Author Archives: Rich Feldenberg

About Rich Feldenberg

I have an M.D. with a specialty in pediatric kidney disease, an undergraduate degree in chemistry, training in molecular biology, and an undying love of science and learning. I'm a proud descendant of hardy bacteria, playful fish, and clever primates. My science blog can be found at: http://darwinskidneys.wordpress.com

How our ancestor’s promiscuous genes became more discriminating.

Just as whole organisms have an evolutionary history that can be traced backwards in time, revealing varying degrees of relatedness to other organisms through common ancestors, so too does each gene have an evolutionary history that can be traced back through time.   Many modern genes are part of gene families, each gene in the family having similar, yet distinct functions, and originally derived from a common gene ancestor.  A new study presented in the January 12, 2016 issue of the Proceedings of the National Academy of Science (PNAS), uncovers one method evolution takes to go from a single primitive gene to multiple genes, each with unique abilities and discrete functions.

The study looked at the evolution of the Steroid Hormone Receptor family of genes.  Steroids are essential molecules in animals, that are chemically derived from cholesterol, to produce a large variety of hormones, from cortisol and aldosterone (products of the adrenal glands), to sex hormones like estrogen and testosterone.  When one of the steroid hormones enters the cell it exerts its influence on DNA through a Steroid Hormone Receptor.  It is the Steroid Hormone Receptor that binds to the appropriate place in the DNA, to either activate or repress other genes.  For example, cortisol can have an anti-inflammatory effect by binding to the Glucocorticoid Receptor,  suppressing genes in cells of the immune system, essentially turning these cells off.  It is this property of corticosteroids that make them so useful for treating pro-inflammatory conditions, like those seen during acute injury or chronic autoimmune disease.  On the other hand, aldosterone can have a pro-inflammatory effect, by binding to the Mineralocorticoid Receptor, and activating a different set of genes.

 

The steroid hormone family and their chemical similarity.

The steroid hormone family and their chemical similarity.

 

Both the Glucocorticoid Receptor and the Mineralocorticoid Receptor are members of the Steroid Hormone Receptor gene family.  There are six known members in all, but only the Glucocorticoid Receptor can repress gene activation.  The other members of the Steroid Hormone Receptors are gene activators.  The study focused on how the Glucocorticoid Receptor developed the capacity to inhibit gene expression.

The team found that all members of the Steroid Hormone Receptor gene family appear to be derived from a distant ancestral gene whose function was promiscuous, in the sense that this Steroid Hormone Receptor had properties that could both up regulate and down regulate genes.  Which ever action predominated may have been influenced by other factors in the cellular environment.  The team reconstructed the DNA sequences of the ancestral Steroid Hormone Receptors at several points along evolutionary history.  What they found was that gene duplication events lead to multiple copies of the ancestral gene, which allowed the new separate copies to evolve down different pathways, acquiring distinct functions from the common ancestor gene.  The common ancestor of all Steroid Hormone Receptors showed both gene up regulating action, along with a mild degree of gene down regulating activity, when tested in cell culture.

 

 

A gene duplication can occur during DNA synthesis and results in a copy of the gene on the chromosome. Over time the copied gene can migrate to new locations in the genome, that may be distant from the original gene.

A gene duplication can occur during DNA synthesis and results in a copy of the gene on the chromosome. Over time the copied gene can migrate to new locations in the genome, that may be distant from the original gene.

 

After the gene duplication event, one copy of the gene became the common ancestor to the Glucocorticoid and Mineral Corticoid Receptors, while the other copy became the common ancestor of the Progesterone and Androgen Receptors, which began specializing their function as they gained new mutations.  Analysis revealed that going from the common ancestor of all Steroid Hormone Receptors to the common ancestor of the Glucocorticoid and Mineral Corticoid Receptors, happened with the acquisition of two simple base changing mutations.  Those two mutations were neutral, meaning that they did not change either the up regulating or down regulating ability of the receptor – it had basically the same activity as the common ancestor of all Steroid Hormones – but it did produce a slight change in the 3-D shape of the molecule.

A later mutation in a single base lead to complete loss of the Mineralocorticoid Receptors ability for gene down regulation.  Interestingly, it was the single base mutation, in combination with the previous two neutral mutations that were necessary to lose the down regulating action.  This seems to suggest that, so called neutral mutations, may still be important to derive new traits, if they prime the system for further change.

 

After gene duplication, the copied gene may evolve to gain new functions.

After gene duplication, the copied gene may evolve to gain new functions.

 

The Glucocorticoid Receptor, on the other hand, gained several more mutations that further enhanced its gene down regulating ability, above and beyond the ancestral gene.  It was the occurrence of several gene duplication events, this last one being in the common ancestor of all bony vertebrates, that provided the raw material to evolve separate genes with more discriminating functions, losing the promiscuity of a single “jack of all trades” gene to gain a family of genes that became specialists, allowing a more finely tuned and regulated system.  By performing X-ray crystallography and Nuclear Magnetic Resonance analysis of the various receptors molecules, the team further showed that changes in up or down regulating activity coincided with minor differences in the 3-D structure of the receptors, affecting their interaction with the DNA.

Journal Reference:

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space.  Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):326-31.   doi:10.1073/pnas.1518960113. Epub 2015 Dec 29. Hudson WH, Kossmann BR, de Vera IM, Chuo SW, Weikum ER, Eick GN, Thornton JW, Ivanov IN, Kojetin DJ, Ortlund EA.

First biological function of mercury discovered

The element mercury (Hg) is extremely toxic to most organisms, including humans.  It’s deadly effects are thought to be due to it’s ability to block the function of certain key metabolic enzymes.  Being so toxic, it has long been thought that mercury had no biological functions in the living world at all.  At least that was presumption until a research team published the first evidence that a unique group of organisms can not only stand being around the stuff, but actually benefit by the presence of Mercury.   In a paper published this month in Nature Geoscience, D. S. Gregoire and A. J. Poulain show that photosynthetic microorganisms called purple non-sulfur bacteria can use mercury as an electron acceptor during photosynthesis.  These bacteria rely on a primitive form of photosynthesis that differs from the type common to plants.  In the case of photosynthesis in plants, water is used as an electron donor, with carbon dioxide the electron acceptor.  The result of this process is the production of sugars, the release of oxygen, and the removal of carbon dioxide from the air.  Purple non-sulfur bacteria, on the other hand, usually prefer to live in watery environments where light is available to them, but the oxygen levels are low.

Image via Wikipedia.

They use hydrogen as the electron donor, and an organic molecule such as glycerol or fatty acids, as the electron acceptor.  This also results in the production of sugars, but does not release oxygen or remove carbon dioxide from the atmosphere.  This process also generates too many electrons for for their organic electron donor to handle, leading to the potential for damage to other molecules in the cell.

The researcher showed that purple non-sulfur bacteria grow better when mercury is in their environment.  The reason seems to be that the bacteria use the mercury to accept those extra electrons, reducing mercury from a high oxidation state to a low one.  The oxidation state refers to the number of electrons that an atom can gain or lose.  In the case of mercury, when it goes to its low oxidation state after gaining the extra electrons, it becomes a vapor and evaporates away into the atmosphere.  In mercury’s high oxidation state it can form the soluble compound methyl-mercury, which can be toxic to other organisms.

It’s quite possible that the impact of mercury reduction by photosynthesis may extend far beyond the health of these unusual little microbes.  Jeffry K. Schaefer, in the Department of Environmental Sciences at Rutgers University speculates that, “By limiting methyl-mercury formation and accumulation in aquatic food webs from microorganisms to fish, this process may even contribute to less toxic mercury ultimately ending up on our dinner plates.”

Journal Reference:

A physiological role for HgII during phototrophic growth.  Nature Geoscience.  February 2016, Volume 9 No 2  pp121 – 125  D. S. Grégoire & A. J. Poulain  doi:10.1038/ngeo2629

Biogeochemistry: Better living through mercury.  Jeffry K. Schaefer.  Nature Geoscience: News and Views.  18, January 2016.

Transplant Organizations issue a guidance statement regarding Zika virus

The Zika virus has been in the headlines lately for its apparent association of microcephaly in the children of mothers infected when they were pregnant. While there is a strong correlation, a true causation has not been completely verified, and is still being investigated.  In most people the virus causes only very mild illness that resolves on its own (such as fever, rash, muscle aches, and headache), and in many individuals is completely asymptomatic. Occasionally, its effects can be more severe, such as leading to reported cases of Guillain-Barre syndrome (a severe neuromuscular illness causing paralysis). It is still not known exactly why some people may develop severe complications while the majority do not. Zika virus has been covered previously on the ZME website.

It is also known that while the Zika virus typically spreads by an insect vector (the mosquito Aedes aegypti in most cases), it is now thought to also spread by sexual contact. It is uncertain if transmission could occur thorough organ donation, but if virus is present in the blood or other body fluids, then this mode of transmission would be possible in principle. Due to concern that this unusual mode of transmission could affect a vulnerable population, the Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) has set up an Ad Hoc Disease Transmission Advisory Committee (DTAC) to provide information and recommendations to transplant physicians, and this month came out with the first guidelines. As a transplant physician myself ( I’m a pediatric nephrologist, caring for children with End-Stage Kidney Disease who will need or have received a kidney transplant), I recognize the need to be certain that our supply of donor organs are safe for our patients, and to be able to advise our current transplant patients about travel to areas where Zika is known to be endemic.

Organ transplant recipients (such as heart, liver, kidney, lung, etc) represent a vulnerable population. In order to prevent rejection of the donor organ, the patient must be immunosuppressed with medications, making it difficult to fight off infections that most of us wouldn’t be very bothered by. It is completely unknown, at the present time, how Zika virus would affect an immunosuppressed individual. It’s affects could remain mild, as it is in most people with a normal immune system, or it could have serious unforeseen consequences.

The DTAC advises caution for people who have already received a transplant, or those who are on the transplant list, if they will be traveling to a Zika endemic area. Those areas would include Mexico, Central America, and South America. They also recommend that when a donor is being considered (and that could include either a living donor or deceased donor), that the transplant center should take into account the donor’s recent travel history, and if they had recent symptoms of viral infection. Again, many people (around 20%) will not have any symptoms at all, making symptomatology an unreliable marker of infection. The committee does not feel that even these factors should result in absolute exclusion of that organ being used, but should be decided on an individual basis for each patient. Some patients may be in more urgent need of an organ, and may not survive if they have to wait too much longer for the next matching organ to come up. In other cases, a person may have already been on the transplant list for a very long time due to having built up a lot of antibodies to other potential donors, and may not get another matching offer for years.  It may be a decision that the patient, their family, and their transplant physicians need to make together if the organ in question is felt to be at a higher than average risk for Zika virus.

Unfortunately, routine screening methods are not yet available for use by clinical laboratories. Screening can be achieved by the CDC in suspected cases of Zika related illness, and therefore it is not yet recommended or possible for organ donor’s to be screened for Zika virus as part of a donor evaluation. With time we will likely have a better understanding of the risk that Zika poses to individuals immunosuppressed for organ transplant. We will also likely have better screening methods that will be more readily available. For now, I think it is prudent to take precautions until more is known, but feel that there is no reason to panic, since there is no evidence at this time that donor organs have been compromised in any way.

 

References and further reading:

“Guidances for organ donation and transplantation professionals regarding the Zika virus”.  Feb. 4 2016.  UNOS Newsroom.

 

Interim Guidelines for Pregnant Women During a Zika virus outbreak – United States 2016.  CDC Morbidity and Mortality Weekly Report.  Jan. 22. 2016.

 

Possible Association Between Zika virus infection and Microcephaly – Brazil 2015.  CDC Morbidity and Mortality Weekly Report.  Jan. 29, 2016.

How Albert Einstein broke the Periodic Table

In a study published in the January 19, 2016 issue of the Journal of the American Chemical Society (JACS), scientists at Tsinghua University in China confirmed that something very unusual is happening inside extremely heavy atoms, causing them to deviate from their expect chemical behavior predicted by their place on the Periodic Table of Elements. Due to the velocity of electrons in these heavy elements getting so close to the speed of light, the effects of special relativity begin to kick-in, altering the chemical features observed.

The study shows that the behavior of the element Seaborgium (Sg) does not follow the same pattern as the other members of its group, which also contain Chromium (Cr), Molybdenum (Mo), and Tungsten (W). Where these other group members can form diatomic molecules such as Cr2, Mo2, or W2, using 6 chemical bonds, diatomic Sg2 forms using only 4 chemical bonds, going unexpectedly from a bond order of 6 to a bond order of only 4. This is not predicted by the periodic nature of the table, which itself arises from quantum mechanical considerations of electrons in energy shells around the nucleus. So what’s happening here? How does relativity throw off the periodic pattern seen in our beloved table of elements?

The Periodic Table of elements was initially conceived by Dmitri Mendeleev in the mid-19th century, well before many of the elements we know today had been discovered, and certainly before there was even an inkling of quantum mechanics and relativity lurking beyond the boundaries of classical physics. Mendeleev recognized that certain elements fell into groups with similar chemical features, and this established a periodic pattern to the elements as they went from light weight elements like hydrogen and helium, to progressively heavier ones. In fact, Mendeleev could predict the very specific properties and features of, as yet, undiscovered elements due to blank spaces in his unfinished table. Many of these predictions turned out to be correct when the elements filling the blank spots were finally discovered. See figure 1.

 

Mendeleev's 1871 version of the periodic table. Blank spaced were provided where predicted new elements would be found.

Figure 1.   Mendeleev’s 1871 version of the periodic table. Blank spaced were provided where predicted new elements would be found.

 

Once quantum theory was developed in the early 20th century, the explanation for the periodic behavior of the table became apparent. The electrons in the atom are arranged in orbital shells around the nucleus. There are several different orbital types, again based on predictions from quantum mechanics, and each type of orbital can hold only a specified number of electrons before the next orbital has to be used. As you go from top to bottom in the Periodic Table, you use orbitals of progressively higher energy levels. Periodic behavior arrises because, although the energy levels keep getting higher, the number of electrons in each orbital type are the same for each group, going from top to bottom. See figure 2.

 

Figure 2. Group 1 as an example of a group in the Periodic Table. As the group goes from top to bottom the energy levels get higher and the elements get heavier.

Figure 2.   Group 1 as an example of a group in the Periodic Table. As the group goes from top to bottom the energy levels get higher and the elements get heavier.

 

The other great area of physics developed in the early 20th century was relativity, which didn’t seem to have much importance on the scale of the very small. Albert Einstein published his ground breaking paper on Special Relativity (SR) in 1905, which described the effects on an object moving close to the speed of light. In 1915 he developed the General Theory of Relativity (GTR), describing the effects due to a massive gravitational field. It is SR that becomes an important consideration in the very heavy elements due their electrons reaching velocities at a significant percentage of the speed of light.

Einstein showed that as the velocity of an object approaches the speed of light its mass increases. This effect is too small to be noticeable at everyday speeds, but becomes pronounced near light speed. It can also be shown that the velocity of an electron in orbit around an atom, is directly proportional to the atomic number of the atom. In other words, the heavier the atom, the faster its outer electrons are moving. For the element hydrogen, with atomic number 1, the electron is calculated to be moving at 1/137 the speed of light, or 0.73% of light speed. For the element gold (Au) with atomic number 79, the electrons are moving at 79/137 the speed of light, or 58% of light speed, and for Seaborgium (Sg) with atomic number 106, the electron is going at an impressive 77% of light speed. At these speeds the crazy effects of special relativity kick-in making the electron mass significantly heavier than it is at rest. For gold this makes the electron 1.22 times more massive than at rest, and for Seaborgium the electron’s mass comes out to be 1.57 times the electron rest mass. This, in turn, has an effect on the radius of the electron’s orbit, squeezing it down closer to the nucleus.

Some relativistic effects have already been known for certain heavy elements. The color of gold, for instance, arises due to the effects of relativity acting on it’s outer electrons, altering the energy spacing between two of it’s orbitals where visible light is being absorbed, and giving gold it’s characteristic color. If not for these relativistic effects, gold would be predicted to appear whitish.

For the elements in Group 6 of the Periodic Table (Cr, Mo, and W) (see Figure 3.) that were studied in the JACS article, they each have five d-orbitals and one s-orbital capable of forming bonds with another atom. Sg breaks the periodic pattern because it’s highest energy s-orbital is so stabilized by the effects of it’s relativistically moving electron, it doesn’t contribute to bonding. Due to the intricacies inherent in molecular orbital theory, this drops the number of bonding orbitals from 6 in Cr, Mo, and W, to only 4 in Sg (even though Sg is a group 6 member). It also means that the bond between Sg and Sg in the Sg2 molecule is 0.3 angstroms longer than expected, even though the Sg radius is only 0.06 angstroms bigger than W. If relativity didn’t have an effect, then the Sg2 molecule would be joined together by 6 orbital bonds, like any respectable Group 6 element should be! The same effect was also found in the Group 7 elements, with Hassium (Hs) showing the drop in bond order due to relativistic effects, just as Sg.

 

Figure 3. A modern version of the Periodic Table of Elements. Notice the Group 6 elements Cr, Mo, W, and Sg.

Figure 3.   A modern version of the Periodic Table of Elements. Notice the Group 6 elements Cr, Mo, W, and Sg.

 

The periodic table of elements is an impressive scientific achievement, who’s periodicity reveals an underlying order in nature. While this periodicity works remarkably well, the few exceptions to the rule also uncover important principles at work. Einstein’s theory of relativity breaks the periodic table in some interesting and unexpected ways. It’s the very heavy elements on the chart that don’t show good “table” manners, thanks to Einstein.

 

Journal Reference and other reading:
1. Relativistic Effects Break Periodicity in Group 6 Diatomic Molecules Yi-Lei Wang, Han-Shi Hu*, Wan-Lu Li, Fan Wei, and Jun Li*
Department of Chemistry & Key Laboratory of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Tsinghua University, Beijing 100084, China  J. Am. Chem. Soc., 2016, 138 (4), pp 1126–1129 DOI: 10.1021/jacs.5b11793 Publication Date (Web): January 19, 2016

2. Relativistic effects in structural chemistry Pekka Pyykko Chem. Rev., 1988, 88 (3), pp 563–594 DOI: 10.1021/cr00085a006 Publication Date: May 1988

3. Why is mercury liquid? Or, why do relativistic effects not get into chemistry textbooks? Lars J. Norrby J. Chem. Educ., 1991, 68 (2), p 110
DOI: 10.1021/ed068p110 Publication Date: February 1991

Observing Alien Armageddon could be our first sign of advanced civilizations in space.

We humans have a lot of reason to be proud.  In the short span of a few million years we have become self-aware and clever, learning to manipulate our world in ways that have greatly enhanced our survival.  The last 100,000 years have seen the evolution of anatomically modern humans, which migrated from our African birthplace to colonize and populate essentially all corners of the globe.  Using sophisticated brains we learned about the world, deciphering patterns in nature, designed and constructed tools, and formed societies and civilizations.  

 

Unfortunately, there has also been much about our success that is less praiseworthy.   At the same time that we have been building ingenious devices to better feed, clothes, shelter, and move ourselves from point A to point B, we have also been in the business of making ever more efficient weapons to destroy one another.  As our technological progress seems to outpace our societal ethics and maturity, we now have it in our power to completely annihilate our entire species.  In the not too distant future it could conceivably be possible to extinguish all life on planet earth, whether through horrible accident or intentional destruction.

 

While we sit on this world powder cake of self destruction, perhaps at times in a little more danger, and at times in a little less, we often wonder if we are alone in the universe.  Not only are we the only example of intelligent life that we know of in the universe, but our little planet is home to the only example of life we know of anywhere.   All evidence seems to indicate that there are a vast number of planetary systems and potential habitable worlds in the universe.  We have detected over 2000 exoplanets, so far, with the first one being discovered only as recently as 1992, and with advancing techniques the numbers have been skyrocketing in recent years.  Yet, there is still no sign of alien life, and even with SETI (Search for Extraterrestrial Intelligence) listening for alien radio transmissions since 1960, we have not detected any confirmed signs of intelligent aliens.  

A few of the exoplanets that the Kepler space telescope has discovered orbiting other stars.

A few of the exoplanets that the Kepler space telescope has discovered orbiting other stars.

 

In the October 23, 2015 issue of The International Journal of Astrobiology, authors Adam Stevens, Duncan Fogan, and Jack O’Malley James, make an interesting case that we may soon have the technology necessary to detect alien civilizations in the act of self-destruction.  In fact, alien armageddon may provide us with our most likely opportunity to detect the presence of intelligent alien life – even if we are only witness to their last moments.  The authors summarize some of the possible ways that an intelligent civilization could go horribly wrong, and how evidence for these tragic events could potentially be detected by our instruments here on earth.

 

The first major scenario would be that of global nuclear war.  There are several characteristics of a world that has been annihilated by an intense exchange of nuclear weapons that might be  detectable from our distant vantage point.  The detonation of the devices would emit high energy gamma radiation that would last for a short period of time – on the order of thousandths of a second.  Even given the high energy involved in the detonation of a world arsenal of nuclear devices, it is not very likely we could detect the energy output from so many light years away.  Naturally occurring gamma ray bursts (GRBs) are some of the most intense energy generating events in the universe, and can be observed at the edges of the visible universe, but they are also around 10 billion billion billion times more energetic than the predicted energy release of all the nuclear weapons on earth combined.  

 

The intense radiation from global nuclear war would, however, ionize the planet’s atmosphere, resulting in an “air glow” due to light emission from energized nitrogen and oxygen.  The atmosphere would have a lovely green glow in the the visible spectrum, is predicted to last several years, and could be observed as an increase in the light intensity at the expected wavelength.  There would also be a depletion of the planet’s ozone layer as reactive chemicals are produced by the explosions.  This too, might be observable as a change in the planet’s atmosphere.  Nuclear war would also generate a great deal of dust and small particles that enter the air, altering the transparency of the atmosphere.  A combination of a gamma ray burst, air glow, drop in ozone concentration, and loss of transparency of the atmosphere would be good evidence for this alien-made disaster.  Any one event on its own might not be enough evidence to be certain of an artificial event.  For example, a change in the atmosphere from transparent to opaque could also be caused by natural events like a large asteroid impact.  

 

Second on the list for a self-induced civilization-stopping calamity would be use of potent biological weapons.  Genetically engineered organisms, like viruses and bacteria, would potentially be much more deadly than any naturally occurring epidemic.  If the infectious agent was designed to attack all animals and plants, the entire biosphere would be jeopardized.  How would such a horror be detected by us?  Well, a rapid demise of the planet’s multicellular life would result in a huge amount of organic material for bacteria to consume.  The result of this massive decay would be the release of certain chemicals such as methane and ethane, that could be observed by spectroscopic analysis of the atmosphere.  

Artistis depiction of an exoplanet surface in a distant solar system.

Artistis depiction of an exoplanet surface in a distant solar system.

 

The next deadly scenario is the so called, “grey goo” event.  This involves the engineering of self-replicating nanomachines – tiny machines that use some building material as substrate and convert it into more tiny nanomachines.  The authors of the paper point out that this could be the result of either “goodbots” or “badbots”.  In the goodbot case the self-replicating nanomachines were never intended for destruction, but due to poor system controls, got out of hand leading to world destruction.  Badbots, on the other hand, were designed to cause complete and total destruction – the ultimate doomsday machine!   These replicators would take all carbon containing material on the planet’s surface, (ie. living organisms), and convert them into a growing mass of more replicators that do the same.  K. Eric Drexler – who coined the term nanotechology- pointed out in his ‘Engines of Creation’:  “Replicators can be more potent than nuclear weapons: to devastate Earth with bombs would require masses of exotic hardware and rare isotopes, but to destroy all life with replicators would require only a single speck made of ordinary elements.”

 

It might take as little as a few weeks to convert the worlds living biomass into a lifeless desert of tiny replicators – grey goo!  Pretty scary!!  From earth we might be able to detect this as a large increase in atmospheric dust (the masses of nanomachines).  The nanomachines would form giant sand dunes (bot dunes in this case) and would change the apparent brightness of the planet as we observe it.  There would be visual effects of shadowing, as the planet orbits its star due to the changing angle that light hits the grains of nanomachines in the bot dunes.  This is similar to the effect we see as light passes through the small particles in Saturn’s rings at different angles.  Over a period of thousands of years the nanomachines would be recycled through the planet’s interior, as the planet’s normal geological processes continue to operate.

 

Another apocalyptic possibility would be intentional pollution of the planet’s star.  To dispose of harmful radioactive waste, a civilization might launch such materials into its parent star.  Detecting uncommon radioactive elements in the star’s atmosphere would be evidence for this unnatural process.  Carl Sagan, called this “salting” the star.   We would know that this was an artificial process by the fact that elements present would be produced only in such high amounts by nuclear processes that don’t occur naturally.  Models have shown that if this was carried out to extremes, it would affect the star’s internal balance of forces and cause it’s size to increase, while dropping the surface temperature.  This change in the star’s characteristics could change the location of the habitable zone around the star, making life difficult or impossible on the alien planet that did the salting.  The authors suggest that, “compiling a sample of stars that are bright, cool, and slightly larger than expected as an initial step to search for this particular death channel.”

 

Finding evidence for intelligent life in the cosmos would radically change our view of ourselves, and our place in the universe.  If aliens have a similar psychology to ourselves (a big if to be sure), they could be prone towards potentially fatal flaws that could escalate to total catastrophe.  Their demise at their own hands (or equivalent body structures) might also be the signal that informs us that they were ever there at all.  Finding one or more civilizations that self-destructed might also give us a way to prognose the long-term health of the human race.  Do civilizations reach a point where their technological power is too great for their wisdom?  Could Homo sapiens one day end up as a signal to the stars that we were here for a brief time, an intelligent species, but just not quite intelligent enough to solve the problem of surviving peacefully with one another?  
Journal Reference:  

Observational signatures of self-destructive civilizations.”  Oct. 23, 2015,  The International Journal of Astrobiology.   Adam Stevens, Duncan Forgan and Jack O’Malley James.

 

 

 

Discarded Thymus glands offer new hope for people with autoimmune disease

The thymus is one of those under appreciated organs you just don’t hear much about. Sitting in your chest, just in front of your heart, the thymus is at its largest and most active during infancy and childhood. By adulthood, the thymus has shrunk to practically nothing, being mostly replaced by fat. It plays an important role in the health of your immune system, and is the location where certain immune cells, called T-cells, go to mature and develop properly.

The thymus is like a schoolhouse for T-cells where they learn important lessons, like “recognize these sets of proteins as part of our own body and don’t attack them, but attack anything you don’t recognize because it must be a foreign intruder”. It allows the immune system to develop what is known as Central Tolerance. Without central tolerance, we develop auto-immune disease, which is essentially your immune system fighting a civil war against other parts of your own body. Diseases like Lupus, Type 1 diabetes, Myasthenia gravis, and many others are autoimmune diseases with the immune system actively damaging some parts of the body. In Type 1 diabetes, for instance, the immune system targets your pancreatic islet cells for destruction, resulting in loss of your bodies ability to make insulin.

 

The thymus is an organ where T-cells mature, and may be a source of regulatory T-cells that have the potential to treat autoimmune disease.

The thymus is an organ where T-cells mature, and may be a source of regulatory T-cells that have the potential to treat autoimmune disease.

 

It is also known that there are many varieties of T-cells, each with unique and important roles to play in immune function. One type of T-cell is known as the Regulatory T-cell or Treg. Tregs are special because they help to keep the other cells of the immune system from getting too wild and out of control (a recipe for autoimmune disease). They can go into an inflammatory situation where lots of immune cells are activated and ready to rumble, and tell those cells, “alright, everyone just calm down”, thereby suppressing the immune response. Some studies have show that Tregs can be infused into patients with autoimmune disease to help control their symptoms. They might even be a valuable way to suppress the immune system in people with an organ transplant, like a kidney or heart. Tregs are a way to use one part of the immune system to control other parts of the immune system – like fighting fire with fire – in the case of autoimmune disease.

These treatments, while promising, are still not fully evaluated and are not standard of care as of yet. One reason that not much research has been done using Tregs as a therapy is that they are hard to come by. They can be collected from the blood of donors, then grown in the lab to try to get enough cells for treatment, but the process is inefficient and doesn’t result in a large number of Treg cells.

This month in the American Journal of Transplantation, a team of Canadian researcher showed that discarded human thymuses are an excellent source of Tregs that can be harvested and used to treat a variety of immune mediated disease. So why would there ever be a discarded thymus? It turns out that when an infant is undergoing heart surgery, as might be done to correct a cardiac birth defect, the thymus is huge and in the surgeons’ way, and must be removed to gain access to the heart. This is true in infants where the thymus is very large compared to the heart, but not a problem in adults where the thymus has already atrophied to a tiny insignificant size.

Tregs can be identified and isolated based on unique protein markers on their cell surfaces such as CD25+,CD4+, and FOXP3. Other immune cells show different sets of markers making it possible to identify the different cell types, and select only the ones needed. The researchers found that they could identify and isolate many more Tregs from one discarded infant thymus, than could be generated from the blood of an adult donor. In fact, they could show that there are more Tregs in an infant thymus than are present in the entire circulation of an adult. They also found that the Tregs from discarded infant thymus function better compared to those recovered from the process of blood donation. It is thought that this might be due to the immaturity of Tregs coming from thymus versus blood, since those in the blood have been around longer and show other markers of cellular aging, such as shorter telomere length.

Perhaps if more Tregs become available from thymus harvesting, more clinical studies studies will be conducted that may hopefully find effective ways to treat autoimmune diseases that today are very difficult to control and create much suffering in the lives of so many people.

 

Reference Article:
1. Am J Transplant. 2016 Jan;16(1):58-71. doi: 10.1111/ajt.13456. Epub 2015 Sep 28.  Discarded Human Thymus Is a Novel Source of Stable and Long-Lived Therapeutic Regulatory T Cells.
Dijke IE1,2, Hoeppli RE3, Ellis T1,2, Pearcey J1,2, Huang Q3, McMurchy AN3, Boer K4, Peeters AM4, Aubert G5, Larsen I1,2, Ross DB2,6, Rebeyka I2,6, Campbell A3, Baan CC4, Levings MK3, West LJ1,2,6.

Intron Retention: a common cause for cancer

Tumor suppressor genes are normally busy keeping your cell’s growth cycle regulated, and when in good working order, prevent cells becoming malignant.  A new study finds that many cancers are caused by mutations that block the tumor suppressor gene’s effect, through a process called Intron Retention. Introns are normally removed after a gene is transcribed into RNA, but in intron retention, one is accidentally left in place.  The result can be disastrous, leading to cancer and possibly other disease.  

3d render of a DNA spirals

3d render of a DNA spirals

Introns are found in complex cells, like those of animals and plants, but not in simple cells like bacteria.  Introns are non-coding sequences, meaning that even though the intron is part of the gene, it’s DNA is not used in the gene’s instruction for making protein.   Within the gene, the introns are placed between exons – the sequences of DNA that are the actual code for protein.  A single gene may contain many introns and exons.   When a gene becomes activated, the cell transcribes the DNA into messanger-RNA (mRNA), which then leaves the cell nucleus to be translated into a protein by ribosomes in the cytoplasm.  Under normal conditions, both intron and exon DNA on the gene get transcribed into mRNA, but the intron is then cut out of the mRNA prior to leaving the cell nucleus, and so never goes on to the ribosome.  Therefore, the mature mRNA comes only from the DNA of the gene’s exons – all unwanted introns having been removed. The removal of the introns from the mRNA is called splicing, and is carried out by complex cellular machinery, composed of both protein and RNA, called the Splicosome.

 Organization of the gene into introns and exons. Splicing of the gene after transcription removes the intron sequences producing the mature mRNA.

Organization of the gene into introns and exons. Splicing of the gene after transcription removes the intron sequences producing the mature mRNA.

Splicing is an important invention of complex cells, leading to greater variation due to Alternative Splicing – different combinations of the exons used to code for the final protein.  Alternative splicing creates the potential for multiple protein product from a single gene.  For example, some proteins might use the code from all the gene’s exons, but others might use only a few exons, the others having been spliced out, leading to very different proteins with different functions.  

Getting back to Intron Retention, this is the situation when an intron escapes being spliced out, and erroneously remains in the mature mRNA.  It can happen due to a mutations at a splice site – sequence of DNA that marks where to splice – and therefore, makes the intron invisible to the Splicosome. 

The study, published in the November 2015 journal of Nature Genetics, by Hyunchul Jung at the National Research Center in Gyeonggi-do, South Korea, describes the analysis of DNA samples from 1812 patients, with a variety of different types of cancer, including breast, colon, lung, kidney, ovarian, and uterine.  After computational analysis of the tumor DNA, Jung found that 31.6% had mutations disrupting normal splicing, with one of the most common type of splicing error being Intron Retention.  

Jung also showed that the mutation disrupting the splice site doesn’t need to be one that would change the amino acid sequence of the future protein – a so called Synonymous Mutation- so might be easily overlooked as being disease causing.  In many cases, the intron contains a warning signal for the cell to destroy the mRNA before making it into protein, so that gene never gets expressed.  In a significant number of the cancers studied, Intron Retention was found to have occurred more frequently in Tumor Suppressor Genes (TSG).  TSGs are like the brakes on the cell cycle, and Intron Retention is like having bad brakes, so the cell cycle speeds out of control, leading to a malignant cell that divides uncontrollably.  As a suggestion for future research the paper states, “…intronic splice sites should be carefully considered for their potential as disease-causing variants, regardless of whether an amino acid change occurs.”  Knowledge of this mechanism of gene disruption may lead to a much better understanding of the causes of certain cancers and other diseases.

Reference Journal:

  1. Intron retention is a widespread mechanism of tumor-suppressor inactivation.  Jung H, Lee D, Lee J, Park D, Kim YJ, Park WY, Hong D, Park PJ, Lee E.  Nat Genet. 2015 Nov;47(11):1242-8. doi: 10.1038/ng.3414. Epub 2015 Oct 5.  PMID: 26437032

Pleasant thought of the Day: the galaxy may be a graveyard full of dead aliens

As astrobiologists continue to find that the basic building blocks of life are littered throughout space, and how easy it seems for complex organic molecules, like amino acids and nucleic acids, to assemble given conditions thought to be prevalent on many worlds throughout the cosmos, the question as to why we haven’t detected life outside of the earth becomes more and more curious. Where are all the aliens? Why haven’t we seen or heard their signals from space? Could we really have been the only planet where life evolved?

Artistic representation of a superhabitable planet.

Artistic representation of a superhabitable planet.

A team of astrobiologists, lead by Dr. Aditya Chopra from The Australian National University (ANU) thinks there may be an answer to these difficult questions, and you may want to take a seat before I give you the news. I’m sorry to have to break it to you like this, but the aliens, well, they didn’t make it.

According to an article published by the team at ANU in the January 2016 issue of Astrobiology, life probably does arise very frequently on planets throughout the galaxy. Life is tough, in the sense that it is easy to get started in environments all over the place, but ironically it is also very brittle, in the sense that to hang on and evolve, its environment has to be very supportive. Dr. Chopra says, “Early life is fragile, so we believe it rarely evolves quickly enough to survive.”

If true, then most life that has arisen in the cosmos is dead! We’re not talking advanced civilizations that destroyed themselves with nuclear war or unleashed the robot apocalypse, we’re talking about the earliest development of life, simple cells, or possibly even porto-cells, that seemed to just be getting started then, wham, environmental catastrophe shuts them down while they’re still vulnerable, inefficient replicators, without much time to have evolved more robust survival features. If the most primitive life forms emerge often, but survive infrequently, then the evolution of very complex and intelligent life will also be very infrequent. The very low probability for survival beyond these most primitive stages is known as the Gaian Bottleneck.

The Gaian Bottleneck may be a type of filter that weeds out a lot of hopeful little worlds creating an essentially barren universe. Somehow earth made it through the Gaian Bottleneck. Earth must have had conditions not only for jump-starting life, but for providing a more stable environment that allowed further evolution of that life. If given the chance, the ANU team believes that life then begins to form feedback loops with the planet that help stabilize it, making it even more habitable for the long haul. Dr. Charley Lineweaver, also of the ANU team commented that, “Early microbial life on Venus and Mars, if there was any, failed to stabilize the rapidly changing environment. Life on Earth probably played a leading role in stabilizing the planet’s climate.”

So the next time life seems to be treating you unfair, look up at the stars and think of all the little aliens that never even had a real shot in this great big cold universe, and maybe it will help to know that you come from a long line of tough survivors.

How dad’s bad diet may have impacted your disease risk

We all know that expecting moms need to take good care of themselves, so that the environment in the womb is as optimal as possible to reduce disease risk to the developing fetus. That means eating a healthy well balanced diet, achieving the appropriate amount of weight gain during pregnancy, managing metabolic problems like gestational diabetes if they arise, and avoiding harmful exposures like alcohol and recreational drugs.

Evidence shows that a father's diet prior to conception, may impact gene expression and future health, in his offspring.

Evidence shows that a father’s diet prior to conception, may impact gene expression and future health, in his offspring.

A growing body of evidence now also implicates a role for dad in the risk of disease imparted to the fetus. By this, we’re not speaking of the inheritance of genetic mutations, but instead effects that arise in the father due to his environmental exposures, which are then passed onto the fetus at the time of conception. These types of inheritable traits are known as epigenetic, as opposed to genetic, because they are not passed on from parent to child through changes in the DNA. In rats, it has been shown that there is good evidence that dad’s diet can have an influence on his offspring’s risk for diabetes, high blood pressure, and high cholesterol (Rando and Simmons). But, if these risks are not passed from father to offspring by the inheritance of his DNA, then how is the affect passed on? In the January 22, 2016 issue of the journal Science, Oliver Rando, in Lyon, France demonstrates one possible mechanism, by which the environment of the father, prior to fertilization of the mother’s egg with his sperm, leads to profound and long-lasting changes in the development of their fetus.

Dr. Rando, and his team, were able to show that when male rats were fed a diet low in protein, there was a measurable shift in the number and types of small RNA molecules found in their mature sperm. A significant increase was observed in the amount of certain transfer-RNA (tRNA) molecules in the sperm of male rats fed the low protein diet versus those on a normal diet. The conventional function of tRNA is to deliver amino acids to the ribosome, so they can be joined together to make a protein. There are different tRNAs molecules that are specific for each amino acid.

Upon fertilization of the egg cell, the sperm introduces small RNA molecules which influence genetic programming of the developing embryo.

Upon fertilization of the egg cell, the sperm introduces small RNA molecules which influence genetic programming of the developing embryo.

Rando’s team found that the increase in sperm tRNA, seen in low protein fed rats, were not whole molecules, but only fragments of tRNA. The tRNA fragments were not produced by the developing sperm cells themselves, as might be expected, but were fragmented in other cells of the male reproductive tract, then transferred into the sperm as they underwent their maturation process. Upon fertilization of the egg, these small RNAs enter the egg from the sperm, altering expression of genes in the developing embryo. Using embryonic stem cells, it was shown that the effect of these tRNA fragments in the fertilized egg, is at least in part, realized by the changes they produce an endogenous retroelement called MERVL, a factor known to be an important in enhancing gene expression in the early embryo. This ultimately leads to an over expression of some genes along the cholesterol pathway in the developing fetal liver, potentially influencing future metabolic health.

The dietary changes in the male rats led to changes in the the small RNA molecules in their reproductive tract, which were transferred into their sperm, ultimately affecting gene expression in the fertilized egg, and adversely affecting the risk of disease in the offspring. It is not known if these same mechanisms would apply to humans -although there is no reason to think that they might not – or which other environmental exposures of the future father could also be important in the health of his offspring. It may still be too early to make any evidence based recommendations for guys hoping to start a family, but perhaps further research will help better define how much impact diet, exercise, and other habits have on their future health of their sons and daughters.

 

Reference Articles:
1. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals.
Science. 2016 Jan 22;351(6271):391-6. doi: 10.1126/science.aad6780. Epub 2015 Dec 31.
Sharma U1, Conine CC1, Shea JM1, Boskovic A1, Derr AG2, Bing XY1, Belleannee C3, Kucukural A2, Serra RW1, Sun F1, Song L1, Carone BR1, Ricci EP4, Li XZ5, Fauquier L1, Moore MJ6, Sullivan R3, Mello CC7, Garber M2, Rando OJ

2. I’m eating for two: parental dietary effects on offspring metabolism.Cell. 2015 Mar 26;161(1):93-105. doi: 10.1016/j.cell. 2015.02.021.
Rando OJ1, Simmons RA2.

3. Retrotransposons shape species-specific embryonic stem cell gene expression. Luisa Robbez-Masson and Helen M Rowe
Retrovirology201512:45 DOI: 10.1186/s12977-015-0173-5

4. Regulation of Mouse Retroelement MuERV-L/MERVL Expression by REX1 and Epigenetic Control of Stem Cell Potency
Front Oncol. 2014; 4: 14. Published online 2014 Feb 6. doi:  10.3389/fonc.2014.00014
Jon Schoorlemmer,1,2,* Raquel Pérez-Palacios,1 María Climent,3,† Diana Guallar,1,† and Pedro Muniesa3