In today's edition:
- 'Junk' DNA proves functional
- Souped-up immune cells catch even disguised HIV
- Forced evolution: Can we mutate viruses to death?
- Previously unknown immune cell may help those with Crohn's and colitis
- Cancer patient genome sequenced for the first time
'Junk' DNA proves functional
More than 50 percent of human DNA has been referred to as "junk" because it consists of copies of nearly identical sequences. A major source of these repeats is internal viruses that have inserted themselves throughout the genome at various times during mammalian evolution.
Using the latest sequencing technologies, GIS researchers showed that many transcription factors, the master proteins that control the expression of other genes, bind specific repeat elements. The researchers showed that from 18 to 33% of the binding sites of five key transcription factors with important roles in cancer and stem cell biology are embedded in distinctive repeat families.
Over evolutionary time, these repeats were dispersed within different species, creating new regulatory sites throughout these genomes. Thus, the set of genes controlled by these transcription factors is likely to significantly differ from species to species and may be a major driver for evolution.
This research also shows that these repeats are anything but "junk DNA," since they provide a great source of evolutionary variability and might hold the key to some of the important physical differences that distinguish humans from all other species.
The GIS study also highlighted the functional importance of portions of the genome that are rich in repetitive sequences.
"The findings by Dr. Bourque and his colleagues at the GIS are very exciting and represent what may be one of the major discoveries in the biology of evolution and gene regulation of the decade," said Raymond White, Ph.D., Rudi Schmid Distinguished Professor at the Department of Neurology at the University of California, San Francisco, and chair of the GIS Scientific Advisory Board.
"We have suspected for some time that one of the major ways species differ from one another – for instance, why rats differ from monkeys – is in the regulation of the expression of their genes: where are the genes expressed in the body, when during development, and how much do they respond to environmental stimuli," he added.
"The means of distribution seem to be a class of genetic components called 'transposable elements' that are able to jump from one site to another at certain times in the history of the organism. The families of these transposable elements vary from species to species, as do the distributed DNA segments which bind the regulatory proteins."
Dr. White also added, "This hypothesis for formation of new species through episodic distributions of families of gene regulatory DNA sequences is a powerful one that will now guide a wealth of experiments to determine the functional relationships of these regulatory DNA sequences to the genes that are near their landing sites. " source
My comments: A little longer one, but very interesting on the evolutionary side of genetics. I completely support the opinion that even if the "important" genes are similar between 2 species, we must inspect the whole genome to make sure that what we're doing is going to behave the same way on another specie. In simply words, it explains on deeper level why a drug working good on a mouse won't work so well on a human.
Souped-up immune cells catch even disguised HIV
WASHINGTON (Reuters) – Genetically engineered immune cells can spot the AIDS virus even when it tries to disguise itself, offering a potential new way to treat the incurable infection, researchers reported on Sunday.
The killer T-cells, dubbed "assassin" cells, were able to recognize other cells infected by HIV and slow the spread of the virus in lab dishes.
If the approach works in people, it might provide a new route of treating infection with the deadly, the researchers in the United States and Britain said.
"Billions of these anti-HIV warriors can be generated in two weeks," said Angel Varela-Rohena of the University of Pennsylvania, who helped lead the study.
In a second, unrelated report, researchers testing Dutch biotechnology firm Crucell NV's experimental AIDS vaccine said it prevented infection in six monkeys.
The animals were infected with a monkey version of HIV called SIV, and the vaccine used a virus that is dangerous to use in humans, so it is not ready for human tests.
The AIDS virus, which infects 33 million people globally, is especially hard to fight. Like all viruses, it hijacks cells in its victims, forcing them to become little viral factories and make more virus.
HIV is even more insidious, attacking immune system cells called CD4 T cells, which help mount a defense. It can also disguise itself to escape CD8 killer cells, also known as cytotoxic T lymphocytes or CTLs.
One good defense allows HIV to hide a protein called HLA-I-associated antigen.
Varela-Rohena and colleagues took T-cells from an HIV patient and created a genetically engineered version that recognizes this deception.
Not only could the engineered T-cells see HIV strains that had escaped detection by natural T-cells, "but the engineered T cells responded in a much more vigorous fashion so that far fewer T-cells were required to control infection," Penn's James Riley, who also worked on the study, said in a statement.
"In the face of our engineered assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way," added Andy Sewell of Britain's Cardiff University.
They plan to test the T-cell treatment in HIV patients next year. source
My comment: Perhaps it will mutate and become harmless, but perhaps it will mutate and become stronger. As fascinating as it is, this news, I still prefer people to be more realistic when making such statements. For me, it's absolutely amazing how we hear about crucial progress in the fight with AIDS and in the same time, we heard only about 1 person ever to be cured, with a totally unrelated method. Odd?
Forced evolution: Can we mutate viruses to death?The study, available online and slated for publication in the journal Physical Review E, offers the most comprehensive mathematical analysis to date of the mechanisms that drive evolution in viruses and bacteria. Rather than focusing solely on random genetic mutations, as past analyses have, the study predicts exactly how evolution is affected by the exchange of entire genes and sets of genes.
"We wanted to focus more attention on the roles that recombination and horizontal gene transfer play in the evolution of viruses and bacteria," said bioengineer Michael Deem, the study's lead researcher. "So, we incorporated both into the leading models that are used to describe bacterial and viral evolution, and we derived exact solutions to the models."
The upshot is a newer, composite formula that more accurately captures what happens in real world evolution
"If you know the recombination rate, mutation rate and fitness function, our formula can analytically predict the properties of the system. So, if you have recombination at a certain frequency, I can say exactly how much that helps or hurts the fitness of the population." said one of the authors.
The new model helps to better describe the evolutionary processes that occur in the real world, and it could be useful for doctors, drug designers and others who study how diseases evolve and how our immune systems react to that evolution.
One idea that was proposed about five years ago is "lethal mutagenesis."-how to design drugs that speed up the mutation rates of viruses and push them beyond a threshold called a "phase transition-if the mutation, recombination or horizontal gene transfer rates are too high, the system delocalizes and gets spread all over sequence space."
Deem said the new results predict which parameter values will lead to this delocalization.
A competing theory is that a mutagenesis drug may eradicate a virus or bacterial population by reducing the fitness to negative values.
Without theoretical tools like the new model, drug designers looking to create pills to induce lethal mutagenesis couldn't say for certain under what parameter ranges the drugs really worked. Deem said the new formula should provide experimental drug testers with a clear picture of whether the drugs -- or something else -- causes mutagenesis. source
My comment: Funny how theoretical this work sounds to me. In any case, I love computer models, now all we need is to see how well they happen in practice. As good as it sounds, mutating a virus to death (though on the other hand, we should be quite careful to induce this only to harmful ones in our bodies, because viruses are important players in evolution), a model is nothing without an experimental confirmation or at least calibration.
Previously unknown immune cell may help those with Crohn's and colitis
"These cells have an anti-inflammatory effect," says the article's lead author Marina Cella, M.D., research associate professor of pathology and immunology. "In the gut, we have beneficial bacteria, and it's important that the body does not recognize them as something detrimental and start an inflammatory reaction, which could ultimately promote tissue damage and inflammatory or autoimmune diseases such as IBD. The cells we've discovered are important for keeping such harmful inflammatory processes in check."
The cells are a type of natural killer (NK) cells, which are white blood cells classically known to eliminate tumor cells and cells infected by viruses. Because of their killer tendencies, NK cells are carefully controlled and don't act until they receive the right signal.
Some of the signals that activate the newly discovered cells are the same signals that turn on a different immune cell with strong inflammatory properties that can promote cell death and tissue damage if chronically active. But the anti-inflammatory cells, termed NK-22 cells, that the Washington University researchers discovered have the opposite effect — they promote cell proliferation and wound healing.
The NK-22 cells are part of the innate immune system, which reacts quickly to invading pathogens. The researchers found that in response to immune signals warning of foreign invaders, the cells produce copious quantities of a compound called IL-22, which is why the researchers chose to name them NK-22 cells. source
My comment: Besides the deeper knowledge of our marvellous immune system, this article is telling us more about the wound healing process-something that is quite important. Imagine if for example, you could put a person with a wound in a sterile environment and turn off only the anti-inflammatory cells. The body then will give all its energy on the healing instead of to watch for potential threat. That's good!
Cancer patient genome sequenced for the first time
The researchers discovered just 10 genetic mutations in the patient's tumor DNA that appeared to be relevant to her disease; eight of the mutations were rare and occurred in genes that had never been linked to AML. They also showed that virtually every cell in the tumor sample had nine of the mutations, and that the single genetic alteration that occurred less frequently was likely the last to be acquired. The scientists suspect that all the mutations were important to the patient's cancer.
Like most cancers, AML - a cancer of blood-forming cells in the bone marrow - arises from mutations that accumulate in people's DNA over the course of their lives. However, little is known about the precise nature of those changes and how they disrupt biological pathways to cause the uncontrolled cell growth that is the hallmark of cancer.
What's striking about the new research is that the scientists were able to sift through the 3 billion pairs of chemical bases that make up the human genome to pull out the mutations that contributed to the patient's cancer.
To date, scientists involved in large-scale genetic studies of cancer have not gone so far as to do a full side-by-side comparison of the genomes of normal cells and tumor cells from the same patient.
Based on genetic testing with traditional methods at the study's outset, the patient was known to have two mutations that are common among AML patients, an indicator she had a typical subtype of the disease, and one of the many reasons why her genome was selected for sequencing.
The researchers sequenced the patient's full genome, meaning DNA from both sets of chromosomes, using genetic material obtained from a skin sample. This gave the scientists a reference DNA sequence to which they could compare genetic alterations in the patient's tumor cells, taken from a bone marrow sample that was comprised only of tumor cells. Both samples were obtained before the patient received cancer treatment, which can further damage DNA.
The scientists then looked for genetic differences - points of single base changes in the DNA - in the patient's tumor genome compared with her normal genome. Of the nearly 2.7 million single nucleotide variants in the patient's tumor genome, almost 98 percent also were detected in DNA from the patient's skin sample, thus narrowing the number of variants that required further study to about 60,000.
Using sophisticated software and analytical tools, some of which the researchers developed specifically for this project, they identified the 10 mutations by looking for single base DNA changes that altered the instructions for making proteins.
Of the eight novel mutations discovered, three were found in genes that normally act to suppress tumor growth. One of these mutations is in the PTPRT tyrosine phosphatase gene, which is frequently altered in colon cancer.
Four other mutated genes appear to be involved in molecular pathways that promote cancer growth. In particular, one mutation was found in a gene family that also is expressed in embryonic stem cells and may be involved with cell self-renewal. Interestingly, the researchers note, self-renewal is thought to be an essential feature of leukemia cells.
Another gene alteration appears to affect the transport of drugs into the cell, and may have contributed to the patient's chemotherapy resistance.
The team also looked to see if the eight novel mutations in the patient's tumor genome also occurred in the DNA of tumor samples from 187 additional AML patients. None of those tumors had any of the eight mutations.
"This suggests that there is a tremendous amount of genetic diversity in cancer, even in this one disease," Wilson says.
Based on their current understanding of cancer, the researchers suspect that the mutations occurred sequentially. The first mutation gave the cell a slight tendency toward cancer, and then one by one, the other genetic alterations were acquired, with each contributing something to the cancer. One mutation, in the FLT3 gene, was not present in all of the tumor cells, and they suspect that it was the last one to occur. "The final mutation may represent a tipping point that causes the cancer cells to become more dangerous," Ley says.
The team is now sequencing the genomes of additional patients with AML, and they are also planning to expand the whole-genome approach to breast and lung cancers. source
My comment:A very long one, but rather important. Even if somewhat ill-stated. The most important part is that the mutation that were found in 1 patient weren't found in other. Which means that cancer is much more complicated than we thought. Also important is that it obviously comes from mutation that we gather during our life. For me, the most important question now is why we accumulate them and how to stop them. Sequencing all the genomes of ill people might be interesting for scientists but I'm not so sure how useful it will be in the fight.