“This work has major implications for modulating the fatty-acid profiles in plants, which is terribly important, not only to sustainable food production and nutrition but now also to biorenewable chemicals and fuels,” said Joseph Noel, a professor and director of the Jack H. Skirball Center for Chemical Biology and Proteomics at the Salk Institute.

“Because very high-energy molecules such as fatty acids are created in the plant using the energy of the sun, these types of molecules may ultimately provide the most cost-effective and efficient sources for biorenewable products,” added Eve Syrkin Wurtele, a professor of genetics, development and cell biology at Iowa State.

The analysis of gene activity (by the Iowa group) and determination of protein structures (by the Salk group) independently identified in the model plant thale cress (Arabidopsis thaliana) three related proteins that appear to be involved in fatty-acid metabolism. The Iowa and Salk researchers then joined forces to test this hypothesis, demonstrating a role of these proteins in regulating the amounts and types of fatty acids accumulated in plants. The researchers also showed that the action of the proteins is very sensitive to temperature and that this feature may play an important role in how plants mitigate temperature stress using fatty acids.

Although the researchers now understand that the three proteins – dubbed fatty-acid-binding proteins one, two and three, or FAP1, FAP2 and FAP3 – are involved in fatty-acid accumulation in plant tissues such as leaves and seeds, Wurtele said researchers still don’t understand the physical mechanism these proteins employ at the molecular level. That knowledge will ultimately allow the two collaborating research groups to predictably engineer better functions in plants.

“The proteins appear to be crucial missing links in the metabolism of fatty acids in Arabidopsis, and likely serve a similar function in other plant species since we find the same genes spread throughout the plant kingdom,” said Ryan Philippe, a post-doctoral researcher in Noel’s lab.

“If the researchers can understand precisely what role the proteins play in seed oil production,” said first author Michelle Ngaki, “they might be able to modify the proteins’ activity in new plant strains that produce more oil or higher quality oil than current crops.”

Further, if the three proteins help plants regulate stress, plant scientists might be able to exploit that trait to develop plants that are more resistant to stress, Wurtele said. And that could allow farmers to grow crops for biorenewable fuels and chemicals on marginal land that’s not suited for food crops.

All of this, she said, could point to new directions in biological studies.

“We are entering the age of predictive biology,” Wurtele said. “That means harnessing computational approaches to deduce gene function, model biological processes and predict the consequences of altering a single gene to the complex biological network of an organism.”

The CNIO team, in collaboration with Eduard Ayuso and Fátima Bosch of the Centre of Animal Biotechnology and Gene Therapy at the Universitat Autònoma de Barcelona (UAB), treated adult (one‐year‐old) and aged (two‐year‐old) mice, with the gene therapy delivering a “rejuvenating” effect in both cases, according to the authors.

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals’ health, delaying the onset of age‐related diseases – like osteoporosis and insulin resistance – and achieving improved readings on aging indicators like neuromuscular coordination.

The gene therapy consisted of treating the animals with a DNA-­modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a key role in aging. Telomerase repairs the extreme ends or tips of chromosomes, known as telomeres, and in doing so slows the cell’s and therefore the body’s biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

This study “shows that it is possible to develop a telomerase-­based anti-­aging gene therapy without increasing the incidence of cancer,” the authors affirm. “Aged organisms accumulate damage in their DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production can repair or delay this kind of damage,” they add.

‘Resetting’ the biological clock

Telomeres are the caps that protect the end of chromosomes, but they cannot do so indefinitely: each time the cell divides the telomeres get shorter, until they are so short that they lose all functionality. The cell, as a result, stops dividing and ages or dies. Telomerase gets around this by preventing telomeres from shortening or even rebuilding them. What it does, in essence, is stop or reset the cell’s biological clock.

But in most cells the telomerase gene is only active before birth; the cells of an adult organism, with few exceptions, have no telomerase. The exceptions in question are adult stem cells and cancer cells, which divide limitlessly and are therefore immortal — in fact several studies have shown that telomerase expression is the key to the immortality of tumour cells.

It is precisely this risk of promoting tumour development that has set back the investigation of telomerase­‐based anti­‐aging therapies.

In 2007, Blasco’s group demonstrated that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the embryonic stage, by causing their cells to express telomerase and, also, extra copies of cancer­‐resistant genes. These animals live 40% longer than normal and do not develop cancer.

The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumors to appear.

Also important is the kind of virus employed to carry the telomerase gene to the cells. The authors selected demonstrably safe viruses that have been successfully used in gene therapy treatment of hemophilia and eye disease. Specifically, they are non-­‐replicating viruses derived from others that are non-­‐pathogenic in humans.

This study is viewed primarily as “a proof-­‐of-­‐principle that telomerase gene therapy is a feasible and generally safe approach to improve healthspan and treat disorders associated with short telomeres,” state Virginia Boccardi (Second University of Naples) and Utz Herbig (New Jersey Medical School-­‐University Hospital Cancer Centre) in a commentary published in the same journal.

Although this therapy may not find application as an anti‐aging treatment in humans, in the short term at least, it could open up a new treatment option for ailments linked with the presence in tissue of abnormally short telomeres, as in some cases of human pulmonary fibrosis.

As Blasco says, “aging is not currently regarded as a disease, but researchers tend increasingly to view it as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence rises with age. In treating cell aging, we could prevent these diseases.”

With regard to the therapy under testing, Bosch explains: “Because the vector we use expresses the target gene (telomerase) over a long period, we were able to apply a single treatment. This might be the only practical solution for an anti‐aging therapy, since other strategies would require the drug to be administered over the patient’s lifetime, multiplying the risk of adverse effects.”

The study is the first example of using bone cell progenitors derived from human embryonic stem cells to grow compact bone tissue in quantities large enough to repair centimeter-sized defects. When implanted in mice and studied over time, the implanted bone tissue supported blood vessel ingrowth, and continued development of normal bone structure, without demonstrating any incidence of tumor growth.

Dr. Marolt’s work is a significant step forward in using pluripotent stem cells to repair and replace bone tissue in patients. Bone replacement therapies are relevant in treating patients with a variety of conditions, including wounded military personnel, patients with birth defects, or patients who have suffered other traumatic injury.

Since conducting this work as proof of principle at Columbia University, Dr. Marolt has continued to build upon this research as an Investigator in the NYSCF Laboratory, developing bone grafts from induced pluripotent stem (iPS) cells. iPS cells are similar to embryonic stem cells in that they can also give rise to nearly any type of cell in the body, but iPS cells are produced from adult cells and as such are individualized to each patient. By using iPS cells rather than embryonic stem cells to engineer tissue, Dr. Marolt hopes to develop personalized bone grafts that will avoid immune rejection and other implant complications.

Researchers from Georgia Institute of Technology and Emory University found that chromatin compaction is required for proper embryonic stem cell differentiation to occur. Chromatin, which is composed of histone proteins and DNA, packages DNA into a smaller volume so that it fits inside a cell. Embryonic stem cells lacking several histone H1 subtypes and exhibiting reduced chromatin compaction suffered from impaired differentiation under multiple scenarios and demonstrated inefficiency in silencing genes that must be suppressed to induce differentiation.

“While researchers have observed that embryonic stem cells exhibit a relaxed, open chromatin structure and differentiated cells exhibit a compact chromatin structure, our study is the first to show that this compaction is not a mere consequence of the differentiation process but is instead a necessity for differentiation to proceed normally,” said Yuhong Fan, an assistant professor in the Georgia Tech School of Biology.

“We are amazed that any single protein has such power,” says the study’s lead investigator Dr. Timothy A. Ryan, professor of Biochemistry and associate professor of Biochemistry in Anesthesiology at Weill Cornell Medical College. “It is indeed rare to identify a biological molecule’s function that is so potent, that seems to be controlling the effectiveness of neurotransmission.”

The researchers found that alpha 2 delta determines how many calcium channels will be present at the synaptic junction between neurons. The transmission of chemical signals is triggered at the synapse by the entry of calcium into these channels, so the volume and speed of neurotransmission depends on the availability of these channels.

Researchers discovered that taking away alpha 2 delta from brain cells prevented calcium channels from getting to the synapse. “But if you add more alpha 2 delta, you can triple the number of channels at synapses,” Dr. Ryan says. “This change in abundance was tightly linked to how well synapses carry out their function, which is to release neurotransmitters.”

The majority of Americans, 74 percent, have some awareness of plant biotechnology and almost 40 percent are favorable toward the use of biotechnology in food production. Of the 35 percent of consumers who expect biotechnology will provide benefits to them or their families in the next five years, 36 percent expect nutrition and health benefits, while 22 percent listed improved quality, taste and variety as beneficial characteristics to expect. In terms of biotech foods consumers would be likely to purchase based on specific attributes, 77 percent indicated they would be somewhat or very likely to purchase foods produced through biotechnology that required fewer pesticide applications; and 71 percent indicated they would likely purchase biotech foods that provided more healthful fats, such as Omega-3 fatty acids.

In addition, a majority (57 percent) of Americans have some awareness of animal biotechnology, while 33 percent say they view the technology somewhat or very favorably. Of those who are “not favorable” (i.e. not very or not at all favorable, or neutral) toward animal biotechnology, 55 percent say not having enough information about the technology is the reason for their answer.

The mistake is the inclusion of individual bits of RNA within the DNA sequence, which the researchers found occurs more than a million times in each cell as it divides. The findings, published in Cell, suggest the RNase H2 enzyme is central to an important DNA repair mechanism necessary to protect the human genome.

Each time a cell divides it must first make an identical copy of its entire genetic material, known as the genome. During this process, which is called DNA replication, the integrity of the genetic code is safeguarded by cellular ‘proofreading’ and error checking mechanisms.

But sometimes mistakes creep into the genetic code, which if not corrected could lead to genetic disease or cancer. Accidental incorporation of RNA is one such mistake. The individual building blocks of RNA (ribonucleotides) are very similar to those that make up DNA, however, they are much less stable and if they remain incorporated in DNA they cause harmful breaks in the double helix. Such breaks are common in cancer cells.

The researchers made the discovery while working on a rare childhood auto-immune disease known as Aicardi-Goutières syndrome, which is caused by mutations in the RNase H2 genes. It leads to inflammation of the brain soon after birth and can be fatal within the first few years of life.

To study this condition in more detail, the scientists knocked out one of the RNase H2 genes in mice. They found that without the enzyme, the developing mouse embryos accumulated more than 1,000,000 single embedded bits of RNA in the genome of every cell, resulting in instability of their DNA.

Dr Andrew Jackson from the MRC IGMM at the University of Edinburgh, who led the research, said:

“The most amazing thing is that by working to understand a rare genetic disease, we’ve uncovered the most common fault in DNA replication by far, which we didn’t even start out looking for! More surprising still is that a single enzyme is so crucial to repairing over a million faults in the DNA of each cell, to protect the integrity of our entire genetic code.

“We expect our findings to have broad implications in the fields of autoimmunity and cancer in the future, but first we need to find out more about what effect the incorporation of RNA nucleotides is actually having on the genome.”

Professor Nick Hastie, director of the MRC IGMM at the University of Edinburgh, said:

“This study is a fantastic example of clinicians working alongside laboratory scientists towards a shared goal of improving our understanding of human health and disease. Such progress would not be possible without the critical mass of scientists at the IGMM, with capabilities in many key areas coupled with access to patient data and clinical expertise.”

Ravi K. Amaravadi, MD, assistant professor of Medicine, and colleagues showed previously that an old malaria drug, hydroxychloroquine, reduces autophagy in cancer cells and makes them more likely to die when exposed to chemotherapy. The strategy is currently being tested in clinical trials, and preliminary results are promising. The catch, though, is that it’s not always possible to give patients a high enough dose of hydroxychloroquine to have an effect on their tumor cells.

Amaravadi teamed up with Jeffrey Winkler, PhD, the Merriam Professor of Chemistry, to design a series of more potent versions of chloroquine. They describe the design, chemical synthesis, and biological evaluation of a highly effective, new compound called Lys05, in the early edition of the Proceedings of the National Academy of Sciences this week. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

Unlike hydroxychloroquine, which has little impact on tumor cells when used as a single agent, the new drug, called Lys05, slows tumor growth in animal models even in the absence of other anti-tumor therapies. What’s more, the Lys05 dose that is toxic to cancer cells, which are addicted to recycling and rely on it much more heavily than healthy cells, has little or no effect on healthy cells.

“We see that Lys05 has anti-tumor activity at doses that are non-toxic for the animals,” Amaravadi says. “This single-agent anti-tumor activity suggests this drug, or its derivative, may be even more effective in patients than hydroxychloroquine.” Remarkably, however, when the investigators increase the dose of Lys05, some animals develop symptoms that mimic a known genetic deficiency in an autophagy gene, ATG16L1, which affects some patients with Crohn’s disease . That similarity — technically called a phenocopy — clearly shows that Lys05 works by interfering with the recycling system in cells.

Lys05, and its companion compound Lys01, aren’t quite ready for testing in patients, according to Amaravadi. Before that can happen, the molecules need to be optimized and undergo more toxicity testing in animals. Amaravadi and Winkler hope to team up with an industry partner for that portion of the project.

In the meantime, though, Amaravadi says the work illustrates just how important autophagy is to cancer cells, and provides an important new step for future therapies.

Published in Nature Medicine, Monoclonal TCR-redirected tumor cell killing examined the potential of molecules on the surface of anti-cancer killer T cells, known as T cell receptors (TCRs) to be used to treat cancers for which few disease-specific targets are available.

The Immunocore team engineered a range of TCRs to bind very tightly to cancer cells and equipped them with the ability to activate non-cancer specific T cells. This new class of drug, named ‘ImmTACs’ (Immune Mobilising mTCR against Cancer), can be used to ‘hi-jack’ the body’s existing T cells that normally kill viruses and redirect them to kill cancer cells instead.

The team included Nat Liddy and Katy Adams, Immunocore employees and PhD students at Cardiff University, as well as Professors Andy Sewell and David Price, School of Medicine.

“With Immuncore’s novel ImmTAC drugs we found we could effectively target cancer cells and mark them for destruction by the killer T cells that might normally fight common infections” said Liddy

“Our initial studies and findings show that administration of ImmTAC could, potentially, result in the regression of established tumors.”

Recent advances have enabled molecular targeting of disease using immune molecules called antigen receptors. There are two main classes of antigen receptor: antibodies and T cell receptors.

Therapeutic application of antibodies has been a huge medical success over the last decade and over 40% of the new drugs on the market in 2011 were based on these molecules.

Exploitation of T cell receptors (TCRs) has so far lagged behind, but research led by Immunocore Ltd, with help from Cardiff University’s Institute of Infection and Immunity, is set to close the gap and open up an entirely new field of medical treatments.

“T cell receptors have advantages over antibodies as these molecules can see inside cells and tell if they are abnormal” said Professor Andy Sewell. “Similar technology based around antibodies has shown great promise in clinical trials. This new TCR-based research technology extends this potential as it could possibly be applied to any form of cancer.”

The most advanced of Immunocore’s ImmTACs, a drug called IMCgp100, is already in clinical trials in the UK and US for the treatment of melanoma. A second oncology ImmTAC, IMCmage1, is set to enter the clinic in both countries later this year and is applicable to the treatment of a large number of poorly served cancer indications.

James Noble, Immunocore’s CEO, said: “The power of this new technology lies in its ability to be used for a host of cancers that are currently very difficult to treat. We look forward to building on the emerging clinical data and generating a robust pipeline of products over the coming years”.

Despite the fact that forgetting is normal, exactly how we forget—the molecular, cellular, and brain circuit mechanisms underlying the process—is poorly understood.

Now, in a study that appears in the May 10, 2012 issue of the journal Neuron, scientists from the Florida campus of The Scripps Research Institute have pinpointed a mechanism that is essential for forming memories in the first place and, as it turns out, is equally essential for eliminating them after memories have formed.

“This study,” Dopamine is required for Learning and Forgetting in Drosophila, “focuses on the molecular biology of active forgetting,” said Ron Davis, chair of the Scripps Research Department of Neuroscience who led the project. “Until now, the basic thought has been that forgetting is mostly a passive process. Our findings make clear that forgetting is an active process that is probably regulated.”

The Two Faces of Dopamine

To better understand the mechanisms for forgetting, Davis and his colleagues studied Drosophila or fruit flies, a key model for studying memory that has been found to be highly applicable to humans. The flies were put in situations where they learned that certain smells were associated with either a positive reinforcement like food or a negative one, such as a mild electric shock. The scientists then observed changes in the flies’ brains as they remembered or forgot the new information.

The results showed that a small subset of dopamine neurons actively regulate the acquisition of memories and the forgetting of these memories after learning, using a pair of dopamine receptors in the brain. Dopamine is a neurotransmitter that plays an important role in a number of processes including punishment and reward, memory, learning and cognition.

But how can a single neurotransmitter, dopamine, have two seemingly opposite roles in both forming and eliminating memories? And how can these two dopamine receptors serve acquiring memory on the one hand, and forgetting on the other?

The study suggests that when a new memory is first formed, there also exists an active, dopamine-based forgetting mechanism—ongoing dopamine neuron activity—that begins to erase those memories unless some importance is attached to them, a process known as consolidation that may shield important memories from the dopamine-driven forgetting process.

The study shows that specific neurons in the brain release dopamine to two different receptors known as dDA1 and DAMB, located on what are called mushroom bodies because of their shape; these densely packed networks of neurons are vital for memory and learning in insects. The study found the dDA1 receptor is responsible for memory acquisition, while DAMB is required for forgetting.

When dopamine neurons begin the signaling process, the dDA1 receptor becomes overstimulated and begins to form memories, an essential part of memory acquisition. Once that memory is acquired, however, these same dopamine neurons continue signaling. Except this time, the signal goes through the DAMB receptor, which triggers forgetting of those recently acquired, but not yet consolidated, memories.

Jacob Berry, a graduate student in the Davis lab who led the experimentation, showed that inhibiting the dopamine signaling after learning enhanced the flies’ memory. Hyperactivating those same neurons after learning erased memory. And, a mutation in one of the receptors, dDA1, produced flies unable to learn, while a mutation in the other, DAMB, blocked forgetting.

Intriguing Issues

While Davis was surprised by the mechanisms the study uncovered, he was not surprised that forgetting is an active process. “Biology isn’t designed to do things in a passive way,” he said. “There are active pathways for constructing things, and active ones for degrading things. Why should forgetting be any different?”

The study also brings into a focus a lot of intriguing issues, Davis said—savant syndrome, for example.

“Savants have a high capacity for memory in some specialized areas,” he said. “But maybe it isn’t memory that gives them this capacity, maybe they have a bad forgetting mechanism. This also might be a strategy for developing drugs to promote cognition and memory—what about drugs that inhibit forgetting as cognitive enhancers?”