Q: How do the Target Health Global articles get selected and posted on this Blog?

A: We try to keep up with the fast pace of science and medical research by reading daily.  We realized that others might also be interested in the same material and decided to share these articles by creating this Blog.  The articles posted are read by us, or intended to be read by us. Even when we have not had the time to finish reading everything on our daily list, we post it anyway for our readers, who now visit this Blog on a daily basis.

In addition, we read a great deal, to fill in the huge gaps in our knowledge.  We figure others are like us and want to know more….we share it all with our readers.  When you read below, the postings for Thursday, you will see that we could not tear ourselves away from the excitement of reading about evolution on the microbiological level.  We end the postings with several videos by the great Carl Sagan, who brings science to the viewer as a spiritual quest.

The intention of this Blog is to pass on interesting cutting edge information in science, medicine and technology.  Occasionally, we post a photograph taken in New York (and elsewhere), which is where we’re located, simply to share what we love or find humorous.  Hope you enjoy it all!

Great Oxygenation Event

The Great Oxygenation Event (GOE), also called the oxygen catastrophe or oxygen crisis or Great Oxidation, was the appearance of free oxygen (O2) in Earth’s atmosphere. This major environmental change happened around 2.4 billion years ago.

Photosynthesis was producing oxygen both before and after the GOE. The difference was that before the GOE, organic matter and dissolved iron chemically captured any free oxygen. The GOE was the point when these minerals became saturated and could not capture any more oxygen. The excess free oxygen started to accumulate in the atmosphere.

The rising oxygen levels may have wiped out a huge portion of the Earth’s anaerobic inhabitants at the time. From their perspective it was a catastrophe (hence the name). Cyanobacteria were essentially responsible for what was likely the largest extinction event in Earth’s history. Additionally the free oxygen combined with atmospheric methane, triggering the Huronian glaciation, possibly the longest snowball Earth episode ever.

The amount of oxygen in the atmosphere has fluctuated ever since.

Prokaryotic and Eukaryotic Cells

Fluorescent Stained Eukaryotic Cells – NIH pub dom

There are only two basic types of cells, primitive prokaryotes and the more complex eukaryotes. Here are the main features that distinguish these cell types.

What Is a Cell?

Living things are constructed of cells and can be unicellular (one cell) or multicellular (many cells).

Limits on Cell Size

Cells size is limited because cells must be able to exchange materials with their surroundings. In other words, surface area relative to the volume decreases as size of cell increases, and this limits the size of cells.

Cell Theory

Only a few hundred years ago it was believed that living things could spontaneously generate from non-living matter — abiogenesis. We now know better. Cell theory lays out the basic rules that apply to the smallest unit of life. This cell doctrine states that:

  • All organisms are composed of one or more cells.
  • Cells are the basic unit of structure and function in organisms.
  • All cells come only from other cells.

Two Basic Types of Cells

All cells fall into one of the two major classifications: prokaryotes or eukaryotes.

Prokaryotic Cells

Prokaryotes are evolutionarily ancient. They were here first and for billions of years were the only form of life. And even with the evolution of more complex eukaryotic cells, prokaryotes are supremely successful. All bacteria and bacteria-like Archaea are prokaryotic organisms.

Eukaryotic Cells

Eukaryotic cells are more complex, evolving from a prokaryote-like predecessor. Most of the living things that we are typically familiar with are composed of eukaryotic cells; animals, plants, fungi and protists. Eukaryotic organisms can either be single-celled or multi-celled.

Features of Prokaryotes

Pro = “before”, karyon = “nucleus”

Prokaryotes, the first living organisms to evolve, are primarily distinguished by the fact that they lack a membrane-bound nucleus. In fact, the only membrane in prokaryotic cells is the plasma membrane–the outer boundary of the cell itself. Their genetic material is naked within the cytoplasm, ribosomes their only type of organelle.

Prokaryotes are most always single-celled, except when they exist in colonies. These ancestral cells, now represented by members of the domains Archaea and Eubacteria, reproduce by means of binary fission, duplicating their genetic material and then essentially splitting to form two daughter cells identical to the parent.

Features of Eukaryotes

Eu = “true”, karyon = “nucleus”

The most noticeable feature that differentiates these more complex cells from prokaryotes is the presence of a nucleus, a double membrane-bound control center separating the genetic material, DNA (deoxyribonucleic acid), from the rest of the cell.

In addition to the plasma membrane, eukaryotic cells contain internal membrane-bound structures called organelles. Organelles, such as mitochondria and chloroplasts, are both believed to have evolved from prokaryotes that began living symbiotically within eukaryotic cells. These vital organelles are involved in metabolism and energy conversion within the cell. Other cellular organelles within eukaryotic cell structure carry out the many additional functions required for the cell to survive, thrive, grow and reproduce.

Eukaryotic cells can reproduce in one of several ways, including meiosis (sexual reproduction) and mitosis (cell division producing identical daughter cells).

Cyanobacteria

Cyanobacteria bloom
Image: Wikimedia commons, Lamiot

Cyanobacteria are arguably the most successful group of microorganisms on earth. They are the most genetically diverse; they occupy a broad range of habitats across all latitudes, widespread in freshwater, marine and terrestrial ecosystems, and they are found in the most extreme niches such as hot springs, salt works, and hypersaline bays. Photoautotrophic, oxygen producing cyanobacteria created the conditions in the planet’s early atmosphere that directed the evolution of aerobic metabolism and eukarotic photosynthesis. Cyanobacteria fulfil vital ecological functions in the world’s oceans, being important contributors to global carbon and nitrogen budgets.

Scientific classification

Kingdom: Bacteria
Phylum: Cyanobacteria

Cyanobacteria ( /saɪˌænoʊbækˈtɪəriə/; also known as blue-green algae, blue-green bacteria, and Cyanophyta) is a phylum of bacteria that obtain their energy through photosynthesis. The name “cyanobacteria” comes from the color of the bacteria (Greek: κυανός (kyanós) = blue).

The ability of cyanobacteria to perform oxygenic photosynthesis is thought to have converted the early reducing atmosphere into an oxidizing one, which dramatically changed the composition of life forms on Earth by stimulating biodiversity and leading to the near-extinction of oxygen-intolerant organisms. According to endosymbiotic theory, chloroplasts in plants and eukaryotic algae have evolved from cyanobacterial ancestors via endosymbiosis.

Cyanobacteria can be found in almost every conceivable environment, from oceans to fresh water to bare rock to soil. They can occur as planktonic cells or form phototrophic biofilms in fresh water and marine environments, they occur in damp soil, or even temporarily moistened rocks in deserts. A few are endosymbionts in lichens, plants, various protists, or sponges and provide energy for the host. Some live in the fur of sloths, providing a form of camouflage. Aquatic cyanobacteria are probably best known for the extensive and highly visible blooms that can form in both freshwater and the marine environment and can have the appearance of blue-green paint or scum. The association of toxicity with such blooms has frequently led to the closure of recreational waters when blooms are observed. Marine bacteriophage are a significant parasite of unicellular, marine cyanobacteria. When they infect cells they lyse them releasing more phages into the water.

Blue-green algae, photosynthetic prokaryotes also known as cyanobacteria, first appeared in the fossil record almost 2.5 billion years ago, and have since populated most of the world in a variety of unicellular and multicellular forms. Using gene sequences from 1,254 species of modern cyanobacteria, a team of researchers led by Bettina Schirrmeister of the University of Zurich
created over 11,000 different phylogenetic trees that helped pinpoint when multicellularity evolved in this lineage.

Their first surprise was that this transition happened numerous times in the distant past more than 2 billion years ago, an unexpected finding if the appearance of multicellularity is a complex evolutionary phenomenon. The researchers also found that many modern unicellular cyanobacteria are descended from multicellular predecessors, suggesting that once multicellularity evolves, it doesn’t always stick around.

If organisms always evolved towards greater complexity, as evolutionary biologists have traditionally thought, the unicellular cyanobacteria should be more similar to each other than to the multicellular cyanobacteria, Schirrmeister said. But this isn’t what they found. Instead, the relationship between uni- and multi-cellular cyanobacteria is a complicated evolutionary web.

But even multicellular cyanobacteria are relatively simple organisms, Knoll said, and there are still a lot of open questions about the evolution of complex multicellular life in eukaryotes. (See The Scientist‘s recent feature on this topic.)

Even so, Schirrmeister said, cyanobacteria are some of the most ancient life forms on Earth, “so to understand how multicellularity evolved in cyanobacteria will help us understand how complexity evolves in organisms generally.”

Read more: Multicellular evolution not linear – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/news/display/58023/#ixzz1EpVtNatd

Characteristics of Cyanobacteria

Cyanobacteria include unicellular and colonial species. Colonies may form filaments, sheets or even hollow balls. Some filamentous colonies show the ability to differentiate into several different cell types: vegetative cells, the normal, photosynthetic cells that are formed under favorable growing conditions; akinetes, the climate-resistant spores that may form when environmental conditions become harsh; and thick-walled heterocysts, which contain the enzyme nitrogenase, vital for nitrogen fixation. Heterocysts may also form under the appropriate environmental conditions (anoxic) when fixed nitrogen is scarce. Heterocyst-forming species are specialized for nitrogen fixation and are able to fix nitrogen gas into ammonia (NH3), nitrites (NO−
2) or nitrates (NO−
3) which can be absorbed by plants and converted to protein and nucleic acids (atmospheric nitrogen cannot be used by plants directly). Rice crops utilize healthy populations of nitrogen-fixing cyanobacteria in some rice paddy fertilizers.

Many cyanobacteria also form motile filaments, called hormogonia, that travel away from the main biomass to bud and form new colonies elsewhere. The cells in a hormogonium are often thinner than in the vegetative state, and the cells on either end of the motile chain may be tapered. In order to break away from the parent colony, a hormogonium often must tear apart a weaker cell in a filament, called a necridium.

Each individual cell of a cyanobacterium typically has a thick, gelatinous cell wall. They lack flagella, but hormogonia and some species may move about by gliding along surfaces. Many of the multi-cellular filamentous forms of Oscillatoria are capable of a waving motion; the filament oscillates back and forth. In water columns some cyanobacteria float by forming gas vesicles, like in archaea. These vesicles are not organelles as such. They are not bounded by lipid membranes but by a protein sheath.

Some of these organisms contribute significantly to global ecology and the oxygen cycle. The tiny marine cyanobacterium Prochlorococcus was discovered in 1986 and accounts for more than half of the photosynthesis of the open ocean. Many cyanobacteria even display the circadian rhythms that were once thought to exist only in eukaryotic cells (see bacterial circadian rhythms).

A cyanobacteria bloom near Fiji

Cyanobacteria account for 20–30% of Earth’s photosynthetic productivity and convert solar energy into biomass-stored chemical energy at the rate of ~450 TW. Cyanobacteria utilize the energy of sunlight to drive photosynthesis, a process where the energy of light is used to split water molecules into oxygen, protons, and electrons. While most of the high-energy electrons derived from water are utilized by the cyanobacterial cells for their own needs, a fraction of these electrons are donated to the external environment via electrogenic activity. Cyanobacterial electrogenic activity is an important microbiological conduit of solar energy into the biosphere.

Cyanobacteria have an elaborate and highly organized system of internal membranes which function in photosynthesis. Cyanobacteria get their name from the bluish pigment phycocyanin, which they use to capture light for photosynthesis. Photosynthesis in cyanobacteria generally uses water as an electron donor and produces oxygen as a by-product, though some may also use hydrogen sulfide as occurs among other photosynthetic bacteria. Carbon dioxide is reduced to form carbohydrates via the Calvin cycle. In most forms the photosynthetic machinery is embedded into folds of the cell membrane, called thylakoids. The large amounts of oxygen in the atmosphere are considered to have been first created by the activities of ancient cyanobacteria. Due to their ability to fix nitrogen in aerobic conditions they are often found as symbionts with a number of other groups of organisms such as fungi (lichens), corals, pteridophytes (Azolla), angiosperms (Gunnera) etc.

Many cyanobacteria are able to reduce nitrogen and carbon dioxide under aerobic conditions, a fact that may be responsible for their evolutionary and ecological success. The water-oxidizing photosynthesis is accomplished by coupling the activity of photosystem (PS) II and I (Z-scheme). In anaerobic conditions, they are also able to use only PS I — cyclic photophosphorylation — with electron donors other than water (hydrogen sulfide, thiosulphate, or even molecular hydrogen just like purple photosynthetic bacteria. Furthermore, they share an archaeal property, the ability to reduce elemental sulfur by anaerobic respiration in the dark. Their photosynthetic electron transport shares the same compartment as the components of respiratory electron transport. Their plasma membrane contains only components of the respiratory chain, while the thylakoid membrane hosts both respiratory and photosynthetic electron transport.

Attached to thylakoid membrane, phycobilisomes act as light harvesting antennae for the photosystems. The phycobilisome components (phycobiliproteins) are responsible for the blue-green pigmentation of most cyanobacteria. The variations to this theme is mainly due to carotenoids and phycoerythrins which give the cells the red-brownish coloration. In some cyanobacteria, the color of light influences the composition of phycobilisomes. In green light, the cells accumulate more phycoerythrin, whereas in red light they produce more phycocyanin. Thus the bacteria appear green in red light and red in green light. This process is known as complementary chromatic adaptation and is a way for the cells to maximize the use of available light for photosynthesis.

A few genera, however, lack phycobilisomes and have chlorophyll b instead (Prochloron, Prochlorococcus, Prochlorothrix). These were originally grouped together as the prochlorophytes or chloroxybacteria, but appear to have developed in several different lines of cyanobacteria. For this reason they are now considered as part of the cyanobacterial group.

Epithilial Cells (eukaryotic), nucleus green.

WikibooksCellBioTextGFDL

How and Why did Single Cells Evolve into Multicellular Organisms?

“There are lots and lots of transitions from single cells to organisms that have more than one cell, but as far as evolving into complex multicellular organisms with cellular differentiation—that only happened a handful of times.”
—Matthew Herron,
University of British Columbia

Given the complexity of most organisms—sophisticated embryogenesis, differentiation of multiple tissue types, intricate coordination among millions of cells—the emergence of multicellularity was ostensibly a major evolutionary leap. Indeed, most biologists consider it one of the most significant transitions in the evolutionary history of Earth’s inhabitants. But single-celled organisms have stuck together or assembled to spawn multicellular descendants more than two dozen times, suggesting that maybe it’s not such a big leap after all.

“The transition from unicellularity to multicellularity is critical for explaining the diversity of life on Earth,” says evolutionary biologist Casey Dunn of Brown University. “We tend to think of it as quite special, but maybe it’s not. Maybe this is an easier transition than we think.”

To understand how and why it happened, scientists are utilizing the recent explosion in genomics data to assemble more accurate phylogenies and piece together each step in the transition to multicellular life. Despite their efforts, however, the origins of this intriguing phenomenon remain shrouded in mystery. Evolution and extinction over hundreds of millions of years have blurred the details of the transition, and the answers provided by genome sequencing only lead to more questions.

“New studies are always pushing the envelope on our thinking,” says evolutionary biologist Mansi Srivastava of the Whitehead Institute for Biomedical Research in Massachusetts. Since scientists began studying a much wider array of animals, far afield from the classic model systems of fruit flies and mice, “our thinking about what having certain kinds of genes means to being an animal has shifted.”

Conventional thought on evolutionary change has led researchers to believe that genetic innovations underlie the transition. Advances in genomics research, however, are revealing that more and more of the genes associated with complex processes also exist in simpler animals and even in their unicellular cousins. This suggests that the appearance of new genes cannot fully explain the appearance of new traits that are key to multicellularity. Sponges are commonly considered the most basal of all the metazoan (animal) lineages, yet a recently published sponge genome revealed genes known to be involved in the development of a neuromuscular system, which sponges lack.1 “These genes that we previously thought were associated with complex multicellular animals really have to do with basic multicellular functions—to get the simplest multicellular animals, you have to have these genes present,” says Srivastava, who coauthored the analysis.

As some of the most ancient animals, sponges can provide information regarding the evolution of the metazoan lineage, but for true insights about the origin of multicellularity, scientists must look even further back on the evolutionary tree. Choanoflagellates, unicellular organisms that look remarkably similar to the feeding structures of sponges, are the closest living relatives of metazoans. It turns out that they also share a number of genes once thought to be unique to multicellular animals. Tyrosine kinases (TK), for example, enzymes that function in cell-cell interactions and regulation of development in animals, were identified in the choanoflagellates in the early part of this decade, and the first sequenced choanoflagellate genome, published in 2008, revealed that they have more TK genes than any animal—and many other components of the TK signaling pathway as well.2

“So this gene family that was thought to be essentially a trigger that unleashed animal origins, we can now say with great confidence evolved long before the origin of animals,” says evolutionary biologist Nicole King of the University of California, Berkeley, who has been studying choanoflagellate biology for over 10 years.

Scientists have also identified choanoflagellate homologs of cadherins, known to be involved in cell-cell adhesion and signaling in animals. And more recently, a widespread search for genes associated with integrin-mediated adhesion and signaling pathways revealed that the integrin adhesion complex originated much earlier than even the choanoflagellates, dating back to the common ancestor of animals and fungi.3

“It’s pretty surprising to find these adhesion genes in far-flung species,” says Srivastava. “We would have thought that integrin signaling has to do with cells sticking together, but it goes much further back in time than our most recent unicellular cousins.”

The genomic exploration of the evolution of multicellularity is really just beginning, but already, a trend is emerging. “Almost every month now we are seeing genes that were supposed to be exclusive to metazoans that are already present in their single-cell relatives,” says evolutionary biologist Iñaki Ruiz-Trillo of the University of Barcelona. “I think that means co-option of ancestral genes into new functions is important for evolutionary innovations like the origin of multicellularity.”

“Probably the more data we collect, the fewer and fewer animal-specific genes there are going to be,” agrees Dunn. “And we’re going to have to explain the origins of multicellularity in terms of changes in the way these gene products interact with each other.”

We tend to think of [the evolution of multicellularity] as quite special, but maybe it’s not. Maybe this is an easier transition than we think.
—Casey Dunn, Brown University

Unfortunately, because the genomics data are so new, experimental data regarding the functions of these genes in single-celled organisms remains limited. Research by biochemist Todd Miller of Stony Brook University in New York and his colleagues, for example, demonstrated that while tyrosine kinases exist in great numbers in choanoflagellates, they lack the tight regulation found in animal signaling pathways, suggesting regulatory elements may have been key to the evolution of multicellularity. But this idea remains speculative, Miller says, as the targets of these enzymes in the unicellular relatives of animals and the details of their activation are still unknown.

“What we’d really like to be able to do is compare signaling pathways overall and see how they evolved,” Miller says. “We know a lot about the proteins themselves, but it would be great to have a glimpse into a simple pathway where we can begin to unravel what the core elements of the pathway are before layers and layers of additional regulatory elements were added, as we see in metazoan cells.”

To confuse matters more, the vast stretches of time that separate most multicellular organisms from their unicellular cousins—more than half a billion years, in most cases—make for a lot of uncertainty. And as sequencing studies raise more questions, phylogenetic studies are also throwing a shadow of doubt on the animal tree. For example, are sponges really the most basal animals, as has long been thought? A recent phylogenetic study performed by Dunn and his colleagues suggested that perhaps ctenophores (comb jellies) are the earliest diverging extant multicellular animals.4 “Either sponges or ctenophores are sister to all other animals,” Dunn says. “The answer you get depends still on the organisms you include in the analysis, the analysis methods you use, and what genes you look at.”

“In order to understand evolutionary transitions, you need to have a robust phylogenetic framework,” says Ruiz-Trillo. The more genomes are sequenced, the better the phylogenies get, and the more similarities and differences are recognized between multicellular organisms and their unicellular cousins. “It’s a really exciting time” for studying the evolution of multicellularity, King says. With so many open questions and more and more sequenced genomes available each year, “there’s a lot of low-hanging fruit.”

A multicellular model?

Animals aren’t the only multicellular organisms, of course, and thus not the only system applicable to the study of multicellularity’s origins. In fact, multicellularity is believed to have evolved as many as 25 different times among living species. So while the search for metazoan origins may be riddled with uncertainty, perhaps scientists can draw inferences from the study of multicellularity in other lineages.

Comparing brown algae to their unicellular diatom relatives, for example, researchers saw an increase in membrane-spanning receptor kinases, a protein family known to play a role in cellular differentiation and patterning in both animals and green plants.5 The independent evolution of more kinase genes in each of these lineages suggests that this family of proteins may have been key to this transition.

Of all the multicellular lineages, however, the volvocine green algae represent the best-studied and most tractable system for teasing out the evolution of multicellularity. In contrast to most other origins of multicellularity, which likely arose close to a billion years ago, the change to multicellularity in these algae may have occurred as little as 200 million years ago—possibly limiting evolution’s mark on their genomes. Furthermore, between the unicellular Chlamydomonas species and the most-derived multicellular Volvox there are several extant intermediate species, some of which appear to have changed little since their divergence from their unicellular ancestors. While recent evidence indicates a complicated evolutionary history, including multiple origins of some traits and reversals,6 this lineage nonetheless presents a phylogenetic road map by which step-by-step transitions can be inferred. (See illustration)

Volvocine algae are aquatic, flagellated eukaryotes that range in complexity from unicellular species to a variety of colonial forms to multicellular Volvox, some of which boast up to 50,000 cells. This transition involved a series of key innovations, including cell-cell adhesion, inversion, and differentiation of somatic and germ cell lines. Two species in particular have become models for the evolution of multicellularity—the single-celled Chlamydomonas reinhardtii and the 2,000-or-so–celled Volvox carteri.

As with animals, comparisons of their recently sequenced genomes have revealed that there are few striking differences among the genetic codes of these organisms that could explain the drastic differences in their morphology. “It was pretty disappointing at first,” admits developmental biologist Stephen Miller of the University of Maryland, Baltimore County, who helped to analyze the Volvox genome (the sequence was published last summer). “We were hoping to see differences that would point to explanations for why Volvox is so much more developmentally complex than Chlamydomonas, but that certainly wasn’t the case.”

Not only do the genes exist in Chlamydomonas, they are so similar to the Volvox versions that they appear to be able to stand in for missing or mutant copies in their multicellular cousins. Volvox’s glsA gene, for example, codes for an essential component of asymmetric division; glsA mutants can only divide symmetrically, resulting in adults comprised entirely of small somatic cells, with none of the large germ cells, known as gonidia, that normally give rise to the next generation. While the homologous protein in Chlamydomonas is only about 70 percent identical to glsA’s protein, it can restore asymmetric cell division when the gene is transformed into glsA mutants. “Its ortholog in Chlamydomonas is perfectly capable of carrying out the same function,” Miller says.

Similarly, invA is essential to the process known as inversion, which gives adult Volvox their spherical shape, with the gonidia on the inside and the small, flagellated somatic cells around the exterior. In invA mutants, inversion fails to occur due to the cells’ inability to move relative to the cytoplasmic bridges that connect them, and the gonidia are exposed on the surface of the spheroid. Just like glsA mutants, however, this phenotype can be rescued by the transformation of the Chlamydomonas ortholog, known as IAR1.

There are exceptions to this pattern, however, such as the appearance in Volvox of many new genes that encode cell wall or extracellular matrix (ECM) proteins, with a dramatic increase in the number and variety of Volvox genes in two major ECM protein families, as compared with Chlamydomonas. While Volvox carteri have only a couple thousand times as many cells as Chlamydomonas, they can grow to more than 100,000 times larger thanks to a dramatic increase in the amount of ECM, which constitutes more than 99 percent of the volume of a mature Volvox.

Another significant genetic change in Volvox becomes evident when examining the mating locus—a region on one chromosome containing sex-specific genes that dictate whether the organism will be male or female during the sexual part of the volvocine life cycle. A notable difference in the sexual strategies of Chlamydomonas and Volvox is the size of their gametes. While the sperm and the egg of Chlamydomonas are nearly indistinguishable and are produced in similar quantities, Volvox eggs are significantly larger than its sperm, and there are far fewer of them. This transition to oogamy, as it’s called, appears to be a hallmark of multicellularity.

“It’s a remarkably conserved trait,” says cell and evolutionary biologist James Umen of The Salk Institute. “When you look at any lineage that becomes multicellular and has sex, it almost invariably goes from having mating types where the gametes are same size to having a sperm/egg system of some sort.” And in contrast to most of the innovations associated with the asexual reproductive phase of the Volvox life cycle, new genes do seem to be a big part of the evolution of dimorphic gametes. The mating locus of Volvox is greatly expanded to more than 500 percent of the size of Chlamydomonas’ 200–300 kilobase mating locus, and contains many genes that fall outside the mating locus in Chlamydomonas, as well as at least 13 new gender-specific genes.7

“Overall the two genomes are very similar, but the mating locus of Volvox kind of exploded in terms of size and context,” says Umen. “In general, things related to sex don’t follow the normal rules regarding evolution; innovation seems to be a really important part of sex.”

But how much can scientists learn about the evolution of the complex multicellularity exhibited by animals and other lineages from studying the volvocine algae? According to some, not much. Volvox represents a relatively simple form of multicellularity, with only two cell types and no organized tissues or organs.

“I think it’s dangerous to generalize too much,” says Stephen Miller. “Because [multicellularity] has evolved independently in each of these cases, there don’t have to be similarities in how it evolved. But I would guess there might end up being some common themes.”

One emerging idea is that complex multicellularity, such as that of animals, plants, and fungi, may have evolved only a handful of times, and that it almost always resulted from the division of a single cell into the components of the larger organism, King says. In contrast to slime molds, for example, which form via aggregation of neighboring cells, the earliest multicellular animals were likely to have evolved by failing to disperse after the mother cell divided.

Evidence of this comes from a recent study out of King’s lab that found choanoflagellates fail to form colonies when cell division is inhibited.8 If the earliest ancestors of animals were anything like modern-day choanoflagellates, this suggests that animal development from a single-celled embryo is core to our evolution, and not a secondary development.

Similarly, the volvocine algae all divide via multiple fission, where the nucleus divides many times before the cytoplasm splits to generate that number of daughter cells. “It’s a way of producing a large number of genetically identical cells all at once,” says evolutionary biologist Matthew Herron of the University of British Columbia. “The only thing you need to do to produce an eight-cell colony [is have] them to stick together.”

The Evolution of Volvox
The volvocine algae are a model system for studying the evolution of multicellularity, as the group contains extant species ranging from the unicellular Chlamydomonas to a variety of colonial species and the full-fledged multicellular Volvox varieties. Comparing the biology of these organisms, evolutionary developmental biologist David Kirk of the Washington University in St. Louis proposed 12 steps that were key to this transition. Here are some highlights that were key to this transition (BioEssays, 27:299-310, 2005).

Lucy Reading-Ikkanda (diagrams and cells); SOURCE: David L. Kirk

Complexity breeds cooperation

Beyond the molecular and developmental logistics of evolving multicellularity, there is the added complication of genetic conflict. An incredible amount of cooperation is required for individual cells to come together and function as one, and with natural selection acting at the level of the individual cell, there will be significant evolutionary pressure to cheat the system and sabotage the success of the multicellular whole.

The collaboration of first a few, then millions of cells to create an entirely new kind of “individual” thus requires a shift in the level of biological organization upon which natural selection acts. In this way, the evolution of multicellularity can be considered what has been termed an “evolutionary transition in individuality” (ETI), where the unit of selection changes from a single cell to a group of cells—the newly evolved multicellular individual. Other ETIs include the congregation of replicating molecules to yield the first prokaryotic cells, the associations of prokaryotic cells to create eukaryotic cells with organelles such as chloroplasts and mitochondria, and the establishment of cooperative societies composed of discrete multicellular individuals, like eusocial insect colonies.

“The general principle is, in any of these kinds of transitions there’s always some form of cooperation that’s needed,” says Herron. “In the example of the ants and bees, it’s the workers that are being cooperative in the sense that they’re sacrificing their own reproduction in order to help the queen reproduce. And in multicellular organisms like us and Volvox, the somatic cells are cooperating in the sense that they’re sacrificing their own reproduction in order to help the reproductive cells reproduce.”

But such transitions are not always smooth, as conflict can arise when selfish mutations result in cheaters that attempt to benefit from the group without contributing their fair share. One of the first cooperative steps required for the evolution of multicellularity in the volvocine algae was the development of the ECM from cell wall components, which can be metabolically costly to produce. The ECM can thus be thought of as a shared resource, and cells that do not contribute to its production may still benefit from its existence, thus gaining a growth or reproductive advantage.

To defend themselves against such cheating, these new kinds of individuals must evolve mechanisms of conflict mediation. One proposed theory for how the volovcine algae defend themselves against ECM cheaters is the evolution of genetic control of cell number. In unicellular Chlamydomonas, the number of cells produced depends on the size of the parent cell, which in turn is contingent on the amount of resources available. Under these circumstances, it is conceivable that a cell in a multicellular organism could benefit from not contributing to ECM production by putting that saved energy to use making more offspring cells. But all volvocine algae that have evolved an ECM have also switched to genetic control over cell number. As a result, cheaters have less to gain because the total number of daughter cells produced by the group is limited.

The differentiation of somatic and germ cells to yield a division of labor between viability and reproduction represents another potential conflict. In essence, somatic cells are giving up their own reproductive output to support the success of the entire colony of cells, presumably by providing enhanced motility. They don’t always cooperate willingly, however, Herron says; mutations still arise that cause some somatic cells in Volvox to try to reproduce on their own rather than support the entire organism’s reproductive success as sterile swimmers.

The somatic regenerator, or regA, gene appears to be one important factor in keeping somatic cells from defecting. In regA mutants, somatic cells develop normally at first, but then they enlarge and develop into gonidia that can divide to yield Volvox offspring. “What it causes is a dysfunctional colony,” Herron says. “In the lab, we can keep these mutant colonies alive, but they sink to the bottom of the test tube. We assume that they would not last long in nature.”

One proposed mechanism of conflict mediation following this transition is the early segregation of the germ line. The Volvox gonidia that will produce the next generation are formed by just a few rounds of asymmetric cell division very early in development, so there is little time for mutations to accumulate in these cells. While somatic cells may still accumulate mutations, these defects will not be passed on. “They are evolutionary dead ends,” Herron says.

These recurrent mutations in Volvox suggest that “the conflict between the individual cells and the interest of colony may still be going on,” he adds. Such conflict may limit the organism’s complexity, as selection on individual cells battles with the whole organism’s attempt to survive and reproduce, suggesting that perhaps the evolution of advanced multicellularity wasn’t so easy after all.

Read more: From Simple To Complex – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/article/display/57883/#ixzz1Eoi8ErSm


Biomedicine

Nano light: Nanoparticles that emit bright infrared light and target melanoma tumors are seen here in mice.
Credit: Ulrich Wiesner

Researchers are testing the safety of a nanoparticle that targets cancer cells

MIT Technology Review, February 22, 2011, by Katherine Bourzac  —   A nanoparticle that targets melanoma and highlights cancerous tissue is entering an early-stage clinical trial. Researchers testing the nanotherapeutic agent, which has been under development for over a decade, hope it provides a way to target melanoma and map its spread throughout the body. Researchers have tested the drug in animals and found no toxicity. Safety tests in five melanoma patients should be completed by the end of the year.

Drugs that help doctors image, characterize, and treat diseases could result in treatments that are better targeted to an individual patient’s disease. “With cancer genome programs, we’re learning more and more about differences between individuals’ diseases,” says Jerry Lee, director of the Office of Physical Sciences-Oncology at the National Cancer Institute. That information will tell doctors what drugs will work best for a patient, and how they might best be delivered. “Multifunctional, tailored nanoplatforms will bridge with that biological information,” enabling doctors to act on it to improve patient care, Lee says.

The new melanoma-targeting nanoparticles were developed by Ulrich Wiesner, professor of materials science at Cornell. He’s worked with a group led by Michelle Bradbury, a radiologist at the Memorial Sloan-Kettering Institute in New York City, to test the nanoparticles in animals. Bradbury is also leading the clinical trial.

The researchers hope to use the nanoparticles to address two major clinical needs. First, they want to use it to develop a therapy that seeks out melanoma tumors. “There’s never been a targeted therapy for melanoma,” says Bradbury. Melanoma starts on the skin, but when it spreads to other parts of the body, it is invisible and deadly. A targeted therapy would seek melanoma out no matter where it has spread.

“Another gap in the field is the lack of an optical imaging agent to visualize lymph nodes,” says Bradbury. Today, surgeons use radioactive labels and a handheld gamma detector to find cancer-carrying lymph nodes in the head and neck during surgery. But this is a tricky process. Bradbury hopes the nano-imaging agent can be used to light up cancer-carrying lymph nodes during surgery, providing a map that helps doctors remove the cancer while avoiding unnecessary cutting that can lead to painful side effects.

The core of the nanoparticles is a silica sphere, about eight nanometers in diameter, surrounding an organic dye molecule that emits infrared light. This is then coated with a biocompatible polymer that helps the nanoparticles stick around in the body. Wiesner and a former student first developed the nanoparticles over 10 years ago. The nanoparticles are made by a company called Hybrid Silica Technologies. The coated nanoparticles can be modified to serve many different purposes. “Through simple biochemistry, you can attach peptides to target tumors, drugs, and radioactive imaging labels,” says Wiesner.

For the initial patient trial, Wiesner and Hybrid Silica Technologies provided the clinical researchers with the nanoparticles. The nanoparticles were treated with radioactive iodine in order to make them visible on PET scans. The advantage of PET scans is their incredible sensitivity, says Bradbury. If an MRI label were added to the particle and that imaging technique were used instead, a much higher dose would be necessary. “PET enables you to do microdosing,” she says. PET scans help provide a very detailed map of where the nanoparticles travel inside the body.

Bradbury hopes that oncologists will eventually use this type of imaging to better understand a patient’s disease. PET imaging is sensitive enough to allow researchers to estimate how many of different types of receptors are present on an individual tumor’s cells, information that should help doctors determine how aggressive a tumor is, where it might spread and when, and how it should be treated.

However, this type of agent must strike the right balance between remaining in the body long enough to do its work but not overstaying its welcome. “It remains in the blood for enough time to target the tumor, yet clears through the kidneys efficiently,” says Bradbury. Drugs that move through the liver stay in the body longer and can get broken down into potentially toxic side-products. In mice, the silica particles are excreted in about 24 hours. Ten years of tests in animals have shown no toxicity.

“If we can get these into the clinic, this is a platform that could really expand what we can do for patients,” says Bradbury.

University of Groningen, ScienceDaily.com  —  The Groningen professors Bauke Dijkstra and Lubbert Dijkhuizen have deciphered the structure and functional mechanism of the glucansucrase enzyme that is responsible for dental plaque sticking to teeth. This knowledge will stimulate the identification of substances that inhibit the enzyme. Just add that substance to toothpaste, or even sweets, and caries will be a thing of the past.

The results of the research have been published this week in the journal Proceedings of the National Academy of Sciences (PNAS).

The University of Groningen researchers analysed glucansucrase from the lactic acid bacterium Lactobacillus reuteri, which is present in the human mouth and digestive tract. The bacteria use the glucansucrase enzyme to convert sugar from food into long, sticky sugar chains. They use this glue to attach themselves to tooth enamel. The main cause of tooth decay, the bacterium Streptococcus mutans, also uses this enzyme. Once attached to tooth enamel, these bacteria ferment sugars releasing acids that dissolve the calcium in teeth. This is how caries develops.

Three dimensional structure

Using protein crystallography, the researchers were able to elucidate the three dimensional (3D) structure of the enzyme. The Groningen researchers are the first to succeed in crystallizing glucansucrase. The crystal structure has revealed that the folding mechanism of the protein is unique. The various domains of the enzyme are not formed from a single, linear amino acid chain but from two parts that assemble via a U-shaped structure of the chain; this is the first report on such a folding mechanism in the literature.

Functional mechanism

The unravelling of the 3D structure provided the researchers with detailed insight into the functional mechanism of the enzyme. The enzyme splits sucrose into fructose and glucose and then adds the glucose molecule to a growing sugar chain. Thus far the scientific community assumed that both processes were performed by different parts of the enzyme. However, the model created by the Groningen researchers has revealed that both activities occur in the same active site of the enzyme.

Inhibitors

Dijkhuizen expects that specific inhibitors for the glucansucrase enzyme may help to prevent attachment of the bacteria to the tooth enamel. Information about the structure and functional mechanism of the enzyme is crucial for developing such inhibitors. Thus far, such research has not been successful, states Dijkhuizen: ‘The various inhibitors studied not only blocked the glucansucrase, but also the digestive enzyme amylase in our saliva, which is needed to degrade starch.’

Evolution

The crystal structure also provides an explanation for this double inhibition. The data published by the Groningen scientists shows that glucansucrase proteins most likely evolved from amylase enzymes that degrade starch. ‘We already knew that the two enzymes were similar’, says Dijkhuizen, ‘but the crystal structure revealed that the active sites are virtually identical. Future inhibitors thus need to be directed towards very specific targets because both enzymes are evolutionary closely related.’

Toothpaste and sweets

Dijkhuizen points out that in future glucansucrase inhibitors may be added to toothpaste and mouthwash. ‘But it may even be possible to add them to sweets’, he suggests. ‘An inhibitor might prevent that sugars released in the mouth cause damage.’ However, Dijkhuizen doesn’t expect that toothbrushes have had their day: ‘it will always be necessary to clean your teeth.’

Credit: Technology Review

Providing developers with machine learning on tap could unleash a flood of smarter apps

MIT Technology Review, by Tom Simonite  —  From Amazon’s product recommendations to Pandora’s ability to find us new songs we like, the smartest Web services around rely on machine learning–algorithms that enable software to learn how to respond with a degree of intelligence to new information or events.

Now Google has launched a service that could bring such smarts to many more apps. Google Prediction API provides a simple way for developers to create software that learns how to handle incoming data. For example, the Google-hosted algorithms could be trained to sort e-mails into categories for “complaints” and “praise” using a dataset that provides many examples of both kinds. Future e-mails could then be screened by software using that API, and handled accordingly.

Currently just “hundreds” of developers have access to the service, says Travis Green, Google’s product manager for Prediction API, “but already we can see people doing some amazing things.” Users range from developers of mobile and Web apps to oil companies, he says. “Many want to do product recommendation, and there are also interesting NGO use cases with ideas such as extracting emergency information from Twitter or other sources online.”

Machine learning is not an easy feature to build into software. Different algorithms and mathematical techniques work best for different kinds of data. Specialized knowledge of machine learning is typically needed to consider using it in a product, says Green.

Google’s service provides a kind of machine-learning black box–data goes in one end, and predictions come out the other. There are three basic commands: one to upload a collection of data, another telling the service to learn what it can from it, and a third to submit new data for the system to react to based on what it learned.

“Developers can deploy it on their site or app within 20 minutes,” says Green. “We’re trying to provide a really easy service that doesn’t require them to spend month after month trying different algorithms.” Google’s black box actually contains a whole suite of different algorithms. When data is uploaded, all of the algorithms are automatically applied to find out which works best for a particular job, and the best algorithm is then used to handle any new information submitted.

“Getting machine learning to a Google scale is significant,” says Joel Confino, a software developer in Philadelphia who builds large-scale Web apps for banks and pharmaceutical companies, and a member of the preview program. He used Prediction API to quickly develop a simple yet effective spam e-mail filter, and he says the service has clear commercial potential.

For example, a bank or credit-card company wanting to use machine learning to build systems that make decisions based on historical transactions is unlikely to have the specialized staff and necessary infrastructure for what is a computationally intensive approach. “This API could be a way to get a capability cheaply that would cost a huge amount through a traditional route.”

Google’s new service may also be more palatable to businesses wary of handing over their data to cloud providers, says Confino. “The data can be completely obfuscated, and you can still use this service. Google doesn’t have to know if those numbers you are sending it are stock prices or housing prices.”

Google does, however, get some information that it can use to improve its machine-learning algorithms. “We don’t look at users’ data, but we do see the same metrics on prediction quality that they do, to help us improve the service,” says Green. The engineers running Prediction API will know if a particular algorithm is rarely used, or if a new one needs to be added to the mix to better process certain types of data.

Prediction API has the potential to be a leveler between established companies and smaller startups, says Pete Warden, an ex-Apple engineer now working on his own startup OpenHeatMap.com. “That’s been a competitive advantage for large companies like Amazon, whose product recommendation is built on machine learning,” he explains. “Now you still have to have a decent set of training data, but you don’t have to have the same level of expertise.”

Warden has yet to gain access to Prediction API, but has plans to use it to improve a service he built that shows where people using a particular word or phrase on Twitter are located. “It would be really interesting to also see where they are saying positive and negative things on a subject,” says Warden. Prediction API could be trained to distinguish between positive and negative tweets to do that, he says.

Chris Bates, a data scientist with online music service Grooveshark and a member of the preview program, agrees that Google’s black box will enable wider use of machine learning, but he contends that the service needs to mature. “Today it is good at predicting which language text is in and also sentiment analysis, for example to pick out positive and negative reviews,” he says.

Ultimately, though, being unable to inspect the inner workings of the algorithms and fine-tune them for a specific use may have its limits. “It’s good for cases that are not mission-critical, where you can afford a few false positives,” Bates says. For example, a spam filter that occasionally lets through the occasional junk message could still be usable, but a credit-card company might be less able to accept any errors.

Dr. Kim Zarse from Jena University investigates how low-dose lithium exposure may affect

mortality in nematodes.   (Credit: Photo: Jan-Peter Kasper/University Jena)

European Journal of Nutrition, February 21, 2011 —  A regular uptake of the trace element lithium can considerably promote longevity. This is the result of a new study by scientists of Friedrich Schiller University Jena.

Professor Dr. Michael Ristow’s team along with Japanese colleagues from universities in Oita and Hiroshima have demonstrated by two independent approaches that even a low concentration of lithium leads to an increased life expectancy in humans as well as in a model organism, the roundworm Caenorhabditis elegans.

The research team presents its results in the online edition of the scientific publication European Journal of Nutrition.

Lithium is one of many nutritional trace elements and is ingested mainly through vegetables and drinking water. “The scientific community doesn’t know much about the physiological function of lithium,” project manager Ristow says. According to an earlier study from the US, highly concentrated lithium showed to be life-prolonging in C. elegans, the Professor of Nutrition in Jena continues. “The dosage that has been analyzed back then, however, is clearly beyond the physiologically relevant range and may be poisonous for human beings,” explains Ristow. To find out if lithium has a life-prolonging impact at much lower concentrations, the scientists then examined the impact of lithium in a concentration that is regularly found in ordinary tap water.

In a collaborative effort with Japanese colleagues, the Jena scientists analyzed the mortality rate in 18 adjacent Japanese municipalities in relation to the amount of lithium contained in tap water from the respective regions. “We found that the mortality rate was considerably lower in those municipalities with more lithium in the drinking water,” Ristow explains the key finding. In a second experiment, the Jena scientists examined exactly this range of concentration in the model organism C. elegans. The result was confirmed: “The average longevity of the worms is higher after they have been treated with lithium at this dosage,” Ristow says.

Even though the underlying mechanisms still remain to be clarified, the scientists assume that the higher longevity they observed in humans as well as in nematodes C. elegans can be induced by the trace element lithium.

Moreover, the scientists speculate about using low-dose lithium as a potential dietary supplement in the future. “From previous studies we know already that a higher uptake of lithium through drinking water is associated with an improvement of psychological well-being and with decreased suicide rates,” Professor Ristow explains. While low-dose lithium uptake on the basis of the new data is clearly thought to be beneficial, more studies will be necessary to thoroughly recommend such a supplementation, the scientists conclude.


Journal Reference:

1.                         Kim Zarse, Takeshi Terao, Jing Tian, Noboru Iwata, Nobuyoshi Ishii, Michael Ristow. Low-dose lithium uptake promotes longevity in humans and metazoans. European Journal of Nutrition, 2011; DOI: 10.1007/s00394-011-0171-x

2.

Friedrich-Schiller-Universitaet Jena (2011, February 18). Fountain of youth from the tap? Environmental lithium uptake promotes longevity, scientists demonstrate.

More About Lithium

WHAT IS LITHIUM?

Lithium is a micromineral or trace element that promotes good mental health.  In this article I discuss the role of lithium in the body in greater detail.

WHEN WAS LITHIUM DISCOVERED?

The first records of lithium date back to 1800 when the Brazilian scientist Jozée Bonifácio de Andrada e Silva discovered the mineral petalite (which contains lithium) in Switzerland.  In 1817 Johan August Arfwedson started to study petalite and realised he could not identify 10% of the mineral.  He concluded that this 10% was a new element which he named lithium.  Arfwedson was unable to isolate lithium but a year later in 1818 both Swedish chemist William Thomas Brand and English chemist Sir Humphry Davy managed to extract it.

HOW DOES YOUR BODY USE LITHIUM?

An average human body contains approximately 7 milligrams (mg) of lithium.  The most well known function of this nutrient is in the treatment of mental disorders such as bipolar disorder.  However, it also has a number of other roles in the body.  The list below outlines the main functions of lithium:
– Assisting in the absorption of vitamin B9 and vitamin B12.
– Assisting in the distribution of iodine throughout the body (which can help treat thyroid diseases).
– Breaking down excess uric acid in the blood and kidneys.
– Controlling and preventing episodes of mania (elevated mood at all times) that occur in people suffering from bipolar disorder.
– Controlling glucose metabolism.
– Enhancing the replication of deoxyribonucleic acid (DNA) (which contains important genetic information that is used in the creation of new cells).
– Increasing the grey matter nerve cells in the brain (which support hearing, memory, muscle control, speech and vision).
– Preventing Alzheimer’s disease and dementia (by reducing brain damage and promoting new neural growth).
– Protecting against the negative effects of mood altering drugs such as alcohol, caffeine, marijuana and tobacco.
– Reducing aggressive, self destructive and violent behaviour (based on a number of different research studies).
– Regulating the production of serotonin (a hormone that regulates mood levels).
– Supporting the transmission of messages over neurons.

HOW MUCH LITHIUM DO YOU NEED?

Currently there is no recommended daily allowance (RDA) for lithium.  The American College of Nutrition have suggested a minimum intake of 1mg per day but research suggests the body may require between 2mg and 3mg of lithium per day.  Most studies suggest people get an average of 2mg of lithium per day from their diet which is adequate for the body’s needs.

WHICH FOODS CONTAIN LITHIUM?

Dairy products are an excellent source of lithium with cheese, eggs and milk all good choices.  Drinking water also contains trace amounts of lithium.  Mineral water from springs can also contain high levels of lithium depending upon their location.  Herbs and vegetables are another excellent source of lithium with peppers and tomatoes being particularly rich foods.

WHAT ARE THE SYMPTOMS OF GETTING TOO MUCH LITHIUM?

Consuming excess levels of lithium can have a number of negative side effects.  There is no specific upper limit for this nutrient but research suggests that consuming 100mg per day or more can have adverse effects.  Doses of 5 grams (g) per day or more can be fatal.

Since most foods only contain trace amounts of lithium it is almost impossible to overdose on this nutrient through your diet.

Journal of Lipid Research — Though it has been prescribed for over 50 years to treat bipolar disorder, there are still many questions regarding exactly how lithium works. However, in a study appearing in this month’s Journal of Lipid Research, researchers have provided solid evidence that lithium reduces brain inflammation by adjusting the metabolism of the health-protective omega-3-fatty acid called DHA.

Inflammation in the brain, like other parts of the body, is an important process to help the brain combat infection or injury. However, excess or unwanted inflammation can damage sensitive brain cells, which can contribute to psychiatric conditions like bipolar disorder or degenerative diseases like Alzheimers.

It’s believed that lithium helps treat bipolar disorder by reducing brain inflammation during the manic phase, thus alleviating some of the symptoms. Exactly how lithium operates, though, has been debated.

Mireille Basselin and colleagues at the National Institute of Aging and University of Colorado, Denver, took a detailed approach to this question by using mass spectrometry analysis to analyze the chemical composition of brain samples of both control and lithium-treated rats stressed by brain inflammation.

They found that in agreement with some other studies, rats given a six-week lithium treatment had reduced levels of arachidonic acid and its products, which can contribute to inflammation.

In addition, they also demonstrated, for the first time, that lithium treatment increased levels of a metabolite called 17-OH-DHA in response to inflammation. 17-OH-DHA is formed from the omega-3 fatty acid DHA (docosahexaenoic acid) and is the precursor to a wide range of anti-inflammatory compounds known as docosanoids. Other anti-inflammatory drugs, like aspirin, are known to also enhance docosanoids in their mode of action.

Basselin and colleagues noted that the concentration of DHA did not increase, which suggests that lithium may increase 17-OH-DHA levels by affecting the enzyme that converts DHA to 17-OH-DHA.

By reducing both pro-inflammatory AA products, and increasing anti-inflammatory DHA products, lithium exerts a double-protective effect which may explain why it works well in bipolar treatment. Now that its mechanism is a little better understood, it may lead to additional uses for this chemical.

Journal Reference:

1. Basselin et al. Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation. The Journal of Lipid Research, 2010; 51 (5): 1049 DOI: 10.1194/jlr.M002469

2. American Society for Biochemistry and Molecular Biology (2010, May 24). Uncovering lithium’s mode of action. ScienceDaily. Retrieved February 21, 2011, from http://www.sciencedaily.com­ /releases/2010/05/100521191440.htm

University of Missouri-Columbia, February 21, 2011  —  Nobody enjoys colonoscopies, including mice. University of Missouri researchers are excited about the potential of using genetic biomarkers to predict colon cancer caused by inflammation. A new method developed at the MU Research Animal Diagnostic Laboratory (RADIL) could eventually lead to a method that might eliminate colonoscopies altogether.

While working to develop novel therapeutics for colon cancer, Craig Franklin, associate professor of veterinary pathobiology in the MU College of Veterinary Medicine; Aaron Ericsson, post-doctoral researcher at MU; Mike Lewis, assistant professor of veterinary medicine and surgery; Matt Myles, assistant professor of veterinary pathobiology and Lillian Maggio-Price, professor of comparative medicine at the University of Washington, found biomarkers in mouse feces that predicted inflammation-associated colon cancer. This is the same type of cancer associated with some common inflammatory bowel diseases such as ulcerative colitis and Crohn’s Disease.

The team found that the bacterium that leads to inflammation-associated colon cancer in mice first results in inflammation that can be detected by screening feces for messenger RNA of genes. Franklin believes this discovery could lead to tests for similar genes that are present in humans with early inflammation associated colon cancer. The study was published recently in Neoplasia.

“The assumption was that the gene expression couldn’t be detected in fecal matter because RNA breaks down very rapidly. Historically, this was something that a lot of scientists, including us, hadn’t considered,” Franklin said. “But technology has evolved, and we now have the means of preserving RNA much better than we did 15 years ago.”

As a laboratory animal veterinarian, Franklin believes this discovery also could decrease the number of animals used in research.

“We’re excited about the potential for application in humans, but this also will decrease animal numbers, which is one of our goals,” Franklin said. “This test determines which mice will get cancer in advance, so we won’t need to have as many animals in an experimental group to achieve statistical significance.”

“There’s also no stress on the animal for us to test their fecal matter,” Ericsson said. “Many people put off colonoscopies longer than they should because of the invasiveness and unpleasant nature of the exam, and it’s not pleasant for mice either. That unpleasantness is negated with this test.”

For this study, the team also used a high-powered MRI machine located in the Department of Veterans Affairs facility located at the Harry S. Truman Memorial Veterans’ Hospital. While effective, this technique was not as sensitive as the fecal biomarkers in predicting cancer, and it requires extensive expertise and very expensive equipment. Franklin credits the success of the project to a multidisciplinary team that included Wade Davis, assistant professor of biostatistics; Lixin Ma, assistant professor of radiology, and a multitude of veterinarians.

“It was a large collaboration, and veterinarians are ideal for collaborative medicine because we know the animal model,” Franklin said. “There are several angles that converge here, and we’re now interested in finding collaborators in human medicine that would like to explore this further. Ultimately, I’d envision panels of tests that predict diseases, with this method in the mix.”

Journal Reference:

1.                         Aaron C Ericsson, Matthew Myles, Wade Davis, Lixin Ma, Michael Lewis, Lillian Maggio-Price, and Craig Franklin. Noninvasive Detection of Inflammation-Associated Colon Cancer in a Mouse Model. Neoplasia, 2010; 12 (12): 1054-1065

2.                         University of Missouri-Columbia (2011, February 17). New testing could replace colonoscopies in the future.

Colonoscopies Miss Many Cancers, Study Finds

The New York Times, by Gina Kolata  —  For years, many doctors and patients thought colonoscopies, the popular screening test for colorectal cancer, were all but infallible. Have a colonoscopy, get any precancerous polyps removed, and you should almost never get colon cancer.

Then, last spring, researchers reported the test may miss a type of polyp, a flat lesion or an indented one that nestles against the colon wall. And now, a Canadian study, published Tuesday in the journal Annals of Internal Medicine, found the test, while still widely recommended, was much less accurate than anyone expected.

In the new study, the test missed just about every cancer in the right side of the colon, where cancers are harder to detect but about 40 percent arise. And it also missed roughly a third of cancers in the left side of the colon.

Instead of preventing 90 percent of cancers, as some doctors have told patients, colonoscopies might actually prevent more like 60 percent to 70 percent.

“This is a really dramatic result,” said Dr. David F. Ransohoff, a gasteroenterologist at the University of North Carolina. “It makes you step back and worry, ‘What do we really know?’ ”

Dr. Ransohoff and other screening experts say patients should continue to have the test, because it is still highly effective. But they also recommend that patients seek the best colonoscopists by, for example, asking pointed questions about how many polyps they find and remove. They also say patients should be scrupulous in the unpleasant bowel cleansing that precedes the test, and promptly report symptoms like bleeding even if they occur soon after a colonoscopy.

The American Cancer Society says that even if the test is less effective than many had believed, it has no plans to change its recommended intervals between screenings — the test still prevents most cancers, but the expense and risk of the test argue against doing it more often.

The cancer society and the Centers for Disease Control and Prevention also are focusing on developing measurements of quality so that doctors who do colonoscopies can assess themselves and improve.

But gastroenterologists say that, if nothing else, the study points up the paucity of evidence for the common suggestion that anyone who had a clean bill of health from a colonoscopy is almost totally protected for at least a decade.

“We have to not overpromise,” said Dr. Ransohoff, who wrote an editorial accompanying the colonoscopy paper. “We need to look at the evidence, and we shouldn’t go beyond it.”

The new study matched each of 10,292 people who died of colon cancer to five people who lived in the same area and were of the same age, sex and socioeconomic status. The researchers asked how many patients and control subjects had had colonoscopies and whether the doctors had removed polyps. Then the researchers compared the groups and asked how much the colon cancer death rate had declined in people who had had the screening test.

The results were “a shock,” said Dr. Nancy N. Baxter, the lead author of the paper and a colorectal surgeon at the University of Toronto. When she saw them, she said, “I asked my analyst to rerun the data.”

Now, researchers say, the challenge is to find out why the test missed so many cancers, in particular, those on the right side of the colon, and whether the problem can be fixed.

About 148,000 people will learn they have colon cancer this year, the American Cancer Society reports, and nearly 50,000 will die of it.

It might be that Canadian doctors were not sufficiently skilled. About a third of the colonoscopies were done by general internists and family practitioners who might not have had the experience to do the test well.

But, said Dr. Douglas K. Rex, director of endoscopy and professor of medicine at Indiana University, that cannot be the entire explanation because at least one study, as yet unpublished, involving California Medi-Cal patients also found the test missed many cancers on the right side of the colon.

That leaves several other possibilities.

Perhaps patients did not sufficiently cleanse their bowels of fecal material, a particular problem for the right side of the colon.

“After the prep has been completed, mucus and intestinal secretions start rolling out of the small intestine and colon,” Dr. Rex explained. The secretions, he added, pour from the base of the appendix into the right side of the colon and are “very sticky” and can obscure polyps.

One solution, supported by six studies, is to be sure there is just a short time between when patients finish taking the strong laxative that cleanses their bowel and the colonoscopy, Dr. Rex said. That usually means taking half of the laxative the night before the screening test and the rest in the morning, something that often is not done, he added, but that he and others recommend.

Cancer may also be different in the right colon, researchers said.

Flat and indented polyps tend to cluster in the right colon. And so do another kind, serrated lesions, which, some studies indicate, might turn into cancer much more quickly than typical polyps.

“It’s possible that we will never get as good a result” in the right colon, said Robert Smith, director of screening for the American Cancer Society.

Still, he said, that does not mean that patients should have more frequent colonoscopies. The tests are “hugely expensive,” he said, and insurers may not pay for more frequent colonoscopies. The test also carries a small risk of perforating the bowel. Even if colonoscopies miss some cancers, colon cancer remains a rare disease and, after a colonoscopy, “the likelihood that you have cancer is very, very low,” Dr. Smith said.

Dr. Harold C. Sox, editor of the Annals of Internal Medicine, is choosing another option. He is having a stool test, the fecal occult blood test, between colonoscopies. It looks for blood in the stool, which can arise from colon cancer.

Dr. Smith does not advocate that strategy, saying that the stool test can have false positives from things like red meat or broccoli that have nothing to do with colon cancer. He worries that frequent stool tests will lead to frequent false alarms and frequent colonoscopies without making much of a dent in the colon cancer death rate.

CT colonoscopies, so-called virtual colonoscopies, are not a solution, some screening experts said.

“The issues are prep quality, flat lesions, serrated lesions and people not being careful enough in the inspection process,” Dr. Rex said. There is no evidence, he added, that a virtual colonoscopy will help with the inspection process. And, he said, “it almost certainly is not as effective a technology as colonoscopy for flat and serrated lesions.”

Instead, patients should be compulsive about their bowel prep and be sure the test is done by one of the best colonoscopists in their area, gastroenterologists said. Doctors should find polyps in at least 25 percent of men and 15 percent of women. They should take at least eight minutes to withdraw an endoscope from the colon. And they should do a high volume of screening. Dr. Smith said a high volume was at least three or four colonoscopies a day.

After the test, patients can ask whether the doctor got to the right side of the colon and how that was documented.

Colon cancer experts said people should realize that even if colonoscopies prevent just 60 percent of colon cancer deaths, that still is a lot. Mammograms, for example, prevent 25 percent of breast cancer deaths, and the PSA test for men has not been shown to prevent prostate cancer deaths.

“If I was to provide one main message, it would be that colonoscopies are the way that colon cancer mortality gets reduced,” Dr. Ransohoff said. “Colonoscopy is a good test, but it isn’t completely effective. And you know what? We ought to be happy with that.”

This is the CASPro blood pressure measurement device. (Credit: University of Leicester)

University of Leicester, February 21, 2011  —  In a scientific breakthrough, a new blood pressure measurement device is set to revolutionise the way patients’ blood pressure is measured. The new approach, invented by scientists at the University of Leicester and in Singapore, has the potential to enable doctors to treat their patients more effectively because it gives a more accurate reading than the current method used. It does this by measuring the pressure close to the heart — the central aortic systolic pressure or CASP.

Blood pressure is currently measured in the arm because it is convenient however this may not always accurately reflect what the pressure is in the larger arteries close to the heart.

The new technology uses a sensor on the wrist to record the pulse wave and then, using computerised mathematical modelling of the pulse wave, scientists are able to accurately read the pressure close to the heart. Patients who have tested the new device found it easier and more comfortable, as it can be worn like a watch.

Being able to measure blood pressure in the aorta which is closer to the heart and brain is important because this is where high blood pressure can cause damage. In addition, the pressure in the aorta can be quite different from that traditionally measured in the arm. The new technology will hopefully lead to better identification of those who will most likely benefit from treatment by identifying those who have a high central aortic systolic pressure value. This will be especially important for younger people in whom the pressure measured in the arm can sometimes be quite exaggerated compared to the pressure in the aorta.

A key question is whether measurement of central aortic pressure will become routine in clinical practice. Professor Williams said: “it is not going to replace what we do overnight but it is a big advance. Further work will define whether such measurements are preferred for everybody or whether there is a more defined role in selective cases to better decide who needs treatment and who doesn’t and whether the treatment is working optimally”

The University’s close collaboration with the Singapore-based medical device company HealthSTATS International (“HealthSTATS”) has led to the development of this world-first technique for more accurate blood pressure measurement.

The research work carried out by the University of Leicester was funded by the Department of Health’s National Institute for Health Research (NIHR). The NIHR has invested £3.4million with a further £2.2million Capital funding from the Department of Health to establish a Biomedical Research Unit at Glenfield Hospital, Leicester, dedicated to translational research in cardiovascular research. The work, led by Professor Bryan Williams, Professor of Medicine at the University of Leicester and consultant physician at University Hospitals of Leicester NHS Trust, has the promise to change the way we measure blood pressure.

Professor Williams, who is based in the University of Leicester’s Department of Cardiovascular Sciences at Glenfield Hospital, said: “I am under no illusion about the magnitude of the change this technique will bring about. It has been a fabulous scientific adventure to get to this point and it will change the way blood pressure has been monitored for more than a century. The beauty of all of this, is that it is difficult to argue against the proposition that the pressure near to your heart and brain is likely to be more relevant to your risk of stroke and heart disease than the pressure in your arm.

“Leicester is one of the UK’s leading centres for cardiovascular research and is founded on the close working relationship between the University and the Hospitals which allows us to translate scientific research into patient care more efficiently. Key to our contribution to this work has been the support from the NIHR without which we would not have been able to contribute to this tremendous advance. The support of the NIHR has been invaluable in backing us to take this project from an idea to the bedside. Critical to the success of this project has been the synergies of combining clinical academic work here with HealthSTATS and their outstanding medical technology platform in Singapore. This has been the game-changer and I really do think this is going to change clinical practice.”

Dr. Choon Meng Ting the Chairman and CEO of HealthSTATS said: “This study has resulted in a very significant translational impact worldwide as it will empower doctors and their patients to monitor their central aortic systolic pressure easily, even in their homes and modify the course of treatment for BP-related ailments. Pharmaceutical companies can also use CASP devices for clinical trials and drug therapy. All these will ultimately bring about more cost savings for patients, reduce the incidences of stroke and heart attacks, and save more lives.”

Health Secretary Andrew Lansley said: “I saw this new technique in action in Leicester when I visited a few months ago. This is a great example of how research breakthroughs and innovation can make a real difference to patients’ lives. We want the NHS to become one of the leading healthcare systems in the world and our financial commitment to the National Institute for Health Research reflects this.

“I believe patients deserve the best treatments available and science research like this helps us move closer to making that happen.”

Professor Dame Sally Davies, Director General of Research and Development and Interim Chief Medical Officer at the Department of Health, said:

“This is fantastic work by Professor Williams and his team and I am delighted to welcome these findings. I am particularly pleased that the clinical research took place at the NIHR Biomedical Research Unit in Leicester. NIHR funding for Biomedical Research Centres and Units across England supports precisely this type of translational research, aimed at pulling-through exciting scientific discoveries into benefits for patients and the NHS by contributing to improved diagnostics and treatments.”

Journal Reference:

1. Bryan Williams, Peter S. Lacy, Peter Yan, Chua-Ngak Hwee, Chen Liang, Choon-Meng Ting. Development and Validation of a Novel Method to Derive Central Aortic Systolic Pressure From the Radial Pressure Waveform Using an N-Point Moving Average Method. Journal of the American College of Cardiology, 2011; 57 (8): 951 DOI: 10.1016/j.jacc.2010.09.054

2. University of Leicester (2011, February 20). Groundbreaking technology will revolutionize blood pressure measurement

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