Mutation

Bad Luck Causes Most Cancer, New Study Finds

Posted by

0


Cancer cells in a culture from human connective tissue.

Humans want to believe we control our own destinies. If we exercise for 30 minutes every day, eat healthy, avoid cigarettes, alcohol, and drugs, meditate, and participate in the health trend du jour, it seems logical that we will live longer, be happier, and avoid diseases like cancer. Unfortunately, it seems fate is more chaotic than that. A new study published in Science suggests that most cancers are unavoidable. They’re caused more often by bad luck than anything else.

Mutation, which drives cancer, is actually totally normal. In fact, its the engine of evolution–if not for mutation, our genes wouldn’t make the random changes that once in a while end up giving us a new, important skill–like making enzymes that break down lactose, or resistance to disease. But often, those mutations get out of control. Cells divide and divide until they overpower the useful cells in our body and kill us. That’s what cancer is.

According to Bert Vogelstein and Cristian Tomasetti at the Johns Hopkins Kimmel Cancer Center, many of these cancers are unavoidable. They’re just part of nature.

“We all agree that 40 percent of cancers are preventable,” Vogelstein said at a press conference. “The question is, what about the other cancers that aren’t known to be preventable?”

Vogelstein explained that each time a cell’s DNA is copied, mistakes are made. Most of these mistakes are harmless, and as noted above, some of them can even be beneficial. “But occasionally they occur in a cancer driver gene. That’s bad luck,” Vogelstein says. Several of these bad-luck mistakes can add up to a cancerous cell.

Their study sets out to determine how often these mistakes are preventable–whether by not smoking or maintaining a healthy weight–how often they are genetic, and how often they occur by chance. The answer may surprise people who have spent decades believing they can control the development of cancer in their bodies. According to the paper, 66% of cancerous mutations are random, 29% are preventable, and only 5% are genetic.

The numbers vary depending on the type of cancer. Lung cancer is indeed usually caused by cigarette smoke, while childhood cancer is often random. The authors hope that these statistics will help some parents feel less responsible for their children’s disease.

An earlier paper by the authors on the same topic stirred up controversy in the scientific community. Some feel that publicizing this viewpoint will make people less likely to follow advice about cancer prevention. This new study is likely to be even more controversial.

Of course, cancer science is incredibly complicated. Mutations are not the only thing that matter in driving cancer. Factors like hormones can also play a role in determining who the disease hits hardest. “We’re not saying the only thing that determines the seriousness of the cancer, or its aggressiveness, or its likelihood to cause the patient’s death, are these mutations,” Vogelstein told NPR. “We’re simply saying that they are necessary to get the cancer.”

Source: Science via NPR

A rare case of Diamond Blackfan anemia: identifying the causative mutation using NGS

Posted by

0


Diamond Blackfan anemia is a rare, inherited bone marrow failure syndrome manifesting as marked red cell aplasia and variable congenital anomalies. We report here a case of Diamond Blackfan anemia, which underscores the role of an integrated diagnostic workflow including hematopathologic evaluation and next-generation sequencing for establishing the diagnosis and potential management of rare, inherited bone marrow failure syndromes.

Case presentation and history. A 42-day-old female infant who was born at 37 weeks gestation presented at an outside medical center for evaluation of anemia. Prenatal history was notable for paternal HIV (mother and infant both tested negative), maternal urinary tract infection, and preterm labor. There was no family history of anemia; the patient had two healthy maternal half siblings and three healthy paternal half siblings.

In the newborn period, the infant was feeding well without respiratory distress. On day two of life, marked pallor and a 2/6 systolic ejection murmur was noted. Subsequent lab evaluation revealed low hemoglobin (8 g/dL) and a reticulocyte index of 3.4 percent. All other hematologic parameters and bilirubin levels were normal, prompting a hematology consultation. A peripheral smear showed the presence of all white blood cell lineages with normal morphology; platelets were increased and displayed variable size (small to large). Red blood cells were decreased and schistocytes, elliptocytes, spherocytes, and Heinz bodies were not present. Hemoglobin on day three remained stable with an appropriate reticulocyte count and no evidence of jaundice.

As the infant had no signs of hemolysis, and the clinical picture was consistent with a compensated anemia, the presence of infectious etiologies or structural abnormalities was evaluated. She had negative studies for HIV, parvovirus, toxoplasmosis, and cytomegalovirus infection. She had a normal electrocardiogram and echocardiogram except that mild mitral and tricuspid valve regurgitation were noted. Hemoglobin analysis by high-performance liquid chromatography showed no abnormalities (HbF, 45 percent; HbA, 53.6 percent; and HbA2, 1.3 percent). This raised the suspicion for a congenital anemia. On day 21 of life, a repeat CBC showed an Hb of 4.7 g/dL, prompting admission for repeat evaluation and possible packed red blood cell (PRBC) transfusion. The infant continued to feed well and showed no signs of cardiovascular compromise. She was transfused PRBCs, and the post-transfusion hemoglobin was approximately 7 g/dL. Despite appearing well clinically, her hemoglobin and reticulocyte counts continued to decline. All other cell lineages remained normal and the platelet count ranged from normal to high. On day 42 of life, she had a hemoglobin of 5.5 g/dL with reticulocyte index of 1.8 percent. At this time, she was referred to our institution for further hematology diagnostic workup and continuation of care.

Results. Physical examination revealed that our patient was non-dysmorphic and normal appearing with no evident anomalies. The feeding and sleeping patterns were normal, and the infant remained asymptomatic despite her normocytic anemia. Since the patient had no compensatory reticulocytosis, a congenital anemia associated with bone marrow failure, such as Diamond Blackfan anemia, was suspected.

Differential count of peripheral blood on day 50 of life showed the following abnormal parameters: RBC, 1.21 × 1012/L (normal range 3.00–5.40 × 1012/L); PLT, 936 × 109/L (range 165–415 × 109/L); Hb, 4.1 g/dL (range 10.0–18.0 g/dL); Hct, 12.3 percent (range 31.0–55.0 percent); MCH, 33.9 pg (range 26.7–31.9 pg); RDW, 21.6 percent (range ≤14.4 percent); and reticulocyte index, 0.5 percent. Morphologic review of the bone marrow aspirate exhibited erythroid hypoplasia, megakaryocytic hyperplasia, and eosinophilia (Fig. 1A and B); platelets were markedly increased. The myeloid to erythroid ratio was >>10:1. Cells of the erythroid series were rare, exhibiting an apparent left shift and megaloblastoid features, findings that are consistent with severe erythroid hypoplasia. Lymphocytes were present in appropriate quantities for age, including a significant population of hematogones. The pattern of iron incorporation in the smears was difficult to assess due to the paucity of erythroid precursors, but ringed sideroblasts were not observed. Erythrocyte adenosine deaminase (ADA) levels were elevated (1143 mU/g Hb, reference units: 400–900).

Flow cytometric analysis of the bone marrow aspirate highlighted a predominant population of T cells without significant downregulation or loss of the pan T-cell antigens and a small population of polytypic B cells, many expressing CD5, in the CD45 bright, low side scatter gate. On analysis of the CD45-dim, low-intermediate side scatter (blast) gate, a predominant population of hematogones was detected. No elevation in CD34+, CD117+ myeloblasts was noted. There was no evidence of non-Hodgkin lymphoma or acute leukemia.

ampquestionsCytogenetic analysis of the bone marrow aspirate to rule out primary lymphohematopoietic neoplasm was carried out. A normal 46,XX female karyotype was found in all of the 20 cells examined. FISH analysis using a myelodysplastic syndrome panel of chromosome probes (5q, 7q, 8, 20q) showed no evidence of clonal abnormalities.

The patient’s skeletal survey and renal sonogram were unremarkable; abdominal ultrasound ruled out hepatosplenomegaly. Based on the presence of anemia without reticulocytosis, erythroid hypoplasia on bone marrow examination (all other cell lineages being normal), and elevated erythrocyte ADA level, a clinical diagnosis of Diamond Blackfan anemia was suggested.

Whole exome sequencing of the peripheral blood sample identified a pathogenic, heterozygous, initiation codon variant predicted to result in an untranslated protein in RPS26 (c.1A>G, p.Met1?, previously p.Met1Val; OMIM:603701; Fig. 2), a ribosomal protein gene known to cause autosomal dominant Diamond Blackfan anemia 10 (OMIM:613309). The mutation seen in the patient has been previously reported.<sup>1</sup> Nucleotide position 1A-G transition in exon 1 of the RPS26 gene causes a met1-to-val (M1V) substitution that eliminates the start codon and is predicted to result in loss of translation of the ribosomal protein.

Discussion. Diamond Blackfan anemia, or DBA, is a rare, congenital, hypoplastic anemia with an estimated incidence ranging from 1:100,000 to 1:200,000 live births.2 It usually presents in the first year of life. Unlike other aplastic anemias, such as Fanconi anemia, the defect is isolated to the red blood cell lineage. Clinically, the anemia manifests as a macrocytic anemia with elevated mean corpuscular volumes, erythrocyte ADA, HbF, and a decreased reticulocyte count.2 The bone marrow shows a near absence of erythroid precursors and unremarkable megakaryocytic and neutrophilic lineages. In about 30 to 50 percent of DBA cases, growth retardation and congenital malformations affecting craniofacial structures, upper limb, heart, and urinary systems can be seen. There is also an increased risk of malignancy. The disorder is thought to result from increased sensitivity of erythroid progenitors to apoptosis, leading to erythropoietic failure.2 Currently, DBA is managed with transfusions, corticosteroid therapy, or stem cell transplantation.

Mutations in 15 ribosomal genes are known to cause DBA. In most cases, it is inherited in an autosomal dominant manner except two ribosomal genes localized on the X chromosome, mutations in which are inherited in an X-linked recessive manner. Point mutations and large deletions in the ribosomal genes have been described as disease-causing mutations. Both incomplete penetrance and variable expressivity have been reported for DBA.2 Congenital anomalies and growth retardation, which may be seen in DBA, were not observed in our patient.

Measurements at age 21 months showed her to be in the 91st percentile for height and 96th percentile for weight. Individuals with the RPS26 gene p.Met1? mutation have been reported to show variable response to steroid therapy.1 Our patient was initially managed with transfusion therapy, and at about age one she was put on a steroid trial that failed and chronic transfusions were therefore resumed. At the time of this writing, she is 22 months old and maintained on PRBC transfusions. Her care has been complicated by chronic transfusion induced iron overload and hospital admissions due to possible infections. She is a candidate for bone marrow transplantation.

Methods. As part of the diagnostic workup, morphologic evaluation of the peripheral blood smear and bone marrow aspirate, flow cytometry, and cytogenetic analysis were performed. Because targeted testing for the 13 known genes associated with DBA identifies mutations in 55 percent of cases of DBA, and due to insurance coverage and cost issues related to send-out versus in-house testing, whole exome sequencing was performed on DNA isolated from the peripheral blood sample of the patient. WES testing was offered to the parents but they declined.

  1. Doherty L, Sheen MR, Vlachos A, et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010;86(2):222–228. Erratum in: Am J Hum Genet. 2010;86(4):655.
  2. Vlachos A, Ball S, Dahl N, et al; Participants of Sixth Annual Daniella Maria Arturi International Consensus Conference. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol. 2008;142(6):859–876.

Yale scientists use gene editing to correct mutation in cystic fibrosis

Posted by

0


Left to right, cystic fibrosis cells treated with gene-correcting PNA/DNA show increasing levels of uptake, or use to correct the mutation. (Images by Rachel Fields)

Yale researchers successfully corrected the most common mutation in the gene that causes cystic fibrosis, a lethal genetic disorder.

The study was published April 27 in Nature Communications.

Cystic fibrosis is an inherited, life-threatening disorder that damages the lungs and digestive system. It is most commonly caused by a mutation in the cystic fibrosis gene known as F508del. The disorder has no cure, and treatment typically consists of symptom management. Previous attempts to treat the disease through gene therapy have been unsuccessful.

To correct the mutation, a multidisciplinary team of Yale researchers developed a novel approach. Led byDr. Peter Glazer, chair of therapeutic radiology, Mark Saltzman, chair of biomedical engineering, and Dr. Marie Egan, professor of pediatrics and of cellular and molecular physiology, the collaborative team used synthetic molecules similar to DNA — called peptide nucleic acids, or PNAs — as well as donor DNA, to edit the genetic defect.

“What the PNA does is clamp to the DNA close to the mutation, triggering DNA repair and recombination pathways in cells,” Egan explained.

The researchers also developed a method of delivering the PNA/DNA via microscopic nanoparticles. These tiny particles, which are billionths of a meter in diameter, are specifically designed to penetrate targeted cells.

In both human airway cells and mouse nasal cells, the researchers observed corrections in the targeted genes. “The percentage of cells in humans and in mice that we were able to edit was higher than has been previously reported in gene editing technology,” said Egan. They also observed that the therapy had minimal off target, or unintended, effects on treated cells.

While the study findings are significant, much more research is needed to refine the genetic engineering strategy, said Egan. “This is step one in a long process. The technology could be used as a way to fix the basic genetic defect in cystic fibrosis.”

DNA clamp to grab cancer before it develops.

Posted by

1


As part of an international research project, a team of researchers has developed a DNA clamp that can detect mutations at the DNA level with greater efficiency than methods currently in use. Their work could facilitate rapid screening of those diseases that have a genetic basis, such as cancer, and provide new tools for more advanced nanotechnology. The results of this research is published this month in the journal ACS Nano.

Toward a new generation of screening tests

An increasing number of genetic mutations have been identified as risk factors for the development of cancer and many other diseases. Several research groups have attempted to develop rapid and inexpensive screening methods for detecting these mutations. “The results of our study have considerable implications in the area of diagnostics and therapeutics,” says Professor Francesco Ricci, “because the DNA clamp can be adapted to provide a fluorescent signal in the presence of DNA sequences having mutations with high risk for certain types cancer. The advantage of our fluorescence clamp, compared to other detection methods, is that it allows distinguishing between mutant and non-mutant DNA with much greater efficiency. This information is critical because it tells patients which cancer(s) they are at risk for or have.”

“Nature is a constant source of inspiration in the development of technologies,” says Professor Alexis Vallée-Bélisle. “For example, in addition to revolutionizing our understanding of how life works, the discovery of the DNA double helix by Watson, Crick and Franklin in 1953 also inspired the development of many diagnostic tests that use the strong affinity between two complementary DNA strands to detect mutations.”

“However, it is also known that DNA can adopt many other architectures, including triple helices, which are obtained in DNA sequences rich in purine (A, G) and pyrimidine (T, C) bases,” says the researcher Andrea Idili, first author of the study. “Inspired by these natural triple helices, we developed a DNA-based clamp to form a triple helix whose specificity is ten times greater than a double helix allows.”

“Beyond the obvious applications in the diagnosis of genetic diseases, I believe this work will pave the way for new applications related in the area of DNA-based nanostructures and nanomachines,” notes Professor Kevin Plaxco, University of California, Santa Barbara. “Such nanomachines could ultimately have a major impact on many aspects of healthcare in the future.”

“The next step is to test the clamp on human samples, and if it is successful, it will begin the process of commercialization,” concludes Professor Vallée-Bélisle.

Image
Artist’s rendering of the discovery: the research team took advantage of the ability of certain DNA sequences to form a triple helix, in order to develop a DNA clamp. This nanometer-scale clamp recognizes and binds DNA sequences more strongly and more specifically, allowing the development of more effective diagnostic. Professor Alexis Vallée-Bélisle, Department of Chemistry, Université de Montréal worked with the researcher Andrea Idili and Professor Francesco Ricci of the University of Rome Tor Vergata, and Professor Kevin W. Plaxco, University of California Santa Barbara, to develop this diagnostic nanomachine

Cancer diversity ‘threatens drugs’

Posted by

0


A single tumour can be made up of many separate cancers needing different treatments, say researchers.

A team at the Institute of Cancer Research, London, have developed a new technique for measuring the diversity within a cancer.

Cancer cells

They showed “extraordinary” differences between cancerous cells and say new targeted drugs may fail as they may be unable to kill all the mutated tissue.

Experts said the findings would have “profound implications” for treatments.

A tumour starts as a single cell, which acquires mutations and eventually divides uncontrollably. But that is not the end of the process.

Cancerous cells continue to mutate and become more aggressive, move round the body and resist drugs.

“Start Quote

Every patient has a completely new tree and doesn’t have one cancer, they have multiple cancers”

Prof Mel Greaves Institute of Cancer Research

This process is chaotic and results in a “diverse” tumour containing cancerous cells that have mutated in different ways.

“This has huge implications for medicine,” researcher Prof Mel Greaves told the BBC.

His team at the Institute of Cancer Research investigated cancer diversity in five children with leukaemia. They compared mutations in individual cancerous cells with a known database of mutations.

Their results, published in the journal Genome Research, showed patients had between two and 10 genetically distinct leukaemias.

Prof Greaves said: “Every patient has a completely new tree and doesn’t have one cancer, they have multiple cancers.

“This is really a technical advance to get at this extraordinary complex diversity, it helps explain why we have such difficulty with advanced diseases.”

Tree of cancer

Scientists compare cancer diversity to a tree. The initial mutations – the trunk – will be common to all cancer cells. But then the tumour branches out.

Tree
Drugs need to target the trunk of a tumour say researchers

It means a treatment that targets one “branch” or sub-clone of the cancer might slow the disease, but they will never stop it.

Prof Charles Swanton, who researches diversity at the University College London Cancer Institute, told the BBC: “We call it pruning the branches not cutting down the tree, targeted therapies will remove some of the sub-clones, but chopping down the tree is hard to do.”

“Start Quote

The bottom line is we need to understand cancer diversity to limit further adaptations, reduce the pace of evolution and prolong the activity of drugs”

Prof Charles Swanton UCL

The study investigated leukaemia as it is less diverse than other types of cancer. Other tumours such as melanoma could feasibly be made of hundreds of branches.

Prof Greaves says one implication of the research is that therapies need to be developed which target the trunk of the tumour and that current targeted therapies being researched may not tackle advanced cancers.

Another idea he suggests is focusing on the cancer’s surroundings as well.

“If it is diversifying like species in a habitat, why not target the habitat – the blood vessels supplying oxygen or inflammation. There’s a lot of interest in that,” he said.

The research also emphasises the importance of catching cancers early before they have become too diverse to treat.

Prof Charles Swanton argues: “The bottom line is we need to understand cancer diversity to limit further adaptations, reduce the pace of evolution and prolong the activity of drugs.”

Prof Chris Bunce, the research director at Leukaemia and Lymphoma Research, commented: “We are beginning to understand how unique and complex each patient’s cancer is and the profound implications that this can have on the success of treatment.

“This study significantly advances our understanding of how cancers start and evolve.”

Cloning Mice.

Posted by

0


For the First Time, a Donor Mouse Has Been Cloned Using a Drop of Peripheral Blood from Its Tail.

From obesity to substance abuse, from anxiety to cancer, genetically modified mice are used extensively in research as models of human disease. Researchers often spend years developing a strain of mouse with the exact genetic mutations necessary to model a particular human disorder. But what if that mouse, due to the mutations themselves or a simple twist of fate, was infertile?

Currently, two methods exist for perpetuating a valuable strain of mouse. If at least one of the remaining mice is male and possesses healthy germ cells, the best option is intracytoplasmic sperm injection (ICSI), an in vitro fertilization procedure in which a single sperm is injected directly into an egg.

However, if the remaining mice cannot produce healthy germ cells, or if they are female, researchers must turn to cloning. Somatic-cell nuclear transfer (SCNT) produces cloned animals by replacing an oocyte’s nucleus with that of an adult somatic cell. An early version of this process was used to produce Dolly the sheep in 1996.

Since then, SCNT techniques have continued to advance. Earlier this year, researchers at the RIKEN Center for Developmental Biology in Kobe, Japan, even devised a technique to avoid the diminishing returns of recloning the same cell; success rates increased from the standard three percent in first-generation clones to ten percent in first-generation and 14 percent in higher-generation clones.

The type of somatic cell used for this process is critical and depends largely on its efficiency in producing live clones, as well as its ease of access and readiness for experimental use. While cumulus cells, which surround oocytes in the ovarian follicle and after ovulation, are currently the preferred cell type, Drs. Satoshi Kamimura, Atsuo Ogura, and colleagues at the RIKEN BioResource Center in Tsukuba, Japan, questioned whether white blood cells (a.k.a., leukocytes) collected from an easily accessed site, such as a tail, would be effective donor cells. Such cells would allow for repeated sampling with minimal risk to the donor mouse.

There are five different types of white blood cells and, as expected, the researchers found that lymphocytes were the type that performed the most poorly: only 1.7 percent of embryos developed into offspring. The physically largest white blood cells, and thus the easiest to filter from the blood sample, were granulocytes and monocytes. The nuclei of these cells performed better, with 2.1 percent of the embryos surviving to term, compared to 2.7 percent for the preferred cell type, cumulus cells.

The granulocytes’ performance was poorer than expected due to a much higher rate of fragmentation in early embryos (22.6 percent): twofold higher than that of lymphocyte cloning and fivefold higher than cumulus cell cloning. The researchers were unable to determine what could be causing the fragmentation and intend to perform further studies to improve the performance of granulocyte donor cells.

Although the blood cells tested did not surpass the success rate of cumulus cells in this study, the researchers have demonstrated, for the first time, that mice can be cloned using the nuclei of peripheral blood cells. These cells may be used for cloning immediately after collection with minimal risk to the donor, helping to generate genetic copies of mouse strains that cannot be preserved by other assisted reproduction techniques.

Why a Lucky Few Can Eat to Their Heart’s Content.

Posted by

1


We all know people who seem to have been born with good genes—they may smoke, never exercise, or consume large amounts of bacon, yet they remain seemingly healthy. Now, researchers have found that individuals who carry a rare genetic mutation that controls the blood levels of certain fats, or lipids, are protected from heart disease. The result, reported here yesterday at the annual meeting of the American Society of Human Genetics, suggests that a drug mimicking this effect could prevent heart disease, a major killer.

Triglycerides are lipids that the body makes from unused calories in food and later burns as fuel. Doctors often monitor patients’ blood levels of these compounds because higher levels have been linked to a greater risk of heart disease.

One player in processing triglycerides is a protein called ApoC-III that is encoded by the gene APOC3. Five years ago, researchers discovered a mutation in APOC3 in 5% of the Amish population in Lancaster County, Pennsylvania. Those with this variant had unusually low levels of triglycerides after consuming a fat-laden milkshake. They also had only half as much ApoC-III protein in their blood, and they were less likely to develop calcification of coronary arteries, which can lead to coronary heart disease.

The Amish group was too small to allow researchers to directly link the genetic mutation to less heart disease, however. And it wasn’t clear whether the gene would show up in non-Amish people.

Now, researchers have found APOC3 mutations in the general U.S. population. They sequenced the protein-coding DNA, or exomes, of 3734 white and African-American volunteers, then combed through the data for genetic variants linked to triglyceride levels. A few people turned out to have either the Amish APOC3 mutation or one of three other variants in APOC3 that also disable this copy of the gene. When the team checked the DNA of a larger group of nearly 111,000 people, they found that about one in 200 carried one of the four APOC3 variants, reported Jacy Crosby of the University of Texas Health Science Center, Houston, who represented a large consortium called the National Heart, Lung, and Blood Institute Exome Sequencing Project.

The 500 or so people with one of these APOC3 variants not only had less ApoC-III in their blood and 38% lower triglyceride levels than the average person; they also had a 40% lower risk of coronary heart disease, whose effects include heart attacks. This result firms up the link between APOC3 and heart disease and also supports a possible prevention strategy, Crosby said: Reducing levels of the ApoC-III protein could potentially lower lipid levels and protect against heart disease. One such drug is already in clinical testing, she noted.

The new study “is exciting, but one has to be cautious” about whether such a drug will work, says geneticist Stephen Rich of the University of Virginia in Charlottesville. That’s because inhibiting ApoC-III late in life may not mimic being born with an APOC3 mutation, which protects for a lifetime, he says.

Metabolism ‘obesity excuse’ true

Posted by

0


Obese child

The mocked “obesity excuse” of being born with a slow metabolism is actually true for some people, say researchers.

A team at the University of Cambridge has found the first proof that mutated DNA does indeed slow metabolism.

The researchers say fewer than one in 100 people are affected and are often severely obese by early childhood.

The findings, published in the journal Cell, may lead to new obesity treatments even for people without the mutation.

Scientists at the Institute of Metabolic Science, in Cambridge, knew that mice born without a section of DNA, a gene called KSR2, gained weight more easily.

It slows the ability to burn calories and that’s important as it’s a new explanation for obesity”

Prof Sadaf Farooqi University of Cambridge

But they did not know what affect it may be having in people, so they analysed the DNA of 2,101 severely obese patients.

Some had mutated versions of KSR2.

It had a twin effect of increasing their appetite while their slowing metabolism.

“You would be hungry and wanting to eat a lot, you would not want to move because of a slower metabolism and would probably also develop type 2 diabetes at a young age,” lead researcher Prof Sadaf Farooqi told the BBC.

She added: “It slows the ability to burn calories and that’s important as it’s a new explanation for obesity.”

Munching on chips
The mutation delivers a double-whammy by increasing the drive to eat and reducing calorie burn

KSR2 is mostly active in the brain and it affects the way individual cells interpret signals, such as the hormone insulin, from the blood. This in turn affects the body’s ability to burn calories.

Prof Farooqi said the metabolism argument had been derided by doctors, as well as wider society, due to a lack of evidence that metabolism was slowed in obese patients. In many cases obese patients have an elevated metabolism to cope with fuelling a much larger body.

She said less than 1% of people had mutated versions of the gene and some would be a normal weight, but about 2% of children who were obese by the age of five would have the mutated gene.

However, if drugs could be developed to target problems with KSR2, then it might be beneficial to anyone who is too fat.

“Other genetic disorders, such as in blood pressure, have shown that even where there’s a normal gene, targeting the pathway can still help,” Prof Farooqi said.

The amount and types of food eaten, as well as levels of exercise, directly affect weight, but some people at more risk of becoming obese that others.

Obesity can run in families. The other obesity genes that have been discovered tend to affect appetite.

People have two copies of the FTO gene – one from each parent – and each copy comes in a high- and a low-risk form. Those with two-high risk copies of the FTO gene are thought to be 70% more likely to become obese than those with low-risk genes.

It makes fatty foods more tempting and alters levels of the hunger hormone ghrelin.

Dr Katarina Kos, from the University of Exeter Medical School, said: “It is an exciting and interesting breakthrough, this is a new pathway predisposing people to obesity.

“But it does exist in obese and lean people so you still need the obesogenic environment.”

‘INDIVIDUALIZED’ THERAPY FOR THE BRAIN TARGETS SPECIFIC GENE MUTATIONS CAUSING DEMENTIA AND ALS.

Posted by

0


Stem cell-based approach manipulates brain cells in test tube studies

Johns Hopkins scientists have developed new drugs that — at least in a laboratory dish — appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from stem cells known as induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” saysJeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online in the journal Neuron. “But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.”

Scientists in 2011 discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene. The mutation also occurs very often in people with frontotemporal dementia, the second-most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2,  needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years. In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.

Rita Sattler, Ph.D., an assistant professor of neurology at Johns Hopkins and the co-investigator of the study, says without iPS technology, the team would have had a difficult time studying the C9ORF72 mutation. “Typically, researchers engineer rodents with mutations that mimic the human glitches they are trying to research and then study them,” she says. “But the nature of the multiple repeats made that nearly impossible.” The iPS cells did the job just as well or even better than an animal model, Sattler says, in part because the experiments could be done using human cells.

“An iPS cell line can be used effectively and rapidly to understand disease mechanisms and as a tool for therapy development,” Rothstein adds. “Now we need to see if our findings translate into a valuable treatment for humans.”

The researchers also analyzed brain tissue from people with the C9ORF72 mutation who died of ALS. They saw evidence of this bunching up and found that the many genes that were altered as a consequence of this mutation in the iPS cells were also abnormal in the brain tissue, thereby showing that iPS cells can be a faithful tool to study the human disease and discover effective therapies.

In the future, the scientists will look at cerebral spinal fluid from ALS patients with the C9ORF72 mutation, searching for proteins that were found both in the fluid and the iPS cells. These may pave the way to develop markers that can be studied by clinicians to see if the treatment is working once the drug therapy is moved to clinical trials.

ALS, sometimes known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, destroys nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary. There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival, Rothstein notes.

Liquorice could hold the key to beating the most lethal forms of skin cancer, scientists say.

Posted by

0


Research carried out in the US has identified a compound found in liquorice root which slowed the growth of cancer cells during laboratory tests. Now they hope the tumour-busting compound can be developed into a new drug to combat malignant melanoma.

Previous studies have found liquorice contains an anti-cancer chemical called glycyrrhizin. But attempts to turn it into a medicine have been hampered by the fact that long-term consumption of glycyrrhizin can cause high blood pressure and even swelling on the brain. But experts at the University of Minnesota in the US have now found another ingredient – called Isoangustone A – which has the same benefits but without the dangerous side-effects. Malignant melanoma kills around 1,700 people a year in the UK and is the third most common cancer in people aged 15 to 39. Over-exposure to the sun’s rays is the biggest cause and since the mid-1990s there has been a 24 per cent increase in cases.

Some evidence suggests even a few early bouts of sunburn in childhood can be enough to trigger the cellular changes in moles that lead to skin cancer later in life. Cells within moles become cancerous and start to divide uncontrollably, eventually spreading through the body.

In the latest research, scientists extracted Isoangustone A from liquorice root and applied it to skin cancer cells in the laboratory. The compound slowed down the rate at which melanoma cells reproduce, partly by blocking the release of certain proteins needed for them to flourish. When the scientists gave the extract to mice with skin cancer, it had the same effect – suppressing growth of the tumour.

Liquorice is already a popular remedy for cold sores. A balm made from the root can reduce the severity of outbreaks. But too much liquorice can be harmful. But don’t eat too much! A Scottish study found children born to women who ate over 100 grammes a week during pregnancy performed worse in intelligence tests at school and the harmful compound glycyrrhizin was blamed. So don’t go out buying the candy and eating tons of it to try to prevent or cure cancer. It’s looking like you need a pure extract.

Published in the journal Cancer Prevention Research, scientists said: ‘Liquorice root is known to possess anti-inflammatory and anti-cancer effects.”

Other ailments liquorice is used to treat include:

Hepatitis The anti-inflammatory properties of liquorice is said to help calm hepatitis-associated liver inflammation. Liquorice is also said to fight the hepatitis C virus and supplies valuable antioxidant compounds that help maintain the overall health of the liver. Results from large-scale high quality studies are not available.

Dyspepsia (Heartburn) According to the US National Library of Medicine, liquorice may be an effective treatment for heartburn when used in combination with other herbs. Sold as Iberogast or STW5, research suggests that the formulation significantly reduces severity of acid reflux and associated pain, cramping, nausea, and vomiting.

Eczema In one study, liquorice gel, applied to the skin, helped relieve symptoms of itching, swelling, and redness, reports the University of Maryland Medical Centre. A gel with 2 per cent liquorice worked better than a gel with 1 per cent liquorice.

Cancer Laboratory studies have identified several substances in liquorice that may help prevent DNA mutations, inhibit tumour formation, or even kill cancer cells, says The American Cancer Society. While animal studies suggest some chemicals from liquorice might be useful in preventing or treating some forms of cancer, human clinical trials are yet to be carried out.

Liquorice has also been associated with weight loss. According to the University of Maryland, consumption of liquorice was linked to body fat mass in one study. Another study found that glycyrrhetinic acid (a component of liquorice) reduced the thickness of fat on the thigh in human subjects. A study carried out by Japanese scientists and published in Obesity Research and Clinical Practice linked the consumption of liquorice flavonoid oil to significant decreases in total body fat mass, weight, BMI and LDL (“bad”) cholesterol.

Medicinal forms of liquorice include wafers, tinctures, tablets, lozenges, teas, loose dried herbs, creams and capsules. To treat a cough, wholehealthmd.com suggests 1 teaspoon of liquid liquorice extract in 1 cup of hot water 3 times a day. For PMS, 200 mg of standardised extract three times a day for the 10 days preceding your period is recommended.

Last year in Germany, where around 500 tonnes of liquorice are imported each year, liquorice was named “the medicinal plant of 2012”. Professor Johannes Mayer, an expert on the history of medicinal botany at the University of Würzburg, noted the myriad indications of liquorice, used medicinally since ancient times. “Liquorice is special because it can quickly soothe sore throats and coughs and was used centuries ago to treat coughing, hoarseness and asthma by Ancient Greek and Egyptian physicians,” he said.