Probiotics: disease preventing bacteria!!

Probiotic Effects on Cold and Influenza-Like Symptom Incidence and Duration in Children
Gregory J. Leyer, Shuguang Li, Mohamed E. Mubasher, Cheryl Reifer, and Arthur C. Ouwehand
Pediatrics 2009; 124: e172-e179.

http://pediatrics.aappublications.org/cgi/content/abstract/124/2/e172

In a double-blind, placebo controlled study done on 326 Chinese children aged 3 to 5 years, researches have found that twice daily administration of probiotics resulted in a marked reduction in incidence of cold and influenza-like symptoms.

The children who participated in this study were divided into three groups. One group received milk that contained Lactobacillus acidophilus (Lactobacillus group), the other received milk containing a combination of Lactobacillus acidophilus and Bifidobacterium animalis (Lactobacillus/Bifidobacterium group) and a third group received plain milk (placebo group). Each group had approximately 100 children. Milk was administered twice daily by school authorities during weekdays and at home during weekends for a period of 6 months. The children were closely monitored during this period and some of the important observations were as follows:

1. Compared to the placebo group, the Lactobacillus group had 53 percent fewer episodes of fevers, 41 percent fewer episodes of cough, and 28 percent fewer episodes of rhinorrhoea (runny nose).

2. The Lactobacillus/Bifidobacterium group had even larger reductions in symptom rates: 72 percent fewer fevers, 62 percent fewer coughs, and 59 percent fewer runny noses.

3. Duration of illnesses when they did occur in children receiving probiotics was significantly lower than the control group. Compared to placebo, the length of illness was decreased by 32 percent with Lactobacillus and by 48 percent with Lactobacillus/Bifidobacterium.

4. Antibiotic use was 68 percent lower in the Lactobacillus group and 84 percent lower in the Lactobacillus/Bifidobacterium group, compared to the placebo group.

5. Children who received the probiotics were absent from day care 28 to 32 percent less often than children in the placebo group.

Earlier studies had shown that probiotics were able to boost the immune response to certain types of bacterial and viral illnesses. However, this is the first time that probiotic use has been convincingly shown to prevent illnesses.

Probiotics are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host. They are usually given as dietary supplements. Lactobacillus and Bifidobacterium are the most commonly used probiotics.

A large amount of research is being done to explore the potential of probiotics in the prevention and treatment of a wide variety of clinical conditions. Some indications for probiotics have sound scientific basis, while others are still in the realms of speculation. Some of the approved indications for probiotics are:

1. Managing lactose intolerance

2. Prevention of colon cancer

3. Lowering cholesterol

4. Lowering blood pressure

5. Improving immune function and preventing infections

6. Helicobacter pylori induced peptic ulcers

7. Antibiotic-associated diarrhea

8. Reducing inflammation

9. Improving mineral absorption

10. Prevents harmful bacterial growth under stress

11. Irritable bowel syndrome and colitis

It was the Russian scientist Eli Metchnikoff who initially introduced the idea of supplementing the diet with friendly bacteria. Metchnikoff, while working at the Pasteur Institute in Paris, noticed that rural people in Bulgaria and other places in Europe, whose diet was rich in “milk fermented with lactic acid bacillus” were exceptionally long lived. He proposed that the lactic acid bacteria replaced harmful proteolytic bacteria (like Clostredia) in the gut. The proteolyic bacteria could produce toxic substances by digesting protein and these toxic substances eventually lead to age related changes and senility. This theory was called the “auto intoxication” theory of Metchnikoff. Metchnikoff himself started supplementing his diet with lactic acid bacilli called the “Bulgerian bacillus” and his health apparently improved. The practice soon caught on and patients were routinely put on a sour milk diet by physicians in Paris.

Five years after Metchnikoff death in 1915, it was demonstrated by Rettger that Metchnikoff’s “Bulgarian bacillus” was not capable of colonizing the human gut. After this discovery, Metchnikoff theory of longevity through consumption of lactic acid bacteria was questioned and soon became unpopular. However, other bacteria with health benefits were being discovered in the meantime. Henry Tissier (also of the Pasteur Institute) discovered the Bifidobacterium and advocated the use of this bacterium in the treatment of childhood diarrhea. A German doctor, Alfred Nissle isolated strains of E. coli that were able to prevent salmonellosis and shigellosis.

Since these discoveries, many more bacteria have been added to the probiotic list. Each bacterium has its own unique mechanisms of producing beneficial effects and mechanisms elucidated in one strain cannot be extrapolated to other probiotics even if they are closely related bacteria.

Recently there have been certain controversies regarding the use of probiotics. In a clinical trial conducted at the University of Western Australia aimed at showing the effectiveness of probiotics in reducing childhood allergies, 178 children were given either a probiotic or a placebo for the first six months of their life. Those given the good bacteria were more, not less, likely to develop a sensitivity to allergens.

In another instance, a double-blind, placebo-controlled therapeutic study on the effects of a probiotic cocktail on pancreatitis at University Medical Center Utrecht (UMC) showed that 24 out of 296 patients died between 2004 and 2007, with more deaths among those receiving the probiotic cocktail.

However, there have also been well designed studies that have shown beneficial effects of probiotics. The study that is described in this post is one such example. Clearly this is not the last we will hear of probiotics and their therapeutic benefits.

Acknowledgements:
Wikipedia article on Probiotics.

Eat less, live long?

Caloric restriction delays disease onset and mortality in rhesus monkeys.

Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R.

Science. 2009 Jul 10;325(5937):201-4.

Caloric restriction has been proposed to increase the lifespan of a number of animals. However, this is for the first time that the benefits of calorie restriction have been shown in a primate. Preliminary results of study started in 1989 (and extended in 1994)on 76 Rhesus monkeys have shown that a 30% calorie restricted diet had many beneficial effects, including an increased disease-free lifespan and delayed onset of senility-associated diseases like diabetes mellitus, cardiovascular diseases, cancer and brain atrophy.

The authors claim that calorie-restricted monkeys "look" younger than their counterparts who were given a free rein at feeding time. In addition they show that there was significantly less mortality due to senility-associated diseases in the calorie restricted animals. These animals were also less prone to developing diabetes and colon adenocarcinoma which is known to be common in aged Rhesus monkeys. Functional MRI images of the brain showed that areas of the brain related to movement and memory were protected from age-related atrophic changes.

This study is interesting because this is probably as near as we can get to doing a large-scale experiment on caloric restriction in a species that is a close relative of man. Although a few descriptive studies in humans do suggest the beneficial effects of a calorie restricted diet in the elderly, ethical considerations virtually preclude a randomized controlled trial of the nature described in this study. The authors say that the study is on-going and the results at the conclusion of the study will reveal more interesting facts.

There have been a number of theories that have tried to explain the apparent ability of calorie restriction to extend life span. A few of the current theories are given below.

1. The "hormesis" theory
The term "hormesis" refers to a wide variety of phenomena where intentional application of a mild stress on an organism elicits a response that enables it to withstand a much stronger stress to which it may be subjected to in future. This kind of response is analogous to the effects of vaccination with a live, attenuated pathogen on the immune system.

I has been shown that when Caenorhabditis elegans is subjected to restriction of glucose availability for metabolism, it induces a state of mild oxidative stress. This elicits a robust antioxidant response in the organism which ultimately resulted in an increased resistance to further oxidative stress. This was probably the first experimental evidence for hormesis being the reason for extended life span following CR.

Read article

2. Sir2/SIRT1 and resveratrol
Sir2 or "silent information regulator 2" is a longevity gene, discovered in baker's yeast cells, that extends lifespan by suppressing DNA instability. In mammals Sir2 is known as SIRT1. Recent discoveries have suggested that the gene Sir2 might underlie the effect of CR. David Sinclair at Harvard Medical School, Boston, showed that in mammals the SIRT1 gene is turned on by a CR diet, and this protects cells from dying under stress.

Read article

Sirtris Pharmaceuticals, Inc., a GlaxoSmithKline-owed biotechnology company based in Cambridge, MA co-founded by Sinclair, is developing resvertrol and other SIRT1 activators for human use. Because life-span extension is not an FDA-approvable indication, the company is developing SIRT1 activators for the treatment of diseases associated with aging including type 2 diabetes and cancer.

3. Free radicals and glycation

A calorie restricted diet provides lesser amounts of energy, thus decreasing the flux through the mitochondrial electron transport chain (ETC). It is known that the ETC is "leaky" and 1-2% of oxygen normally gets converted to superoxide, a free radical that can cause oxidative tissue damage (oxidative stress). Decreased calorie intake can therefore lead to reduced oxidative stress.

Reduced caloric intake will also result in reduced mean glucose levels in blood. It is known that glucose can form adducts with a variety of macromolecules by a non-enzymatic, spontaneous process called "glycation". Glycation of proteins is one of the major mechanisms of pathogenesis of long-term diabetes mellitus. A reduced mean glucose levels would result in decreased glycation and tissue abnormalities associated with protein glycation.

Read article

4. Longevity and subclinical hypothyroidism

A recent study in Ashkenazi Jews has shown that a low thyroid activity as evidenced by moderately elevated TSH levels is associated with extreme longevity. The authors suggest that lowered metabolism associated with low thyroid hormone levels is probably responsible for this effect. They cite the example of the elephant with a very low basal metabolism having a long average lifespan as compared to a mouse with a very high basal metabolism having a very short lifespan.

Read article

5. Neuropeptide Y

One popular hypothesis suggests that the neuroendocrine response to low energy availability mediated by neuropeptide Y released by the arcuate nucleus of the hypothalamus plays a primary role in calorie restriction mediated lifespan extension. A recent review published in Molecular and Cellular Endocrinology explains the scientific basis of this hypothesis.

Read article

References:
Wikipedia article on "Caloric restriction"

Genetically engineered children :)

Find below a link to an article published in Clinical Chemistry by Eleftherios P. Diamandis entitled, “How to Win Wimbledon Championships: Creating Beklof and Vamos”. It’s a funny take on the probability of genetically engineered children in the near future.
http://www.clinchem.org/cgi/content/full/55/6/1253

Rhes and Huntingtin - The odd couple!!

Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity.
Subramaniam S, Sixt KM, Barrow R, Snyder SH.
Science. 2009 Jun 5;324(5932):1327-30.

Huntington’s disease (HD) is an inherited neurodegenerative disorder, characterized by the gradual, irreversible impairment of psychological, motor, and cognitive functions. Symptoms typically appear in middle age, but onset can occur at almost any age. The course of the disease can last 15 to 20 years. The genetic mutation underlying HD has been traced to a gene encoding a protein called Huntingtin (Mr 350,000). The normal function of Huntingtin is not yet known. In individuals who will not develop HD, a region of the gene that encodes the amino terminus of the protein has a sequence of CAG codons (for glutamine) that is repeated 6 to 39 times in succession. In individuals with adult-onset HD, this codon is typically repeated 40 to 55 times. In individuals with childhood-onset HD, this codon is repeated more than 70 times. The length of this simple trinucleotide repeat indicates whether an individual will develop HD, and at approximately what age the first symptoms will occur.

The abnormal Huntingtin protein is produced in almost all cells of the body, but the pathology is limited to the corpus striatum in the brain. In fact, the corpus striatum is almost paper-thin in patients with advanced HD. The possible reason for localization of pathology in what is essentially a global genetic defect is not known. However, the authors of this paper have come up with an explanation to this perplexing phenomenon.

Rhes is a monomeric G protein that is almost exclusively expressed in the corpus striatum. The normal function of Rhes has not been elucidated but it is known to modify proteins by a process called sumolyation. Sumoylation is a post-translational modification. It involves the addition of a small protein called SUMO. SUMO proteins are similar to ubiquitin, and sumoylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation. SUMO modification of proteins has many functions like protein stability, nuclear-cytosolic transport, and transcriptional regulation.

In this paper, the authors have shown that Rhes causes the sumoylation of the mutated Huntingtin protein. In the absence of sumoylation, abnormal Huntingtin tends to aggregate within the cell. Sumoylation seems to inhibit this aggregation. It has long been thought that cellular toxicity was caused by the protein aggregates. However, this paper suggests that the soluble form of abnormal Huntingtin is harmful to the cell. Rhes by sumoylating Huntingtin, seemed to inhibit aggregation, thus increasing the concentration of soluble Huntingtin in the cell. Since, Rhes, as pointed out earlier, is exclusively expressed in the corpus striatum, the pathology in HD is therefore localized to the corpus striatum, though all cells in the body have the abnormal gene.

The obvious next step in research in this field would be to find out the normal function of Rhes. This could be done in vivo by using transgenic Rhes knock-out mice and in vitro by siRNA based techiniques. If Rhes is not shown to have critical functions in the cell, a drug that decreases Rhes expression could be the basis of treatment of HD in the future.

Why are patients with Down’s syndrome protected from cancer?

Discovery of novel anti-tumor proteins in patients with Down’s syndrome.

In a very interesting study published in Nature this month, scientists from Harvard Medical School have zeroed in on a gene that might explain why patients with Down’s syndrome have a very low rate of cancer compared to the general population (Baek et al., 2009).
Down syndrome is one of the most common inherited causes of mental retardation. It occurs with an approximate frequency of 1:700 births. The association between Down's syndrome and decreased cancer incidence had earlier been explored by Harvard's Dr. Judah Folkman who died last year. Dr. Folkman had noticed that cancer is rare among Down's patients, except for leukemia. He studied nearly 18,000 Down's patients and showed that they had 10 percent the expected rate of cancer.
Down’s syndrome is characterized by the presence of an extra copy of chromosome 21 in the genome (trisomy 21). Chromosome 21 has 231 genes in it. Scientists have proposed that a protein coded for by one of the genes on the 21st chromosome called “Down's syndrome candidate region-1” (DSCR1, also known as RCAN1) may explain the low incidence of cancer in Down’s syndrome. This protein inhibits Vascular Endothelial Growth Factor (VEGF). VEGF is one of the many factors that help cancer cells to stimulate formation of new blood vessels (angiogenesis). Inhibition of this factor by DSCR 1 can therefore retard the growth of cancers. People with Down syndrome have three copies of this gene while normal individuals only have two. It was shown that the levels of this protein is higher in patients with Down’s syndrome. In this study, the scientists also developed a mouse model of trisomy 21. The mouse model, like the humans, showed higher levels of DSCR-1 protein, and as expected, was resistant to development of tumors.

It is possible that more genes on the 21st chromosome can have anti-tumor properties that will explain the rarity of cancer in Down’s syndrome. Further research will reveal some of these genes. As of now, researchers say that three new proteins have been identified as potential targets in treatment of cancer. One is DSCR-1 and the others are calcineurin (a protein regulated by DSCR-1) and DYRK1A (a DSCR-1 like protein).

References:
Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S (2009) Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature. 2009 May 20.

http://www.ncbi.nlm.nih.gov/pubmed/19458618?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Hypertension, an infectious disease!!??

Cytomegalovirus Infection Causes an Increase of Arterial Blood Pressure
PLoS Pathog. 2009 May.

Jilin Cheng1, Qingen Ke, Zhuang Jin, Haibin Wang, Olivier Kocher, James P. Morgan, Jielin Zhang1, Clyde S. Crumpacker

Free full text: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000427

The debate on the role played by chronic CMV infection in the pathogenesis of atheroschlerosis and associated cardiovascular diseases is not new. While some studies have supported this association (Grahame-Clarke C et al., 2003, Valantine et al., 1999, Hsich et al., 2001), others have not (Zhou et al., 1996, Adler et al, 1998, Saetta et al., 2000, Stassen et al., 2006).

In this paper, this group of authors from Harvard Medical School has shown, using in vitro and in vivo methods, that CMV infection increases arterial blood pressure and accelerates atheroschlerosis in mice fed with a high cholesterol diet. The authors say, “CMV infection alone causes an increase in blood pressure. CMV infection augments the increased blood pressure induced by a high cholesterol diet. CMV infection alone, however, does not cause atherosclerosis in aortas. CMV infection along with a high cholesterol diet, however, causes the classic atherosclerotic plaque formation in the main artery connected to the heart. Further studies show that CMV infection induces renin and angiotensin II (Ang II) expression in blood and in vessel cells, in a persistent infection manner. An increased expression of renin and Ang II has been known to cause an increase in blood pressure or hypertension in humans. Expression of viral genes and viral persistent infection of blood vessel endothelial cells resulting in an increased expression of inflammatory cytokines, including renin and Ang II, may underpin the molecular mechanism by which CMV infection induces an increase in blood pressure. Therefore, non-lytic CMV infection and the perturbed cellular gene expression, specifically the components of RAS, underlie a molecular mechanism by which CMV infection causes an increase of blood pressure”.

The significance of these findings lies in the fact that CMV infection is very prevalent all over the world. Several studies have shown that the prevalence of chronic CMV infection in the general population to vary between 60 to 99%. Hypertension and cardiovascular diseases are also very common in the general population. If CMV infection is proved to play an important role, either in the initiation of atheroschlerosis or in its evolution, control of CMV infection (using drugs or vaccines) may provide a new strategy to prevent cardiovascular diseases in the population.

References:
Grahame-Clarke C, Chan NN, Andrew D, Ridgway GL, Betteridge DJ, et al. (2003) Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation 108: 678–683

Valantine HA, Gao SZ, Menon SG, Renlund DG, Hunt SA, et al. (1999) Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study. Circulation 100: 61–66.

Hsich E, Zhou YF, Paigen B, Johnson TM, Burnett MS, et al. (2001) Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice. Atheroslcerosis 156: 23–28.

Zhou YF, Leon MB, Waclawiw MA, Popma JJ, Yu ZX, et al. (1996) Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 335: 624–630.

Adler SP, Hur JK, Wang JB, Vetrovec GW (1998) Prior infection with cytomegalovirus is not a major risk factor for angiographically demonstrated coronary artery atherosclerosis. J Infect Dis 177: 209–212.

Saetta A, Fanourakis G, Agapitos E, Davaris PS (2000) Atherosclerosis of the carotid artery: absence of evidence for CMV involvement in atheroma formation. Cardiovasc Pathol 9: 181–183.

Stassen FR, Vega-Cordova X, Vliegen I, Bruggeman CA (2006) Immune activation following cytomegalovirus infection: more important than direct viral effects in cardiovascular disease? J Clin Virol 35: 349–353.

A simple drug, a complex mechanism of action

Lithium levels in drinking water and risk of suicide.
Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N.
Br J Psychiatry. 2009 May;194(5):464-5

A group of Japanese researchers have suggested that lithium in drinking water could decrease the risk of suicide in the general population. The researchers did a systematic study of lithium content of drinking water in 18 municipalities in the prefecture of Oita, Kyushu, Japan. They compared the drinking water lithium levels and the suicide rate in the municipalities during 2002 to 2004. They found that lithium in drinking water was significantly negatively correlated to suicide in the general population.

Lithium has potent mood stabilizing properties and is widely used in psychiatric practice in the treatment of serious mood disorders. It is known to reduce the risk of suicide in such patients. However, its presence in drinking water and its effect on suicide risk in the general population had not been established yet. An earlier study done in 27 counties in Texas had also suggested that lithium in drinking water significantly reduced the incidence of suicides (Shrauzer et al., 1990). Other studies, however, have not supported this claim (Oliver et al., 1976).

The authors of this paper have called for further research to confirm their findings in other countries but they stopped short of any suggestion that lithium be added to drinking water. The discussion around adding fluoride to water to improve dental health has proved controversial and has been criticized by many as mass involuntary medication.

Lithium is perhaps the only metal that is used in the treatment of organic disease. Its therapeutic properties were discovered by Dr. John Cade. As with all landmark discoveries, the discovery of lithium had its fair share of serendipity and happy coincidences.

Dr. John Cade was a World War II veteran having served in the Australian Army Medical Corps. After the fall of Singapore to Japan in 1942, he spent three years as a prisoner of war in the Changi Prison in Singapore. During his stay in the prison, Dr. Cade observed many of his fellow inmates suffer from strange vacillating behavior that he believed was caused by a toxin that was excreted in the urine.

After the war, the battle scarred doctor returned to work in the Bundoora Repatriation Mental Hospital in Melbourne. Here, he converted an unused kitchen in the hospital into a laboratory where he performed experiments that would eventually lead to the discovery of the therapeutic properties of lithium. Dr. Cade believed that a toxin that is excreted in the urine was responsible for mental illnesses like schizophrenia and depression. He injected the urine of mentally ill patients into the peritoneal cavity of guinea pigs. He found that the urine of mentally ill patients was more toxic to the animals compared to that from healthy controls. The prevailing belief that uric acid present in urine had important effects on neuronal function lead Dr. Cade to investigate the effects of intraperitoneal injections of uric acid. In an effort to increase the solubility of uric acid, he used a lithium salt of urate. He found that lithium urate had a remarkable calming effect on the guinea pigs. However, due the careful use of controls, Dr. Cade was able to conclude that the calming effect was a property of the lithium ion itself. He published his finding in the Australian Medical Journal in 1949.

The discovery of lithium was landmark in treatment of psychiatric disorders. It provided a valuable alternative to shock treatments, lobotomies and Freudian psychotherapy which were the main treatments for depression at that time. However the use of lithium as a drug was not welcomed by all, especially the drug companies. Lithium was a cheap and commonly available metal that could not be patented. It was not a drug that could rake in the big bucks for the pharmaceutical industry. It was not until 1970 (20 years after Dr. Cade’s discovery) that FDA approved the use of lithium in the treatment of bipolar disorders in the USA.

Despite the use of lithium for well over five decades now, its mechanism of action has not been fully elucidated. Some theories that have been put forward are:

1. Lithium may produce its effects by interacting with the transport of monovalent or divalent cations in neurons. However, because it is a poor substrate at the sodium pump, it cannot maintain a membrane potential and only sustains a small gradient across biological membranes.

2. Lithium may deactivate the glycogen synthase kinase 3B (GSK-3B) enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. When GSK-3B is activated, the protein Bmal1 is unable to reset the "master clock" inside the brain. As a result, the body's natural circadian cycle is disrupted. When the cycle is disrupted, the routine schedules of many functions (metabolism, sleep, body temperature) are disturbed. This may explain many of the features of mania and depression. Lithium, by inhibiting GSK-3B, may restore normal brain function after it is disrupted in some people.

3. Lithium treatment has been found to inhibit the enzyme inositol monophosphatase leading to disruption of the phosphoinositide cycle. This interferes in the formation of phosphoinositide diphosphate which is important in the intracellular signaling pathway of several neurotransmitters.

Evidence from both in vitro and in vivo studies has demonstrated that lithium exerts multiple effects on neurotransmitter/receptor-mediated signaling, ion transport, signal transduction cascades, hormonal and circadian regulation, and profoundly alters gene expression. It is surprising that a small ion like lithium that has many properties that are similar to sodium could exert such diverse effects.

References:
Oliver SL, Comstock GW, Helsing KJ. 1976. Mood and lithium in drinking water. Arch Environ Health. Mar-Apr;31(2):92-5.

Schrauzer GN, Shrestha KP. 1990. Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res. May; 25(2):105-13.

Stem Cells Stimulate Egg Development in Adult Mice

Production of offspring from a germline stem cell line derived from neonatal ovaries.

Zou K, Yuan Z, Yang Z, Luo H, Sun K, Zhou L, Xiang J, Shi L, Yu Q, Zhang Y, Hou R, Wu J.
School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.

Nat Cell Biol. 2009 Apr 12

During embryonic development in human females and most mammalian species, cells in the ovary called oogonia proliferate by numerous mitotic divisions to form primary oocytes. About one million form per ovary. These begin the fist meiotic division and then stop before the birth of the female in a prolonged diplonema stage called the dictyotene. A primary oocyte does not resume meiosis until the female is past puberty, when under hormonal control, ovulation takes place. This process usually occurs for only one oocyte per month during the female’s entire reproductive lifespan (from twelve to fifty years of age). The first meiotic division is completed and this is followed by the second meiotic division, thus completing the process of gamete formation in the female.

However, the idea that females have lost the capacity for oocyte production at birth has been challenged by this article which gives evidence for the existence of female germline stem cells (FGSCs) in postnatal mammalian ovaries. The authors have isolated FGSCs from young and adult mice and cultured them for more than 6 months. These FGSCs were infected with a green fluorescent protein (GFP) virus and transplanted into ovaries of infertile mice. Eighty percent of these mice went on to produce offspring that had the GFP transgene after natural mating.

This finding, if corroborated by other researchers, may help infertile women conceive and have children. A question that comes to mind is: do infertile women have FGSCs in their ovary? If the answer is “yes”, how can they be stimulated to undergo oogenesis? On the other hand, if the answer is “no”, then treatment will involve transplantation of FGSCs from a donor to the infertile recipient, in which case immunosuppression may be required to prevent rejection. Another possible application would be in prolonging the reproductive lifespan of women. Generation of new oocytes could help older women conceive. In addition, it could be a boon for those with premature ovarian failure.

A new target for cancer therapy.

An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Teresa A. Soucy et al.
Nature 458, 732-736 (9 April 2009)

This group of authors has discovered a compound that inhibits the never-before-targeted NEDD8-activating enzyme (NAE), and show that this compound suppresses the growth of human lung-tumour tissue transplanted into mice.

The new drug principally targets the ubiquitin-proteasome system (UPS). One of main disadvantages in targeting the UPS is its non-specificity. A wide variety of vital cellular processes are intimately liked to the UPS. However, the UPS was shown to be a effective target for cancer chemotherapeutics when Bortezomib, a E3 ligase inhibitor, was successfully developed for the treatment of refractory multiple myeloma.

This paper reports a clever way around the problem of non-specificity of the UPS. Instead of targeting E3 ligase enzymes directly, they targeted NEDD8-activating enzyme (NAE), which is required to activate a subset of E3 enzymes known as cullin-RING ubiquitin ligases (CRLs). Inhibition of NAE leads to the accumulation of the substrates of CRLs in the cell. This induced apoptosis in the proliferating cancer cells possibly as a result of the deregulation of DNA synthesis. This phenomenon was already seen in vitro when cancer cell lines were exposed to this drug. What is most interesting and promising is the fact that the authors report nearly complete regression of transplanted human lung-tumour tissue in the drug-treated mice, with no obvious side effects. It remains unclear, however, why a drug that inactivates so many different CRLs (presumably also those in healthy cells) should kill only cancer cells.

These are exciting findings, but it is prudent to remember that many promising drug candidates have been shown to cure cancer in mice, only to fail spectacularly in humans. It remains to be seen whether it will become the second marketed drug that deliberately targets components of the UPS after Bortezomib.

Our experiences don't just last a lifetime.....

Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene.

Roth TL, Lubin FD, Funk AJ, Sweatt JD.

Department of Neurobiology and the Evelyn F. McKnight Brain Institute, University of Alabama-Birmingham, Birmingham, Alabama.

Biol Psychiatry. 2009 Jan 14. [Epub ahead of print]

This is an interesting study which again shows inheritance of acquired characteristics.But there is more to it. Read on.......

“In this study, researchers found that rats raised by stressed mothers that neglected and physically abused their offspring showed specific epigenetic modifications to their DNA. The abused mice grew up to be poor mothers, and appeared to pass down these changes to their offspring. Previous research has shown that bad rat mothering can be passed down through this kind of DNA modification--but those changes are thought to be triggered specifically by maternal behavior. In this study, researchers also had healthy mothers raise the offspring of stressed mothers, and found that the problems were only partially fixed. That suggests that the changes were not due to their neonatal experience but were already there when they were born.”

- From: "A Comeback for Lamarckian Evolution? – Technology Review (published by MIT) Wednesday, February 04, 2009.

Also read a mini-review by the author of this paper published in Biological Psychiatry.

The results of the papers discussed in my last two posts suggest that childhood experiences could make lasting impressions on the individual. This may be due to epigenetic modification of DNA. These DNA modifications have a profound effect on adult behavior of these individuals. In addition, these researchers claim that the offspring of these individuals too have the same DNA modifications. This can occur in two ways: First, a hormone or some other factor (a gene altering factor) produced by individuals exposed to these stimuli can alter genes in the germ cells, probably by DNA methylation (or other epigenetic mechanisms). This is particularly important in females because they are born with all the eggs that they will ever have (spermatogenesis in males, on the other hand, is an ongoing process and occurs during in the entire adult life of the male). Second, the hormone/gene altering factor may not affect germ cell directly, but may affect the DNA methylation pattern of the fetus as it develops in utero.

In either case, the hormone/gene altering factor is a throw back to Darwin’s theory of Pangenesis. Pangenesis, which was Darwin’s take on Lamarckism, was based on the idea that somatic cells would, in response to environmental stimulation, throw off 'gemmules’ which traveled around the body (though not necessarily in the bloodstream). These pangenes were proposed to be microscopic particles that supposedly contained information about the characteristics of their parent cell, and Darwin believed that they eventually accumulated in the germ cells where they could pass on to the next generation the newly acquired characteristics of the parents. Thus, it seems like the days of Lamarck and his theory of inheritance of acquired characteristics are back. The next challenge is to find this factor or hormone that brings about inheritable epigenetic changes. It is unlikely that the same hormone is responsible for specifically modifying a wide variety of genes. We are probably looking at a family of related “messengers”. It is also highly improbable that we are going to discover a totally novel class of such agents. It is more likely that certain known molecules have this additional function. The stage is set for a landmark discovery and it will come sooner rather than later.

At this point, I would like to draw your attention back to my first post on Lysenko. Lysenko’s research was on improving crop yields by propagating desirable acquired characteristics in plants. His research was thrashed as “not having a rational basis”. Today we know that there is a rational basis for his theory. I am not suggesting that Lysenko was right (only time will tell). However, what I am suggesting is that the rational basis for anything in science is based on existing knowledge. What is thought to be impossible today may become possible tomorrow. We should never be too hasty to dismiss anything as a scientific impossibility.

Transgenerational rescue of gene defect - Lamarckian style!

Transgenerational Rescue of a Genetic Defect in Long-Term Potentiation and Memory Formation by Juvenile Enrichment
Junko A. Arai, Shaomin Li, Dean M. Hartley, and Larry A. Feig
The Journal of Neuroscience, February 4, 2009, 29(5):1496-1502; doi:10.1523/JNEUROSCI.5057-08.2009
URL: http://www.jneurosci.org/cgi/content/abstract/29/5/1496

In an interesting experiment, scientists at the Tufts University School of Medicine, Boston, and Rush University Medical Center, Chicago, demonstrated that exposure of mice that have a genetically engineered defect in long term memory, to two weeks of an "enriched environment" (that includes exposure to novel objects, elevated social interactions and voluntary exercise) enhances memory not only in these "enriched" mice but also in their future offspring even if the offspring never experience the enriched environment. The transgenerational transmission of this effect occurs from the enriched mother to her offspring during embryogenesis.

What this research article is hinting at is that acquired characteristics - like habits, phobia etc. can be inherited. This was previously believed to be an impossibility. For example, if a parent has a particular learned skill, his offspring cannot be expected to be born with the same skill. This is because the skill is an acquired characteristic and such characteristics are not inheritable. At least that was what was previously accepted and this research challenges that premise. If this phenomenon is indeed true in humans, this would mean that a person's childhood experiences could influence behavior, not only in the same person as he/she grows up, but also in his/her offspring who have never been exposed to such experiences.

So, we ask the question: Are acquired characteristics inheritable?

It has been accepted for some time now that acquired characteristics are not inheritable. Proponents of the theory of inheritance of acquired characteristics, like Lysenko (discussed in last week's post) have been discredited and their research thrashed as "unsound science", if not fraudulent science. The theory of inheritance of acquired characteristics, however, is not Lysenko's creation. It was proposed more than 200 years ago by Jean-Baptiste Lamarck and was once widely accepted. Over the next century, publication of Darwin's, and then Mendel's theories led to the general abandonment of the Lamarckian theory of evolution in biology. However, recently Lamarckian evolution has made a comeback of sorts. \

Lamarckian views of evolution are based on two principles:
1. Use and disuse - Individuals lose characteristics they do not require (or use) and develop characteristics that are useful.
2. Inheritance of acquired traits - Individuals inherit the traits of their ancestors.

These principles could be exemplified in the giraffe. Giraffes, while stretching their necks to reach leaves high in trees, strengthen and gradually lengthen their necks. These giraffes have offspring with slightly longer necks. While this example is appealing in its simplicity, there is no evolutionary evidence for this having happened. The theory gained wide acceptance because Darwin and Mendal put forward their theories only after Lamarck's death in 1829.

In any case, Lamarck's views were not completely dead at any point of time. There were many famous scientists who prescribed to Lamarckism in part or in full. These included William McDougall and Ivan Pavlov. William McDougall was a researcher at Harvard who studied the abilities of rats to solve mazes. He found that offspring of rats that had learned solve the maze solved them faster even though they were not exposed to the maze earlier. McDougall attributed this to some sort of Lamarckian evolutionary process. At around the same time, Ivan Pavlov, who was also a Lamarckist, claimed to have observed similar phenomena in animals being subjected to conditioned reflex experiments. He claimed that with each generation, the animals became easier to condition. The claims of McDougall and Pavlov were never proven to be true.

In the first few months of this year, scientists have published research that has shown that Lamarckian type inheritance of acquired characteristics is possible. The actual mechanism underlying these patterns of inheritance is still mystifying to scientists, but the answers seem to be around the corner as we continue to better understand the phenomenon of Epigenetics. More about epigenetics and neo-Darwinism in my next post.

Genetics, society and ethics - The Lysenko Affair

This first week, lets start of with a real life story you may or may not be aware of. I thought I will start with this because it illustrates two most fundamental principles of science.

At the peak of its powers, Soviet Russia supported several scientific endeavors aimed towards improving society and the doctrine of communism itself. The Lysenko affair involved one such Soviet attempt to meddle with science in an effort to promote its communist manifesto. Trofim Denisovich Lysenko was a biologist who believed acquired characteristics could be inherited, a fundamentally erroneous theory in genetics. His Soviet masters, however, liked the idea. Stalin and later, Krushchev aggressively pursued "Lysenkoism" and put Lysenko in charge of their crop yield improvement programmes. Lysenko's gain was Vavilov's loss. Nikolai Vavilov was an eminent genetics expert who did not prescribe to Lysenko's views. Vavilov was imprisoned and later died in prison. For the better part of 30 years, genetics in Russia went down a blind alley. It was only after Krushchev's reign ended that Lysenko's pseudoscience was recognized and abandoned.

This is one example of political influence of scientific research that led to great loss for society. Political interest in science, however, is not always a bad thing. The Human Genome Project would never have proceeded at the speed and efficiency with which it did, if it were not for political and societal backing. The Lysenko affair should remind us that "science, to be effective, must be in a climate of open inquiry and free expression of ideas". The message here is that politicians must support research done in an open scientific atmosphere by researchers who have no vested political interest. The scientific method must not be subverted by political bullies. This is the first principle I wanted to discuss - the independence of science. The second priciple will be discussed in my next post.

Acknowledgment:
Priniples of Genetics, 7th edition, Robert H. Tamarin.

The sunrise post

Statutory warning: This is a blog for the intellectuals, especially those with an inclination towards biochemistry, genetics and molecular biology.

Hello there,
That was probably a scary beginning with the statutory warning and all. You probably feel like you're looking at a cigarette packet or something.

Anyway, this is a blog for people who take science seriously. Even though it's meant primarily for those of you who have an academic background in biochemistry and molecular biology, I would like to believe that, over time, the posts here will be of broader relevance. The fact is that life is fascinating and mysterious. Everyday research shines a beam of light that only reveals greater mysteries and takes one on a trip that gets more exciting and fascinating by the day.

What I propose to do through this blog is to post a research article and discuss its background, importance and relevance. Through this, the I hope the reader, not only keeps abreast with what is new and cracking in the world of research, but also gains knowledge and understanding of the basic principles of science being discussed in the article.

So, here goes.......