Blissful Ignorance: How Environmental Activists Shut Down Molecular Biology Labs in High Schools

Hearing about the HannoverGEN project made me feel envious and excited. Envious, because I wish my high school had offered the kind of hands-on molecular biology training provided to high school students in Hannover, the capital of the German state of Niedersachsen. Excited, because it reminded me of the joy I felt when I first isolated DNA and ran gels after restriction enzyme digests during my first year of university in Munich. I knew that many of the students at the HannoverGEN high schools would be similarly thrilled by their laboratory experience and perhaps even pursue careers as biologists or biochemists.

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What did HannoverGEN entail? It was an optional pilot program initiated and funded by the state government of Niedersachsen at four high schools in the Hannover area. Students enrolled in the HannoverGEN classes would learn to use molecular biology tools typically reserved for college-level or graduate school courses in order to study plant genetics. Some of the basic experiments involved isolating DNA from cabbage or how learning how bacteria transfer genes to plants, more advanced experiments enabled the students to analyze whether or not the genome of a provided maize sample had been genetically modified. Each experimental unit was accompanied by relevant theoretical instruction on the molecular mechanisms of gene expression and biotechnology as well as ethical discussions regarding the benefits and risks of generating genetically modified organisms (“GMOs”). The details of the HannoverGEN program are only accessible through the the Wayback Machine Internet archive because the award-winning educational program and the associated website were shut down in 2013 at the behest of German anti-GMO activist groups, environmental activists, Greenpeace, the Niedersachsen Green Party and the German organic food industry.

Why did these activists and organic food industry lobbyists oppose a government-funded educational program which improved the molecular biology knowledge and expertise of high school students? A press release entitled “Keine Akzeptanzbeschaffung für Agro-Gentechnik an Schulen!” (“No Acceptance for Agricultural Gene Technology at Schools“) in 2012 by an alliance representing “organic” or “natural food” farmers accompanied by the publication of a critical “study” with the same title (PDF), which was funded by this alliance as well as its anti-GMO partners, gives us some clues. They feared that the high school students might become too accepting of biotechnology in agriculture and that the curriculum did not sufficiently highlight all the potential dangers of GMOs. By allowing the ethical discussions to not only discuss the risks but also mention the benefits of genetically modifying crops, students might walk away with the idea that GMOs could be beneficial for humankind. The group believed that taxpayer money should not be used to foster special interests such as those of the agricultural industry which may want to use GMOs.

A response by the University of Hannover (PDF), which had helped develop the curriculum and coordinated the classes for the high school students, carefully analyzed the complaints of the anti-GMO activists. The author of the anti-HannoverGEN “study” had not visited the HannoverGEN laboratories, nor had he had interviewed the biology teachers or students enrolled in the classes. In fact, his critique was based on weblinks that were not even used in the curriculum by the HannoverGEN teachers or students. His analysis ignored the balanced presentation of biotechnology that formed the basis of the HannoverGEN curriculum and that discussing potential risks of genetic modification was a core topic in all the classes.

Unfortunately, this shoddily prepared “study” had a significant impact, in part because it was widely promoted by partner organizations. Its release in the autumn of 2012 came at an opportune time for political activists because Niedersachsen was about to have an election. Campaigning against GMOs seemed like a perfect cause for the Green Party and a high school program which taught the use of biotechnology to high school students became a convenient lightning rod. When the Social Democrats and the Green Party formed a coalition after winning the election in early 2013, nixing the HannoverGEN high school program was formally included in the so-called coalition contract. This is a document in which coalition partners outline the key goals for the upcoming four year period. When one considers how many major issues and problems the government of a large German state has to face, such as healthcare, education, unemployment or immigration, it is mind-boggling that de-funding a program involving only four high schools received so much attention that it needed to be anchored in the coalition contract. In fact, it is a testimony to the influence and zeal of the anti-GMO lobby.

Once the cancellation of HannoverGEN was announced, the Hannover branch of Greenpeace also took credit for campaigning against this high school program and celebrated its victory. The Greenpeace anti-GMO activist David Petersen said that the program was too cost intensive because equipping high school laboratories with state-of-the-art molecular biology equipment had already cost more than 1 million Euros. The previous center-right government which had initiated the HannoverGEN project was planning on expanding the program to even more high schools because of the program’s success and national recognition for innovative teaching. According to Petersen, this would have wasted even more taxpayer money without adequately conveying the dangers of using GMOs in agriculture.

The scientific community was shaken up by the decision of the new Social Democrat-Green Party coalition government in Niedersachsen. This was an attack on the academic freedom of schools under the guise of accusing them of promoting special interests while ignoring that the anti-GMO activists were representing their own special interests. The “study” attacking HannoverGEN was funded by the lucrative “organic” or “natural food” food industry! Scientists and science writers such as Martin Ballaschk or Lars Fischer wrote excellent critical articles stating that squashing high-quality, hand-on science programs could not lead to better decision-making. How could ignorant students have a better grasp of GMO risks and benefits than those who receive relevant formal science education and thus make truly informed decisions? Sadly, this outcry by scientists and science writers did not make much of a difference. It did not seem that the media felt this was much of a cause to fight for. I wonder if the media response would have been just as lackluster if the government had de-funded a hands-on science lab to study the effects of climate change.

In 2014, the government of Niedersachsen then announced that they would resurrect an advanced biology laboratory program for high schools with the generic and vague title “Life Science Lab”. By removing the word “Gen” from its title which seems to trigger visceral antipathy among anti-GMO activists, de-emphasizing genome science and by also removing any discussion of GMOs from the curriculum, this new program would leave students in the dark about GMOs. Ignorance is bliss from an anti-GMO activist perspective because the void of scientific ignorance can be filled with fear.

From the very first day that I could vote in Germany during the federal election of 1990, I always viewed the Green Party as a party that represented my generation. A party of progressive ideas, concerned about our environment and social causes. However, the HannoverGEN incident is just one example of how the Green Party is caving in to ideologies, thus losing its open-mindedness and progressive nature. In the United States, the anti-science movement, which attacks teaching climate change science or evolutionary biology at schools, tends to be rooted in the right wing political spectrum. Right wingers or libertarians are the ones who always complain about taxpayer dollars being wasted and used to promote agendas in schools and universities. But we should not forget that there is also a different anti-science movement rooted in the leftist and pro-environmental political spectrum – not just in Germany. As a scientist, I feel that it is becoming increasingly difficult to support the Green Party because of its anti-science stance.

I worry about all anti-science movements, especially those which attack science education. There is nothing wrong with questioning special interests and ensuring that school and university science curricula are truly balanced. But the balance needs to be rooted in scientific principles, not political ideologies. Science education has a natural bias – it is biased towards knowledge that is backed up by scientific evidence. We can hypothetically discuss dangers of GMOs but the science behind the dangers of GMO crops is very questionable. Just like environmental activists and leftists agree with us scientists that we do not need to give climate change deniers and creationists “balanced” treatment in our science curricula, they should also accept that much of the “anti-GMO science” is currently more based on ideology than on actual scientific data. Our job is to provide excellent science education so that our students can critically analyze and understand scientific research, independent of whether or not it supports our personal ideologies.

 

Note: An earlier version of this article was first published on the 3Quarksdaily blog.

How Viruses Feign Death to Survive and Thrive

Billions of cells die each day in the human body in a process called “apoptosis” or “programmed cell death”. When cells encounter stress such as inflammation, toxins or pollutants, they initiate an internal repair program which gets rid of the damaged proteins and DNA molecules. But if the damage exceeds their capacity for repair then cells are forced to activate the apoptosis program. Apoptotic cells do not suddenly die and vanish, instead they execute a well-coordinated series of molecular and cellular signals which result in a gradual disintegration of the cell over a period of several hours.

The remains of an apoptotic cell are being engulfed and ingested by a phagocytic white blood cell. Image via National Library of Medicine.
The remains of an apoptotic cell are being engulfed and ingested by a phagocytic white blood cell. Image via National Library of Medicine.

What happens to the cellular debris that is generated when a cell dies via apoptosis? It consists of fragmented cellular compartments, proteins, fat molecules that are released from the cellular corpse. This “trash” could cause even more damage to neighboring cells because it exposes them to molecules that normally reside inside a cell and could trigger harmful reactions on the outside. Other cells therefore have to clean up the mess as soon as possible. Macrophages are cells which act as professional garbage collectors and patrol our tissues, on the look-out for dead cells and cellular debris. The remains of the apoptotic cell act as an “Eat me!” signal to which macrophages respond by engulfing and gobbling up the debris (“phagocytosis“) before it can cause any further harm. Macrophages aren’t always around to clean up the debris which is why other cells such as fibroblasts or epithelial cells can act as non-professional phagocytes and also ingest the dead cell’s remains. Nobody likes to be surrounded by trash.

Clearance of apoptotic cells and their remains is thus crucial to maintain the health and function of a tissue. Conversely, if phagocytosis is inhibited or prevented, then the lingering debris can activate inflammatory signals and cause disease. Multiple autoimmune diseases, lung diseases and even neurologic diseases such as Alzheimer’s disease are associated with reduced clearance. The cause and effect relationship is not always clear because these diseases can promote cell death. Are the diseases just killing so many cells that the phagocytosis capacity is overwhelmed, does the debris actually promote the diseased state, or is it a bit of both, resulting in a vicious cycle of apoptotic debris resulting in more cell death and more trash buildup? Researchers are currently investigating whether specifically tweaking phagocytosis could be used as a novel way to treat diseases with impaired clearance of debris.

During the past decade, multiple groups of researchers have come across a fascinating phenomenon by which viruses hijack the phagocytosis process in order to thrive. One of the “Eat Me!” signals for phagocytes is that debris derived from an apoptotic cell is coated by a membrane enriched with phosphatidylserines which are negatively charged molecules. Phosphatidylserines are present in all cells but they are usually tucked away on the inside of cells and are not seen by other cells. When a cell undergoes apoptosis, phosphatidylserines are flipped inside out. When particles or cell fragments present high levels of phosphatidylserines on their outer membranes then a phagocyte knows that it is encountering the remains of a formerly functioning cell that needs to be cleared by phagocytosis.

However, it turns out that not all membranes rich in phosphatidylserines are remains of apoptotic cells. Recent research studies suggest that certain viruses invade cells, replicate within the cell and when they exit their diseased host cell, they cloak themselves in membranes rich in phosphatidylserines. How the viruses precisely appropriate the phosphatidylserines of a cell that is not yet apoptotic and then adorn their viral membranes with the cell’s “Eat Me!” signal is not yet fully understood and a very exciting area of research at the interface of virology, immunology and the biology of cell death.

What happens when the newly synthesized viral particles leave the infected cell? Because these viral particles are coated in phosphatidylserine, professional phagocytes such as macrophages or non-professional phagocytes such as fibroblasts or epithelial cells will assume they are encountering phosphatidylserine-rich dead cell debris and ingest it in their roles as diligent garbage collectors. This ingestion of the viral particles has at least two great benefits for the virus: First and foremost, it allows the virus entry into a new host cell which it can then convert into another virus-producing factory. Entering cells usually requires specific receptors by which viruses gain access to selected cell types. This is why many viruses can only infect certain cell types because not all cells have the receptors that allow for viral entry. However, when viruses hijack the apoptotic debris phagocytosis mechanism then the phagocytic cell is “inviting” the viral particle inside, assuming that it is just dead debris. But there is perhaps an even more insidious advantage for the virus. During clearance of apoptotic cells, certain immune pathways are suppressed by the phagocytes in order to pre-emptively dampen excessive inflammation that might be caused by the debris. It is therefore possible that by pretending to be fragments of dead cells, viruses coated with phosphatidylserines may also suppress the immune response of the infected host, thus evading detection and destruction by the immune systems.

Colorized scanning electron micrograph of filamentous Ebola virus particles (blue) budding from a chronically infected cell (yellow). Credit: National Institute of Allergy and Infectious Diseases, NIH.
Colorized scanning electron micrograph of filamentous Ebola virus particles (blue) budding from a chronically infected cell (yellow). Credit: National Institute of Allergy and Infectious Diseases, NIH.

Viruses for which this process of apoptotic mimicry has been described include the deadly Ebola virus or the Dengue virus, each using its own mechanism to create its fake mask of death. The Ebola virus buds directly from the fat-rich outer membrane of the infected host cell in the form of elongated, thread-like particles coated with the cell’s phosphatidylserines. The Dengue virus, on the other hand, is synthesized and packaged inside the cell and appears to purloin the cell’s phosphatidylserines during its synthesis long before it even reaches the cell’s outer membrane. As of now, it appears that viruses from at least nine distinct families of viruses use the apoptotic mimicry strategy but the research on apoptotic mimicry is still fairly new and it is likely that scientists will discover many more viruses which rely on this and similar evolutionary strategies to evade the infected host’s immune response and spread throughout the body.

Uncovering the phenomenon of apoptotic mimicry gives new hope in the battle against viruses for which we have few targeted treatments. In order to develop feasible therapies, it is important to precisely understand the molecular mechanisms by which the hijacking occurs.  One cannot block all apoptotic clearance in the body because that would have disastrous consequences due to the buildup of legitimate apoptotic debris that needs to be cleared. However, once scientists understand how viruses concentrate phosphatidylserines or other “Eat Me!” signals in their membranes, it may be possible to specifically uncloak these renegade viruses without compromising the much needed clearance of conventional cell debris.

References:

Elliott, M. R. and Ravichandran, K.S. “Clearance of apoptotic cells: implications in health and disease” The Journal of Cell Biology 189.7 (2010): 1059-1070.

Amara, A and Mercer, J. “Viral apoptotic mimicry.” Nature Reviews Microbiology (2015).

 

Note: An earlier version of this article first appeared on the 3Quarksdaily Blog.

 

ResearchBlogging.org

Amara A, & Mercer J (2015). Viral apoptotic mimicry Nature Reviews Microbiology, 13 (8), 461-9 PMID: 26052667

Cellular Alchemy: Converting Fibroblasts Into Heart Cells

Medieval alchemists devoted their lives to the pursuit of the infamous Philosopher’s Stone, an elusive substance that was thought to convert base metals into valuable gold. Needless to say, nobody ever discovered the Philosopher’s Stone. Well, perhaps some alchemist did get lucky but was wise enough to keep the discovery secret. Instead of publishing the discovery and receiving the Nobel Prize for Alchemy, the lucky alchemist probably just walked around in junkyards, surreptitiously collected scraps of metal and brought them to home to create a Scrooge-McDuck-style money bin.  Today, we view the Philosopher’s Stone as just a myth that occasionally resurfaces in the titles of popular fantasy novels, but cell biologists have discovered their own version of the Philosopher’s Stone: The conversion of fibroblast cells into precious heart cells (cardiomyocytes) or brain cells (neurons).

 

Fibroblasts are an abundant cell type, found in many organs such as the heart, liver and the skin. One of their main functions is to repair wounds and form scars in this process. They are fairly easy to grow or to expand, both in the body as well as in a culture dish. The easy access to large quantities of fibroblasts makes them analogous to the “base metals” of the alchemist. Adult cardiomyocytes, on the other hand, are not able to grow, which is why a heart attack which causes death of cardiomyocytes can be so devastating. There is a tiny fraction of regenerative stem-cell like cells in the heart that are activated after a heart attack and regenerate some cardiomyocytes, but most of the damaged and dying heart cells are replaced by a scar – formed by the fibroblasts in the heart. This scar keeps the heart intact so that the wall of the heart does not rupture, but it is unable to contract or beat, thus weakening the overall pump function of the heart. In a large heart attack, a substantial portion of cardiomycoytes are replaced with scar tissue, which can result in heart failure and heart failure.

A few years back, a research group at the Gladstone Institute of Cardiovascular Disease (University of California, San Francisco) headed by Deepak Srivastava pioneered a very interesting new approach to rescuing heart function after a heart attack.  In a 2010 paper published in the journal Cell, the researchers were able to show that plain-old fibroblasts from the heart or from the tail of a mouse could be converted into beating cardiomyocytes! The key to this cellular alchemy was the introduction of three genes – Gata4, Mef2C and Tbx5 also known as the GMT cocktail– into the fibroblasts. These genes encode for developmental cardiac transcription factors, i.e. proteins that regulate the expression of genes which direct the formation of heart cells. The basic idea was that by introducing these regulatory factors, they would act as switches that turn on the whole heart gene program machinery. Unlike the approach of the Nobel Prize laureate Shinya Yamanaka, who had developed a method to generate stem cells (induced pluripotent stem cells or iPSCs) from fibroblasts, Srivastava’s group bypassed the whole stem cell generation process and directly created heart cells from fibroblasts. In a follow-up paper published in the journal Nature in 2012, the Srivastava group took this research to the next level by introducing the GMT cocktail directly into the heart of mice and showing that this substantially improved heart function after a heart attack. Instead of merely forming scars, the fibroblasts in the heart were being converted into functional, beating heart cells – cellular alchemy with great promise for new cardiovascular therapies.

As exciting as these discoveries were, many researchers remained skeptical because the cardiac stem cell field has so often seen paradigm-shifting discoveries appear on the horizon, only to later on find out that they cannot be replicated by other laboratories. Fortunately, Eric Olson’s group at the University of Texas, Southwestern Medical Center also published a paper in Nature in 2012, independently confirming that cardiac fibroblasts could indeed be converted into cardiomyocytes. They added on a fourth factor to the GMT cocktail because it appeared to increase the success of conversion. Olson’s group was also able to confirm Srivastava’s finding that directly treating the mouse hearts with these genes helped convert cardiac fibroblasts into heart cells. They also noticed an interesting oddity. Their success of creating heart cells from fibroblasts in the living mouse was far better than what they would have expected from their experiments in a dish. They attributed this to the special cardiac environment and the presence of other cells in the heart that may have helped the fibroblasts convert to beating heart cells. However, another group of scientists attempted to replicate the findings of the 2010 Cell paper and found that their success rate was far lower than that of the Srivastava group. In the paper entitled “Inefficient Reprogramming of Fibroblasts into Cardiomyocytes Using Gata4, Mef2c, and Tbx5” published in the journal Circulation Research in 2012, Chen and colleagues found that very few fibroblasts could be converted into cardiomyocytes and that the electrical properties of the newly generated heart cells did not match up to those of adult heart cells. One of the key differences between this Circulation Research paper and the 2010 paper of the Srivastava group was that Chen and colleagues used fibroblasts from older mice, whereas the Srivastava group had used fibroblasts from newly born mice. Arguably, the use of older cells by Chen and colleagues might be a closer approximation to the cells one would use in patients. Most patients with heart attacks are older than 40 years and not newborns.

These studies were all performed on mouse fibroblasts being converted into heart cells, but they did not address the question whether human fibroblasts would behave the same way. A recent paper in the Proceedings of the National Academy of Sciences by Eric Olson’s laboratory (published online before print on March 4, 2013 by Nam and colleagues) has now attempted to answer this question. Their findings confirm that human fibroblasts can also be converted into beating heart cells, however the group of genes required to coax the fibroblasts into converting is slightly different and also requires the introduction of microRNAs – tiny RNA molecules that can also regulate the expression of a whole group of genes. Their paper also points out an important caveat.  The generated heart-like cells were not uniform and showed a broad range of function, with only some of the spontaneously contracting and with an electrical activity pattern that was not the same as in adult heart cells.

Where does this whole body of work leave us? One major finding seems to be fairly solid. Fibroblasts can be converted into beating heart cells. The efficiency of conversion and the quality of the generated heart cells – from mouse or human fibroblasts – still needs to be optimized. Even though the idea of cellular alchemy sounds fascinating, there are many additional obstacles that need to be overcome before such therapies could ever be tested in humans. The method to introduce these genes into the fibroblasts used viruses which permanently integrate into the DNA of the fibroblast and could cause genetic anomalies in the fibroblasts. It is unlikely that such viruses could be used in patients. The fact that the generated heart cells show heterogeneity in their electrical activity could become a major problem for patients because patches of newly generated heart cells in one portion of the heart might be beating at a different rate of rhythm than other patches. Such electrical dyssynchony can cause life threatening heart rhythm problems, which means that the electrical properties of the generated cells need to be carefully understood and standardized. We also know little about the long-term survival of these converted cells in the heart and whether the converted cells maintain their heart-cell-like activity for months or years. The idea of directly converting fibroblasts by introducing the genes into the heart instead of first obtaining the fibroblasts, then converting them in a dish and lastly implanting the converted cells back into the heart sounds very convenient. But this convenience comes at a price. It requires human gene therapy which has its own risks and it is very difficult to control the cell conversion process in an intact heart of a patient. On the other hand, if cells are converted in a dish, one can easily test and discard the suboptimal cells and only implant the most mature or functional heart cells.

This process of cellular alchemy is still in its infancy. It is one of the most exciting new areas in the field of regenerative medicine, because it shows how plastic cells are. Hopefully, as more and more labs begin to investigate the direct reprogramming of cells, we will be able to address the obstacles and challenges posed by this emerging field.

 

Image credit: Painting in 1771 by Joseph Wright of Derby – The Alchymist, In Search of the Philosopher’s Stone via Wikimedia Commons

 

ResearchBlogging.org
Nam, Y., Song, K., Luo, X., Daniel, E., Lambeth, K., West, K., Hill, J., DiMaio, J., Baker, L., Bassel-Duby, R., & Olson, E. (2013). Reprogramming of human fibroblasts toward a cardiac fate Proceedings of the National Academy of Sciences, 110 (14), 5588-5593 DOI: 10.1073/pnas.1301019110

Can The Heart Regenerate Itself After A Heart Attack?

Some cardiovascular researchers believe that the heart contains cardiac stem cells or progenitor cells which can become mature cardiomyocytes (beating heart cells) following an injury and regenerate the damaged heart. The paper “Mammalian heart renewal by pre-existing cardiomyocytes” published in the journal Nature by Senyo and colleagues (online publication on December 5, 2012), on the other hand, suggests that the endogenous regenerative potential of the adult heart is very limited. The researchers studied the regeneration of cardiomyocytes in mice using a genetic label that marks cardiomyocytes with a green fluorescent protein and they also used the nonradioactive stable isotope 15N (Nitrogen-15) to track the growth of cardiomyocytes. They found that the adult mouse heart has a very low rate of cardiomyocyte regeneration and projected the annual proliferation rate to be only 0.76%. This means that less than one out of a hundred cardiomyocytes in the adult heart undergoes cell division during a one year period. Even though this number is derived from studying the turnover of cardiomyocytes in mice, it correlates very well with the proposed rate of annual cardiomyocyte self-renewal (0.5% to 1%) that Bergmann and colleagues estimated for the human heart in a 2009 paper published in Science. The key novelty of the paper by Senyo and colleagues is that they identified the source of these new cardiomyocytes. They do not arise from cardiac stem cells or cardiac progenitor cells, but are primarily derived from pre-existing adult cardiomyocytes. Does this low rate of cardiomyocyte turnover increase after an injury? Senyo and colleagues found that eight weeks after a heart attack, only 3.2% of the mouse cardiomyocytes located near the injured areas had undergone cell division.

 

This low rate of self-renewal in the adult heart sounds like bad news for researchers who thought that the adult heart had the ability to heal itself after a heart attack. However, the journal Nature also published the paper “Functional screening identifies miRNAs inducing cardiac regeneration” by Eulalio and colleagues on the same day (online publication on December 5, 2012), which indicates that the low levels of cardiomyocyte growth can be increased using certain microRNAs. A microRNA is a small RNA molecule that can regulate the expression of hundreds of genes and can play an important role in controlling many cellular processes such as cell growth, cell metabolism and cell survival. Eulalio and colleagues performed a broad screen using 875 microRNA mimics in new-born rat cardiomyocytes and identified 204 microRNAs that increase the growth of the cells. They narrowed down the number of microRNAs and were able to show that two distinct microRNAs increased the growth of cardiomyocytes after heart attacks in mice. The effect was quite significant and mice treated with these microRNAs had near-normal heart function 60 days after a heart attack.

Based on these two Nature papers, it appears that the cardiomyocytes in the adult heart have a kind of “brake” that prevents them from proliferating. Addition of specific microRNAs seems to relieve the “brake” and allow the adult heart cells to regenerate the heart after a heart attack. This could lead to potential new therapies for patients who suffer from heart attacks, but some important caveats need to be considered. MicroRNAs (and many other cardiovascular therapies) that work in mice or rats do not necessarily have the same beneficial effects in humans. The mice in the study by Eulalio and colleagues also did not receive any medications that patients routinely receive after a heart attack. Patients usually show some improvement in their heart function after a heart attack, if they are treated with the appropriate medications. Since the mice were not treated with the medications, it is difficult to assess whether the microRNAs would have a benefit beyond that what is achieved by conventional post-heart attack medications. Finally, the delivery and dosing of microRNAs is comparatively easy in mice but much more challenging in a heterogeneous group of patients.

The studies represent an important step forward towards identifying the self-renewal mechanisms in the adult heart and suggest that microRNAs are major regulators of these processes, but many additional studies are necessary before their therapeutic value for patients can be assessed.

 

Image credit: Wikimedia Commons

Somatic Mosaicism: Genetic Differences Between Individual Cells

The cells in the body of a healthy person all have the same DNA, right? Not really! It has been known for quite some time now that there are genetic differences between cells within one person. The expression to describe these between-cell differences is “somatic mosaicism“, because cells can represent a mosaic of genetic profiles, even within a single organ. During embryonic development, all cells are derived from one fertilized egg and ought to be genetically identical. However, during every cell division errors and differences during DNA replication can occur and this can lead to genetic differences between cells. This process not only occurs during embryonic development but continues after birth.

As we age, our cells are exposed to numerous factors such as radiation, chemicals or other stressors which can causes genetic alterations, ranging from single nucleotide mutations to duplications and deletions of large chunks of DNA. Some mutations are known to cause cancer by making a single cell grow rapidly, but not all mutations lead to cancer. Many spontaneous mutations can either result in the death of a cell or do not even impact its function in any significant manner. DNA copy number variations (CNVs) is an expression used to describe a variable copy number of larger DNA segments of one kilobase (kb). Most recent studies on CNVs have compared CNVs between people, i.e. how many CNVs does person A have when compared to person B. It turns out that there may be quite a bit of genetic diversity between people that had previously been overlooked.

A new paper published in the journal Nature takes this one step further. It not only shows that there are significant CNVs between people, but even within a single person. In the study “Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells“, Alexej Abyzov and colleagues found significant CNVs in induced pluripotent stem cells (iPSCs) that they had generated from the adult skin cells of human subjects. Importantly, most of these CNVs were not the result of reprogramming adult skin cells to the stem cell state. They were already present in the skin fibroblasts obtained from the human subjects. Most analyses of CNVs are performed on whole tissues or biopsies, but not on single cells, which is why so little is known about between cell CNV differences. However, when iPSCs are generated from skin fibroblast cells, they are often derived from a single cell. This enables the evaluation of genetic diversity between cells.

Abyzov and colleagues estimate that 30% of adult skin fibroblasts carry large CNVs. This estimate is based on a very small number of fibroblast samples. It is not clear whether other cells such as neurons or heart cells also have similar CNVs and whether the 30% estimate would hold up in a larger sample. Their work leads to the intriguing question: What percentage of neighboring cells in a single heart, brain or kidney are actually genetically identical? Cell types, such as heart cells or adult neurons cannot be clonally expanded so it may be difficult to determine the genetic diversity within a heart or a brain using the methods employed by Abyzov and colleagues.

What are the implications of this work? On a practical level, this study suggests that it may be important to derive multiple iPSC clones from a subject’s or patient’s skin cells, if one wants to use the iPSCs for disease modeling. This will help control for the genetic diversity that exists among the skin cells. However, a much more profound implication of this work is that we have to think about between-cell diversity within a single organ. We need to develop better tools for how to analyze genetic diversity between individual cells, and more importantly, we have to understand how this genetic diversity impacts health and disease.

Image Credit: Wikimedia / Alexander Mosaic (Public Domain)

ResearchBlogging.org

Abyzov A, Mariani J, Palejev D, Zhang Y, Haney MS, Tomasini L, Ferrandino AF, Rosenberg Belmaker LA, Szekely A, Wilson M, Kocabas A, Calixto NE, Grigorenko EL, Huttner A, Chawarska K, Weissman S, Urban AE, Gerstein M, & Vaccarino FM (2012). Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature, 492 (7429), 438-42 PMID: 23160490