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Category: Cell Biology

Genetically “curing” an infertile crop plant into fertile again

Plant geneticists from the University of Tokyo are onto creating novel plant lines that seem to be “more polite” than they already are.1,2,3 However, their technique does not involve implanting a “social” gene of some sort. Rather, scientists would edit plant mitochondrial DNA. In that way, they can, for instance, make a plant bow down even more due to the heavier seeds it would yield. Thus, this could mean a more secured food supply. More interestingly, this genetic modification was accordingly the first time ever to be done on a plant mitochondrial DNA.

Mitochondrial DNA

Mitochondria are one of the three organelles containing nuclear material. The nucleus and the chloroplast are the other two. Scientists have already done successful modifications of the nuclear DNA since1970s. Then, another team of researchers pioneered modification of chloroplast DNA in 1988. However, in terms of mitochondrial DNA, researchers had only found success on animals but not on plants. The first successful animal mitochondrial DNA modification happened in 2008. Then recently, a team of researchers from the University of Tokyo apparently showed success in doing it as well on a plant mitochondrial DNA. In this case, this was the first time.

Basically, mitochondrial DNA is the genetic material in the mitochondrion that carries code for the manufacturing of RNAs and proteins essential to the various functions of the said organelle. Since a mitochondrion has its own genetic material it is described as a semi-autonomous, self-reproducing organelle.

First plant mitochondrial DNA modification

Researchers from the University of Tokyo devised genetic tools that can edit plant mitochondrial DNA. Accordingly, they came up with four new lines of rice and three new lines of rapeseed (canola) using their technique. Between plant and animal mitochondrial genes, those in plants are larger and more complex. Prof. Arimura explicated that plant mitochondrial genes are more complicated in a way that some mitochondria have duplicated genes whereas others lack them. Thus, manipulating plant mitochondrial genome proved more challenging. Their collaboration with other researchers, particularly from Tohoku University and Tamagawa University, led them to their use of the technique mitoTALENs. With it, they were able to manipulate mitochondrial genes in plants.1 To learn their methods in detail you may read their published work here.


The plant mitochondria rapidly moving around the cell (Arabidopsis leaf epidermal cell). Artificially made to glow green to show their actual speed. Video by Shin-ichi Arimura CC-BY

What plant mitochondrial DNA modification can do

After the successful editing of plant mitochondrial DNA, what could be the next big thing? Associate Professor Shin-ichi Arimura, leader of the research team, was enthusiastic indeed about their accomplishment. With a jest, he said, “We knew we were successful when we saw that the rice plant was more polite — it had a deep bow” – implying that a fertile rice plant would bend more due to the heavier weight of the seeds it would yield.1,3

A weak genetic diversity in crops could impose a threat to species survival through time. As a domino effect, that is bad news to our food supply.  Thus, their team hope to use their technique by providing solutions that could significantly enhance genetic diversity in crops, and therefore improve plant species survival and yield. Arimura further said, “We still have a big risk now because there are so few plant mitochondrial genomes used in the world.”1 Furthermore, he mentioned of using their technique for the purpose of adding the much needed mitochondrial DNA diversity among plants.

Cytoplasmic male sterility

plant mitochondrial DNA modification technique
Plant mitochondrial DNA modification technique to enhance crop yield and genetic diversity

Cytoplasmic male sterility (CMS) refers to the male sterility in plants by not producing functional pollen, anthers, or male gametes. It occurs naturally although rarely and probably involve certain nuclear and mitochondrial interactions.4 Nonetheless, others believe that CMS is caused primarily by plant mitochondrial genes.1  In particular, the presence of CMS gene leads to this condition in plants. Thus, removing the CMS gene could convert the plant into becoming fertile again. This is just a start but they are already optimistic that with their technique they could improve crop lines and consequently secure food supply.

plant mitochondrial DNA modification
A mitochondrial gene that causes cytoplasmic male infertility was deleted using a mitoTALENs technique. Infertile rice (right) stands straight, but fertile rice (left) bends under the weight of heavy seeds. Image by Tomohiko Kazama, CC-BY

— written by Maria Victoria Gonzaga

References:

1 University of Tokyo. (2019, July 8). Researchers can finally modify plant mitochondrial DNA: Tool could ensure genetic diversity of crops. ScienceDaily. Retrieved from [Link]

2 Arimura, S. -i., Yamamoto, J., Aida, G. P., Nakazono, M., & Tsutsumi, N. (2004). Frequent fusion and fission of plant mitochondria with unequal nucleoid distribution. Proceedings of the National Academy of Sciences101(20), 7805–7808. [Link]

3 Researchers can finally modify plant mitochondrial DNA | The University of Tokyo. (2019). Retrieved from The University of Tokyo website: [Link]

4 Campo, C. (1999). Biology of Brassica coenospecies. Amsterdam New York: Elsevier. pp.186-89.

RASER proteins selectively “hack” and “shut down” cancer cells

According to World Health Organization, cancer is the second leading cause of death worldwide. The record showed that it caused about 9.6 million deaths last year (2018). Accordingly, one in every six deaths is attributed to cancer.[1]

Cancer defined

Cancer refers to the disease that arises from the faulty uncontrolled proliferation of cell, usually at a rate faster than the normal, and spread to other parts of the body. Benign tumors are also a form of atypical cell proliferation. However, the latter does not spread.

Pathophysiology in cancer cells

Why cancer cells lead to a disease is largely due to the tendency of the cancerous cell to detach and leave its original location to set itself to another site in the body. It could spread locally or drift through the bloodstream and lymphatic system to reach distant parts of the body. As a result, the affected body part eventually cannot carry out its function as it normally would due to the obstructing cancer cells that ought not to be there in the first place. Under those circumstances, our immune system is fashioned to detect cells that have gone “rogue” and then respond by eliminating them accordingly. Nevertheless, cancer cells tend to undergo series of mutations until such time that the genes for tumor suppression have been significantly inactivated while the proto-oncogenes modify into oncogenes.

RASER proteins

A novel approach dubbed as RASER (Rewiring of Aberrant Signaling to Effector Release) showed promising results when it killed cancer cells grown in the lab while sparing non-cancerous healthy cells. Researchers from Stanford Medicine[2] designed RASER system, which, in essence, consists of two proteins fused together. Accordingly, the first protein responds to cancer-causing cell surface signals. It does so by binding to active ErbB receptors, which are always “on” (expressed) in cancer cells. The second protein redirects the cancer cell from cell growth and survival toward programmed cell death (by releasing a customizable “cargo” into the cell). When the first protein binds to an active ErbB receptor, the second protein component is cut off from the RASER moiety and then binds to the inner surface of the plasma membrane of the targeted cell. The researchers customized the “cargo” sequence that the second protein carries. Once inside the cell, the second protein releases the RASER “cargo” — in this case, one that triggers the cell to undergo cell death.[2]


Top:  Illustration of cancer growth where cell surface proteins signal the nucleus to proliferate uncontrollably and survive (see green pathway). Bottom: Illustration of how RASER works by redirecting the signal away from cell proliferation and survival toward programmed cell death (see orange pathway). Image credit: Michael Lin and Stuart Jantzen (Ref.2)

One of the researchers, Michael Lin, MD, PhD, said that with this new approach they could rewire cancer cells and bring about an outcome according to their choosing. Furthermore, he said, “We’ve always searched for a way to kill cancer cells but not normal cells. Cancer cells arise from faulty signals that allow them to grow inappropriately, so we’ve hacked into cancer cells to redirect these faulty signals to something useful.” [2]

Although it could take time, still, the conception and the future progress of RASER is an auspicious cancer treatment. In due course, cancer patients may reap from its stance of being more highly selective to cancer cells while sparing the healthy ones in which the current cancer treatments are failing at.

— written by Maria Victoria Gonzaga

References:

1 World Health Organization (WHO). (2018, September 12). Cancer. Retrieved from Who.int website: [Link]

 2 Conger, K. (2019). Synthetic biology used to target cancer cells while sparing healthy tissue. Retrieved from News Center website: [Link]

Scientists brought dead pig brain partly back to life

Death is inevitable to any entity that has life. When there is a beginning there ought to be an end.  However, the recent findings of a team of researchers seemed to paint a gray line between what’s supposedly dead and what’s alive. Accordingly, they were able to restore certain functions on pig brains that had been dead for hours and were essentially isolated from the body. Does it mean resurrecting a dead brain could eventually be made possible by science?

Bringing a dead brain back to life

A research team conjured up a special chemical liquid that apparently restored some of the functions of dead pig brains. They isolated the brain from the heads of post-mortem pigs. The researchers then hooked up the device pumping the concoction for six hours through the blood vessels of the dead brain. They used 32 pigs that had been dead for about four hours after being slaughtered (for food). 1 As such, the pig brains were bereft of circulating blood and glucose for four hours prior to the treatment.

The research team discovered that the pig brains that received the treatment looked different from the pig brains that did not (controls). Apparently, the tissues and cell structures of the treated pig brains appeared preserved. Moreover, certain cellular functions seemed restored.

The resurrecting BrainEx

The patented chemical solution (a perfusate) was delivered by a pulsatile-perfusion system (referred to as BrainEx2). The authors described the perfusate as hemoglobin-based, acellular, non-coagulative, cytoprotective, and echogenic.3 In essence, the system was contrived to mimic blood circulating through the organ. Thus, its role is to rehydrate the post-mortem pig brains, at least for six hours. The results were indeed astounding. The dead brain had some of the basic cell functions restored. ‌

The authors attributed the following effects3 to the BrainEx system:

  • recovery from anoxia
  • edema prevention
  • reduced reperfusion injury
  • metabolic support to the brain’s energy demand
  • preservation of cell structure
  • attenuated cell death
  • revived blood vessel structure
  • localized synaptic activity and glial immune response

The authors, though, noted that they had not observed any higher level functional activity, like electrical signaling that normally would indicate consciousness.

Immunofluorescent staining of dead brains of pig
Immunofluorescent stains of the post-mortem pig brain “un-perfused” (left) vs. that perfused with BrainEx technology (right). After ten hours post-mortem, neurons (green) and astrocytes (red) of the dead brain underwent cellular disintegration unless salvaged by BrainEx (Ref: 4). [Credit: Stefano G. Daniele & Zvonimir Vrselja; Sestan Laboratory; Yale School of Medicine]

Implications

The brain exposed to hypoxic condition for even a few minutes could end up suffering an irreparable damage. In fact, the human brain can survive oxygen deficiency as long as the oxygen supply is swiftly restored idyllically within about six minutes. Otherwise, the brain will start to die. With this recent breakthrough, this means that a dead brain may have its functions restored. Nenad Sestan, the lead author, was quick to point out though that the brain administered with the perfusion was revived not as a living brain per se but as a “cellularly active brain”1. Nonetheless, the research team believed that their findings could one day find its invaluable use in helping out victims of brain trauma, strokes and heart attacks. These life-threatening conditions could abruptly cut blood flow and oxygen supply leading to brain injuries considered as irreversible, even fatal. This revolutionary finding, now, gives hope.

human brain photo by Rev314159 flickr
Human brain. [Credit: Rev314159, Flickr, by CC BY-ND 2.0]

Ethical issues

In spite of the promising breakthrough in neuroscience and medicine, their findings trigger ethical concerns. Could this be the start of resurrecting the dead? Stephen Latham, from Yale’s Centre of Bioethics and one of the authors, reassured, “If some activity shows up that indicated consciousness, we would have to stop the experiment”.5 They made it clear that they did not intend to awaken consciousness. And, if inadvertently they did so they would immediately resort to anesthetics and temperature-reduction in order to stop electrical signaling as soon as it emerged. Still, they hope to gain insights involving post-mortem human brains. All the same, they will only do so within the confines of utmost ethical considerations.

— written by Maria Victoria Gonzaga

References:

1  Scientists Restore Some Function In The Brains Of Dead Pigs. (2019, April 17). Retrieved from NPR.org website: [Link]

2   Ranosa, T. (2019, April 19). Are We Close To Resurrecting The Dead? Scientists Revive Brain Cell Activities In Dead Pigs. Retrieved from Tech Times website: [Link]

3    Vrselja, Z., Daniele, S. G., Silbereis, J., Talpo, F., Morozov, Y. M., Sousa, A. M. Mario, S., Mihovil, P., Navjot, K., Zhuan, Z. W., Liu, Z., Alkawadri, R., Sinusas, A. J., Latham, S.R., Waxman, S. G., & Sestan, N. (2019). Restoration of brain circulation and cellular functions hours post-mortem. Nature568(7752), 336–343. [Link]

4  Yale University. (2019, April 17). Scientists restore some functions in a pig’s brain hours after death. ScienceDaily. Retrieved from [Link]

5   Researchers Restore Some Function To Brains Of Dead Pigs. (2019, April 17). Retrieved from Yahoo.com website: [Link]

Mitochondrial DNA not just from moms but also from dads?

If one wants to trace down lineage, that person could turn to the cell’s powerhouse, the mitochondrion. This organelle contains its own special set of DNA believed as inherited solely from mothers across generations.  Thus, looking at the mitochondrial DNA (by mtDNA genealogical DNA testing) could help track down lineage, and for this reason, help determine ancestral or familial connection. Recently though, a team of scientists reported that the mitochondrial DNA is not solely inherited from the mothers. New empirical evidence of biparental inheritance of mitochondrial DNA implicates the need to rectify the long-held notion that the inheritance of mitochondrial genome is exclusively matrilineal or female line.

 

 

Mitochondrial DNA

The mitochondrion (plural: mitochondria), reckoned as the powerhouse of the cell, generates metabolic energy, especially the form of adenosine triphosphate (ATP). And it does so through the process referred to as cellular respiration. Apart from that, the organelle is also described as semi-autonomous since it has its own genetic material distinct from that found in the nucleus. The nucleus contains more genes organized into chromosomes and in charge for almost all of the metabolic processes in the body. On the contrary, the genetic material in the mitochondrion – referred to as mitochondrial DNA – is relatively fewer in number. It carries the genetic code for the manufacturing of RNAs and proteins necessary to the various functions of the mitochondrion, such as energy production.

 

(Recent news on the evolutionary origin of mitochondria, read: Prokaryotic Ancestor of Mitochondria: on the hunt)

 

(You may also want to read: Mitochondrial DNA – hallmark of psychological stress)

 

Mitochondrial inheritance

In humans, the mitochondrial DNA is believed to be inherited solely from the mother. This notion stems from the events that happen at fertilization. The sperm contains on its neck a helix of mitochondria that power up the tail to swim toward the ovum. And when the sperm finally makes its way into the ovum, it leaves its neck and tail on the cell surface of the ovum. Mitochondria that are brought into the ovum would eventually be inactivated and disintegrated. Thus, the mitochondria in the ovum are the only ones that the zygote eventually inherits. A human ovum has an average of 200,000 mtDNA molecules.1 For this, certain traits and diseases involving mitochondrional DNA implicate maternal origin.

 

 

 

Inheritance of mitochondrial DNA– not exclusive

mitochondrial dna eve
The theory of Mitochondrial Eve is based on the exclusivity of human mitochondrial DNA inheritance to the female line, which when traced would lead to only one most recent woman, “Eve”. (Image credit: Ludela, Creative Commons Attribution-Share Alike 3.0 Unported)

 

The theory of Mitochondrial Eve holds that tracing the matrilineal lineage of all recent human beings would lead to all lines converging to one woman referred to as “Eve“. The theory is based on the exclusivity of human mitochondrial DNA inheritance to female line. Nevertheless, independent empirical findings and clinical studies challenge this precept.

 

For instance, Schwartz and Vissing2 reported the case of a 28-year-old man with mitochondrial myopathy. Accordingly, the patient had a mutation (a novel 2-bp mtDNA deletion in ND2 gene). Normally, the gene encodes for a subunit of the enzyme complex I of the mitochondrial respiratory chain. Thus, the faulty gene affected the production of such enzyme, which, in turn, led to the patient’s severe, lifelong exercise intolerance. Furhter, Schwartz and Vissing2 pointed out that the patient’s mitochondrial myopathy was paternal in origin.

 

Recently, a team of researchers observed paternal inheritance of mitochondrial DNA, but this time, on 17 people from three different families.3 They sequenced their mitochondrial DNAs and they discovered father-to-offspring transmission.

 

 

Conclusion

The mitochondrial DNA is said to be a mother’s legacy to her offspring. However, recent studies indicate that the father could also transmit it to his progeny. Somehow, paternal mitochondrial DNA gets into the ovum. Rather than disintegrated or inactivated, it gets expressed. Mitochondrial DNA from the fathers may not be as rare as once thought.  If more studies will corroborate soon, this could debunk Mitochondrial Eve theory. It might also render mtDNA genealogical DNA testing questionable. And, we may also need to start looking to the other side of our lineage to fathom hereditary diseases arising from faulty mitochondrial DNA.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Mitochondrial DNA. (2018). Biology-Online Dictionary. Retrieved from https://biology-online.org/dictionary/Mitochondrial_DNA

 

2 Schwartz, M. & Vissing, J. (2002). “Paternal Inheritance of Mitochondrial DNA”. New England Journal of Medicine. 347 (8): 576–580.

 

3 Luo, S.,  Valencia, C.A.,  Zhang, J., Lee, N., Slone, J., Gui, B., Wang, X.,  Li, Z.,  Dell, S., Brown, J., Chen, S.M.,  Chien, Y., Hwu, W., Fan, P.,  Wong, L.,  Atwal, P.S., & Huang, T. (2018). Biparental Inheritance of Mitochondrial DNA in Humans. Proceedings of the National Academy of Sciences 201810946. DOI:10.1073/pnas.1810946115

Pathobiology of allergy and its most severe form, anaphylaxis

When allergy season looms, some people with serious hypersensitivity to allergens tend to be apprehensive of what may come. Some would rather stay indoors than risking the odds of sucking up triggers that could instigate severe allergic reactions. Apart from triggers from the environment, other common factors for allergy include food, medication, certain toxins, venom from insect stings or bites, stress, and heredity. How does an allergy manifest? Which cells are involved in forming an allergic reaction?

 

 

 

The immune system

allergy
How does an allergy occur? The pathobiological mechanism involves several white blood cells that play a role in mounting an allergic reaction.

 

The immune system protects the body from foreign substances (generally referred to as antigens) that could pose a threat to our well-being.  It prevents harmful bacteria, viruses, parasites, etc. from invading and causing harm. The white blood cells (also called leukocytes) constantly scout for antigens in order to destroy or disable them. The white blood cells include lymphocytes, neutrophils, basophils, eosinophils, monocytes, macrophages, mast cells, and dendritic cells.

 

 

 

Allergy – overview

 

allergy pathway
The allergy pathway.
Image (by Sari Sabban) distributed under the CC 3.0 Unported license.

 

An allergy is a state of hypersensitivity of the immune system in response to an allergen (i.e. a substance capable of inciting an allergic reaction). In this regard, several white blood cells play a role in mounting an allergic reaction.

In summary, the entry of an allergen into the body triggers an antigen-presenting cell, such as a dendritic cell. The dendritic cell takes up the allergen, process it, and then present its epitopes through its MHC II receptor on its cell surface. It, then, migrates to a nearby lymph node, waiting for a T lymphocyte to recognize it.

Upon recognition, the T lymphocyte may differentiate into a Th2 cell (type 2 helper T cells), which is capable of activating B lymphocyte. B lymphocyte, when activated, matures into a plasma cell that could synthesize and release IgE antibody in the bloodstream. Some of the circulating IgE may bind to mast cell and basophil. Thus, re-entry of such allergen could incite the IgE on mast cells and basophils to recognize its epitope. In effect, this activates the mast cell or basophil to release inflammatory substances (e.g. histamine, cytokines, proteases, chemotactic factors) into the bloodstream.

 

 

 

Anaphylaxis – a dreadful allergic reaction

The allergic reaction mounted by the immune system is supposed to protect the body. However, the allergens perceived by the body as a threat are generally harmless. The body tends to overly react to the allergens, and so leads to symptoms. Histamine, for instance, brings about the common symptoms of allergy: pain, heat, swelling, erythema, and itchiness.

 

Anaphylaxis is the most severe form of allergic reaction. It can occur rapidly and it affects more than one body system, such as respiratory, cardiovascular, cutaneous, and gastrointestinal systems. It occurs as a result of the release of inflammatory substances from mast cells and basophils upon exposure to an allergen. Within minutes to an hour, symptoms could manifest as a red rash, swelling, wheezing, lowered blood pressure, and in severe cases, anaphylactic shock.

 

In the presence of breathing difficulties, racing heart, weak pulse, and/or a change in voice, the situation is precarious. It calls for an immediate medical attention.

 

Why does anaphylaxis occur? IgE-mediated anaphylaxis is the common form of anaphylaxis. Initial exposure to an allergen leads to the release of IgE so that re-exposure to the allergen leads to its identification and the eventual activation of mast cells and basophils.  Apart from immunologic factors, though, other causes of anaphylaxis are non-immunologic. For example, temperature (hot or cold), exercise, and vibration may cause anaphylaxis. In this case, IgE is not involved. Rather, these agents directly cause the mast cells and the basophils to degranulate.

 

 

 

Novel mechanism identified

Recently, a team of researchers1,2 found a novel mechanism that could explicate the hasty allergic reaction during anaphylaxis. They were first to uncover a mechanism involving the dendritic cells. Accordingly, a set of dendritic cells seem to “fish” allergens from the blood vessel using their dendrites. The dendritic cell near the blood vessel takes up the blood-borne allergen. Rather than initially processing it, and then presenting the epitope on its surface, it hands over the allergen inside a micro-vesicle to the adjacent mast cells.

 

Mast cells, unlike basophils that are in the bloodstream, are located in tissues, such as connective tissue. Thus, the question as to how the mast cells detect blood-borne allergen could be answered by the recent findings.

 

Rather than being internalized by the dendritic cells for processing, the allergen was merely taken into a micro-vesicle that budded off from the surface of dendritic cells. This, thus, saves time. It cuts the process, leading to a much rapid allergic reaction.

 

However, these findings were observed in mouse models. Therefore, the researchers have yet to observe if this novel mechanism also holds true on humans. If so, this could lead to possible therapeutic regulation of allergies, especially the most dreadful form, anaphylaxis.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Choi, H.W., Suwanpradid, J. Il, Kim, H., Staats, H. F., Haniffa, M., MacLeod, A.S., & Abraham, S. N.. (2018). Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesiclesScience 362 (6415): eaao0666 DOI: 1126/science.aao0666
2 Duke University Medical Center. (2018, November 8). Using mice, researchers identify how allergic shock occurs so quickly: A newly identified immune cell mines the blood for allergens to directly trigger inflammation. ScienceDaily. Retrieved November 22, 2018 from www.sciencedaily.com/releases/2018/11/181108142440.htm

 

First time! Human blood cell turned into a young sex cell

In essence, our body consists of two major types of cells – one group involved directly in reproducing sexually (called sex cells) and another group that are not (called somatic cells). In particular, the female sex cell is referred to as the ovum (also called egg cell) whereas the male sex cell, the sperm cell. The somatic cells, in turn, are the cells in the body that have varying functions, such as nourishing the sex cells as well as keeping the body thriving and functional.

 

 

 

Origin of sex cells

Our body produces sex cells through the process called gametogenesis. The process is essentially a step-by-step process of meiosis. Oogenesis (i.e. gametogenesis in females) takes place in the ovaries to produce ova or egg cells. In brevity, the oogonium (the female primordial germ cell) undergoes meiosis to produce four haploid egg cells. Conversely, spermatogenesis (i.e. gametogenesis in males) occurs in the testes to yield sperm cells. Quintessentially, the spermatogonium (the male primordial germ cell) will go through meiosis to give rise to four haploid sperm cells.

 

 

 

Sex cells vs somatic cells

In humans, a sex cell may be identified from a somatic cell in being a haploid cell. That means a sex cell would have half the number of chromosomes as that of a somatic cell. Hence, an egg cell or a sperm cell would have 23 chromosomes whereas a somatic cell would have 46. Haploidy in sex cells is important in order to maintain the chromosomal integrity in humans across generations.

 

At fertilization, the sperm cell and the egg cell unite to form a diploid cell (called zygote). The zygote, then, divides mitotically, giving rise to pluripotent stem cells. A pluripotent stem cell is a cell capable of giving rise to various precursors that eventually will acquire specific identity and physiological function via a process called differentiation. A differentiated cell means that the cell has matured and acquired a more specific role, for instance as a skin cell, a blood cell, a liver cell, etc.

 

 

 

Somatic cell converted to sex cell

sex cell
Soon, a somatic cell could be converted into human sex cells.
[Image credit: Karl-Ludwig Poggemann, Flicker.com, CC by 2.0]

 

Intrinsically, a human somatic cell that has “differentiated” could never become a sex cell just as a sex cell could neither become nor give rise to a somatic cell. However, this may no longer hold true in the years to come.

 

Japanese researchers have, for the first time, successfully converted a somatic cell into a sex cell precursor.1 In particular, they had successfully created an oogonium from a human blood cell. They turned blood cells into “induced pluripotent stem cells” (iPS).2 Essentially, the blood cells – turned iPS – appeared to have undergone “molecular amnesia”. It means they forget their initial identity. As a result, they could become any type of cell, even as a sex cell.

 

The researchers transformed human blood cells into oogonia (plural of oogonium). They did so by incubating them for four months in artificial ovaries derived from embryonic mouse cells. They retrieved promising results. Admittedly though, they acknowledged they are still in the early steps of a rather long journey of research. The oogonia, indeed precursors to egg cells, are, at this point, still young, and thereby, unfit for fertilization. The researchers have yet to induce them to become mature, fully differentiated egg cells. Nevertheless, they remain optimistic in having reached this point, and, undeniably, pioneered an important milestone.

 

 

 

 

Ethical issues

If, in the future, research on the conversion of a somatic cell into a sex cell pushes through to completion, it could lead to significant resolves to infertility issues. However, ethical concerns shall, likely, surface as well. For instance, a possibility could occur in time. A mere hair cell or a skin cell from an unsuspecting person could be turned into an egg or a sperm cell. And from there, an offspring could come into existence.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Yamashiro, C., Sasaki, K., Yabuta, Y., Kojima, Y., Nakamura, T., Okamoto, I., Yokobayashi, S., Murase, Y., Ishikura, Y., Shirane, K., Sasaki, H., Yamamoto, T., & Saitou, M. (2018 Oct 19).Generation of human oogonia from induced pluripotent stem cells in vitro. Science, 362(6412):356-360. doi: 10.1126/science.aat1674.

 

2 Solly, M. (2018 Sept. 24). Scientists create immature Human Eggs Out of Blood Cells For the First Time. Retrieved from [link]

 

Mitochondrial DNA – hallmark of psychological stress

We often hear that stress can be unsettling as it could make us ill when it becomes chronic and overwhelming. However, is there really a biological ratification behind it? Is it scientifically founded? Apparently, independent studies hinted a biological connection indicating how stress can cause biological damage, and eventually lead to certain ailments. And, the mitochondrial DNA — the genome in the mitochondrion appears to play a role.

 

 

 

Biological features of mitochondria

mitochondrial process
Mitochondrial processes that lead to the generation of ATP.
Credit: Boumphreyfr, under the Creative Commons Attribution-Share Alike 3.0 Unported license

 

The mitochondrion (plural: mitochondria) is an organelle that supplies molecular energy for various biological activities. In essence, this rod-shaped structure found within the cell accounts for the generation of ATP, the cell’s major energy source. Thus, the mitochondrion is known to be the “powerhouse of the cell“.

 

Through the process of cellular respiration, glucose (a monosaccharide) is “churned” to extract energy, primarily, in the form of ATP. Firstly, a series of reactions leads to the conversion of glucose to pyruvate. Then, it uses pyruvate, converting it into acetyl coenzyme A for oxidation via enzyme-driven cyclic reaction called Krebs cycle. Finally, a cascade of reactions (redox reactions) involving the electron transport chain leads to the production of ATPs (via chemiosmosis).

 

The mitochondria have their own genetic material, called mitochondrial DNA. Because of this, the mitochondrion is regarded as semi-autonomous and self-reproducing organelle. It means it can manufacture its own RNAs and proteins.  Generally, we inherit the mitochondrial genome maternally, as opposed to the nuclear genome that we inherit from both parents.

mitochondrial DNA
Mitochondrial DNA.
Credit: National Institutes of Health

 

 

 

Mitochondrial fate during stress

mitochondrial DNA and stress
Psychological stress can cause biological damage, such as the release of mitochondrial DNA from damaged and worn-out mitochondria.

 

When confronted with a stressful situation, our body responds intrinsically. We tend to breathe fast. The heartbeat goes wild. Our muscles tense up. And, we sweat profusely. All these responses (so-called “fight-or-flight“) can be an arduous task as they abruptly demand energy. When triggered for so long, eventually, we feel exhausted.  Sooner or later, stress sets in and it takes its toll on our health.

 

The mitochondria work for an extended time just to meet up the spike of demand for energy. In effect, they become vulnerable to damage from too much work.  Inopportunely, the mitochondria have limited repair mechanisms unlike the nucleus.1 And in the end, it results in the disruption of the organelle, thereby, releasing the mitochondrial DNA into the cytoplasm. Eventually, the genetic material reaches the bloodstream where they become genetic cast-offs.

 

 

 

Mitochondrial DNA cast-offs

The ejected mitochondrial DNA, apparently, becomes genetic wastes and stress might have something to do with this outcome. This theory came about based on a series of studies. Firstly, Gong et al. found that chronic mild stress resulted in mitochondrial damage in hippocampus, hypothalamus, and cortex in mouse brains.2

 

Secondly, another team of researchers (Lindqvist et al.) reported that individuals who had recent suicide attempt had higher plasma level of freely circulating mitochondrial DNA in blood than those of healthy individuals.3

 

Thirdly, Martin Picard (a psychobiologist at Columbia University), together with his team, observed similar findings in their participants exposed to a stressful situation. Accordingly, their participants – healthy men and women – were asked to defend themselves against a false accusation. Their blood samples were taken before and after the interview. The researchers found that the mitochondrial DNA in the serum of the participants increased twice 30 minutes after the test. 1 Picard explained that the mitochondrial DNA might have acted like a hormone. Furthermore, he theorized that the ejection of these genetic cast-offs might have mimicked the adrenal gland cells releasing cortisol in response to stress. 1

 

 

 

Mitochondrial DNA as an inflammatory factor

Zhang et al. observed that circulating mitochondrial DNA triggered inflammatory responses. Accordingly, the genetic cast-offs can bind to TLR9 (a receptor) on the immune cell. This binding might have incited the immune cell to respond the same way as they do when reacting with antigens. It might have stimulated the cell to release cytokines that call for other immune cells to the site. 1

 

 

 

So far, these conjectures from independent studies disclose the possible direct biological damage due to stress. There could be a biological insinuation that stress could play a part in the manifestation of ill-health conditions. And, the upsurge of circulating mitochondrial DNA cast-offs is one of them. More information and studies on mitochondrial DNA are delineated on a report on mental health published in Scientific American.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Sheikh, K. (2018 Sept 13). Brain’s Dumped DNA May Lead to Stress, Depression. Scientific American. Retrieved from https://www.scientificamerican.com/article/brain-rsquo-s-dumped-dna-may-lead-to-stress-depression/
2 Gong, Y. Chai, Y., Ding, J. H., Sun, X. L., & Hu, G. (2011).Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neuroscience Letters, 488 (1): 76-80. https://doi.org/10.1016/j.neulet.2010.11.006
3 Lindqvist, D., Fernström, J., Grudet, C., Ljunggren, L., Träskman-Bendz, L., Ohlsson, L., & Westrin, Å. (2016). Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity. Translational Psychiatry, 6 (12), e971–. http://doi.org/10.1038/tp.2016.236

Porphyromonas gingivalis: Periodontitis bacterium induces memory impairment and neuroinflammation

Porphyromonas gingivalis is a bacterium commonly associated in periodontitis a chronic inflammatory disease in the oral cavity.  Periodontium is composed of periodontal ligament, cementum, alveolar bone and gingiva. Porphyromonas gingivalis is a gram-negative bacterium that contains toxic components. It is characterized by the presence of edema and destruction of tissue supporting the teeth. In which periodontal bacteria enters into circulation that leads to bacteremia and system dissemination of bacterial products. Moreover, Porphyromonas gingivalis can promotes systemic effects through expression of inflammatory mediators like pro-inflammatory cytokines. As a consequence it is confirmed to be associated with systemic diseases such as diabetes, respiratory disease and cardiovascular disease.

Potential effects of Porphyromonas gingivalis

Neurodegenerative diseases have been recognized as the major cause of cognitive and behavioral damage. It is known that peripheral infections could activate microglial cells within the nervous system enhancing development of neurodegeneration. Thus, the inflammatory molecules in the brain could be enhanced by periodontitis that increase inflammatory levels promoting the development of Alzheimer’s disease. In this particular research Porphyromonas gingivalis infection may impair cognition by elevating expression of pro-inflammatory cytokines. It is also shown that the infected mice displayed impaired memory and learning abilities. Elevated levels of pro-inflammatory mediators in the blood can lead to direct or indirect transport to the brain.

 

Periodontal infection caused by Porphyromonas gingivalis promotes neuro-inflammatory response via releasing pro-inflammatory cytokines. In which inflammation induces alterations in neurovascular functions causing increased in blood brain barrier permeability and aggregation of toxins. In brain trauma, infection and presence of endogenic abnormal protein aggregates can activate secretions of TNF-α. That plays a pivotal role in the development and functions of central nervous system. Moreover, aging is also associated to chronic inflammation which exerts additional stress to the brain nerve cells. Additionally, during systemic inflammation the functions of the blood-cerebrospinal fluid barrier were also significantly affected.

 

Therefore, Porphyromonas gingivalis periodontal infection may induce age-dependent brain inflammation. Also periodontitis can cause memory impairment which has a similar effect on the development of Alzheimer’s disease. Furthermore, aging is the major risk factor of Alzheimer’s disease and is correlated with elevated glial responsiveness. And in due course might increase the brain’s susceptibility to injury and disease.

 

Source: Prepared by Joan Tura from BMC Immunity and Aging

Volume 15:6, January 30, 2018

 

Cells know when to separate at mitosis

How do cells know when to separate during mitosis? A molecule called BubR1 was found to regulate the timing of the division of a parent cell into two progeny cells. Researchers who identified the role of BubR1 were optimistic that their discovery could lead to a potential cancer treatment by inducing cancer cells to undergo premature mitosis.

 

 

 

Phases of mitosis

When a cell enters the Synthesis phase (S phase) of the cell cycle, it is likely that it will subsequently go through the sequential phases of mitosis in which a single cell ultimately gives rise to two cells, each with its own copy of chromosomes. Firstly, the cell enters prophase, which is the phase of mitosis largely characterized by the condensation of chromatin (becoming distinct chromosomes), the beginning of spindle fiber formation, and the disintegration of the nucleolus, nuclear membrane, and organelles. This is then followed by a phase, called metaphase, wherein the chromosomes align along the metaphase plate and the microtubules attach to the kinetochores. Then, the chromosomes are pulled apart toward the opposite poles of the cell during anaphase. In the last phase of mitosis called telophase, the chromosomes have completely moved to the opposite poles of the cell resulting in two sets of nuclei. The cytoplasm divides ultimately giving rise to two new cells.

 

 

 

Delaying strategy of BubR1 during mitosis

Mitotic checkpoint complex.1

 

Researchers from Institute of Cancer Research reported in their paper published in Molecular Cell the role of BubR1 in mitosis.  Accordingly, the spindle assembly checkpoint (SAC) prevents the separation of sister chromatids until all chromosomes are properly attached to the spindle. It also catalyzes the formation of the Mitotic Checkpoint Complex (MCC).1 The BubR1 is part of this molecular complex that regulates the Anaphase Promoting Complex/Cyclosome (APC/C). In particular, the BubR1 is part of the molecular machinery that delays the onset of anaphase during mitosis. The delay is crucial as it ensures the chromosomes to be properly positioned before they will be segregated.2

 

The researchers further reported that the N-terminal half of BubR1 contains two ABBA motifs. When they mutated these BubR1motifs, the cells become unable to normally delay mitosis. Moreover, the two resulting cells following mitosis had unevenly divided chromosomes. They explained that without the normal ABBA sequences of BubR1, the MCC failed to bind to the APC/C. Consequently, mitosis progressed despite the chromosomes not yet being properly positioned.

 

 

 

Premature mitosis for cancer cells

The researchers made note of the importance of the ABBA sequence of BubR1. It served as a “safety catch” – preventing the machinery from progressing prematurely. Accordingly, cancer cells rely on this safety catch much more than normal cells as they usually have extra chromosomes to be put into place, and thereby need more time for mitosis.2 This could therefore be used to design cancer treatment, such as a drug that could switch off the “safety catch” of BubR1, and forcing cancer cells to divide prematurely with an unevenly divided chromosomes following mitosis.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Fiore, B.D.,  Wurzenberger, C., Davey, N.E., & Pines, J. (2018).Molecular Cell. https://doi.org/10.1016/j.molcel.2016.11.006

2 Institute of Cancer Research. (2016, December 8). Scientists reveal ‘safety catch’ within all dividing cells: Major discovery could lead to new cancer treatments. ScienceDaily. Retrieved August 7, 2018 from www.sciencedaily.com/releases/2016/12/161208143306.htm

Parental chromosomes are together but still apart at first mitosis

A recent finding by a team of researchers from European Molecular Biology Laboratory on the parental chromosomes during the first mitosis of an embryo implicates a possible revision in biology textbooks. What they observed during the first mitotic division after the supposed “union” of gametes in mouse models apparently invalidates what is currently believed. Biologists assume that there is only one spindle apparatus that works to separate the two parental chromosomes during the first cell division of a mammalian zygote. It turns out that there are two. Their finding could also help explicate the common errors occurring during the first divisions in the early embryos of mammals, and possibly of humans.

 

 

Early model of mitosis in mammalian zygote

Mitosis of a human cell. In this image, the microtubules are shown in green, chromosomes (DNA) in blue, and kinetochores in red.

 

The first mitosis in mammals occurs during the union of male and female chromosomes. Upon fertilization, the zygote holds two parental chromosomes that unite, and then separated, triggering the formation of two cells (each with own nucleus) after the first mitosis. This marks the two-cell stage embryo.

The first mitosis is thought to proceed initially by the break-down of the nuclear envelope. This enabled the two parental chromosomes to unite thereafter. A single spindle assembly then forms. The spindles attach to the chromosomes, align them at metaphase, and then pull them apart during anaphase. The first mitosis ends at telophase where the cell divides into two cells, each with its own nucleus.

 

 

Viewing first mitosis through light-sheet microscopy

Researchers from European Molecular Biology Laboratory found out that there is not one but two spindle apparatus at work during the first mitosis of the mouse embryo. Using a light-sheet microscopy approach, they were able to conduct real-time, 3D imaging of the mouse embryo.1 Without this innovative technology, capturing an image at this stage will not be feasible because embryos are sensitive to light. With it, the researchers were able to track the chromosomes during the supposed union and saw differently what has long been held. They were surprised to find out that (1) the maternal and the paternal chromosomes assembled their own autonomous spindle structure and (2) the parental chromosomes remain in separate regions and did not mix prior to and during the first mitosis.1,2

 

 

Current model of first mitosis

Based on the current mouse embryo model, what transpires at first mitosis after the nuclear envelope disintegration post-fertilization event is that both the maternal and the paternal chromosomes form their own spindle apparatus. The mitotic spindles then attach to the chromosomes. Even so, the maternal and the paternal chromosomes remain in separate regions of the spindle. The spindles align them in a way that the maternal chromosomes align juxtapose to where the paternal chromosomes align. The two spindle apparatus then autonomously pull them apart towards opposite poles. The cell finally divides into two, where each has only one nucleus. Conversely, an erroneous axis alignment of paternal chromosomes during metaphase was observed to lead to the formation of one of the cells with multiple nuclei after the first mitosis.

The recent findings could help explain certain errors (e.g. multiple-nucleated cell) following the first mitosis. If this mechanism holds true to humans as well it could lead to new targets for treatment (particularly an erring first mitotic spindle apparatus) in a developing embryo. It might also provide an insight as to when life can be assumed to first exist — is it during the first meet-up of the male and the female chromosomes that do not mix yet… or is it that point at which they unite — but apparently occurs only after the first mitosis.

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:

1 Reichmann, J., Nijmeijer, B., Hossain, M. J., Eguren, M., Schneider, I., Politi, A.Z., Roberti, M.J., Hufnagel, L., Hiiragi, T. & Ellenberg, J. (2018). Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryosScience. DOI: 10.1126/science.aar7462

2 Zielinska, A.P. & Schuh, M. (2018). Double trouble at the beginning of life. Science  361 (6398): 128-129. DOI: 10.1126/science.aau3216