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Author: Maria Victoria Gonzaga

CRISPR DIY – biohacking genes at home

Have you ever thought of changing yourself for the better — genetically-speaking? Lately, CRISPR company has been selling a CRISPR DIY, i.e. a gene-therapy kit purchasable online. Thus, you could biohack and strike genes at your convenience, practically whenever and wherever — even right at the comfort of your home.

 

 

CRISPR – a scientific breakthrough

CRISPR would not be considered as Science’s Breakthrough of the Year in 2015[1] for nothing. Previously, I wrote a blog how mosquitoes could be wiped out by CRISPR–Cas9 gene drive. I delineated how CRISPR could serve apparently as our “last resort” against one of the deadliest animals on Earth, the mosquitoes.

 

We all know these miniscule mosquitoes could pose a huge threat on the lives of many. They are deadly not because they can directly kill us but because they are harbingers of pathogens of medically-important diseases such as malaria, dengue fever, Zika diseaselymphatic filariasis, yellow fevertularemia chikungunya,  and several forms of encephalitis. Recently, researchers identified mosquitoes as carriers of Keystone virus and the pathogen of Rift Valley fever as well.

 

In effect, researchers from around the globe have constantly sought for a way to mitigate the disease-transmission spree of these deadly blood-suckers. Just last year, scientists from Imperial College London came up with a means to destroy mosquitoes — by biohacking their DNA using CRISPR technology. Using CRISPR–Cas9 gene, the scientists suppressed the population of caged Anopheles gambiae mosquitoes (human malarial vector).

 

In brief, they modified the gene responsible for determining sex in male mosquitoes and turned the male gene dominant. Then, they added these “hacked’ mosquitoes to a caged population of unaltered male and female mosquitoes. As a result, the next generations of females could no longer lay eggs and could not bite. And then by the eight generation, the population no longer had females [2].

 

 

Doing it the CRISPR way

CRISPR (acronym for Clustered Regularly Interspaced Short Palindromic Repeats) is a gene-hacking tool of bacteria. Hence, we can say that these bacteria are the original biohackers. They use it as a tool to protect themselves from re-invading bacteriophages, similar to our immune system’s adaptive immunity. The gene-hacking tool of bacteria makes use of gRNA and Cas9 enzyme. While gRNA binds to the target DNA, Cas9 cuts the DNA target to disable it. Now, scientists exploit it as a way to splice specific DNA targets and then replace them with a DNA that would yield the desired effect. For instance, CRISPR can correct physiological anomalies caused by gene mutations or defective genes.[3]

 

 

First clinical trials

With the potential to treat thousands of genetic disorders, CRISPR has now been making a huge step towards becoming a legitimate, doctor-prescribed treatment. In 2016, US FDA approved the clinical trial study wherein CRISPR technology was used to treat patients with cancers.[4] Apparently, CRISPR can switch off a gene in immune cells or hack their genes to boost them into combating cancer. Hence, it has the potential to cure certain cancers.

 

Furthermore, CRISPR seemingly can treat people with inherited blindness. In essence, researchers look through it by injecting it into the patient’s eye with the intent that it will snip out the mutation. If successful, it could be used to treat a wide variety of genetic disorders, such as Duchenne muscular dystrophy, cystic fibrosis, and so on.[5]

 

According to the bioethicist, Laurie Zoloth from the University of Chicago Divinity School, CRISPR is allowed to be done in clinical trials for these genetic conditions because it is believed not to cause heritable DNA changes. However, precautionary measures are still warranted.[5]

 

 

CRISPR DIY biohacking

 

CRISPR DIY
CRISPR DIY kit. (Image credit: Sylvia Fredriksson, Flickr, CC by 2.0)

 

Aside from its medical potentialities, CRISPR has many other applications. Scientists eye its use in producing more resilient crops, in making biofuel, reviving extinct species, creating new ones, and so on. The fact that living things are in essence made up of genes then the usage of CRISPR could only be limited by one’s imagination. There is even a concern over its use as a means for an ethically-refuted purpose. That is by creating new species designed for biological weapon poised as a treatment that could be purchased online. It might be a stretch. However, the possibility remains.

 

As noted earlier, its breadth of use is as far as where one’s imagination can reach, especially now that a CRISPR lab kit can now be easily obtained, i.e. simply by ordering online for just under $150.[6] It comes with the instructions. So in an instant, you can become a biohacker, capable of re-engineering DNA at home, with the added benefit of doing it away from the prying eyes of anybody.

 

CRISPR is undeniable a breakthrough and poises to be the most-promising medical cure of the millennium. It could be the straight answer we need to resolve many genetic problems. However, we should not be too hasty. Care should be taken in utmost regard to make sure that no ethical issues and caveats over potential dangers are left unheeded.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1  Science News Staff. (2015). And Science’s 2015 Breakthrough of the Year is…

ScienceMag.org. Retrieved from [Link]

2  Houser, K. (2018 Sept. 25). SCIENTISTS WIPED OUT A MOSQUITO POPULATION BY HACKING THEIR DNA WITH CRISPR. Futurism.com. Retrieved from [Link]

 

3  Gonzaga, M. V. (2018). CRISPR caused gene damage? Rise and pitfall of the gene-editor. Biology-Online.org. Retrieved from [Link]

4  Reardon, S. (2016). First CRISPR clinical trial gets green light from US panel. Retrieved from

[Link]

 

5  Saey, T. H. (AUGUST 14, 2019). CRISPR enters its first human clinical trials. ScienceNews.org. Retrieved from [Link]

 

6  Al-Ghaili, H. (2019). DIY CRISPR. Retrieved from [Link]

Hallucination – Are we the only ones “seeing” things or animals hallucinate, too?

Hallucination is defined as perceiving something that seems real but in fact it is not. Some references take it as a synonym for delusion. Both hallucination and delusion are a perception or belief that something seems real. However, the individual that experiences hallucination senses a vision, sound, or other perceptions later on denies it to be real based on evidence or logic. People with delusion, in contrast, believe something as real in spite of refuting evidence.  

hallucination
Hallucinations – a brain glitch – apparently could occur in animals, too. At least, according to a recent experiment on lab mice using optogenetics technique. [Img credit: Rick Harris (Flickr), by CC BY-SA 2.0]

Common causes of hallucination

Hallucination does not occur frequently. Nonetheless, it could be a common experience in individuals suffering from mental disorders like schizophrenia. Accordingly, >70% of those suffering from schizophrenia experience visual hallucinations whereas 60-90% believe they heard voices.[1] Additionally, other conditions that result in hallucinations include certain cases of Parkinson’s disease, Alzheimer’s disease, migraines, brain tumor, and epilepsy. Apart from these conditions certain medications – called “hallucinogens”  — have also caused hallucinations. For example, “Lysergic acid diethylamide” drug causes hallucination, in particular, by acting on serotonin (5-hydroxytryptamine [5-HT])-receptors.

High caffeine intake was also implicated to hallucinations. Accordingly, people who drink more than seven cups of instant coffee in a day turned out to be three times more likely to “hear voices” than those who drink less.[2] In this case, scientists explicated that high caffeine intake led to an increased cortisol (a stress hormone), which, in turn increased proneness to hallucinate.

People experiencing hallucinations may feel afraid from the perceptual experience. Seeing a vision like a seemingly floating light, hearing sounds like footsteps, or a crawling feeling on the skin that later on are construed as not real could really be scary.  

Neurobiological factors

Why does hallucination occur? In essence, hallucinations involve defects in the structure and function of the primary and secondary sensory cortices of the brain. In the case of Alzheimer’s disease, visual hallucinations are associated with grey and white matter abnormalities. “Seeing”, “hearing”, or “feeling” things is by chance spontaneous and also a transitory personal experience. Thus, understanding the biological phenomenon of hallucination remains a challenge to neurobiologists and scientists alike to this day.

Do animals hallucinate?

Do animals hallucinate, too? Scientists can hardly tell but studies implicate animal models such as lab mice making a head-twitch response (a hallucinatory behavior) when administered with hallucinogen.[3] However, some scientists argue it was not a compelling proof of such animals hallucinating.

Recently, though, a team of researchers from Stanford Medicine claim that they made lab mice hallucinate without injecting hallucinogen. Instead, they made use of optogenetics technique. In this case, they inserted light-sensitive genes into their brain. As a result, certain neurons tend to fire with particular light wavelengths. The genes would produce two types of proteins: one, causing neurons to fire when exposed to infared laser light and another, causing neurons to glow green when activated.[4]

The scientists, then, trained the mice to lick a water spout when exposed to a pattern of moving parallel lines (i.e. perfectly vertical or horizontal lines). Based on the green glow response of the visual cortex, the scientists knew which neurons were firing, thus responding. These neurons supposedly were the ones responsible for “seeing” the pattern of lines. [4,5]

Gradually, researchers dimmed the projections while triggering the target neurons with their special laser. Eventually, they stopped showing the line patterns and yet the mice would still lick the water spout when scientists hit the same target neurons with laser. The result therefore implies that the mice might have experienced “true hallucination”, seeing “ghost” line patterns.[5]

— written by Maria Victoria Gonzaga

References:

1  Fowler, P. (2015, August 27). Hallucinations. Retrieved from WebMD website: Link

2  Durham University. (2009, January 14). High Caffeine Intake Linked To Hallucination Proneness. ScienceDaily. Retrieved from Link

3  Can animals have hallucinations? – Quora. (2018). Retrieved from Quora.com website: Link

4  Stanford Medicine. (2019, July 18). Scientists stimulate neurons to induce particular perceptions in mice’s minds. ScienceDaily. Retrieved from Link

5  Specktor, B. (2019, July 19). It’s a Mystery Why We Are Not Constantly Hallucinating, Trippy New Study Suggests. Retrieved from Live Science website: Link

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.

A New Theory on the Origin of Animal Multicellularity

Multicellular life, purportedly, started around 600 million years ago. From single-celled, certain organisms eventually evolved into the more complex multicellular forms. Several theories arise trying to explain how multi-celled animals came about. As of this time, there remains no consensus as to the origin of animal multicellularity. Recently, another theory emerged and it apparently challenges the widely held notion on the origin of animal multicellularity.

On the origin of animal multicellularity

Ediacaran biota
An imagined Ediacaran biota on the seafloor Credit: Ryan Somma (by Flickr, CC BY-SA 2.0)

In particular,multicellularity is defined as a condition or state of having or being comprised of many cells, each seemingly performing distinct function(s). One of the popular theories held is the “Gastraea Theory of Haeckel“.  Accordingly, multicellularity first occurred when cells of the same species group together in a blastula-like colony. In due time, certain cells in the colony underwent cell differentiation.[1] Still, this theory seems inadequate to explain the origin of multicellularity.

What scientists agree on is that, in essence, multicellularity occurred several times in biological history. In Neoproterozoic era, particularly in the Ediacaran period (around 600 million years ago), the first multicellular form emerged. Also in this period, sponge-like organisms evolved based on the recovered fossils of Ediacaran biota. Correspondingly, they were presumed to be the first animals.[2]  They resemble the sponges (choanocytes) with size ranging from 1 cm to less than 1m.[3]

The earliest ancestors of multi-celled animals could likely be sponge-like because a sponge has no organs but an assemblage of different cells with specialized functions.

sponge- origin of animal multicellularity
Sponge biodiversity and morphotypes: the yellow tube sponge (Aplysina fistularis), the purple vase sponge (Niphates digitalis), the red encrusting sponge (Spiratrella coccinea) and the gray rope sponge (Callyspongia sp.) in Caribbean Sea, Cayman Islands. Credit: Twilight Zone Expedition Team 2007, NOAA-OE. (Creative Commons Attribution 2.0)

New theory

In contrast to these popular tenets, a new theory on the origin of multicellularity in animals surfaced. Accordingly, scientists at the University of Queensland claim that the present-day multi-celled animals might have evolved from primitive multicellular organisms that were probably not like the modern-day sponges. As a matter of fact, they, too, were surprised at the outcome of their analyses as their findings apparently contradict the widely held notion on animal multicellularity.  

According to Professor Bernie  Degnan [4], “We’ve found that the first multicellular animals probably weren’t like the modern-day sponge cells, but were more like a collection of convertible cells.”

Moreover, he said: “The great-great-great-grandmother of all cells in the animal kingdom, so to speak, was probably quite similar to a stem cell. This is somewhat intuitive as, compared to plants and fungi, animals have many more cell types, used in very different ways — from neurons to muscles — and cell-flexibility has been critical to animal evolution from the start.”

Accordingly, they based their theory on their comparisons on the transcriptomes, fates and behaviors of different sponge cell types. Surprisingly, they found out that the transcriptome of sponge choanocytes did not match the transcriptomes of choanoflagellates. Furthermore, the results point towards pluripotency (i.e. the tendency of a cell to develop into more than one cell type).

Also, they found that the choanocytes in the sponge Amphimedon queenslandica could readily transdifferentiate into archaeocytes. The archaocytes, likewise, could differentiate into other cell types.

Concluding remark

Rather than steering towards the anticipated homology of sponge choanocytes and choanoflagellates, their results apparently swerved away from it and took a different direction.

Correspondingly, their analyses indicate that the origin of animal multicellularity might have been a primitive multicellular animal. And as has been noted, these animals could transition between multiple states just as the modern-day stem cells can do.[5]

— written by Maria Victoria Gonzaga

References:

1 Biology-Online Editors. (2014, May 12). Living thing. Retrieved from Biology-online.org website: [Link]

2 Biology-Online Editors. (2014, May 12). Evolution. Retrieved from Biology-online.org website: [Link]

3 The History of Animal Evolution. (2000, January 1). Retrieved from Link

4 University of Queensland. (2019, June 12). How multi-celled animals developed: Evolutionary discovery to rewrite textbooks. ScienceDaily. Retrieved June 20, 2019 from [Link]

5 Shunsuke Sogabe, William L. Hatleberg, Kevin M. Kocot, Tahsha E. Say, Daniel Stoupin, Kathrein E. Roper, Selene L. Fernandez-Valverde, Sandie M. Degnan, Bernard M. Degnan. Pluripotency and the origin of animal multicellularityNature, 2019; DOI: 10.1038/s41586-019-1290-4

Rabies pathobiology and its RNA virus agent – Lyssavirus

Having a dog as a pet presents myriad of benefits. One of them is having a companion reputed for being charismatic and loyal. Dogs, apparently, render a “cure” when melancholy “strikes“. However, there are repercussions to avoid or deal with when handling a dog. One of the most important concerns when domesticating a dog is preventing dog bites. Getting bitten by a dog is, in fact, how microbes could find their way through the skin.  Dogs, inopportunely, can be agents of medically-important diseases like rabies.

dog rabies
Dog infected with rabies

Rabies transmission

Rabies is a viral disease that is almost always deadly. It can be acquired chiefly through a single bite by an infective dog. One could also get it when a broken skin is exposed to infected saliva. Other potential routes include eyes, mouth, and nose. Nonetheless, not all dogs carry the virus causing the disease. Also, dogs are not the only ones that can transmit rabies virus. Most warm-blooded vertebrates (e.g. monkeys, raccoons, cattle, cats, bats, etc.) can carry the virus and transmit it to a human host. The virus has further adapted, and hence, could grow as well as in cold-blooded vertebrates.[1] However, because of the widespread domestication of dogs in human households dogs have consequently incited most rabies cases in humans.[2]  

Lyssavirus – the viral agent

The virus of rabies disease is a Lyssavirus, a type of RNA virus belonging to the family Rhabdoviridae, order Mononegavirales. It has a bullet shape. It carries a single negative-strand RNA as its genome, enough to code for proteins[3] — namely, nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and RNA polymerase — to establish within the host cell.

Lyssavirus rabies virus
A coloured transmission electron micrograph of Australian bat lyssavirus (finger-like projections and the one that bud off from a host cell). Credit: Electron Microscopy Unit AAHL, CSIRO, CC 3.0 Unported license

In particular, the virus makes its way inside the host cell (e.g. muscle cell or nerve cell) through receptor binding and membrane fusion by way of endosome using its glycoprotein G. The virus transcribes its genome by its polymerase inside the endosome. Then, it fuses to the endosome to release its newly transcribed proteins and RNA into the cytosol.

The matrix protein regulates both transcription and replication of the virus. From transcribing, the polymerase shifts into replicating its genome. The nucleoprotein tightly binds to the newly replicated genome, thus, forming ribonucleoprotein complex. This, in turn, can now form new viruses.[4]

The virus performs transcription and replication processes via a specialized inclusion body referred to as the Negri body. In fact, the presence of Negri bodies in the cytoplasm of the host cell indicates histological proof of Lyssavirus infection.

Rabies – two types

Early symptoms of rabies disease include fever, discomfort, and paraesthesia (burning sensation at the bite site). Eventually, the symptoms progress to behavioral changes when the virus spreads to the central nervous system.

Lyssavirus enters and hijacks muscle cells to replicate. From the muscle tissue, it travels to the nervous system through the neuromuscular junctions.[5] The virus enters the peripheral nervous system directly and then spreads to the central nervous system where it can cause fatal inflammation in the brain and spinal cord.

Depending on the symptoms, the rabies may be described as “furious” or “paralytic“. The furious rabies — the more common form (80% [5]) — is characterized by hyperactivity, confusion, abnormal behavior, paranoia, terror, hallucinations, and hydrophobia (“fear of water“). The paralytic rabies, as the name implies, causes paralysis starting from the site of bite (or entry). Both of these types may lead to coma and eventually to death of the patient. However, patients with the furious type have higher risks, due to the likely cardio-respiratory arrest.[2]  Without an early and a proper medical intervention, death may ensue typically two to ten days after these symptoms manifest.

Rabies – pathobiology

How rabies causes behavioural changes baffles scientists. In 1980s and 1990s, researchers explicated how the virus caused paralysis. Accordingly, the glycoprotein at the cell surface of the Lyssavirus competes against acetylcholine in terms of binding affinities to specific muscle receptors (e.g. nicotinic acetylcholine receptors).[6] Lately, researchers conjectured that the virus could also be doing the same with the similar receptors found in the brain. Furthermore, they presumed that the interaction could have affected how the brain cells normally communicate, and thereby induced changes in the behavior of the host.[6] 

Further research

Recently, researchers from the Ohio State University College of Medicine and The Ohio State University Wexner Medical Center conducted a study aimed at identifying dog breeds and physical traits that pose high risk of biting with severe injury.[7] Their data could provide empirical basis when deciding which dogs to own. Still, further studies on rabies are necessary since the disease is marked as fatal as soon as the clinical symptoms set in.[2]  Although vaccine-preventable, rabies, especially via a dog bite, remains a significant cause of annual deaths in humans, both young and old. Novel treatments and vaccines that are effective and economical could preclude death. At present, the staggering cost of treatment remains a major health-care restraint. Without the proper and early treatment, death from rabies, unfortunately, is almost always certain.

— written by Maria Victoria Gonzaga

References:

1 Campbell, J. B. & Charlton, K.M. (1988). Developments in Veterinary Virology: Rabies. Springer. p. 48. ISBN 978-0-89838-390-4.

2 World Health Organization (WHO). (2019, May 21). Rabies. Retrieved from Who.int website: [Link]

3  Finke, S. & Conzelmann, K. K. (August 2005). “Replication strategies of rabies virus”. Virus Res111 (2): 120–131. doi:10.1016/j.virusres.2005.04.004  

4 Albertini, A. A., Schoehn, G., Weissenhorn, W., & Ruigrok, R. W. (January 2008). “Structural aspects of rabies virus replication”. Cell. Mol. Life Sci65 (2): 282–294. doi:10.1007/s00018-007-7298-1

5 Newman, T. (2017, November 15). Rabies: Symptoms, causes, treatment, and prevention. Retrieved May 23, 2019, from Medical News Today website: https://www.medicalnewstoday.com/articles/181980.php

6 University of Alaska Fairbanks. (2017, October 11). How rabies can induce frenzied behavior: Researchers better understand the disease that kills 59,000 people annually. ScienceDaily. Retrieved from website: [Link]

7 The Ohio State University Wexner Medical Center. (2019, May 22). Study identifies dog breeds, physical traits that pose highest risk of biting children. ScienceDaily. Retrieved from website: [Link]

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]

RNA-DNA World Hypothesis?

How did life start as we know it? In the scientific community, the RNA World Hypothesis has many adherents. Many believed that life came about as a result of the existence of the simplest molecule, such as RNA. Perceptibly, RNA shows signs of somewhat being “alive” — at least in the sense that it carries a genetic code and capable of self-replicating. In essence, RNA could be the earliest biomolecule. Subsequently, other organic molecules came about. However, a new hypothesis is gaining a grip. Accordingly, RNA and its close relative – DNA – might have existed side by side during the primordial times, even before life began.

RNA World Hypothesis

RNA world hypothesis
According to RNA World Hyopothesis, RNA dominated the ancient Earth and served as descendants to life. [Photo: public domain, from Pxhere]

In RNA world hypothesis, primitive life is presumably RNA-based. This assumption arose from the notion that RNA could act both as a genetic material and as a catalyst. In due time, primitive RNA-based entities have transitioned into compartmentalized life forms (in the form of cells) for over many millions of years. Possibly, the RNA-based life dominated the primitive Earth and then served as the descendant of the present-day living organisms.1 Carl Woese, an American microbiologist and biophysicist, is hailed as the originator of the RNA World hypothesis. Accordingly, he conjectured in 1967 that the earliest self-replicating life entities could have relied on RNA.2

Theory on the Origin of RNA

How RNA emerged or came about still puzzles scientists. Where did RNA come from? Did it come from the Earth’s more nascent, rudimentary units?or perhaps, the building blocks for RNA came down to Earth from the outer space? According to scientists, RNA seemingly came from, and synthesized in, the asteroids from the outer space. Apparently, they reached the Earth through meteorites. NASA reported that they found RNA and DNA nucleobases (e.g. adenine, guanine) in meteorites. These could have led to the spontaneous creation of RNA and DNA on Earth.3 In March 2015, researchers reported that pyrimidines uracil, cytosine, and thymine formed in their laboratory under outer space conditions and using precursors such as compounds present in meteorites.4

RNA-DNA world?

In essence, DNA is a more complex compound than RNA. While RNA occurs as a single strand, DNA exists as two strands that typically wound in a helix. Similar to RNA, DNA consists of multiple nucleotides covalently bonded by 3′, 5′ phosphodiester linkages. Each nucleotide, in turn, contains phosphoric acid, a deoxyribose sugar (5-carbon), and a nucleobase (particularly, cytosineguanine, adenine, and thymine). Thymine is a distinctive structural feature of DNA. In DNA, thymine takes the place of uracil. Having discovered that these building blocks could form under pre-biotic conditions causes scientists to rethink the origin of life.

A research team reported how chains of nucleic acids could form in a pre-biotic environment and how RNA could easily turn into DNA components even without the assistance of enzymes. Ramanarayanan Krishnamurthy, one of the researchers, said, “These new findings suggest that it may not be reasonable for chemists to be so heavily guided by the RNA World hypothesis in investigating the origins of life on Earth.”5

They surmised that the primitive Earth is no pure RNA. DNA might have existed side by side with RNA and it probably even competed for supremacy, until the DNA system eventually reigned over.

They published their report in Nature.6

— written by Maria Victoria Gonzaga

References:

1  Biology-Online Editors. (2014, May 12). Ribonucleic acid. Retrieved from Biology-online.org website: [Link]

2  Woese, C. (1967). The Genetic Code: the Molecular basis for Genetic Expression. New York: Harper & Row.

3  NASA – NASA Researchers: DNA Building Blocks Can Be Made in Space. (2011, January 1). Retrieved NASA website: [Link

4 Marlaire, R. (3 March 2015). “NASA Ames Reproduces the Building Blocks of Life in Laboratory”. Retrieved from NASA website: [Link]

5 McRae, M. (2019). DNA And RNA May Have Existed Together Before Life Began on Earth. Retrieved April 6, 2019, from ScienceAlert website: [Link]

6 Xu, J., Green, N. J., Gibard, C., Krishnamurthy, R., & Sutherland, J. D. (2019). Prebiotic phosphorylation of 2-thiouridine provides either nucleotides or DNA building blocks via photoreduction. Nature Chemistry. [Link]

FAAH-OUT mutation for a life of no pain – No FAAH, no pain

A Scottish woman claims that she has not experienced pain over some supposedly painful conditions, like a severe joint degeneration or a post-operation she underwent for her hand due to osteoarthritis. Accordingly, she never needed painkillers and her case astounded doctors.

A baffling case

Doctors were baffled when the 71-year old Scottish woman, Jo Cameron, came to seek treatment for her hip problem six years ago (at age 65). Astonished, the doctors found out that her joint severely degenerated and by that they expected her to experience excruciating pain just as a typical person would. However, she showed no signs of discomfort over it. Furthermore, she said that at age 66 she underwent a supposedly painful operation on her hand due to osteoarthritis yet felt no pain after. According to the news1, Cameron was not aware at first for feeling virtually no pain over such situations. Purportedly, she thought that what she felt (i.e. lack of a thwarting pain) was normal. She later learned about her lack of pain and the plausible reason only recently.

FAAH-OUT

Researchers went on to see what caused Cameron’s bizarre lack of pain. They suspected that her genes could shed light to her case. Hence, they analyzed her genes. Subsequently, they found mutations, thereby, affirming their hunch. According to their genetic analyses2, Cameron had two mutations: (1) a microdeletion in a pseudogene and (2) a mutation in a nearby gene controlling the enzyme fatty acid amide hydrolase (FAAH).2

The pseudogene was only partly annotated in the medical literature. Thus, researchers describing the gene and subsequently calling it FAAH-OUT was a first. Previously thought of as a “junk gene”, FAAH-OUT could probably be more than that. It likely regulates FAAH expression as postulated by the research team.2 Consequently, they now look upon how it works.

FAAH gene

With regard to the FAAH gene, researchers know this gene encodes for the FAAH enzyme involved in endocannabinoid signaling. In essence, FAAH normally degrades anandamide (a fatty acid neurotransmitter) into free arachidonic acid and ethanolamine. Thus, without FAAH, the levels of anandamide would increase significantly. This, in turn, leads to a reduced pain sensation, as observed in FAAH knockout mice.3 FAAH knockout mice demonstrated not only the absence of pain but reduced anxiety and faster wound healing as well.2,3

Likewise, Cameron purportedly exhibits similar traits. According to her, she never panics (even in dangerous situations), has no fears, and is immune to anxiety. She would also have bouts of cuts and burns in which she would not notice sometimes albeit her injuries would heal very quickly.2 The tests revealed that she had elevated levels of anandamide – an indication of a lack of FAAH function.2

Novel pain treatment targets

FAAH-OUT gene mutation
Mutation in FAAH-OUT gene resulted in more anandamides, which in turn leads to feeling of no pain, reduced anxiety, and quick wound healing. [Photo by juan mendez from Pexels]

One of the lead researchers of the study, Dr. James Cox, said that Cameron has a genotype that reduced gene activity. Cox and his research team are optimistic that their discovery could possibly lead to novel pain and anxiety treatments that target this newly-identified gene.2 Their findings might lead to novel strategies that would eventually help patients suffering from severe pain despite receiving advance pain killer medications.

— written by Maria Victoria Gonzaga

References:

1 Hunt, K. (2019 March 28). “Woman who feels no pain could help scientists develop new painkillers”. Retrieved from CNN website [Link]

2  University College London. (2019 March 27). “Woman with novel gene mutation lives almost pain-free”. Retrieved from Eureka website [Link].

3 Cravatt, B.F., Demarest, K., Patricelli, M.P., Bracey, M.H., Giang, D.K., Martin, B.R., & Lichtman, A.H. (2001). “Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase”. Proceedings of the National Academy of Sciences of the United States of America, 98 (16): 9371–6. 

Regeneration in humans – Finding the gene switch

Regeneration in humans is much more limited compared in other animals. Say for instance when one lost a limb, much as well say goodbye to it for the rest of one’s life. Perhaps, it would be nice if we have higher capacity to regenerate many of our indispensable body parts, like head, limbs, and many other “regeneration-incapables”. Then probably, we might not have to worry much about losing any of them knowing that they will eventually re-grow in due time.

 

 

Regeneration vs. Healing

Humans have the capacity to regenerate. However, we have a very limited capabiltiy to restoring parts of our skin, hair, nails, fingertips, and liver. At the tissue level, surely we have dedicated cells to replace lost and damaged cells. For instance, our non-injured bone eventually replenishes into a full new bone but in a span of ten years. Our skin naturally renews but give it two weeks. The story swerves differently though in the case of an injury.

 

Rather than expending energy into having it replaced with a new one, our body directs its efforts into healing it. So when our skin is deeply damaged, our body fixes it with a scar. Tissue repair mechanisms such as wound healing aren’t really a snag. They forestall pathogenic microbes from using an injured body part as an easy gateway into our body. (Besides, we do have ample microbiota naturally thriving inside of us already) The main goal is to fix it efficaciously, with relatively less effort.

 

 

 

Natural regeneration in humans

In humans, the only tissue that regenerates naturally, consistently, and completely is the endometrium.1 After it slough-offs during a woman’s menstrual period, it grows back by re-epithelialization until the next period. Humans can also regenerate an injured liver provided that the restoration involves as little as 25% of the original liver mass. The liver can grow back to its original size but may not to its original shape. Damaged tubular parts of the kidney can also re-grow. The surviving epithelial cells undergo migration, dedifferentiation, proliferation, and re-differentiation to set a new epithelial lining of the tubule.

 

 

 

Animals with higher regeneration capacities

 

axolotl regeneration
Axolotl (Ambystoma mexicanum) is one of the animals dubbed as masters of regeneration. It can grow back its limbs, even a heart, without a scar. [Photo credit: Mike Licht, Flickr]
 

 

Some animals have higher capacity to re-grow lost body parts. Sharks, skates, and rays can regenerate their kidneys. They can regrow an entire nephron, which humans cannot. A lizard would drop its tail as a mode of escape; its tail will be fully restored over time anyway. Sharks do not have qualms about losing teeth. They can replace any of them more than a hundred times in their lifetime. Axolotl can replace its broken heart. A starfish will once again be stellar upon the return of a lost arm. In fact, even its lost arm can fully regenerate into an entire starfish as long as the central nerve ring remains intact.2 A decapitated planarian worm needs not worry about losing its head; it can grow back, together with its brain, including the memories.2 Without a doubt, many of these animals are simply masters of their craft – regeneration.

 

 

Regeneration genes

Researchers from Harvard University published their new findings on whole-body regeneration capacity of the three-banded panther worm.3 They uncovered DNA switches that seemed to regulate genes that have a role in the regeneration process. Accordingly, they found a section of a non-coding DNA that controlled the activation of a master gene in which they called the “early growth response” (EGR) gene. When active, the EGR gene seemed like a power switch that turns on and off certain genes in the coding region during regeneration. On the contrary, when deactivated, no regeneration occurred.

 

Surprisingly, humans have EGR gene, too.  So why doesn’t it lead to greater regeneration capacities as it does in the three-banded panther worm? The researchers explained that while it works in the worm, it doesn’t work the same way in humans. The wiring may be different. The worm’s EGR gene may have germane connections that are absent in humans.

 

 

 

Switching the gene on

Regeneration in humans
Regeneration in humans is limited. If only we knew the switch that could amplify our regeneration capacity then we might not have to worry much about losing a body part. [Photo credit: Pete Johnson, Pexels]
 

 

Induced regeneration in humans is one of the goals of regenerative medicine. This field of medicine seeks new ways to give our regenerative capacity a boost. One of the ways is to look “molecularly”. Researchers are looking into the gene “Lin28a“. When active, this gene can reprogram somatic cells into embryonic-like stem cells. Accordingly, it has a role in tissue regeneration and recovery. However, the gene is naturally turned off in adults. Research in boosting our regenerative capacities is ongoing. Switching our organs from being regeneration-incapable to regeneration-capable may just be a matter of discovering the gene switch that could enhance regeneration capacity of humans.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Min, S., Wang, S. W., & Orr, W. (2006). “Graphic general pathology: 2.2 complete regeneration”Pathology. pathol.med.stu.edu.cn. Retrieved from [Link]

2  Langley, L. (2013, August 28). “Pictures: 5 Animals That Regrow Body Parts”. National Geographic News. Retrieved from [Link] ‌