Mutations in numerous pathways need to accumulate for cancer to progress. Given the ability of transposons to cause mutation and the role of mutation in cancer, it seemed likely that transposons would play a role in cancer. A few years ago, Iskow and colleagues showed that transposons jump in some lung tumors, suggesting a link to cancer progression. They also showed that methylation levels are often lower in lung cancers. Methylation is important for transposons silencing, so they hypothesized that lowered methylation in cancer could lead to more transposon jumps. This would “destabilize” the genome, allowing more mutations to accumulate, and accelerating cancer progression.

However, very little evidence of this connection existed until recently. With the advent of high-throughput sequencing, it is becoming possible to examine changes in the genomes of cancer cells. Lee and colleagues report on one such study. They decided to look at the effect of retrotransposons by comparing the location of these jumping genes in normal and cancer cells. Retrotransposons copy their sequence from one location to another by going through an RNA intermediate that is read “backwards” from RNA to DNA.

In their study, they had to overcome a problem: because transposons are found throughout the genome and are mostly the same in different individuals, it is hard to figure out exactly where new transposons are located. To sort this out, they developed a bioinformatics tool that could align sequence to a reference genome and identify new transposon sequence associated with this sequence. They then used normal tissue and cancer tissue from the same individual to identify transposition events in cancer cells.

Interestingly, different cancer types had different numbers of transposon jumps. Brain and blood cancers did not have many transposon-induced mutations, while epithelial cancers had frequent insertions. These jumping-gene insertions are probably important for cancer, as many of the insertions occur within genes known to affect cancer biology.

If these jumping genes cause mutations and promote cancer, why are they there? It’s still an area of contention, but all that jumping around helps provide diversity in our genomes. Sometimes that will prove to be bad, but it also allows natural selection to act on the diversity, allowing new, helpful innovations in our DNA power evolution.

Iskow el al, 2010. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell. 141(7):1253-61.

Lee et. al, 2012. Landscape of Somatic Retrotransposition in Human Cancers. Science. 337(6097): 967-971.

Tumor cells are a mosaic of different cell types

For the last decade or so, progressive cancer treatments involved taking samples of tumors, testing the cells to determine the genetic makeup, and then prescribing medicines targeted to specific mutations. There are many benefits to this approach, but it doesn’t always work.

It turns out that tumors aren’t uniform; they are mosaics of cells that can be genetically very different. A recent paper in the New England Journal of Medicine showed that a cell in one area may not be the same as a call in another area (a phenomenon called “intratumor heterogeneity”). So a treatment based on a sample from one area may not work for the whole tumor. Some tumor cells may be resistant to the drug so the cancer persists, or even grows.

In this British pilot study, cells from 9 different locations within a primary kidney tumor, and several metastatic tumors, were analyzed using next generation DNA sequencing. Only 34% of the 118 mutations identified were present in all the samples, and several of the major cancer genes were mutated in different ways in different locations. This turned traditional ideas about cancer cells being “clones” of a single, mutated cell on its head.

Previously, it was thought that a tumor develops when a single cell accumulates sufficient mutations over time that eventually lead to it dividing uncontrollably. Therefore if you could find the original mutation, and target treatment to that, then every cell would react to the treatment. But if the tumor is made up of a mosaic of cells, then they could all react differently to the drug. The researchers then created a phylogenetic “tree,” identifying which cells were more persistent, being in the trunk of the tree. They proposed that if those cells were receptive to a targeted medicine, the treatment might be more effective; if not, less so.

Although this study only involved four patients, the results provide a new way of thinking for researchers and clinicians. If we remove the presumption that all tumor cells are identical, we open the way for more creative thinking about how to tackle the problem.

Alu is an example of a so-called “jumping gene” – a transposable DNA sequence that “reproduces” by copying itself and inserting into new locations throughout the genome. Alu elements are classified as SINEs, or Short INterspersed Elements. All Alus are approximately 300 bp in length and derive their name from a single recognition site for the restriction enzyme AluI located near the middle of the Alu element. Alus are also classified as retrotransposons, because they need a special enzyme (a reverse transcriptase) to produce mobile copies. However Alus are “defective transposons” as they depend on the enzymes of other transposons for mobility, like the best characterized retrotransposon family called L1, a Long INterspersed Element (LINE).

Once an Alu inserts at a chromosome locus, it can copy itself for transposition, but there is no evidence that it is ever excised or lost from a chromosome locus. So, each Alu insertion gets fixed through evolutionary time. Like genes, Alu insertions are inherited in a Mendelian fashion from parents to children.

First discovered in corn about 60 years ago by Nobel laureate Barbara McClintock of Cold Spring Harbor Laboratory, jumping genes are now known to make up more than 40 percent of the entire human genome and may play an important role in genome evolution by creating new mutations and gene combinations.

Until this recent study, L1 retrotransposition was assumed to take place during early development mainly in germ cells (ovaries and testes) and rarely in somatic tissues (non-sex cells). Now researchers from the Roslin Institute near Edinburgh, Scotland, have capaciously mapped retrotransposon insertion sites in the genomes of normal human brain cells.

The researchers used state-of-the-art DNA sequencing technology to identify retrotransposons in brain tissue samples taken at postmortem from three individuals who were healthy when alive and had no neurological disease, nor signs of abnormality in their brain tissue. Focusing on two regions—the hippocampus and caudate nucleus (that is also involved in memory)—they identified nearly 25,000 different sites for the three main retrotransposon families: L1, Alu and SVA.

The numbers are impressive: their analyses identified a total of 7,743 insertions of L1s in the hippocampus and caudate nucleus, areas that were known to show cell division after embryogenesis. They also found nearly 14,000 insertion sites for the Alu family, which has not been encountered before in the brain.

Interestingly each sample showed its own set of unique retrotransposition events, which meant each one had an individual mutagenesis background. According to the study, retrotransposons more likely to be integrated in genes that were expressed in the brain, perhaps because these genes are more susceptible, as their DNA is packaged in a more accessible way.

So what is the consequence when retrotransposons preferentially jump within genes that play key roles in normal brain function? They cause normal gene expression to shut down, disrupting normal gene function. Affected genes include those genes encoding receptors for the neurotransmitter dopamine and membrane transporters. Others integrated in tumor-suppressor genes, which are deleted in several different types of brain cancer. Jumping genes were also found within genes encoding regulatory proteins linked to psychiatric illnesses, such as schizophrenia and Alzheimer’s disease. As well as generating mutations by inserting themselves into and disrupting genes, retrotransposons can alter gene activity if inserted into adjacent regulatory regions of DNA. Such alterations can have a valuable or harmful outcome, without doubt a powerful tool driving evolution.

The researchers also reported that jumping genes were more active in the hippocampus compared to the caudate nucleus. This is highly interesting, because the hippocampus is known to be critical for memory and learning, and is thought to be one of the few parts of the brain that continues to produce new cells throughout life. Are jumping genes therefore involved in how we learn? Researchers are now beginning to investigate whether jumping genes help us adapt processing information through learning.
So when do jumping genes actually get mobile?  It has to happen during the brain’s development because retrotransposition requires cell division. After early childhood this does not take place in the brain; new neurons are generated in the hippocampus from stem cells, through a process called neurogenesis.  Retrotransposons then take the opportunity to jump randomly (!) into parts of the chromosome that have been opened up for DNA replication.

Once thought to be rare, these neural integration events actually take place surprisingly often. The analyses in this latest study suggested that most brain cells undergo an average of 80 L1 integration events! This means each neuron is likely subjected to a unique combination of insertions, leading to a “genomic plasticity” within populations of cells.

This research completely overturns the belief that the genetic make-up of brain cells remains static throughout life. It indicates that neuronal networks are constantly changing with each new experience as novelty and challenge both trigger neurogenesis. It may finally result in differences in brain function among individuals, even in genetically identical twins.

Further reading:

Video link about Alu elements and Autism.

Nature papers about L1 transposition in human neurons and the impact of Alus on human evolution.

Originally Gustafson and his colleagues dated the mastodon hunting at Manis to more than 13,500 years ago. This was nearly 1,000 years before the Clovis culture, long considered to be the first culture in the New World. Their research was heavily criticized, due to limitations in the radiocarbon methodology used for dating the archaeological findings. However a recent publication supported their finding; an international group of researchers led by Michael Waters of Texas A&M University used a refined radiocarbon dating methodology and DNA analyses to demonstrate that the projectile found at the site came from a mastodon bone shaped as a spear point, handcrafted 13,800 years ago.

After careful DNA extractions of the hunted mastodon rib and the bone projectile found, the researchers successfully amplified a 69 base pair DNA fragment from the mitochondrial control region. Both samples produced identical sequences to mastodon DNA obtained previously, but distinct from other proboscideans (mammoth or elephant) by nine single nucleotide polymorphisms (SNPs).

These findings support the hypothesis that humans had permanent settlements in the Americas earlier than the Clovis culture (11,500 years ago). The bone projectile also shows that humans actively hunted megafauna (i.e., animals bigger than 50 kg) in this region. In addition, it suggests that the slow process of extinction of the biggest mammals inhabiting the Americas after the last glacial period (approximately 15,000 years ago), such as mammoths and mastodons, may have begun earlier than the time of the Clovis people.

Find out more about all these fascinating discoveries:

• Gustafson, C. E., et al. (1979). The Manis mastodon site: early man on the Olympic Peninsula. Canadian Journal of Archaeology, 3: 157-164.
• Radiocarbon dating methodology:
  • www.c14dating.com
  • http://en.wikipedia.org/wiki/Radiocarbon_dating
• Waters, M. R., et al. (2011). Pre-Clovis mastodon hunting 13,800 years ago at the Manis Site, Washington. Science 334, 6054: 351-353.
• Waters, M. R. et al. (2011). The Buttermilk Creek complex and the Origins of the Clovis at the Debra L. Friedkin Site, Texas. Science, 331, 6024: 1599-1603.

While most students don’t fully grasp this idea, there are a few examples we can use that can help to explain this.  I have always used examples of giraffes and the development of long necks, or antibiotic resistance in bacteria, but these seem to be a bit out of the realm of many 5^th grade students.  So what better example than ourselves!

During another lesson, I introduced the development of lactase persistence, or having the ability to drink and eat dairy products past infancy.  Digesting the sugar in milk (lactose) is dependent on whether or not the cells of your small intestine are producing the enzyme lactase.  Lactase is responsible for breaking lactose into smaller components that then get absorbed into the bloodstream.  For mammals that get milk from mother early in life, this enzyme is essential.  Would a mutation in the DNA that would allow a cell to continue to make lactase past infancy be beneficial?  It all depends on which population of humans you ask.

If it is a population of humans that began drinking the milk of other animals after the development of agriculture, like those of Northern European descent, it would be selected for.  These populations now show the highest frequency of lactase persistence among all human populations.  If dairy was not a part of your diet after infancy, this mutation wouldn’t be considered beneficial and would not have been selected for, such as in African, Asian and South American populations.

So, when teaching evolution and the changes that we see in species over time, it is nice to be able to give an example that we can see in humans.  Using an example that is a recent development in humans over the last 10,000 years, may help students to understand this concept better, and apply it across any species.

In a brilliant example of multidisciplinary research, Harvard Medical School’s Shawn Douglas, Ido Bachelet, and George Church combined forces to build nanostructures that would mimic the body’s immune system to recognize cancer cells and trick them into self-destructing. Their research is published today in Science but the discovery didn’t just happen overnight. It’s the culmination of several key discoveries going back several years, by researchers around the globe.

In 2006, Paul Rothemund at the California Institute of Technology, discovered  “DNA origami,” where the Watson-Crick base-pairing rules are exploited to create molecules from viral DNA in specific 3-dimensional shapes. The molecules use small, “staple” strands to bind longer strands and hold them in place. In 2009, chemists and nano-technologists at the Danish National Research Foundation’s Center for DNA Nanotechnology then used DNA origami to create a nano-cube that self-assembled, using staple strands to open a lid.

The Harvard group wondered if there was a way to deliver a nano-cube “robot” to cancer cells and kill them. This is where the immunology expertise paid off: antibodies patrol the bloodstream, honing in on specific cells, binding to them, and signalling them to self-destruct. So how can a DNA nano-robot deliver antibodies to the surface of cancer cells? Remember the cube’s lid?

“We could actually make an open-ended container and then all it would need to do is just turn itself inside out,” Douglas said.

A visual rendering of the DNA "nano-robot." Image courtesy of the Wyss Institute.

They created a “nano-clam” with antibodies waiting inside, ready to launch their attack. The nano-clam springs open when one of the staple strands is broken, just like turning a key in a lock.

And the really clever thing? The lock can be designed so that the key is in the shape of certain cancer cells. So when the cube encounters a cancer cell, such as lymphoma or leukemia cells, it springs open, exposing antibody fragments to the surface of the cell in a “surgical strike.” Unlike chemotherapy, which doesn’t discriminate between cell types, these DNA nano-robots only strike down cancer cells, leaving good cells alone.

The beauty of this discovery is that the underlying mechanism can be adapted for different diseases, by using different combinations of locks and antibodies. As the Danish chemist Kurt Gothelf commented, “People have been talking a lot about robots that enter your body, and go to a place where something is wrong and fix it. This is the first example that this might come true one day.”

The next step is to work out scalability. The current research was in Petri dishes in the lab, with 100 billion copies of the robot, but trillions are required for animals and humans. And the robot needs to become more robust to travel through the bloodstream, rather than through a pipette. Our body is very adept at getting rid of foreign bodies so they have to figure out a way for the nano-clams to swim “under the radar.”

Watch this space…

Biologists would like to understand how a bear, who eats continuously throughout the summer to lay down fat reserves for the winter, can have cholesterol levels that would be high for a human, but not suffer the hardening of arteries that one might expect. And what about the bone loss one would expect from months of inactivity?  Humans on bed rest can lose 3-4% of their hip bone minerals from lack of weight bearing exercise.  Bears show no signs of bone loss or osteoporosis as a result of their long rests.  It is likely that the genes involved exist in our cells too, but they just aren’t being used in the same way.

We clearly have a lot to learn from our hibernating friends. Teams of researchers in Sweden have actually been studying Brown bears to learn about these interesting phenomena.  How do you study wild Brown bears you ask?  You tranquilize them while they are hibernating, collect as many samples as you can, and get out before they wake up!  For the full story on hibernation, go to: http://www.sciencenews.org/view/feature/id/338318/title/Lessons_from_the_Torpid.

Well what do I mean by lasting changes? Research has shown that depending on what your mother eats may influence your genes and health in the long run. The gene agouti is found in humans and mice. The agouti/melanocortin system is an important regulator of body weight homeostasis. Mouse studies have shown that when the agouti gene is not methylated the result is obese yellow coated mice which may be at risk for cancer and diabetes. When the gene is methylated mice are brown, of normal weight and size. The only difference between the two types of mice is the methylation control on the agouti gene. In parallel experiments were carried out where yellow female mice were fed a methyl enriched diet; the offspring grew to be normal weight, size and were brown in color and remained so for the rest of their adulthood. This study identified that an individual’s wellbeing is not only determined by what they eat but also what their parents ate.

References
Nutrition and the epigenome. Retrieved February 8, 2012, from http://learn.genetics.utah.edu/content/epigenetics/nutrition/

Incidentally, water can taste funny due to substances and/or forms of life found in it.    Too bad Bo wasn’t a scientist.  Perhaps she could have extracted DNA from each glass of water and found out the kinds of organisms that have existed in this water.

Dutch scientists (Thomsen et. al., 2011) have been successful in identifying organisms that have been swimming through as little as a cup of freshwater. These scientists claim that organisms that swam through these waters within two weeks of collection left traces of DNA behind. This is quite a useful tool in determining the ecology of any given freshwater area. Scientists can use this information to identify rare or invasive species and monitor the activity of organisms found in a particular habitat within a period of time.

For more information, please go to:

http://www.scientificamerican.com/podcast/episode.cfm?id=dna-in-a-cup-of-water-reveals-lake-11-12-19#comments

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-294X.2011.05418.x/abstract

Your meat indeed could be a high risk for your health. In some cases this can be a public concern, because meat can be a source of pathogens that could cause a disease outbreak. In fact, it has been documented that close interaction among wildlife, domestic animals, and humans could provide the perfect environment for pathogen exchange.[1] Even more alarmingly, almost 75% of diseases that have recently emerged in humans have their origin in animals, a process technically known as zoonosis.[2] Hunting and butchering of wild animals has been increasingly recognized as a source of disease emergence. The most common zoonotic pathogens are RNA viruses, such as the severe acute respiratory syndrome (SARS) coronavirus,[3] and the H5N1 influenza virus, that causes flu.[4] Wildlife products that have not been inspected for sanitary conditions could thus be a serious threat to public health.

The United States is one of the world’s largest importers of wildlife and wildlife products.[5] Every year approximately 120 million live wild animals and 25,000 tons of wildlife products are imported into the US. New York City is the busiest port of entry into the US, and in combination with the Los Angeles and Miami international airports, accounts for more than 50% of all wildlife imports. One of the main concerns with importation of wild animals and wildlife products is the introduction of pathogens that are associated with them. Examples of diseases introduced to the US by wildlife include amphibian chytridiomycosis, exotic Newcastle’s disease, and monkey pox.

In a study published this month in PLoS ONE, a large collaborative team composed by researchers from EcoHealth Alliance, Columbia University, the American Museum of Natural History, the US Centers for Disease Control and Prevention (CDC), the US Geological Survey, and the Wildlife Conservation Society tested samples from approximately 44 different meat products confiscated at five US international airports, the majority coming from JFK Airport.[6] Using DNA barcoding they identified that the bushmeat (term used to define product obtained from hunting and butchering of wild animals) came from chimpanzees, mangabeys, and green monkeys, among other animals. Both simian foamy viruses (SFV) and herpes viruses were detected in the wildlife products. Both type of viruses have been associated with infections and diseases in humans, such as malignant catarrhal fever or herpes B virus.[7] This is yet another study highlighting the manifold applications of DNA barcoding.

This PLoS ONE study⁶ was the first to conduct surveillance for zoonotic viruses in bushmeat products illegally imported into the US and establishes a precedent of the threat these products could represent for our public health.