induced pluripotent stem cell | The Science of Parkinson’s

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Feb 03 2019

Parkinsons is a neurodegenerative condition. This means that cells in the brain are being lost over time. Any cure for Parkinsons is going to require some form of cell replacement therapy introducing new cells that can replace those that were lost.

Cell transplantation represents one approach to cell replacement therapy, and this week we learned that the Japanese regulatory authorities have given the green light for a new cell transplantation clinical trial to take place in Kyoto.

This new trial will involve cells derived from induced pluripotent stem cells (or IPS cells).

Intodays post we will discuss whatinduced pluripotent stem cells are, what previous research has been conducted on these cells, and what we know about the new trial.

Source:Glastone Institute

The man in the image above is ProfShinya Yamanaka.

Hes a rockstar in the biomedical research community.

ProfYamanaka is the director ofCenter forinduced Pluripotent Stem CellResearch and Application(CiRA); and a professor at theInstitute for Frontier Medical SciencesatKyoto University.

But more importantly, in 2006 he published a research report that would quite literally change everything.

In that report, he demonstrated a method by which someonecould take a simple skin cell (called a fibroblast), grow it in cell culture for a while, and then re-programit so that it would transform into a stem cell a cell that is capable of becoming any kind of cell in the body.

The transformed cells were calledinduced pluripotent stem (IPS) cell pluripotent meaning capable of any fate.

It was an amazing feat that made the hypothetical idea of personalised medicine suddenly very possible take skin cells from anyone with a particular medical condition, turn them into whatever cell type you like, and then either test drugs on those cells or transplant them back into their body (replacing the cells that have been lost due to the medical condition).

Personalised medicine with IPS cells. Source:Bodyhacks

IPS cells are now being used all over the world, for all kinds of biomedical research. And many research groups are rushing to bring IPS cell-based therapies to the clinic in the hope of providing the long sort-after dream of personalised medicine.

This week the Parkinsons community received word that the Pharmaceuticals and Medical Devices Agency (PMDA) the Japanese regulatory agency that oversees clinical trials have agreed for researchers at Kyoto University to conduct a cell transplantation trial for Parkinsons, using dopamine neurons derived from IPS cells. And the researchers are planning to begin their study in the next month.

In todays post we are going to discuss this exciting development, but we should probably start at the beginning with the obvious question:

What exactly is an IPS cell?

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New research provides some interesting insight into particular cellular functions and possibly sleep issues associated with Parkinsons.

Researchers in Belgium have recently published interesting findings that a genetic model of Parkinsons exhibits sleep issues, which are not caused by neurodegeneration, but rather neuronal dysfunction. And as a result, they were able to treat it in flies at least.

In todays post, we will review this new research and consider its implications.

Source:Dlanham

I am a night owl.

One that is extremely reluctant to give up each day to sleep. There is always something else that can be done before going to bed. And I can often be found pottering around at 1 or 2am on a week night.

As a result of this foolish attitude, I am probably one of the many who live in a state of sleep deprivation.

I am a little bit nervous about doing the spoon test:

But I do understand that sleep is very important for our general level of health and well being. And as a researcher on the topic, I know that sleep complications can be a problem for people with Parkinsons.

What sleep issues are there for people with Parkinsons?

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This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinsons disease research.

The results could explain way mice do not get Parkinsons disease, and theymay also partly explain why humans do.

In todays post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.

The humble lab mouse. Source: PBS

Much of our understanding of modern biology is derived from the lower organisms.

From yeast to snails (there is a post coming shortly on a snail model of Parkinsons disease I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.

Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say until now because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinsons disease is these creatures.

You see, heres the thing: Flies dont naturally develop Parkinsons disease.

Nor do mice. Or snails.

Or yeast for that matter.

So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that dont necessarily apply to human beings. And this may explain our long history of failed clinical trials.

We work with the best tools we have, but it those tools are flawed

What did the new research report find?

This is the study:

Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinsons disease Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krger R, Surmeier DJ, Krainc D Journal: Science, 07 Sept 2017 Early online publication PMID:28882997

The researchers who conducted this study began by growing dopamine neurons a type of cell badly affected by Parkinsons disease from induced pluripotent stem (IPS) cells.

What are induced pluripotent stem cells?

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Two months ago a research report was published in the scientific journal Nature and it caused a bit of a fuss in the embryonic stem cell world.

Embryonic stem (ES) cells are currently being pushed towards the clinic as a possible source of cells for regenerative medicine. But this new report suggested that quite a few of the embryonic stem cells being tested may be carrying genetic variations that could be bad. Bad as in cancer bad.

In this post, I will review the study and discuss what it means for cell transplantation therapy for Parkinsons disease.

Source: Medicalexpress

For folks in the stem cell field, the absolute go-to source for all things stem cell related isProf Paul Knoepflers blog The Niche. From the latest scientific research to exciting new stem cell biotech ventures (and even all of the regulatory changes being proposed in congress), Pauls blog is a daily must read for anyone serious about stem cell research. He has his finger on the pulse and takes the whole field very, very seriously.

Prof Paul Knoepfler during his TED talk.Source: ipscell

For a long time now, Paul has been on a personal crusade. Like many others in the field (including yours truly), he has been expressing concern about the unsavoury practices of the growing direct-to-consumer, stem cell clinic industry. You may have seen him mentioned in the media regarding this topic (such as this article).

The real concern is that while much of the field is still experimental, many stem cell clinics are making grossly unsubstantiated claims to draw in customers. From exaggerated levels of successful outcomes (100% satisfaction rate?) all the way through to talking about clinical trials that simply do not exist.The industry is badly (read: barely) regulated which is ultimately putting patients at risk (one example: three patients were left blind after undergoing an unproven stem cell treatment click here to read more on this).

While the stem cell research field fully understands and appreciates the desperate desire of the communities affected by various degenerative conditions, there has to be regulations and strict control standards that all practitioners must abide by. And first amongst any proposed standards should be that the therapy has been proven to be effective for a particular condition in independently audited double blind, placebo controlled trials. Until such proof is provided, the sellers of such products are simply preying on the desperation of the people seeking these types of procedures.

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Last weekscientists in Sweden published researchdemonstrating a method by which the supportive cells of the brain (called astrocytes) can be re-programmed into dopamine neurons in the brain of a live animal!

It was a reallyimpressive trick and it could have major implications for Parkinsons disease.

In todays post is a long read, but in it we will review the research leading up to the study, explain the science behindthe impressive feat, and discuss where things go from here.

Different types of cells in the body. Source: Dreamstime

In your body at this present moment in time, there is approximately 40 trillion cells (Source).

The vast majority of those cells have developedinto mature types of cell and they are undertaking veryspecific functions. Muscle cells, heart cells, brain cells all working together in order to keep you verticaland ticking.

Now, once upon a time we believed that the maturation (or the more technical term: differentiation) of a cell was a one-way street. That is to say, once acellbecame what it was destined to become, there was no going back. This was biological dogma.

Then aguy in Japan did something rather amazing.

Who is he and what did he do?

This is ProfShinya Yamanaka:

ProfShinya Yamanaka. Source: Glastone Institute

Hes a rockstar in the scientific research community.

ProfYamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application(CiRA); and a professor at theInstitute for Frontier Medical Sciences at Kyoto University.

But more importantly, in 2006 he published a research reportdemonstrating how someonecould take a skin cell and re-programit so that was now a stem cell capable of becoming any kind of cell in the body.

Heres the study:

Title: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Authors: Takahashi K, Yamanaka S. Journal: Cell. 2006 Aug 25;126(4):663-76. PMID: 16904174 (This article is OPEN ACCESS if you would like to read it)

Shinya Yamanakas team started with the hypothesis that genes which are important to the maintenance of embryonic stem cells (the cells that give rise to all cells in the body) might also be able to cause an embryonic state in mature adult cells. They selected twenty-four genes that had been previously identified as important in embryonic stem cells to test this idea. They used re-engineered retroviruses to deliver these genes to mouse skin cells. The retroviruses were emptied of all their disease causing properties, and could thus function as very efficient biological delivery systems.

The skin cells were engineered so that only cells in which reactivation of the embryonic stem cells-associated gene, Fbx15, would survive the testing process. If Fbx15 was not turned on in the cells, they would die. When the researchers infected the cells with all twenty-four embryonic stem cells genes, remarkably some of the cells survived and began to divide like stem cells.

In order to identify the genes necessary for the reprogramming, the researchers began removing one gene at a time from the pool of twenty-four. Through this process, they were able to narrow down the most effective genes to justfour: Oct4, Sox2, cMyc, and Klf4, which became known as the Yamanaka factors.

This new type of cell is called an induced pluripotent stem (IPS) cell pluripotent meaning capable of any fate.

The discovery of IPS cells turned biological dogma on its head.

And in acknowledgement of this amazing bit of research, in 2012 ProfYamanaka and Prof John Gurdon (University of Cambridge)were awarded the Nobel prize for Physiology and Medicinefor the discovery that mature cells can be converted back to stem cells.

Prof Yamanaka and Prof Gurdon. Source: UCSF

Prof Gurdon achieved the feat in 1962 when he removed the nucleus of a fertilised frog egg cell and replaced it with the nucleus of a cell taken from a tadpoles intestine. The modified egg cell then grew into an adult frog! This fascinatingresearchproved that the mature cell still contained the genetic information needed to form all types of cells.

EDITORS NOTE: We do not want to be accused of taking anything away from Prof Gurdons contribution to this field (which was great!) by not mentioning his efforts here. For the sake of saving time and space, we are focusing onProf Yamanakas research as it is more directly related to todays post.

Making IPS cells. Source: learn.genetics

Link:
induced pluripotent stem cell | The Science of Parkinson's

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