saunders, and Nicholas D. Hastie. "Mouse small eye results from mutations in a paired-like homeobox-containing gene." Nature 354 (1991): 19.Adler, Ruben. "Curing blindness with stem cells: hope, reality, and challenges." Recent Advances in Retinal Degeneration. Springer New York, 2008. 3-20.

Jordan, Craig T., Monica L. Guzman, and Mark Noble. "Cancer Stem Cells." New England Journal Of Medicine (2006): n. pag. Web. 16 July 2015.

7

Invention Portfolio

Revised Research Questions

Can blindness be cured with the use of stem cells?

Can a cloned eye be implanted into the eye?

How far can we go when using stem cells in the eye?

Ethics of cloning?

Can we use the same techniques of stem cells on other parts of the body on

the eyes?

Launch Texts

"Adult stem cell advances." Ethics & Medicine: an international journal of bioethics 22.2 (2006): 124. Academic OneFile. Web. 24 June 2015.

Horton, Sarah J., and Brian J.P. Huntly. “Recent Advances in Acute Myeloid Leukemia Stem Cell Biology.” Haematologica 97.7 (2012): 966–974. PMC. Web. 24 June 2015.

Viczian, Andrea S. “Advances in Retinal Stem Cell Biology.” Journal of Ophthalmic & Vision Research 8.2 (2013): 147–159. Print.

Graphic Organizer

8

Shitty Rough DraftBoth my articles are two versions of journals based around stem cell

research. One of them is an academic journal and the other is a research journal,

they both focus around the progression of stem cell research and the future

discoveries that can be made. Just one person does more generally not write these

journals. The academic journal uses information from other sources to tie it

together and present preexisting information. Research articles are doing active

research and making new discoveries about planned topic.

My research article focuses on the progression of stem cells in retinal

transplants. They are trying to figure out how using stem cells can regenerate

eyesight in patients who have had damage to their retinas. Their initial goal is to see

how they can get stem cells to mimic the behavior of retinal cells and they are trying

to document the steps it takes for the cells to get to the same state as the other cells.

The process begins by trying to understand what differentiates a retinal cell

from others. They do this by looking at all markers and confinements on the genes

9

in retinal cells. The goal is to replicate all actions of proteins from a retinal cell to

stem cells. Once this process is achieved, they begin actually applying the factors

onto the cells. This process shows to be tricky because not all of the proteins will

attach to the genes in the way you intend them too, so as result they include a very

detailed map showing what processes worked as opposed to others. Once the cells

have been molded into replicas of the retinal cells, they allow the cells to grow, both

to see how they behave as well as to understand if they will take on similar activities

to the real retinal cells. When they complete their research, they find that there are

ways to replicate the activities of retinal cells through stem cells.

In the academic journal I chose, they are laying out all the capabilities of stem

cells. They connect many articles to show the strength of stem sells and how they

can help with progression of cancer treatments, dementia, and genetic diseases. The

bulk of the content is based around cancer. Many studies have been done to show

that through using stem cells, you can create a cell meant to attack specific

cancerous cells. This is something the body naturally attempts to do but the cells are

to weak to act on tumors. By creating these specific attack cells, you are able to gain

control over growing tumor cells.

Another cancer research in this journal shows that by creating replicas of

tumors outside of the body, we can track how they progress and change through

different stages in order to create the best plan of attack for when this mass is still

inside the body. This is something that can be done very broadly for all different

types of tumors and cancers. By creating more forward movement in this research

10

we see that cancer discoveries are at our fingertips, but is just a matter of doing the

research to progress.

11