Dr.Young,question about stem cell transplantation

[pecla]

Dr.Young, I want to know something more about the risks that the stem cell transplants develop in a tumor.Because stem cells can dividing over 300 times they can develop tumors if they don't stop.But if the stem cells are differentiated into specialized cells before transplantation they're not immortal anymore and so couldn't become cancerous.I've the following questions:
1.Is my assumption right?
2.Is it difficult to differentiate all stem cells into specialized cells before transplantation and do you think they can do that job in Moscow?(if my assumption is right then apparently it is otherwise you shouldn't have to be afraid of tumors)
3.After how many time can the cells form tumors, in other words what does the fact that more than 150 people(only for SCI) which received stem cells untill now didn't get tumors mean?
4.I know Dr.Gearhart is experimenting with embryoid body-derived cells which couldn't turn into tumors,according to Dr.Gearhart, because they die after dividing 70-80 times.Is this an important finding and do you think this can go into human trials relatively soon (because there's much less risk involved for the patients and the fact that Geron is involved)?

[Wise Young]

Stem cells (and tumor cells) produce progeny stem cells (or tumor cells) that divide further. Both embryonic and adult stem cells divide 1-2 times a week when exposed to basic fibroblast growth factor (bFGF). It is true that adult stem cells can divide perhaps 50 times while embryonic stem cells can probably divide over 300 times. Each succeeding generation can divide fewer times. But only 50 generations will produce a tumor of substantial size.

Let me illustrate. A stem cell and its progeny that divide once a week for a year will generate 2^50 or 1.13•10^15 cells. This is one quadrillion cells (10^15, a thousand trillion). The volume of a trillion cells is about 10 liters and therefore the volume of a quadrillion cells is about 10000 liters (10 liters * 1000). This tumor would be more than 200 times bigger than your body!

We all were once embryos and fetuses with lots of stem cells. Something really powerful must inhibit stem cell proliferation or else we would all be dead of cellular overgrowth, long before we reach one year of age. Embryonic stem cells must be particularly sensitive to factors that stop proliferation during development because oversized embryos and embryonic cancer are very rare.

Both animal and human studies indicate that stem cells do not proliferate out of control when they are transplanted into normal brains. Several studies suggest that embryonic stem cells may grow out of control when they are transplanted into damaged tissues. However, scientists have discovered that if the cells are incubated in retinoic acid for a while, they do not respond with as much proliferation in injured tissues.

Note that the act of transplantation itself damages the tissue around the transplant site. Almost all the studies that have transplanted neural stem cells (whether embryonic, neonatal, or adult) have shown that the stem cells become glial cells. This is not so surprising since injury of the brain and spinal cord causes gliosis in the injury area and the stem cells are probably responding to the signals of the injured tissues.

Several recent studies indicate that stem cells behave very differently when they are injected intravascularly or intrathecally at a remote site and allowed to migrate into the tissue. When they do that to the brain or spinal cord, they do not become glial cells but form neurons instead. So, in summary, there are ways to control the growth of the stem cells and ways to implant them so that they are less likely to become carcinogenic.

The above the reason why so much more research is necessary and why access to human embryonic stem cells are required to make progress in the field. It is doable but not yet a slam dunk. We have to make sure that we develop the technology to control the cells after transplantation.

Wise.e

[The Human Cannonball]

What can I say. Even a layman such as myself can even understand this. Thanks

[pecla]

Thanks Dr,Young.After reading your answer I think I've to conclude that my assumption is completely wrong.But because you didn't say anything about it I still don't know why.I came to my conclusion after reading the next text from Dr.Gearhart:

``We can't take the embryonic (stem) cells that we have and transplant them into anything,'' said Dr. John D. Gearhart, of Johns Hopkins University in Baltimore, Maryland. They will ''just as likely form a tumor as they will differentiate into some sort of tissue,'' he said.
Stem cells never stop dividing, so if the cells were to be transplanted before they had begun to form more specialized cells, they might form a tumor instead of normal tissue, Gearhart explained.
The key to overcoming this problem is to transplant cells that have already specialized somewhat, a process known as differentiation, according to the Johns Hopkins researcher. Differentiated cells are no longer immortal, so they do not run the risk of becoming cancerous, Gearhart noted. ``Once a cell commits, it won't become a tumor,'' he said.
In a report in the January 2nd issue of the Proceedings of the National Academy of Sciences, Gearhart and his colleagues detail their successful efforts to produce cells that can still form many different types of cells, but do not carry a risk of forming tumors.
The researchers started by coaxing embryonic stem cells to form clusters of cells known as embryoid bodies. From these small masses, the scientists then isolated cells called embryoid body-derived cells, which they grew in culture dishes to form different types of cells.

I know they can differentiate stem cells into neurons,astrocytes,oligodendrocytes in vitro(before transplantation) and thought that Dr.Gearhart meant this with differentiated cells which wouldn't be immortal anymore and according to him couldn't become cancerous.But there must be something wrong in my argument but I don't know what(or is Dr.Gearhart's theory maybe wrong?).Can you please explain to me Dr.Young?

Änd one more question,you said"Several recent studies indicate that stem cells behave very differently when they are injected intravascularly or intrathecally at a remote site and allowed to migrate into the tissue. When they do that to the brain or spinal cord, they do not become glial cells but form neurons instead".Are they usually using neural stem cells instead of more differentiated cells like neurons and glial cells(like they injected in Dmitriys cord).And I thought they become glial cells as well because they remyelinate the axons and that must be from the oligodendrocytes, or is the remyelination only ocurring when they differentiate them into oligodendrocytes before transplantation?

Sorry for all my questions but I am a bit confused after this article and I am really interested in the stem cell transplantation treatment.

[robin]

Could you comment on this Dr.Young?

[Wise Young]

Many companies and laboratories are exposing stem cells to a variety of chemicals and factors to see how they respond. John Gearhart is correct in pointing out that embryonic stem cells may keep growing in some conditions and behave like a cancer. They are also not the panacea that the media suggests. It is not a matter of transplant the cells and hope for the best. It must be a matter of knowing what they turn into and why. Research must minimize the risks and maximize the benefits of this promising therapy. Demonstrating possibility is not the same as establishing safety and efficacy.

However, I do want to emphasize that we have quite a bit of data indicating that it is safe to transplant stem cells into the spinal cord. Several hundred patients have received human fetal cells to the spinal cord (Russia, Sweden, Florida, China, etc.). Several hundred have received fetal neuronal transplants for Parkinson's disease. Over a hundred have received porcine fetal cell transplants to the brain and several to the spinal cord. To my knowledge, none of these cells were treated beforehand to prevent tumor formation and many of these transplants must include stem cells. Not a single case of tumor has been reported. This would seem to suggest that there are robust mechanisms that prevent overgrowth of the transplants.

The field is moving very rapidly. The mantra right now is differentiation to reduce the risk and use of genetic modification to manipulate the cells. But there are many other factors in the equation. Let me give a few examples.

1. The immune system must play an important role in the control of stem cells. After all, the immune system is key to control of cancer in our body. It can be used to shape the direction and growth of the cells.

2. Programmed cell death or apoptosis is another mechanism by which the body gets rid of unwanted cells during development. So, cells that don't achieve a particular goal or criterion will automatically self-destruct.

3. Guiding the migration and growth of the cells is critical to replacing and repairing tissues. At the present, we are uncertain what factors do this in tissues and how to manipulate them.

4. Making the cells part of the circuitry, a member of the team, so to speak, must be the goal of cell transplantation therapy. Harnessing the mechanisms of plasticity to achieve this goal must be part of the plan.

The first generation therapies may yield some therapies that improve some function in some people but second generation therapies will require detailed understanding of the therapy to understand the best way to apply them. The third generation therapies will require ability to control the therapies so that they do what we want them to do.

Many people will probably read this and say that there is no hope, that it will take decades to achieve these goals. On the other hand, I want to point out how far we have come just. In 1998, when spinewire came into existence, we did not even know that pluripotent adult stem cells existed in the brains of humans. By 2000, it became clear that such cells can be isolated, transplanted, and restore function in animals. In the past year, we have developed many tools to manipulate the fates of embryonic stem cells. It has also become clear that stem cells are capable of far more than we had imagined. They can migrate long distances and integrate themselves into the tissue, survive, and improve function. Clinical trials have begun.

You know, one of the reasons why I wanted to try to get the old Cando/Spinewire forums intact is so that we could look back and see the progress that we have made in the past three years. Our forum discussions reflect the progress that we have made in the field. When spinewire started, we were arguing whether a cure was possible. Last year, we are discussing how best to implement the cure. This year, we are talking mostly about safety and efficacy issues. By next year, I predict that we will be discussing which therapy is better. This is a truly amazing transformation.

Wise.

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