spinal cord injury research

8/13/2019 Spinal Cord Injury Research

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Spinal Cord Injury Research

Anthony Chow | Page 1

SPINAL CORD INJURY

RESEARCH


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CONTENT

What is Spinal Cord Injury?

Causes and Statistics

The Problem

Current Research

Implications: Is the money well spent?

Is gene therapy ethical?

Benefits: Human resources

Curing what is incurable

Risks or Disadvantages

Alternatives: Chondroitinase

High tech engineering

Evaluation of References

WHAT IS SPINAL CORD INJURY

Spinal Cord Injury (SCI) is an injury to the spinal cord caused by

trauma or accidents, instead of diseases. The spinal cord carries

electrical signals back and forth between the brain and thebody. A spinal cord injury disrupts the signals.

i SCI can be as

minor as leading to pain, or to something really serious like

incontinence, where patients cannot control their bladder and

leak urine all the time. Spinal Cord Injury is usually caused by a

hit that fractures or dislocates the vertebrate, the bones that

make up your spine. This often causes permanent changes in

strength, sensation, and other body functions below the site of

the injury (paralysis).ii

The spinal cord contains cells called neurons. And within the

healthy neurons, the axon (also known as nerve fiber) carriesthe electrical messages from or towards the brain along the

spinal cord.iii When the spinal cord is injured, the initial trauma

causes cell damage and destruction. The axons are crushed and

torn, hence signal cannot get across the injured area. The

oligodendrocytes, the nerve cells that make up the insulating

myelin sheath around the axons, begin to die. This exposes the

axons, and they begin to degenerate, disrupting the


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Another study done by the Christopher and Dana

Reeve Foundation

Dr M.H. Tuszynski and Team

communication between the brain the spinal cord.v

About 273,000 people who are alive in the US in 2013 have spinal cord injuries.iv61% of all SCIs are males whilst

39% female.ivNot including those who die at the scene of the accident, there are 40 cases per million population

in the USA or approximately 12,000 new cases each year.v

CAUSES AND STATISTICS

The causes of SCI vary a lot; the reasons may be something

like: bike accident, or snow skiing injury, or even hit by falling

/ flying object. Nearly half of the injuries occurred between

16 to 20 years old in the USA.vi Within 4,528 sufferers

submitted to the Spinal Cord Injury Model Systems of Care in

the USA between 2005 and 2012, 1,774 cases were caused

by vehicular accidents (39.19%), whilst accidental falls

accounted for 1,294 cases (28.59%), and acts of violence

such as gunshot wounds or assaults accounted for 694 cases.

There are also other reasons for the cases such as diving

accidents, or surgical accidents. The most common cause is

automobile (cars, jeeps, trucks etc.) accidents.v

THE PROBLEM

The cure for SCI has yet not been found, patients can only be

treated. The main problem with the spinal cord is that it does not heal; it is scarred after the damage. The

molecule chondroitin sulphate proteoglycans stops the cells from repairing and forming new connections.viThere

are a few aims in different researchesvii

:

Neuroprotection -protect surviving cells fromfurther damage

Regeneration -stimulate regrowth in cells Replacement -replace damaged nerves Retraining -retrain CNS circuits and

plasticity to restore body functions

In this report, Im going to talk about the research being

done by Doctor Mark Tuszynski, a neuroscientist and his

team, who does researches into regenerating the axon

cells in the spinal cord, enabling signals to be passed

along, and restore movement in the body. The theory

behind this experiment is that there are neural stem cells in

the spinal cord, but they do not regenerate and become neurons. This is because the cells are influenced by the

chemicals in their environment, such as neurotrophic factors (proteins that help axon regeneration). By inserting

these stem cells in with the neurotrophic factor NT-3, the team aim to regenerate the axons across the lesion

site.viii


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CURRENT RESEARCH

2006

In September 2006, Dr Mark Tuszynski and his team from the Department of Neurosciences, University of

California, published their results from a series of experiments they have done on rats. They cut the rats spinalcord at the C3 region. Then they implanted some stem cells into the lesion. The following paragraph describes

their method in detail:

1. The team first used the vector pLV to construct lentiviral vectors (cells that can infect cells with the geneswe want to transfer)

ixNT-3 (neurotrophin-3) and GFP (Green Fluorescent Protein) vectors. NT-3 is very

important in spinal cord gene therapy because they promote axon growth and extension, whilst GFP can

aid the researchers to observe the axon growth; they act as a dye for the controlled group.

2. Some rat primary marrow stromal cells (MSCs)were genetically modified to produce and

secrete human NT-3.

3. The rats used in this experiment are all adultfemale Fischer 344 rats, and there are in total 79

of them, weighing 150 to 200g. They are divided

into different groups based on the types of cells

grafted to the lesion site.

4. The rats underwent dorsal column wire knifelesions (as shown in the image) at C3 to transect

ascending sensory axons.

5. After 4 weeks, the mice are killed, and NT-3gradients beyond the lesion were seen by ELISA

(method used to identify the NT-3 concentration).

With the ELISA scanning result, we can see that the concentration of NT-3 (one of the most important axon growth

factor) is highest if we inject MSC (marrow stromal cells) with human NT-3 with NT-3 as a vector. This relates to

how Dr Tuszynski reported that the axon density was significantly higher in MSC-NT-3 grafts than in MSC grafts

when only Lenti-GFP was used. This suggests that the extent of axons extension beyond the lesion site is very

dependent to the local availability of NT-3, showing

that the method with MSC-NT3 and Lenti-NT3 is the

most successful.

However, despite axon bridging beyond the lesion is

seen, the regenerating axons did not continue to grow

over very long, even in the presence of a continuing

growth factor beyond the lesion. The maximum

distance of axon growth with Lenti-NT-3 vector was

1000m, whilst the NT-3 gradient extended beyond

this point for an additional 1-1.5mmx


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2012

Moving onwards, on November 1st

, 2012, Dr Mark Tuszynski, spoke to the public about the latest findings of his

team through Unite 2 Fight Paralysis Organisation. They have changed their method slightly this time; the team

used E14 Neural Stem cells derived from GFP transgenic (genetically modified) rats and grafted the cells after 14

days of the SCI. Their method is as follows:

1. The rats used in these experiments are Fischer 344 adult rats.2. Neural stem cells (NSCs) that expresses GFP were mixed in fibrin/

thrombin matrix with growth factor cocktail (such as Tuj1, MAP2), to

support graft survival. The matrix is highly important in this

experiment because in the previous ones, the matrix was not used,

and the stem cells did not stay in place, and hence very few of

them survived.xi

3. The rats are completely transected this time, at T3. Two weeks later,the graft is implanted into the lesion site. After six weeks, the

implanted cells completely filled the injury site.

4. The grafted cells primarily differentiated into neurons and axons(28%), oligodendroglia (27%) and astrocytes (16%). As the axons

grow down the spinal cord, they are reinsulated. The host spinal cord

also grows axon into the graft.

5. The graft derived axons extended to C6 from the T3 transectioncavity -25mm. The grafted neurons supported formation of

electrophysiological relays across sites of the transection, resulting in

functional recovery.

As shown by the image on the right, the axons grow from

the graft at 1-2mm / day, where the light green substance

signifies the presence of axons, which provides a very

good sign of recovery.

Moreover, the functional and behavioral outcomes of the

rats are measured over the course of the experiment. The

rats with the graft shows a significant improvement in the

BBB scale, (a scale for measuring rats mobility, with the

highest score of 21 points) as shown by the graph on the

right. The controlled group (rats that were only

transected, no treatment) shows an approximate value of

2 on the BBB scale, whilst the ones treated with the graft has

shown improvements over 6 weeks, with the highest value being 7on the BBB scale. To determine whether this recovery depended on

the graft, some of the rats were re-transected above the graft site

one week later. The graph below shows a significant drop after the

re-transection (week 6 week 7), suggesting that it was the graft

that has caused this recovery.xii

This is taken 7 weeks after grafting

the cocktail into the spinal cord,

the light green substance signifies

the presence of the axons.


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DISCUSSION

The method that Dr. Tuszynski uses has shown a very promising cure to the spinal cord injury; the 2012 experiment

shows extensive axons increase in both number and distance. The 5 point increase in the BBB scale shows that the

method is quite successful in regenerating the axons. There are huge potential clinical implications to this research;

the next stage of Dr. Tuszynskis research will be on larger animals, such as monkeys, and he predicts within a few

year, there will be the first human clinical trial.

IMPLICATIONS

IS THIS MONEY WELL SPENT?

Doing research on spinal cord injury is extremely expensive. The Fiscal Year 2012 Defense Appropriations Act

provided 9.6 million USD to the Department of Defense Spinal Cord Injury Research Program.xiii

SCI is not lethal,

whilst cancer is. More people are affected by cancer than SCI; in 2010 there are 13 million cancer suffersxiv

in the

US, whilst there are only about 0.3 million SCI patients in the US. Is it worth the money to spend on these people,

who are not dying? Should we not focus more resources on cancer researches, which is seemingly more important?

On the other hand, unlike cancer suffers, spinal cord injury patients are usually quite young; they have a bright

future in front of them, and therefore should they not have priority over the older cancer patients? In addition, the

number of SCI patients is increasing daily, whilst the cancer mortality rates for men and women is fallingxv

, showing

that the treatment and cure for some cancer is getting better. Surely this means the resources for cancer research

can be used by other departments, like SCI research?

IS GENE THERAPY ETHICAL?

One of the main issues with genetic therapy is that often embryonic stem cells are used, as they are not specialized

in anything yet. However, according to the Roman Catholic Church, using somatic (adult) stem cells is in principle

morally acceptable, but in no form of experimenting on embryos or use of embryonic stem cells is at all acceptable

in any form.xvi

The somatic stem cells used by Dr Tuszynski are embryonic mouse stem cells (E14). Will this mean

that because of our religious belief, the potential cure provided by Dr Tuszynski and his team cannot be applied?

On the other hand, this potential cure provided by the team can save many lives; in America alone, the cure can

turn about 300,000 paralysed people to healthy humans again. Surely this is something that is extremely beneficial?

However, it should be remembered that in the Catholic view, the embryonic stem cell represents a human life.

Having this cure means that we are sacrificing a human being for the patient. Is that ethical?

BENEFITS

RESOURCES

Although this research may take quite long to accomplish, this can provide a cure for what is yet known to be an

incurable disease. Curing paralyzed patients by genetic engineering can provide more healthy people to work. The

implication of the research is enormous. If Dr Tuszynski and his team are successful, their work may even result in

curing different diseases such as Alzeimers diseasesor spinal cord infections. The average life time cost a 25 years

old patient with incomplete motor function at any level is about 1.5 million USDxvii

. The money which can be spent

helping the economy, instead of paying for medical treatment, is enormous. Moreover, because SCI is such a


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complicated injury, it often requires special care unit, which requires much of the hospitals resources. Now that

there is a cure for SCI, these resources can be re-allocated to other patients, such as AIDs sufferers.

CURING WHAT IS INCURABLE

SCI is a devastating condition. Patients with high Tetraplegia (injury between C1 to C4), on average, they will have

to pay 1 million USD in their first year to treat the condition. And each subsequent year, their cost of living will be

about 170 thousand USD. The cost of research may be great, and the treatment may also be very expensive.

However, if you are 25 years old with high Tetraplegia, your lifetime cost is estimated to be 4.5 million USDxi ,

despite the fact that you would be paralyzed, and cannot work and earn that money. The patients usually view

themselves as a burden to their family, and hence can get depressed very easily. Providing a cure for SCI not only

changes the patients physical and health condition, but can encourage them to become part of the community

again, to become a useful person again.

RISK OR DISADVANTAGES

FALSE IMPROVEMENTS

There have been many cases of doctors lying to the patients about false recovery and results. It is very easy for

unethical doctors to prey on those who are suffering from SCI, and produce false results, deceiving them to believe

that the doctors have found a cure to SCI. SCI is a devastating condition; desperate sufferers will blindly believe

these doctors, paying millions and millions of pounds, just to discover that they are another victim of these cons.

EXPENSIVE CURE

New, advanced technology is usually quite expensive, and no doubt, Dr Tuszynskis treatment will cost a fortune.

This new technology will cost more than most treatments because it involves genetic engineering. This cure will

require embryos fertilized by the patients gametes, then these embryonic cells will have to be genetically

modified. This process can be quite lengthy, hence making the whole treatment more expensive. Not many people

will be able to afford this treatment, especially those patients who rely on government benefits.

ALTERNATIVE SOLUTION

CHONDROITINASE

Although it is possible for the neurons to regenerate, they are blocked by the scar tissue formed at the site of the

injury. A research team from Cambridge, identified that a bacteria enzyme called Chondroitinase which can digest

the molecules in that scar tissue.xviii

This enables injured neurons to regenerate through the scar tissue, and may

even encourage uninjured neurons to grow into the lesion site and replace the damaged neurons. The rats that

received the treatment were better at ladder walking, but had worse functions in other aspects than the rats

received no treatmentxix, suggesting that chondoitinase is still a good potential cure to SCI.

HIGH-TECH ENGINEERING

One of the greatest problems of SCI is that it causes paralysis. The sufferers with a lower spinal injury is not too

bad, as they can still move their upper body, and hence be able to take control of their life a bit more. However, if

you are a sufferer of high Tetraplegia, where you have no control of your body, but your head, you might need

some other help.


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EVALUATION OF REFERENCES

There are two sources of mine which do not go well together. They are both about the SCI statistics. The fact that

one is taken from a university paper, one is taken from the Christopher and Dana Reeve foundation means that

they are both very reliable; Christopher Reeve foundation has been doing spinal cord research for more than 30

years. This is why I have put the data retrieved from the university paper in text, whilst putting the table from theReeve foundation next to the texts.

My main sources for this report are taken from two different medical journals, where both of the articles are

written by Dr. Tuszynski and his team. These two journals are: the Cell Press; and the Journal of Neuroscience.

Both of these journals are peer reviewed, and so the problem of Dr. Tuszynski lying is non-existent. Moreover, we

know that the team is making real progress, because they have just received about 4 million USD grant from the

Californias stem cell agencyxx

, which suggests that they are achieving something really marvelous. Moreover, Dr

Tuszynskis team has received the second largest grant among the 14 other research teams that applied for the

funding, providing evidence that the teams research has huge potential.In conclusion, the cure for SCI is possibly

just round the corner; within 10-15 years, we shall see paralyzed patients walking

IMAGE SOURCES

1. http://www.spinal-research.org/research/first-cell-transplantation-in-a-patient-with-a-spinal-cord-injury-takes-place-in-the-us/

2. http://www.fairview.org/healthlibrary/Article/411713. http://tuszynskilab.ucsd.edu/index.php4. Copied from paper5. Copied from paper6. http://www.youtube.com/watch?v=don00FkOz4E

i http://www.nlm.nih.gov/medlineplus/spinalcordinjuries.html

ii http://www.mayoclinic.com/health/spinal-cord-injury/DS00460

iii http://www.eurostemcell.org/factsheet/spinal-cord-injuries-how-could-stem-cells-help

iv University of Alabama at Birmingham, National Spinal Cord Injury Statistical Centre. Facts and Figures At a

Glance [online] 2013 Available from:

https://www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/Facts%202013.pdf [Accessed 26th October 2013]

v University of Alabama at Birmingham, National Spinal Cord Injury Statistical Centre. Fact Sheet: Recent

Trends in Causes of SCI [online] 2013 Available from:

https://www.nscisc.uab.edu/PublicDocuments/fact_sheets/Recent%20trends%20in%20causes%20of%20SCI.pdf

[Accessed 26th October 2013]

vi Carulli D, Laabs T, Geller HM, Fawcett JW. Chondroitin sulphate proteoglycans in neural development and

regeneration 2005 Apr;15(2):252, PubMed ID:15721753

vii http://www.ninds.nih.gov/disorders/sci/detail_sci.htmviii M. Selzer, B. Dobkin Spinal Cord Injury New York, USA, AAN Enterprises; 2008, p. 129

ix http://biology.kenyon.edu/slonc/gene-web/Lentiviral/Lentivi2.html

x L. Taylor, L. Jones, M. Tuszynski, A. Blesch Neurotrophin-3 Gradients Established by Lentiviral Gene

Delivery Promote Short-Distance Axonal Bridging beyond Cellular Grafts in the Injured Spinal Cord. The Journal of

Neuroscience 2006; 26(38):9713-9721

xi Unite2fightparalysis. Neural Stem Cells for Severe Spinal Cord Injury Dr. Mark Tuszynski [video] 2012

Available from:http://www.youtube.com/watch?v=don00FkOz4E
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xii P. Lu, Y. Wang, L. Graham, M. Tuszynski, Long Distance Growth and Connectivity of Neural Stem Cells after

Severe Spinal Cord Injury. Cell Press 2012; 150:1264-1273

xiii http://cdmrp.army.mil/pubs/press/2012/12scirppreann.shtml

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xv http://news.stv.tv/scotland/257193-cancer-death-rates-drop-18-since-1990-says-cancer-research-uk/

xvi Dignitas Personae Vatican City 2008xvii

http://www.christopherreeve.org/site/c.mtKZKgMWKwG/b.5193227/k.FC2/The_Costs_of_Living_with_Spinal_Cor

d_Injury.htm

xviii http://news.bbc.co.uk/2/hi/health/7240898.stm

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