My statement paper

Hello everyone!

Today is the deadline of my thesis -excited!- and also for the statement paper, which is partly about this blog. In this short paper I discuss the statement ‘Are induced pluripotent stem cells a better research tool than human embryonic stem cells?’. You can find this paper in the link below. Enjoy reading it and feel free to post your opinion about this statement!

My statement paper iPSCs vs hESCs

Human embryonic stem cells and their alternatives

Welcome to this last blog post!

You might have read the purpose of this blog (you can see it in the “welcome” section), but I will repeat it now: So, I am a student at Group T in Leuven and this year I’m doing my thesis at the Research Unit of Stem Cell Research (former lab. Tissue Plasticity) at KULeuven with the research group of professor Hugo Vankelecom. In brief, we investigate the role of a certain adult stem cell type in the pituitary gland (this is the little part of the research that I follow, they are of course doing a lot more there). You can see some more information in my first blog post “introduction to my thesis subject”. 

Because I investigate the role of those stem cells, I found it interesting to make a statement about the human embryonic stem cells (hESCs) and their ethical problems. As you can read in some of my previous blog post, not everyone likes it that they are doing research on these! In Belgium we have the luck that it is legal to do research on hESCs and even “produce” our own embryos (which isn’t the preferred method, but sometimes necessary). As you might already know: President Obama lifted an eight-year-old ban on embryonic stem cell research, signing on March 9 2009 an executive order that he called “an important step in advancing the cause of science in America.” So hooray for Obama (and a bit boo to Bush, like you can see in the cartoon)! (http://www.scientificamerican.com/blog/post/obama-ends-embryonic-stem-cell-rese-2009-03-09/?id=obama-ends-embryonic-stem-cell-rese-2009-03-09)

But of course we would like to find alternatives for the use of hESCs. And in 2006, Yamanaka brought us a bit closer to realizing this with the discovery of induced pluripotent stem cells (iPSCs). 

I also talked about the STAP cells, a very recent discovery of pluritpotency induction with the use of external factors like stress (in the blog post I discussed: the use of an acid bath). But it is possible that these cells aren’t as magical as I first hoped. They are investigating the reliability of the used methodology, so now it’s waiting time… (you can find more info on this in a comment I made on that post).

I would like to thank you all for reading my blog and posting comments! Feel free to still ask questions or give your opinion on the blog posts, they could be very useful for me to write my statement paper! I hope that you found the blog interesting and instructive 🙂

WCTDS: a web-server of cell type discrimination system

In February 2013 Anyou Wang et al. published an article about a quantitative system to discriminate the embryonic stem cells (ESCs), the induced pluripotent stem cells (iPSCs) and the somatic cells (SCs). These cell types provide promising resources for regenerative medicine and medical research, which results in different cell lines that need to be distinguished from each other. Until then, there wasn’t an efficient system to accomplish this. The quantitative system discussed in the article is based on DNA-methylation biomarkers and mathematical models. DNA-methylation plays an important role for the epigenetic gene regulation in development and disease and it may stably alter the expression of genes in cells when cells divide and differentiate from ESCs into specific tissues (thus into SCs). The degree of DNA-methylation is variable in the different species and also in the different cell types, which makes this discrimination system possible.

In the past, they also used biomarkers to discriminate the SCs from the pluripotent cells (PCs), including the ESCs and iPSCs. But these biomarkers, for example OCT4 biomaker, have a low sensitivity and may give inaccurate results. The DNA-methylation biomarker quantitative system can discriminate SCs from PCs with almost 100% accuracy. With approximately 100 biomarkers, the system can distinguish ESCs from iPSCs with an accuracy of 95%. 

 

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The left figure shows how the three different cell types are distinguished with the use of micro-array and DNA-methylation biomarkers.  First the SCs are separated from the PCs, and then almost all the ESCs and iPSCs were discriminated. In the right figure, iPSCs and ESCs were further classified by correspondence analysis in 3D space. It is also possible to separate the adult from the fetal SCs and the female from the male iPSCs.

This quantitative system just needed an easy accessible server, allowing public users to employ the system. This user-friendly system is developed by the same group that invented the quantitative system from above (Anyou Wang et al., 2014). They created WCTDS, which stands for a web-server of cell type discrimination system.

“WCTDS works as a user-friendly framework to discriminate cell types and subtypes and it can also be expended to detect other cell types like cancer cells.”

So it is a promising tool to discriminate different cell types and subtypes of these cells that can be employed by all public users, without need for computational skills!

References:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0056095

http://www.hindawi.com/journals/tswj/2014/459064/

Human embryonic stem cells and the law

In my second blog post, I already talked about the ethics around stem cell research and the use of human embryonic stem (hES) cells in this research. But what does the law say?

Because of the diversity in Europe, the regulations that exist in the EU member states are also very varying. The next pdf file shows an overview of some regulations in the EU member states about the use of hES cells:

http://archive.eurostemcell.org/Documents/Outreach/stemcell_hesc_regulations_2007FEB.pdf

In this table you can see that Belgium is one of the few EU member states that allows creation of human embryos for procurement of hES cells. Also the use of the so-called “surplus” embryos to obtain hES cells is legal. As a couple makes use of in vitro fertilization, they will fertilize more eggs than needed. This excess of fertilized eggs are the surplus embryos and can be donated to another infertile couple or to further research.

In Belgium we have the “embryo law” which is operational since May 2005 (but signed since May 2003). This law specifies under which conditions, within what limits and which procedures need to be followed for scientific research on embryos in vitro. But it is also extended to the regulations for the use of hES cells and gamete donors.

The “production” of hES cells starts with a normal human blastocyst  (see picture below) or from blastocysts with a certain genetic condition. The ICM is then extracted and kept in specific conditions to maintain the proliferation or to start differentiation to the functional cells of the body (depends on the goal of the research). It is so that the research must happen within 14 days of the embryonic development.

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Another method to obtain embryos is cloning. This often raises extreme thoughts of cloning humans and things like that. There is a clear distinction between therapeutic cloning and reproduction cloning. The first one is legal in Belgium, the second one is NOT! Therapeutic cloning happens as follows: you have a donor egg and a somatic cell of a certain patient. The core of the egg is removed and replaced with the core of the somatic cell. Then the cell division is again started. After a while, the hES  cells can be removed, and with this the embryo will be destroyed (which must happen, otherwise it isn’t legal). This stands in contrast with the reproduction cloning, because it will result in another human identical to the patient who donated the somatic cell.

Of course the use of surplus embryos is preferred, but it seems that these aren’t always good enough for some studies, and then we have the possibility to produce our own embryos in Belgium. I find this a very good regulation, because it makes many studies possible, which isn’t the case in all the other countries. So go Belgium (and some others)!

References:

http://www.eurostemcell.org/stem-cell-faq/english/stem-cells-and-law#t56n63

http://www.kerknet.be/microsite/smslgv/content.php?ID=8697 (dutch)

The long road to diagnosis: prolactinomas

In my previous post, I talked about the pituitary tumors and what can be done if you are diagnosed with these tumors. But it isn’t always easy to get correctly diagnosed because of unclear/general symptoms. For example severe headache (migraine) can be caused through various disorders or even with an unknown cause…
In the video Amy, a woman who suffered a prolactinoma a few years back, tells her story. This was a very long road, and some doctors just said that she had a depression and anxiety problems. While the symptoms get worse, she just keeps looking for a doctor who will believe her and will come up with the right diagnosis. But of course she is starting to doubt herself and thinking that she is getting crazy and so… But finally, after 18 months (!!) she finds a doctor who says that it could be a pituitary tumor. And indeed, Amy got the diagnose of a prolactinoma. I already explained in a comment on my previous post that in the case of a prolactinoma, medicines are first used to shrink the tumor and to get rid of the symptoms. Unfortunately, the medicines didn’t work with Amy’s tumor, like it doesn’t work with many other patients. Surgery was necessary to remove the tumor. In Amy’s case, this was luckily succeeded very well! A few weeks after the surgery, she was able to work again (for desk jobs this is possible, but for physical jobs the revalidation is more like 2-3 months) and she didn’t need hormone replacement therapy like some others do need.
So you can see that also in the case of a pituitary tumor, which is a benign tumor, the road to healing is long! Perhaps you know a story of someone who has gone through this?

Reference: https://www.youtube.com/watch?v=4d6oeaMt0zY

Pituitary tumors: What to do?

Pituitary tumors: What to do?

The most common problem with the pituitary gland is the formation of benign, but often locally infiltrative, tumors also called adenomas. When non-selected autopsy is performed, a prevalence from more than 20% is observed, but not all the pituitary tumors give clear symptoms. Only 1 per 1,000 persons experience clinical symptoms like severe headaches, visual disturbance, sexual dysfunction and hormone-related symptoms (acromegaly, Cushing’s disease, …).

When a patient is diagnosed with a pituitary tumor, three different treatment methods are possible:
1. surgically removing the tumor (see picture);
2. radiation;
3. medical therapy.

The specific choice of therapy depends on the type of tumor that is diagnosed (and hence which hormone(s) is/are affected). In most cases, the tumor will be removed surgically. After such a surgery, it is common that hypopituitarism occurs (too much tissue is removed during surgery for example). Then the patient needs to take a hormone-replacement drug treatment. Some recover relatively fast of this hypopituitarism (regeneration of tissue possibly). But others need to take the hormone-replacement drugs for the rest of their life, which of course has a major impact on their social lives! So there is a high need for other treatment methods than surgery. The currently available medicine also aren’t perfect… This is why research to tumorigenesis (part of my thesis) is a very important topic! What are your thoughts about this?

Reference: http://www.cancer.org/cancer/pituitarytumors/detailedguide/pituitary-tumors-after-follow-up

iPS cells as an in vitro model for many diseases and disorders

A week ago I gave some general information about the induced pluripotent stem (iPS) cells. In the comments on that post you can read that they are doing a clinical trial on humans with these iPS cells for the very first time! But the iPS cells are not only for regenerative medicine a great tool, they can also be used as an in vitro model to investigate many different disorders.
For one example: a model for Down Syndrome (see video). People with Down Syndrome (DS) have one chromosome 21 too much, so they have three of them instead of two. This extra chromosome causes lots of problems! In the video they talk about an excess of reactive oxygen species (ROS) in the brain, which causes oxidative stress in the cells and leads to damaging of these cells. They hypothesized that this oxidative stress has a relation to the progression of DS. The research for this hypothesis can be done by taking skin cells of the DS patient and turn them into iPS cells. These iPS cells can then be differentiated into the “sick” brain cells and be used as a model to examine DS mechanisms in the early development state. This is necessary as you can read in one of the articles “Even though Down syndrome is very common, it’s surprising how little we know about what goes wrong in the brain,” says Bhattacharyya” . At the end of the article they say: “we could potentially use these cells to test or intelligently design drugs to target symptoms of Down syndrome.”, hence the iPS cells are a very promising tool for helping DS patients!

References:
http://www.news.wisc.edu/21827
http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302848/pdf

Of course there are many other applications of the iPS cells as an in vitro model. One other example is for cancer research: “In this study, the authors made the following hypothesis: if human pancreatic ductal adenocarcinoma cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. So, the iPSCs technology can provide a live human cell model of early pancreatic cancer and disease progression.” This technique is also used for other kinds of cancer. It is also used in the department where I’m doing my thesis, but I do not know the details of this (and confidentiality and stuff like that, you know 😉 ). Would you like to know more about this, feel free to ask!

Reference: http://www.hindawi.com/journals/bmri/2013/430290/

Induced pluripotent stem cells, a Nobel Prize worthy invention

In my previous post I talked about a new method to form stem cells, namely with the aid of external stress. The formation of induced pluripotent stem (iPS) cells is another method, also invented by a Japanese team (team of Yamanaka) in 2006. The Nobel Prize in Physiology and Medicine 2012 was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka for this discovery.

In the figure below this technique is explained in an easy and short manner.

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So you can see that somatic cells (cells of an adult tissue) are obtained and transformed to a pluripotent (embryonic-like) state by using four different transcription factors, the OSKM factors (Oct4, Sox2, Klf4 and c-Myc). After a few weeks, iPS cells are formed. Different sort of somatic cells can be used to form these iPS cells.

The iPS cells have the potential to differentiate into many mature cell types. Many researchers hope that cells created in this way will eventually be used in regenerative medicine, providing replacement tissue for damaged or diseased organs. Thus the iPS cells could be used as a replacement for the embryonic stem cells, which bring a big ethical problem. This could be an amazing breakthrough for the regenerative medicine! What’s your opinion about this?

References:

http://www.nature.com/news/cell-rewind-wins-medicine-nobel-1.11553

http://www.cellectis.com/what-are-ips-cells

Please cells, step in my acid bath, it will be magically!

You might have read something about this in the newspaper: putting somatic cells in an acid bath can turn them pluripotent! This reaction to the acid bath, and other external stresses like squeezing, is called stimulus-triggered acquisition of pluripotency (STAP) and is discovered by a Japanese team. This reprogramming into pluripotent cells does not require nuclear transfer or genetic manipulation. Obokata (part of the Japanese team) discovered this phenomenon when she was culturing cells and noticed that some, after being squeezed through a capillary tube, would shrink to a size similar to that of stem cells. One of the most surprising findings is that these STAP cells can also form placental tissue, something that embryonic stem cells cannot do. 

So this all sounds great: a new and easier method to obtain pluripotent (or even totipotent) cells that are even better than embryonic stem cells! The STAP cells have a limited self-renewal capacity under the conditions used for establishment. But in the context of the embryonic environment, a small fragment of a STAP cell cluster could even grow into a whole embryo!

The results of this research can be used to examine how reprogramming in the body is related to the activity of stem cells.

Reference: http://www.nature.com/news/acid-bath-offers-easy-path-to-stem-cells-1.14600

Stem cells and ethics

EuroStemCell has published a very interesting video about the ethics of stem cell research. In this video, scientists and doctors give their opinion about the use of human embryonic stem cell lines. Embryonic stem cell lines are derived from totipotent cells of the early mammalian embryo (the blastocyst) and are capable of unlimited, undifferentiated proliferation in vitro.

The main question that they ask themselves is “are these embryos persons?”. It is true that a potential life, the blastocyst, is destroyed in order to do research. But when does this embryo become a real person with rights? Some say that all potential lives need to be protected, and thus embryonic stem cells should not be used for research. Others say that the embryo will only be a person when it is implanted in the womb and crosses a certain level of development. The blastocysts used for the cell lines are just 100 to 200 cells, not greater than a grain of sand. Can you really call this a person?

A nice quote in the beginning of the video is “you destroy human life in order to save human lives”. Many incurable diseases like Parkinson’s, diabetes and Alzheimer could have a potential treatment because of the stem cell research. So we need to find a balance between paying a price (the blastocysts) and saving many lives. This can be done by accepting embryonic stem cell research and carefully regulating it. It is our moral obligation to cure diseases, relief pain and restore health, is also said in the video. I completely agree with this, but it is necessary to have a clear legislation about what is permitted and what isn’t.

What do you think about this?