Happy Darwin Day 2016

February 12th, 2016 is Charles Darwin’s 207th birthday. Charles also happened to share the exact same date of birth with Abraham Lincoln – so happy birthday Mr. Lincoln, as well! Since this blog is dedicated to science, with a special emphasis on evolution, and in fact, has the name Darwin in the title, I want to be sure to honor our dear Mr. Darwin properly.

There are Darwin Day celebrations planned in the USA and around the world, but no ‘Official Darwin Day’ is recognized nationally. That could change as some efforts are being made to make it official. In fact, this year the Governor of Delaware declared an official Darwin Day in his state. In some cities there are lectures or parties to celebrate.  The Center for Inquiry has a take action page, where you can send your name in a letter  to members of congress to express the importance of creating a Darwin’s Day for public education of science.

Charles Darwin’s theory of evolution was the beginning of modern biological science. As the Russian evolutionary biologist Theodosius Dobzhansky is quoted as saying, “Nothing in biology makes sense except in the light of evolution”. Evolution is the thread that binds all of biology together. Every aspect of biology, from molecular genetics, embryology, comparative anatomy, populations and ecosystems all “make sense in the light of evolution”.

Darwin’s theory was a realization of origin from common decent. Evolution does not address the emergence of life from non-biological origins, but does an excellent job explaining the illusion of design seen in the complex structures of the living world. Of course, Darwin realized that the illusion was the product of natural selection working on variations in living things. Darwin had no idea about genetics, DNA, mutations, and so on, but as those fields of biology developed they only reinforced Darwin’s big idea. It could easily have been otherwise. If evolution by natural selection was not how the world worked, then molecular genetics, phylogenetic, developmental biology, and so on would not have provided additional support to a 150 year old theory. Yet, all these modern sciences fit in perfectly, continuing to build on the original theory. Even without the fossil record modern biology would still point the way to evolution. By the way, the fossil record also supports evolution, and has only become more robust during the last 150 years as many more fossil species have now been discovered.

I’m sure Darwin would have been delighted to learn about genes, how new mutations arise by damage due to radiation, chemical mutagens, or simply errors in the normal process of DNA synthesis. He would have loved to see how the genome is cluttered with the remains of dead viruses, pseudogenes, copying errors that we have been copying and passing down to our children for geological eons. And he would have certainly understood that we can see our degree of relatedness to any living species on the planet by looking at, not just the working genes and how closely they match to us, but also these dead viruses and pseudogenes.

Darwin’s voyage on the H.M.S Beagle remains one of the most exciting and most epic expeditions of discovery in history – certainly one of the most productive, since it resulted in much of the data Darwin needed to formulate his theory over the next several decades. Darwin was an amazing naturalist and keen observer. There is hardly any area of natural science of his time that he didn’t seem to make some meaningful contributions. Not just in biology but in geology, as well.

So this Darwin’s day I plan to celebrate at home with my family. Perhaps have a piece of Common Decent Cake or Evolution Pie, learn something new I didn’t know about evolution, and honor our Dear Mr. Darwin.  Let me know how you plan to celebrate.

Other Reading:

1. Darwin Day:  Wikipedia
2. Natural Selection:  Wikipedia
3. Youtube.  Climbing Mount Improbable.  Lecture by Richard Dawkins.
4. OxoG is how radiation turns your own water against you.  Darwin’s Kidneys blog
5. Cytosine Deamination.  Darwin’s Kidneys blog.  (another mechanism of mutation).
6. Another Clever Mesign by Mother Nature.  Darwin’s Kidneys blog.  New word mesign to differentiate apparent design in nature from when we mean a designed object.
7. How our ancestors promiscuous genes became more discriminating.  ZME Science. Feb. 9, 2016.  Article on how gene families arise by gene duplications.

Book Review: “The Vital Question”

By Rich Feldenberg:

On this episode of Darwin’s Kidneys – first of 2016- I’ll be reviewing a book by Nick Lane called, “The Vital Question: Energy, Evolution, and the Origins of Complex Life”. This book attempts to tackle some of the toughest questions in biology today, such as how, and in what environments, life originated, how the complex eukaryotic cell evolved, how the cellular mechanisms to generate energy echo back to the days before biology, and why sexual reproduction is the way it is based constraints placed on us by our energy generating systems -the mitochondria. It is a lot of territory to cover, but Dr. Lane does an amazing job of bringing all these seemingly diverse themes together, synthesizing them into a coherent narrative that flows as easily from one topic to the next, as electrons flow down the mitochondrial respiratory chain (a central subject of the book).

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For those of you, who like me, love the topic of biological origins, this book will keep you engaged, and I had trouble putting it down, as I waiting for the next amazing revelation to be exposed. The early part of the book describes the common thread between the most essential metabolic activities of all living cells on earth -whether they are bacteria, archaea, or complex eukaryotes – and the natural geochemical activity of Alkaline Hydrothermal Vents. All life generates its energy by using proton gradients to drive the production of ATP (the energy currency of the cell). In all cells today, special pumps have evolved to pump protons (hydrogen ions) across a membrane. This creates a proton gradient (more protons on one side of the membrane than the other) which will naturally lead to those protons tending to diffuse back across the membrane. Cells use this proton gradient to run the protein ATP-synthase, to generate ATP, just like running water can be used to turn a water wheel to do work at a mill. In order to get the proton, it has to be separated from its electron, and that is done through a series of oxidation-reduction (redox) reactions, where the electron is transferred from one compound to another with each subsequent compound having a greater affinity for the electron than the last compound. It ends with the electron being transferred to oxygen (O2), which has the most affinity for the electron, converting the oxygen to water. The compounds where the electron is being transferred, are the respiratory transport chain of proteins. It is also found in plants as part of their photosynthesis machinery.

 

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This process mirrors a naturally occurring geological process found in Alkaline Hydrothermal Vents on the ocean floor. These vents are different from the “Black Smokers” that have been better popularized, as sites of chemosynthesis, where an ecology of organisms survive using the energy of the vent, and are not directly dependent on energy of the sun. The Alkaline Vents, on the other hand, are not quite so hot, but more importantly are composed of a matrix of mineral with thin walls that mimics a cell membrane. The vent fluid is more alkaline, with a pH of around 10, and the ocean water more acidic. It is thought that the ocean pH, 4.5 billion years ago might have been even more acidic that it is today with a pH of around 6. Since pH is a measure of the proton concentration, there is a natural proton gradient between vent fluid and ocean water separated by a thin mineral. The mineral also contains Iron-Sulfer complexes and other minerals that can act as redox centers, producing the electron transfer that we also still see today in our respiratory transport chain.

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Dr. Lane argues that this environment provides a very plausible explanation for how life originated and why all life uses the unusual proton gradient method to generate energy. His own research is, in part, using reactors to replicate the Alkaline Vent environment to study this theory further.
He goes on to discuss how life could then have evolved more effective cell membranes making wondering further from the vent location possible, as long as these simple organisms could begin to pump protons on their own, at this point. This movement into the new environment, and an existence independent of the Alkaline Vent, is where the split between bacteria and archaea probably occurred. He shows the evidence for this hypothesis.
A great deal of the rest of the book describes the evolution of the complex cell, by the synthesis of an archaea host cell, with a bacterial endosymbiont which went on to become the mitochondria. He also describes, in detail, the genetic evidence, as well as, that logical considerations, that suggest this occurred, it occurred only once, and how the other features of the complex cell -such as nuclear membrane developed.

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The book is beautifully written, but I will say some background in biology certain helps, but his writing is clear, entertaining, and well focused.
I just finished reading, “The Vital Question” this month, but it is now in my top 10 all time favorite science books. The last Nick Lane book I read was called, “Oxygen” and was equally good. It was also about the biochemistry of energy generation in organisms. I urge you to check out, “The Vital Question”, and let me know what you think.

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References:
1. The Vital Question, by Nick Lane

2. Nick Lane webpage.

3. Darwin’s Kidney Article on Molecular Fossils (EMMAs).

4. Article on the necessity of a new word, Mesign, to help differentiate between something purposefully designed and something that has the false appearance of design being evolved by natural selection.

Gene Drives: so you want to change the world!

By Rich Feldenberg:
Want to change the genetic landscape of whole populations and ecosystems? Tired of having to do it the old fashioned way by genetically engineering one organism at a time? Well now there’s Gene Drive! The fast and efficient way to spread your desired genetic design! Just send $19.99 plus shipping and handling for your Gene Driver Kit today!

If the “Fake Advertisement” in the paragraph above, made it sound as though the Gene Drive concept is some crazy kind of internet scam that is to good to be true, actually nothing could be further from the truth. Well no, you can’t just send in money for a gene drive kit yet, but it turns out that gene drives are real, they’re awesome, they’re controversial, and they can in principle, change the gene pool of an entire population of an organism. In fact, this method of gene editing is so new that very few experiments have even been done, and its founder, Kevin Esvelt, feels that the technology is so powerful that he wants to put a halt on experimentation until society can come together and discuss whether we collectively feel this is an area of science we should pursue, not just one that we can pursue. To understand gene drives we first have to remind ourselves of how the CRISPR-Cas9 system works, which I reviewed in an earlier Darwin’s Kidney post.

Briefly, the CRISPR-Cas9 system is a new and powerful gene editing technique that can be used in living organisms. This system is found naturally in many bacteria, as part of their immune defense mechanism against viral attack. There are two major parts to the system. The first is a guide RNA and the second is the Cas9 enzyme. The guide RNA is a small strand of RNA (somewhere around 20-40 base pairs in length). When the guide RNA finds a perfect base pair match with a DNA strand somewhere in the cell, the Cas9 enzyme cuts that piece of DNA. In the case of bacteria, this allows the them to match one of their guide RNAs to a sequence of DNA from an invading virus, then cut the viral DNA, which disables the virus from taking over the bacterial cell. The guide RNA came from a previous viral attack that the bacteria survived, and when the bacterial enzymes chopped up the invaders DNA into small bits, some was incorporated into CRISPR so that exposure to that same virus the next time would quickly result in recognition by the bacteria – an immune system! In the last few years scientists have discovered how to make guide RNA for any desired gene, and along with the Cas9 enzyme, can then “snip out” the gene or any piece of DNA in question. This can be used to silence genes, or can also be used to replace genes if the cell has access to a DNA sequence that can fill the gap left by the Cas9 enzyme. This may turn out to be a great way to cure genetic diseases through gene therapy.

Gene drive systems, take this concept a step further. Gene drives rely on the gene editing to take place in germ line cells versus somatic cells. Germ-line cells are the cells that will become egg or sperm, and will be used to create new organisms through sexual reproduction. Somatic cells are all the other body cells, such as skin, kidney, brain, pancreas, etc. If a gene is edited in a somatic cell, that change will effect the organism in whom the change was made, but would not be passed down to the next generation.

As an example, lets say you want to be able to provide gene therapy for a genetic disease such as Nephrogenic Diabetes Insipidus (NDI). This disorder is X-linked, meaning that the gene is on the X chromosme. Since males have an X and Y chromosome, with the X coming from their mother and the Y coming from their father, if the mother’s X chromosome has the mutant gene for NDI they will have inherited the disease, which leads to the kidneys inability to regulate water loss. People with this disorder can die of dehydration because even when dehydrated they continue to produce too much urine. A female, having two X chromosomes, one from her mother and the other from her father, might be a carrier for NDI if her mother’s X had the mutant NDI gene, but she still wouldn’t develop the actual disease since her normal NDI gene from her father’s X chromosome will compensate.

In principle you could use the CRISPR system to edit the defect gene, so that the male patient with NDI can now regulate water loss through the kidneys normally. There is still no way to really do this yet. You would need to deliver the CRISPR-Cas9 system, to the appropriate kidney cells of the affected individual. At the present time, a way to target and deliver the system is still not available, but if it could be delivered to the kidney cells it would excise the defective DNA. The cells own repair mechanisms will then look for a replacement to fix the DNA break made by the CRISPR-Cas9. If the normal gene was also delivered to the cell it will be incorporated into the place where CRISPR-Cas9 made the break. This will result in having removed the defective disease causing gene and replaced it with the normal healthy gene, and should therefore cure the disease – Nephrogenic Diabetes Insipidus kidney disease in our example. However, even if this could really work – its never been tried yet for this disease – but was unsuccessfully attempted for Hemophilia, the cured individual would still be able to pass the disease on to their children. The reason is that only the kidney cells were altered, and not the germ-line cells.

Gene drives, on the other hand, effects the germ-line, but they have an even bigger, more ingenious twist to their potential to alter future generations. With gene drives, in addition to supplying the new gene, the genetic code for more CRISPR-Cas9 is also inserted into the target genome. So here is how it might work. Let simplify the example by calling the two alleles of the gene (one allele comes from mom and the other from dad) as Normal and Engineered. It could be any gene in the genome that you’re interested in, such as the gene for making insulin or for making neurotransmitters in the brain, or transcription factors that tell more genes what to do. In this example we want the Engineered gene to take over because it has some trait we have engineered for it that we find desirable. It could be to fix a defective gene or it could be to give the organism some new property. We’ll get to some examples of new properties shortly.

 

The first step might need to take place in the lab when the organism at its earliest stage, the fertilized egg. You place the CRISPR-Cas9 into the fertilized egg with guide RNA that recognizes the Normal gene. You also place the Engineered gene in the cell to replace the Normal gene once Cas9 has cut it. The cell will now have the Engineered gene as part of its entire genome. This will effect both somatic cells and germ-line cells since the fertilized egg will continue its job of dividing into more and more cells, which will eventually become all the cells of the body. Eventually this organism will develop into an adult and find a mate to produce more offspring. The offspring will have an approximately 50% chance that the Engineered gene will be passed on to the the next generation. That is because each offspring will get one copy of Engineered gene from our genetically modified organism and the other gene from its mate, which would carry the Normal gene version since it was never modified. So this is where the special ingenious twist comes in!

Not only does the gene you inserted into the fertilized egg contain the DNA of your engineered gene, but it contains the DNA for making a CRISPR-Cas9 system, as well. This CRISPR-Cas9 is hidden somewhere in the middle of your Engineered gene so that the cells DNA repair enzymes don’t recognize it as being novel to the cell. They only recognize the ends that need to fit in the space that Cas9 cut out. So in this way, the gene we pasted into the genome is Engineered-CRISPR-Cas9. Now when the cell transcribes that gene the CRISPR-Cas9 is also transcribed which leads to a guide RNA and a working Cas9 enzyme. The guide RNA will then match to the Normal gene and Cas9 will cut it. This is important because when the genetically modified organism mates with a wild type organism the offspring will have one Normal gene from the wild type and one Engineered-CRISPR-Cas9 gene from the genetically modified organism. CRISPR-Cas9 then gets transcribed, seeks out the Normal gene, and replaces it with the Engineered-CRISPR-Cas9 gene, so the offspring actually ends up with two copies of the Engineered-CRISPR-Cas9 gene. In this way the rate of transfer of the Engineered gene, to successive generations, goes from 50% to 100%. The Engineered-CRISPR-Cas9 gene effectively edits every other allele that matches its guide RNA, turning it into the Engineered gene. Now the gene can spread rapidly through a population because the odds are always in favor of this gene being passed down to all offspring. See the excellent Mosquito chart in the following article I’ve linked to in order to get a visual on how the inheritance would be effected.

It should be pointed out that this is only effective for organism that reproduce sexually. Asexually reproducing organisms (such as bacteria) won’t be influenced by this mechanism. For organism that have short generation time this is ideal. One proposed problem that gene drives might be able to solve would be in the fight against malaria. Malaria kills millions of people each year (see Darwin’s Kidneys article: Diseases with an Upside). If mosquitos were released into the wild, that were engineered to have a malaria resistant gene and also the CRISPR-Cas9 system, then that gene would spread rapidly throughout the mosquito population. The result would be malaria resistant mosquitos and possibly an end to suffering and death in many parts of the world due to this parasitic infection.

There’s no guarantee, however, that the malaria organism – Plasmodium – would not find a way to evolve around the mosquito’s malaria resistance given enough time. There is also no guarantee that the malaria resistant gene might not somehow decrease the “genetic fitness” of the mosquito making them less likely to survive and reproduce. Mosquitos would be an ideal organism for this type of engineering, however, since they have a rapid generation time, so within several years to decades a gene system of this type could theoretically pass to all members of the population. Humans, on the other hand, reproduce slowly so a gene drive in humans would probably take hundreds of years to spread through the population. Still, you could imagine an attempt to eliminate many genetic diseases completely from existence by using gene drives that over the course of centuries might be effective. One could also imagine the ability to produce a civilization of future generations of humans that are more intelligent, more rational, less violent, more empathetic, and so on, if the genes involved in producing those traits could be identified. It is harder to imagine, however, that society as a whole would ever agree to such a mass alteration of the human genome – creating something beyond human – by directing human evolution in a desired direction. Its too early to know if such changes to the human genome could even be done safely without creating damaging consequence that are impossible to predict. I’m not necessarily advocating for changing the human race for the better, but more just advocating for discussion of the potential positive and negative effects might result from such grandiose dreams.

Because the implications for gene drives are so powerful and large scale, there is currently a call for a hold on research until the ethical considerations can be more fully considered. I think this seems wise at our current state of understanding. Changing an ecosystem could have unforeseen consequences. There may be ways to alter some behavior in organisms with gene drives that would not necessarily eliminate those organisms from the ecosystem – and so may have a mild impact on the ecosystem as a whole. For example, one could engineer a pest to dislike the taste of a crop that it normally damages, and therefore protect the crop without the need for as much pesticide use. The pest is now no longer a pest, but remains in the ecosystem where it can feed on other plants and remain part of the normal food chain for other organisms. Could gene drives be used to engineer plants to more efficiently remove CO2 from the atmosphere, and combat global warming while increasing crop yields?

Gene drives are an exciting new method of changing the genetic makeup of populations of organisms. Whether they will be used to prevent diseases like malaria from killing so many or making crops less prone towards pests and therefore reducing the amount of insecticides released into the environment, is up to society at large to decide if we are ready to pursue such far reaching technology. My hope is that we may find ways to safely use gene drives to improve life on planet earth for ourselves and our fellow species.

References:
1. “Genetically Engineering Almost Anything” by Tim De Chant and Eleanor Nelson, Nova Next. July 17, 2014.
http://www.pbs.org/wgbh/nova/next/evolution/crispr-gene-drives/
2. “Gene Drives and CRISPR could revolutionize ecosystem management”, by Kevin Esvelt, George Church, and Jeantine Lunshof; Scientific American Blog. July 17, 2014.
http://blogs.scientificamerican.com/guest-blog/gene-drives-and-crispr-could-revolutionize-ecosystem-management/
3. Gene Drive Wikipedia: https://en.wikipedia.org/wiki/Gene_drive
4. “Gene editing in Humans”; Neurologica blog by Steven Novella; Nov. 19, 2015
http://theness.com/neurologicablog/index.php/gene-editing-humans/
5. “CRISPR: what’s the big deal?”, Darwin’s Kidney blog by Rich Feldenberg. Nov. 28, 2015.
http://darwinskidneys-science.com/2015/11/28/crispr-whats-the-big-deal/
6. “Can we genetically engineer Rubisco to feed the world?”; Darwin’s Kidney blog by Rich Feldenberg.
July 22, 2015.
http://darwinskidneys-science.com/2015/11/28/crispr-whats-the-big-deal/
7. “Diseases with an upside”; Darwin’s Kidney blog by Rich Feldenberg. July 29, 2015.
http://darwinskidneys-science.com/2015/07/29/diseases-with-an-upside/
8. “Live at the NESS: New Dilemmas in Bioethics”; The Rationally Speaking Podcast. April 24, 2011.
With Massimo Pigliucci and Julia Galef as hosts.
http://rationallyspeakingpodcast.org/show/rs33-live-at-necss-new-dilemmas-in-bioethics.html

9. “Sculpting Evolution”; website of Kevin Esvelt, PhD.  Founder of gene drives.   http://www.sculptingevolution.org/kevin-m-esvelt

 

 

 

You once had six kidneys, and no you’re not an alien!

By Rich Feldenberg

This article is the first in a series of articles that relates back to the name of this blog. Darwin’s Kidneys is the blog name and also the name of the book that I am currently in the process of writing. It is an attempt to illustrate the convoluted evolutionary path that kidneys have taken down our ancestral line. More importantly, it is an attempt to highlight the importance of the kidneys in allowing animals to adapt into new environment along that evolutionary road. In the case of our ancestors, and all land vertebrates, that road began in the oceans, detoured into fresh water habitats, then rose up onto dry land. Be aware that that is simply the road that lead from the first animal ancestors to humans. Other animals began at the same starting line, but took different turns along the way, sometimes taking them far from where our particular road has taken us. In many cases, the road for certain creatures came to an abrupt dead end, as extinction ended that journey. Along the way, kidneys helped creatures survive by keeping their internal environment stable even as they moved into environments very different from which they originally evolved. To meet those new challenges, kidneys had to evolve to prevent the internal environment from reaching chemical equilibrium with the external environment.

So what’s all this about you having had six kidneys? Well, our earliest development betrays something of our evolutionary past. Think back to when you were just a little fetus in the womb. I know, it was a long time ago, but think hard. As a fetus you didn’t have to worry about very much. Mom took care of you. For instance, you didn’t need kidneys to clean your blood back then. That’s what mom’s kidney’s were doing for you through the intermediate organ of the placenta. The placenta, which is the only organ that was part you and part mom, was the portal between the two worlds. The nice warm watery world you were floating in, and the harsh outside world that you had no idea you would be rudely tossed into in a short 9 months. But, since you were going to need kidneys when the connection between the two worlds was eventually lost, your genetic programming was instructing your developing body to start making kidneys.

You might think that a good way to make kidneys would be to have certain cells in your developing body begin to transform into kidney cells, and arrange themselves into the proper architecture to create the complex tubules, glomeruli, blood vessels, and so on necessary for a functional organ we know as the kidney. That would probably make a lot of sense to an engineer, architect, or designer, but that is not how nature decided to go about this particular project. To make human kidneys, or any mammalian kidneys for that matter, we first have to go through two false starts, then finally get to the real deal.

Your first set of kidneys starts to take place somewhere around where your upper chest or neck will eventually be, when you are a mere 22 days gestation (ah, the joys of youth). Tissue known as the intermediate mesoderm receives chemical signals, called morphogens, from the nearby anterior somites to start forming a duct named the pronephric duct. These morphogens effect which genes get turned on or off in the cells that come into contact with them. Cells in the pronephric duct then begin a migration to nearby tissue and cause more of the intermediate mesoderm to start forming little tubules. By the way, tubules are what the kidney is all about, so tubules are a good start at this point. These tubules form the pronephros. Nephros refers to kidney, and pronephros doesn’t mean “go kidney!”, it means first kidney. Why? Because this is your first set of kidneys, but luckily not your last. Now if you happen to be a fish or an amphibian, this is about as good as it gets. These are the final kidneys for these groups of creatures. In mammals the pronephros is not thought to be functional, but keep in mind that as mammals, our distant ancestors included fish and amphibians – hint hint- so our non-functional pronephros may be evolutionary baggage that we are stuck lugging around from generation to generation.

The pronephros begins to degenerate not long after it forms, but before it does so it produces a duct that begins to grow in a downward direction towards the lower body. This duct is called the nephric duct, or sometimes the Wolffian duct, secretes chemical morphogens in the the tissue below where the pronephros had previously appeared then disappeared. This time the morphogens secreted by the pronephros start the generation of tubules in our second pair of kidneys – the mesonephros. In humans the mesonephros forms around day number 25, but alas, it too has only a brief ethereal existence and begins to degenerate soon after forming it’s mere 30 or so tubules.

Curiously, while the mesonephros doesn’t appear to filter blood like an decent kidney would, it does have some interesting functions and lead to some important structures. For one thing it happens to be an important site for the production of blood cells in the early fetus. The so called, hematopoietic stem cells begin to form in the mesoderm at the aorta-gonad-mesonephros region (AGM). So your second pair of kidneys is important as an early red blood cell production factory. The hematopoietic stem cells jump ship, however, as the mesonephros eventually disintegrates away, and they travel to the nearby liver where they reside for another brief interval, producing blood cells for the fetus. Eventually they move on from this location too, and set up shop in the bone marrow, where they eventually settle down for the long duration of your adult life.

The second important legacy left by the mesonephros is that some of the tubules become components of the male reproductive tract. The tubules of the mesonephros connect the Wolffian duct to the testis and the Wolffian duct itself transforms into the epididymis and vas deferens of the male gonads. In female, lower levels of testosterone allow degeneration of all the Wolffian duct structures so these male structures don’t form in the female fetus.

In the mean time, as the mesonephros follows the unfortunate fate of the doomed pronephros, the Wolffian duct continues to grow downward on it’s journey towards the pelvis. When it reaches a certain patch of cells, called the metanephric mesenchyme (MM), it pops off a little shoot called the ureteric bud. How the ureteric bud knows where to sprout off the Wolffian duct and which direction to grow is due to it having received an important, and tongue twistingly named chemical signal from the MM called glial cell line-derived neurotrophic factor or the easier to say GDNF. The bud cells have protein receptors that can recognize the GDNF diffusing into the area. Experiments where mice had their GDNF receptor gene deleted failed to form kidneys at all, illustrating the importance of this chemical interaction for renal organ development. The ureteric bud then kindly replies to the MM with it’s own suite of chemical morphogens which tell the MM to please not die by apoptosis (apoptosis is programmed cell death and is an important means of removing unnecessary tissue during organ development) and then to cause the cells to begin to cluster around the bud itself.

Further chemical interactions between the MM and ureteric bud cause the bud to begin branching, like branches and twigs on a tree, and for the cells of the MM to transform into epithelial cells and arrange themselves into tubules. This time -third times a charm- the tubules don’t disintegrate, as they did with the pronephros and mesonephros. Instead, they go on to produce the final and permanent set of kidneys – the kidneys that you’ll use for your lifetime – and the third set of kidneys that you made! The first four kidneys are gone by the time you’re born, so it is true that the metaphros is the only set of kidneys that you’re born with. Although, it you’re a male then some remnants of the previous kidneys still remain as part of the reproductive tract – weird, right?!The dance between the MM and the ureteric bud continues, resulting in the formation of nephrons from the MM end, and collecting ducts and ureters from the ureteric bud end.

While the pronephros and the mesonephros do not function as kidneys for us, they none the less, are absolutely necessary to get to the metanephros stage. If something goes wrong at one of the first two stages, then the final kidney will either not form at all, or be malformed in some horrible way. As in nearly every case, evolution uses what it has already available to work with, and modifies that in some way to produce new structures, and structures with new functions. It seems that evolution used many of the genetic pathways that were already in place to produce fish kidneys, to eventually get to a mammalian-type kidney, which has many different functions than a fish kidney is required to perform. Wouldn’t it seem more logical to produce the mammalian kidney in a more direct manner, bypassing the unnecessary and complicated steps taken to begin the 1st the 2nd sets of kidneys? This might even have reduced the risk of many types of birth defects in the kidneys, that are so common, but nature does not operate by logic or foresight. Systems that are in place are simply prone toward variation through mutation. Vary rarely one of those mutations may improve the odds of survival, and because there are so many organisms born over long periods of time, these rare advantageous mutations are almost inevitable. Environmental pressures will continue to filter out the disadvantageous variations and increase the advantageous ones in the gene pool.

So yes, you’ve had six kidneys and no, you’re not an alien. You’re simply a result of the long process of evolution. Your distant ancestors live on, in you, in the way your genetic programming is constructed and operates.