Giving “junk DNA” the credit that it’s due

When the Human Genome Project was completed over a decade ago, in 2001, many biologists were surprised that the human genome only contains about 20000 to 25000 genes, which occupy less than 1% of the total DNA sequence. This was surprising news: how could such a complex system as a human being be coded for by only 25000 instructions, when a microscopic worm (C. elegans) has 21000, and a bacterium (E. coli) has 5000? And what was the point of carrying all this other DNA around? The term “junk DNA” was coined to refer to these non-protein-coding sequences. Are they really junk — relics of past evolution, gene duplication, viral infection, and other hypothesized mechanisms of sequence accumulation — or do they have a function that we simply haven’t found out about yet?

The ENCODE (Encyclopedia of DNA Elements) project has recently released its first results in a series of publications in Nature and other scientific journals. There was plenty of news surrounding it; not surprising given the $180 million that have already been spent, and the over 400 scientists working on it. Articles appeared in major newspapers and news outlets, but then I got an email from a college friend, who’s not a biologist, asking me what all this fuss was about. He’d read the newspaper articles, which were full of quotes from scientists lavishing praise on the project and its promise, but couldn’t quite figure out exactly what it was about. The generic-sounding name of the project doesn’t give many clues, either. And so, even though I’m supposed to be a microbiologist and not a human geneticist, I thought I’d take a shot at explaining the significance of the ENCODE results.

The idea of the “gene” has been a long and problematic one. It has a peculiar history for a biological concept, because the existence of genes was predicted by theory (the experiments of Mendel and his successors) long before we had any clue of what the physical nature of genes were. Eventually biologists figured out that DNA was the hereditary material, and the Central Dogma took shape: that genetic information stored on DNA was first transcribed to RNA, which was then translated to proteins, and that proteins were the main functioning parts of the cell: the scaffolding, motors, and carriers that performed the business of life. A gene was just the information needed to make a protein, and if asked to define the physical manifestation of a gene, one would have said that it was the stretch of DNA that held the instructions for making that protein.

As we found out more about genes and how they were regulated, however, the story began to get complicated. It wasn’t necessarily true that one gene = one protein: some genes could be spliced in different ways to give different products. Nor was it true that proteins were the only functional pieces of the cell: sure, we’ve known about ribosomal RNAs (rRNA) and transfer RNAs (tRNA) for a long time, but other small RNAs, some with catalytic functions, have also been discovered. Gradually, we’ve also come to appreciate that the complexity of life is not just the result of proteins interacting with other proteins, with DNA sitting passively by; many proteins also interact with DNA, determining which genes are going to be expressed, and which should stay silent. In the classical textbook examples, regulatory elements lie close to the genes which they administer, but it is now known that this isn’t necessarily so. New mechanisms of silencing genes have been discovered, some which work by chemically modifying DNA (methylation), and others which involve a dizzying dance of RNA and protein molecules (RNA interference). Is it time to revise the concept of the “gene”, or should we simply acknowledge that protein-coding genes are not the only significant pieces of a genome?

The ENCODE project has shown this very clearly. Far from being “junk”, the non-protein-coding sequences in a genome are actually doing something and not just sitting there passively. At least 80% of the genome can be experimentally shown to have some kind of function (recall that less than 1% of the genome codes for proteins), or as the authors put it: a “demonstrable biochemical function”. They may be regulators or promoters, i.e. sequences which control the expression of genes by binding to proteins involved in the machinery of transcription. They could be regions that are controlled by DNA methylation, which silences expression. Or they could be regions which are exposed to transcription factors, instead of being coiled up in histones.

This was a large scale project with many participants. What they did to discover this was a process of systematic cataloging. They used almost 150 different human cell lines in culture (including the famous HeLa cells) and performed different experiments to spot different functions. For example, to see what portion of the DNA was actually being transcribed, they extracted and sequenced RNA en masse, an approach made possible by new methods of nucleic acid sequencing which can sequence huge numbers of small lengths very quickly. To see what sequences bind to known proteins, they performed a method called ChIP, chromatin immunoprecipitation. For a protein which is thought to bind to DNA, antibodies are raised against it. The protein is then exposed to genomic DNA; it seeks out and binds to the specific sequence that it interacts with. A chemical is added to cross-link the protein and DNA, and this complex is fished out using the antibodies developed earlier. The crosslinks are removed, and the DNA is sequenced, to find out what region of the genome this protein interacts with. Other types of experiments were performed to find out which parts of the genome are methylated, are accessible to transcription factors, and so on. They’ve also analyzed how the regulatory elements in a genome interact with each other, and how the three-dimensional folding of the DNA itself affects the interactions between different parts of the genome.

One of the surprising findings was that much of the genome (75%) is actually transcribed to RNA at some point or another, even though most of these don’t end up being translated to proteins. Textbooks usually mention the three classical types of RNA: messenger RNA (mRNA), rRNA, and tRNA (described above), but aside from these workhorses, RNA was usually thought of as a sort of “relic” molecule, doing only these few menial jobs. But recent research is accumulating evidence for the importance of various kinds of small RNAs in the eukaryotic cell, and the ENCODE project could help the task of cataloging them all. 

There are a whole bunch of other sub-projects (or “threads”, as they call them on the ENCODE website) that have been carried out by the ENCODE consortium. As a way of doing science, I think it points the way to the future: big consortia collecting big data and crunching big numbers. For biology, the new sequencing technologies (collectively called “next-generation sequencing”, or NGS) are a tremendous advance over traditional Sanger-type sequencing, which was developed decades ago and still based on the same principles. NGS came into the market just in time for the ENCODE project, allowing them to sequence several times as much DNA for the same cost. We are now reaching the point when you could have your own personal genome sequence for a thousand dollars or even less. The limit on what we can do is imposed instead by our ability to store, transmit, and compute such massive quantities of data. 

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The first batch of papers published by the ENCODE consortium are available via the website of Nature. They’ve also got some snazzy interactive graphics. 

The world's largest virus

Back in January I blogged about how the physical constraint of capsid size may be forcing some viruses to squeeze their genomes into such a compact state that their genes overlap. Now we visit the other end of the scale to the largest virus yet discovered, appropriately called Megavirus chilensis, found in ocean waters off the coast of Chile.

As one of the paper's coauthors told BBC News, "You don't need an electron microscope to see it; you can see it with an ordinary light microscope." Each virus particle is about 680 nm across, or just under a micrometer, making it just barely visible as specks by light microscopy. They're structurally interesting, bearing a covering of fibers ("hair") all over the surface, and a five-pronged star-shaped structure on one vertex that the authors have called a "stargate", which the virus uses to release its nuclear material into the host cytoplasm.

Latest named cat species actually two subspecies

The Sunda clouded leopard (Neofelis diardi) was recognized as a distinct species, separate from the mainland Southeast Asian clouded leopard N. nebulosa, in 2008. Both are Vulnerable species, according to the IUCN.

Based on molecular genetic data, researchers suspected that the Sunda clouded leopard might actually represent two different subspecies, and this has been confirmed by a combination of molecular genetics and skull/dental features. There may be additional differences in coat patterning, but the number of specimens available for inspection is not enough to make a definitive statement.

The two subspecies are geographically separated: the Sumatran subspecies (N. diardi diardi) and the Borneo subspecies (N. diardi borneensis). They were probably isolated from each other after Sundaland land bridges were cut off when sea levels rose after the last ice age.

The BBC has a good summary article including a rare video of the animal from Dermakot National Park in Sabah, Borneo.

John Hunter and the Giants

This isn't the name of a band. John Hunter, the great 18th century surgeon whose anatomical collection now forms the Hunterian Museum of the Royal College of Surgeons, was fascinated by 'freaks' of nature. Among them, the Irish giant Charles Byrne, who measured 2.34 meters in height and became a celebrity when he showed up in London.

Hunter met Byrne in life, and had designs to acquire the giant's skeleton after his death, for his museum. However, Byrne tried to thwart Hunter's plans, and after he died at the age of 22, he had made his friends promise to bury him at sea. Hunter's hired hands, unfortunately for Byrne, managed to bribe or intoxicate the funeral party, or so the story goes, and stole the body away to Hunter's back door in the upmarket Leicester Square neighborhood, where in his basement the body was boiled down to a skeleton.

According to the Guardian, an endocrinologist named Márta Korbonits at London's Barts hospital has found a possible genetic cause for Byrne's gigantism. His growth spurt (and subsequent early death) was due to an excess of growth hormone produced by the pituitary gland. Pituitary tumors are the most common cause of gigantism, and today is treated by surgical removal of the tumor.

She studies a genetic condition called familial isolated pituitary adenoma, which is caused by a mutation in a gene called AIP (Aryl Hydrocarbon Receptor Interacting Protein). According to her work, Byrne's mutation (discovered by sequencing DNA from his teeth) came from a common ancestor as a population of people bearing the AIP mutation in Ireland today. As the article says:

Both Holland and McCloskey [a FIPA survivor and film-maker] came from Tyrone and were fascinated by the number of actual giants in the area, and by the way they figured in Irish folklore not as freaks, but as kings, seers and poets.

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John Hunter himself was also a colorful character, living in a colorful age. He might be called the prototype of the 'brash surgeon', more interested in showing off their surgical chops (and in Hunter's case - acquiring specimens for his collection) than the comfort of their terrified patients.

A good recent biography of him is Wendy Moore's The Knife Man. In his time (and indeed until the modern age), there was no clear line between medicine and natural history, and many of his famous experiments and observation concern the latter subject.

He was one of the first to experiment with surgical grafting. Among the grafts he performed was that of a freshly-pulled human incisor onto the comb of a rooster. We are told that this required repeated trials–I wonder who donated all those teeth! Eventually, the graft did 'take', and he sacrificed the animal, in order to bisect its comb to see how it connected to the tooth. He found that blood vessels from the rooster had indeed penetrated the tooth pulp: "The uniting of parts of different animals when brought into contact he attributed to the production of adhesive instead of suppurative inflammation, owing to their possession of 'the simple living principle.' " (Encyclopedia Britannica).

After his death, his anatomical collection found its way to the Company of Surgeons. It suffered damage during World War II, but is still on display today in London.

House Too Small? – Overlapping Genes in Viruses

Protein coding genes are complicated things: the four bases of DNA are arranged into triplet codons, each of which codes for one of 21 (more or less) amino acids, which are strung up in a polypeptide chain, folded into a complex 3-dimensional structure where precise shape and chemistry determines function... It would seem that any perturbation would throw this finely-tuned system off-kilter.

Even more outrageous is the notion that genes can overlap and still code for perfectly functional proteins, because this implies that, for part of the gene at least, a different reading frame still has functional meaning. This flies against our intuition that frame-shift mutations are the deadliest of all, and has been likened to taking a paragraph of text, moving all the spaces between words down by a character, and still being able to read it, but this time with a completely different meaning!

Viruses, though, are capable of this sort of contortion, and a number of hypotheses have been proposed to explain why they find it necessary to do so. Is it a way to reduce the overall genome length in the face of a high mutation rate? Or is it a means to couple together the expression of more than one gene? Looking at a number of viral genomes, a team from Italy and the UK claim to have found the reason: overlapping genes are a response to the constraints placed by viral capsid size.

For viruses that use RNA for their genetic material, there is a known inverse relationship between genome size and gene overlap: the longer the genome, the less gene overlap is present. They confirmed that this also held for DNA viruses. But when they grouped viruses by the kind of capsids they have–icosahedral vs. flexible–they found that this relationship is strong in the icosahedral capsid viruses, but weak in those with flexible capsids. Capsids are protein 'coats' that encase the viral genome; icosahedral capsids are particularly rigid and constrained in size, because their geometric configuration (icosahedra are one of the five Platonic solids of classical geometry) is the result of the interlocking of the protein units that make up the coat. There are precise mathematical rules that govern the assembly of these units.

Icosahedral adenoviruses (electron micrographs) with cartoon of icosahedron. (Wikimedia Commons)

On the surface, it seems like an extreme solution, even reminiscent of the infamous Bed of Procrustes. These viruses appear to have found a way of surviving the ordeal. It's so striking because we wouldn't expect to see what is patently a physical constraint leaving such a distinctive genomic signature, the latter being strictly informational. At the molecular level, though, there may be a fuzzier line between the two.

This is one of those things which writers used to attribute to the 'ingenuity of Nature', but speaking in materialist terms:

"In effect, the capsid poses an engineering problem for the creation of genomic novelty, and gene overlap is the way around it."

Panthers and Leopards in the Malay Peninsula

The term 'panther' has a confusing history - it's been used to refer to any big, black (i.e. 'melanic') cat, usually the leopard in particular. Leopards and panthers used to be thought of as different species, but they are in fact merely different color variants, and this so-called melanic coat coloration is a recessive Mendelian trait. To complicate matters, the four big cats - leopards, tigers, lions, jaguars - have been grouped in the genus Panthera, based on the same etymological root.

In Southeast Asia, the leopard Panthera pardus exists in two color morphs: the usual spotted variety, and the melanic 'panthers'. However, a recent evaluation of camera-trap data could not find any spotted leopards South of the Isthmus of Kra; all the animals that were photographed by these traps were black leopards. Anecdotal evidence from interviews with aboriginal peoples living in national parks also found that they were unfamiliar with the spotted leopards but could recognize the black ones. Although 'absence of evidence is not evidence of absence', it does show that spotted leopards are at the very least rare in Malaysia. The authors of this study suggest that this trait has become genetically fixed because of a bottleneck event sometime in the history of this population. This is a neat intersection between basic natural history and genetics, having implications for the genetic variability of the Malayan leopards, and hence their conservation viability.

Down with Kin Selection?

Oecophylla weaver ants in Gombe. Photo by Axel Rouvin via Wikimedia Commons.

The concepts of kin selection and inclusive fitness are centerpieces of modern evolutionary biology. Almost every biologist has some familiarity with at least the outline of the issue, and they are staples in textbooks and in the classroom. Briefly, these ideas were introduced in the mid-20th century to explain the apparent paradox of how altruism and cooperation might evolve in a biological system. If natural selection favors the spread and fixation of genes that cause an individual to have more offspring, how can we explain the evolution of traits which involve one individual aiding another at some cost to itself?

Cooperation might seem to be intuitively beneficial, but consider a population of animals which all sacrifice a bit of their potential individual fitness in order to cooperate for some greater good, e.g. defending the nest from predators. They will get good returns on their investment if they all cooperated honestly. However, such a group is prone to invasion by so-called 'cheaters', which take but do not give back. A group of cooperators without defences against cheating will rapidly be overtaken by cheaters, and hence any cooperative endeavour is doomed to crumble.

It was to resolve theoretical problems like these that the idea of inclusive fitness was introduced. Individual fitness is simply the number of offspring that one produces. Inclusive fitness, on the other hand, counts not just one's own offspring, but the offspring of relatives, multiplied by the factor of relatedness. The process by which it functions is kin selection - if one helps one's relatives and contributes to their individual fitness, then one is contributing to one's inclusive fitness. A gene for cooperation could hence spread and be resistant to cheating, because it is more likely to be present in relatives of an individual that already bears that gene, than in unrelated individuals. The essence of the idea is found in a prescient quip by the geneticist JBS Haldane, who said that he "would [lay down his life] to save two brothers or eight cousins" (Wikiquote) - because the relatedness (more rigorously, the probability that a gene is identical by descent) of siblings is 1/2 and that of cousins is 1/8.

A new look at the math (the derivations are in the supplementary material, but the main paper is unfortunately hidden behind a paywall) behind inclusive fitness theory is now claiming that it is no better than standard natural selection theory in explaining one of the key problems of biology, the evolution of eusociality (edit 28/8/2010: Harvard Gazette press release). The group, comprising mathematical biologists Martin Nowak and Corina Tarnita, and the father of sociobiology EO Wilson, explain that inclusive fitness is merely a different way of 'doing the accounting' which is somewhat more complicated than it needs to be. That is, it is too specific, relying on certain assumptions (additive fitness effects, pairwise interactions only, weak selection) which are fulfilled in only a few exceptional cases. It is not an adequately general theory, in the mathematical sense of the word. They also challenge the validity of Hamilton's rule, the simple-looking equation that states that a gene for a cooperative behavior will spread if:

Relatedness > cost/benefit

Population biologists trying to test Hamilton's rule in actual organisms have found it difficult to measure these quantities. The authors of this paper, using a more explicit derivation, found that cooperation does spread when something is greater than the cost to benefit ratio, but this 'something' (as they put it) is not relatedness. In place of inclusive fitness theory, they propose that the more general game-theoretic theory of natural selection, used in conjunction with precise models of population structure, is adequate to explain the evolution of cooperation, without invoking kin selection.

What then, of the crown jewel of kin selection, the explanation of eusociality in hymenopterans? Hymenopterans are the insects which include bees, wasps, and ants. They have an unusual genetic system called haplodiploidy: females lay either fertilized (diploid) or unfertilized (haploid) eggs. The former hatch into females, and the latter into males. The ants are perhaps the most successful and best known eusocial animals. Kin selection theory explains the cooperation between female, sterile worker ants (who might easily defect and start laying eggs of their own) in terms of their relatedness - sisters are more closely related to each other (relatedness of 3/4) than daughters are to mothers (1/2), and so cooperation among sisters can spread. Not all eusocial animals have haplodiploid sex determination - termites, for example, do not. As more eusocial animals have been found, it turns out that the number of haplodiploid lineages is in the minority. An alternative explanation has to be found for eusociality, because the kin-selection based explanation as given above was now most probably an exception to the rule.

Naked mole rats are eusocial mammals. Photo via Wikimedia Commons.

Ed Wilson has proposed for some time now that eusociality is to be explained by theories other than the traditional haplodiploid hypothesis (in Quarterly Rev. Biol., Bioscience (pdf), PNAS) . Briefly summarizing, his model, which is adopted and refined in this paper, involves the formation of groups subject to selection, the predisposition to group-formation by certain 'preadaptations' (they cite the example of solitary bees being behaviorally programmed to complete tasks in sequence - hence they naturally divide labor when forced to cohabit), and selection acting at multiple levels. Hence organismal traits and population structure are sufficient, without having to invoke the concept of inclusive fitness.

This analysis is quite satisfying because it represents the convergence of two different approaches to population biology: that rooted in mathematical theory and that rooted in natural history. The strong claims that it makes will certainly trigger robust debate. However it turns out, it will be interesting to see how the study of eusociality will respond. As the authors note (quite provocatively, given the highly charged reception to the original publication of Sociobiology in the 1970s), "[w]e have not addressed the evolution of human social behavior here, but parallels with the scenarios of animal eusocial evolution exist, and they are, we believe, well worth examining."

DNA Barcoding and Taxonomic Tangles

DNA barcoding is an intuitively compelling idea - since every species's DNA is unique, why not use it as a 'barcode' to identify it? In this way, we might be able to catalogue all life on Earth. It sounds so simple that it might surprise some people that such a catalogue is not already in place.

Despite some detractors - I've heard one person mutter "there's more interesting things to do with that data than just species identification" - barcoding initiatives are now well under way around the world. A new review in PLoS Biology looks at the state of barcoding today (and gives links to the major consortia carrying out barcoding projects), and some issues that surround it, including the politically sensitive problem of 'genetic resources'.

Many countries, especially developing countries with rich biodiversity, have laws protecting biological resources, including genetic information, reasoning that bioprospectors might profit from them without paying their dues to the country from which the resources are taken. This review argues that genetic barcodes must be recognized as 'non commercial' research, not least because it is a valuable tool for conservation.

Barcoding also has potential to address one problem that faces biology today: the lack of taxonomists to classify organisms. Biology programs in universities no longer produce as many students with taxonomic expertise, and the ones already out there are either retiring or dying off. As a result, there are groups of organisms for which only a handful of people might be able to identify new species or sort out existing ones. This problem is widely acknowledged, and there are some initiatives, such as the PEET program of the US National Science Foundation, for addressing it. However, the ubiquity of molecular techniques in biology labs today (most biologists now know their way around a micropipette even if they can't tell a calyx from a corolla) makes barcoding potentially an easier way to get a quick ID or to pin down an ambiguous specimen.

That all depends, of course, on the quality of barcoding databases. They're only as good as the specimens and data put into them. This means that whoever is matching scientific names to molecular sequences had better know what he or she is doing, because misidentifications can propagate themselves indefinitely if no one has the expertise to recognize the mistake. Misidentifications are definitely a problem on GenBank and other public sequence databases.

Which brings me around to the taxonomic tangle: a Yale paleontologist has found that a dinosaur specimen in the American Museum of Natural History is actually a genus new to science, but had lain undetected (despite being on public display) for decades because the partial specimen had been restored to look like an existing genus that it resembles.

Mr. Longrich has made a career out of digging through museum collections and tying up loose ends left by previous generations of paleontologists, avoiding the more glamorous but expensive work of digging up new fossils out in the field. Two of his previous discoveries were made in this way, and he said he has two more in the works.

“I’m just kind of doing mop-up work,” Mr. Longrich said.

As the molecular revolution in biology starts to move beyond well-characterized model species, we need a good mop-up crew now more than ever.

Ownership of Mendel's Pea Breeding Manuscript in Dispute

Gregor Mendel's 1865 paper, "Experiments in Plant Hybridization" is the foundational work of modern genetics. Although its significance was not widely appreciated until its rediscovery at the turn of the century by the trio of de Vries, Correns, and Tschermak, today every student of botany will have heard of this Augustinian monk from Brünn (now Brno, Czech Republic) and his pea garden.

The original manuscript of his work was almost discarded in 1911, and then disappeared entirely after World War II, behind the Iron Curtain. It finally resurfaced in 1988 and was placed in the care of an Augustinian monk in Germany who was also a descendant of the Mendel family. He intended to have it placed in the family's possession; the descendants applied to have it declared a German cultural treasure, but the Augustinian order now disputes the ownership of the manuscript, saying that it should belong to the order. Nicholas Wade reports on the feud in the New York Times.

The Story of Maize

The story of how maize (or corn) was domesticated by human beings is a fascinating mix of biology (both classical and modern) and archaeology. It's a tale of careful observation and empirical reasoning that began not in the past century but over 9000 years ago:

"These people were living in small groups and shifting their settlements seasonally. Yet they were able to transform a grass with many inconvenient, unwanted features into a high-yielding, easily harvested food crop."

Cool fact from the article: George Beadle, of Beadle and Tatum fame, was the first modern biologist to suggest that teosinte was the wild ancestor of domesticated maize.

The first self-replicating artificial cell created

 

 

 

 

 

 

 

 

 

 

 

 

 

 

We report the design, synthesis and assembly of the 1.08- Mbp Mycoplasma mycoides JCVI-syn1.0 genome starting from digitized genome sequence information and its transplantation into a Mycoplasma capricolum recipient cell to create new Mycoplasma mycoides cells that are controlled only by the synthetic chromosome. The only DNA in the cells is the designed synthetic DNA sequence, including “watermark” sequences and other designed gene deletions and polymorphisms, and mutations acquired during the building process. The new cells have expected phenotypic properties and are capable of continuous self-replication.

One year after synthesizing a synthetic genome, the Craig Venter Center finally published their results in Science. For this paper, Science has kindly allowed free access.

Of course this created alot of discussion amongst the scientific circle. Even President Obama penned a letter to the research team.

In the basic criteria of what life is like, most scientists agree that three basic components has to exist: a container, a way to harvest energy and an information carrier like RNA or another nucleic acid.

This is a step from similar protocellular work by Szostak from Havard Medical School. The Craig Venter Center team's bacteria can grow and divide.

Reading list suggested by Carl Zimmer.

 

 

Fungus-Derived Genes Make Aphids Red

Carotenoids are pigments produced by many organisms, among them bacteria, plants, algae, and fungi. They're what gives carrots, red leaves, and some flowers their reddish/orange color. However, no animal has been known to produce them or to have the metabolic pathways required for carotenoid biosynthesis, until now.

In Science, Nancy Moran and Tyler Jarvik report the discovery of carotenoid biosynthesis genes in the genome of the pea aphid, Acyrthosiphon pisum, which has a body color polymorphism (some individuals are red, others are green). It was formerly thought that they got their pigmentation from their diet, or from their bacterial gut symbionts. Suspicions were raised, however, when no trace of a carotenoid pathway could be found in the primary bacterial symbiont of aphids, Buchnera, which is among the best-studied of bacterial symbioses, and in two other symbiont bacteria. Because the genome of the pea aphid was recently released, they searched for, and found, carotenoid synthesis genes, which are most closely related to similar genes in the fungi. This led them to conclude that aphids have gained the carotenoid biosynthesis pathway by lateral gene transfer from fungi.

Lateral gene transfer (also horizontal gene transfer) was long thought to be a rare or exceptional phenomenon, but this adds one more example to a growing list of transfer events which have been uncovered by new genomic methods.

References:
Moran & Jarvik, Lateral Transfer of Genes from Fungi Underlies Carotenoid Production in Aphids, Science 328, 624-627 (30 Apr 2010). (DOI: 10.1126/science.1187113)
Takema Fukatsu, Perspectives: A Fungal Past to Insect Color, Science 328, 574-575 (30 Apr 2010).

Are heart cells and mammal eggs regenerated?

Two of the dogmas that most biology students learn in school are that cardiac muscle is not renewed, and that women (and almost all female mammals) are born with their full complement of eggs - they can't make new ones. Two recent studies have shown that these dogmas may not be as clear cut as they originally seem to be.

The first of these studies (New York Times article) was carried out by a team at the Karolinska Instituet in Sweden. They wanted to see if any of the cardiac muscle cells in humans were formed after the person's birth. In biology, the classic method to do such a tracing experiment in animals is to feed the animals some sort of radioactive tracer, which would then become incorporated into the DNA of cells that are being formed during the period that the the radioactive tracer was being fed to the individual. Cells formed after that period would not have radioactive tracer in their DNA. Obviously there are ethical implications of feeding humans radioactive tracers, but the experiment has already been done on unwitting subjects at a global scale.

During the 1950s, Cold War powers tested nuclear bombs above ground, releasing significant and measurable quantities of carbon 14 into the atmosphere. Individuals born during that time would have incorporated this carbon 14 signal into their tissue. After the test ban treaty in 1963, carbon 14 levels gradually diminished, and this changed isotope ratio can be detected in DNA synthesized after that date. The team applied their method to heart muscle cells, and found that for individuals born before the test ban, some of their heart muscle cells had a lower carbon 14 isotope ratio, meaning that those cells were produced after that date - evidence for regeneration.

The second study was carried out at the Shanghai Jiaotong University, and involved mice and not humans (NY Times article, Science feature). They also used a really cool technique, but one which operates on a less grandiose scale. Before this study, the debate in the field was whether supposed female germline stem cells (FGSCs) in mouse ovaries thought to be responsible for generating new oöcytes were in fact capable of doing so. The method used to isolate the FGSCs is called immunomagnetic isolation. Antibodies to a protein found only on FGSC surfaces were raised, and coated onto magnetic particles. Therefore, a magnetic filter would be able to isolate the supposed FGSCs. After isolation, they were transformed with green fluorescent protein, and introduced into the ovaries of sterile mice. The sterile mice were then mated with normal males, and offspring, expressing green fluorescent protein, were produced. This demonstrates that ovaries possess stem cells that are capable of regenerating oöcytes. Given the similarity of mouse and human reproduction, it is possible that humans have similar capabilities.

In both cases, therapeutic applications are a long way off, but it is still intellectually exciting to be aware that what has long been "known" as fact is still open to reassessment by pure empirical work, showing that biology is still a young and growing field.

Human Genome Project

I am relooking at some notes and slides I prepared for this topic. Its an interesting topic not only because of the science behind it but also the ethical, social and legal implications (that makes the acronym "ELSI") which blur the lines between right and wrong. Here are two very good resources

The first is the NOVA programs. The videos capture authentic situations that individuals face with regards to genetic diseases and also feature the scientists, science behind the project. Its more information packed in multimedia than I can summarize in a set of lecture notes. More information meaning the drama of the video that will contribute to affective learning and hence motivate students to learn more about the subject.



The 2nd is this free,... yes free, online book you can download. Its easy to read and the examples giving illustrate clearly the perplexing "ELSI" issues about genetic testing, abortions, genetic determinism... that will surface once genetic tests become more accessible..



Think ELSI and genetic testing are still far off... well read this groundbreaking and probably as "Brave New World" as it can get article in the New York Times on how you can pay just under USD$1000 for the company 23andMe to scan your genome for 580,000 SNPs (Single Nucleotide Polymorphisms). You actually can order the kit.. not sure how it works but I guess you can do it at home for yourself and children. There are at least 3 companies who will do that for around that price.


Just spit..




This NYT journalist got her own genome scanned by just spitting saliva into a little test tube . Here's a snippet of the article titled "My Genome, Myself: Seeking Clues in DNA"

"I don't like brussels sprouts. Who knew it was genetic? But I have the snippet of DNA that gives me the ability to taste a compound that makes many vegetables taste bitter. I differ from people who are blind to bitter taste -- who actually like brussels sprouts -- by a single spelling change in our four-letter genetic alphabet: somewhere on human chromosome 7, I have a G where they have a C."

But that's just information.... trivia about your genes. It gets more serious when people actually use that information to determine the genetics of their progeny. This couple actually had their daughter "genetically determined" so that she wouldn't inherit forms of genes that would make her highly susceptible to a certain form of colon cancer. This testing is termed preimplantation genetic diagnosis, or P.G.D., which means you need to cull embryos to get the right one. An eight-cell embryo has gone through fertilization.

For this couple, 4 were culled leaving 10 good ones that didn't have those forms of genes that cause cancer, 2 more were culled when a Down's syndrome test was done. Think that is unethical? Well there are people who actually remove their large intestines or breasts as a prophylactic measure against such cancers once they find they harbour just the forms of genes that make them susceptible. They may have siblings who have died because of that disease. Watch the 3rd video called One Wrong Letter in the set of videos on Nova and you will know why it becomes so grey.

(thanks to Kevin Lam who pointed out the genome scan link).

Birdsong and Human Speech

Speech and language seem to be uniquely human traits, which begs the question of how they arose. It turns out that a key regulatory gene controlling human speech, the FOXP2 (forkhead box transcription factor) gene, is also found in other animals, including songbirds. Knocking out these genes in humans (though accidental mutations) results in speech disorders associated with abnormalities in the basal ganglia, though exactly how they control the ability to speak is unknown. A team of German scientists used songbirds as a model for understanding the development of human speech. Instead of simply knocking out the gene, they used RNA interference to reduce FOXP2 levels in a specific area of the basal ganglia, known as Area X, in zebra finches, while they were in the stage of learning their song. This resulted in abnormal song patterns and provides a very persuasive example of how some genes can be directly linked to certain elements of behavior. However, note that the FOXP2 gene is a transcription factor gene that is part of the developmental toolkit, and so functions by regulating the expression of several other genes, so the actual pathway may be much more complicated that it first appears to be, so it would be misleading to simply call FOXP2 the 'speech gene'.