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Immunity: How your Body Protects Itself from Infections

November 19, 2012, 5:42 am
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What is immunity and types of immunity:

Human body is a store house of wonders and astonishing features and functions making it an interesting and curious subject to understand and deal with. Made up of millions of cells, the role of each cell, tissue and organ right from the date of manufacture (embryo) till expiry (death) is quite amazing. Our body takes care of itself very well and also knows how to protect itself from molecules foreign to the body. In this regard our body has a well developed defensive system always ready to fight with the pathogen entering the body called as the immune system and the resistance towards a pathogen is called as the immunity. Here let us discuss the two types of immunity, the innate immunity and the acquired immunity and the phenomenon of defense in both these types of immunity.

Innate Immunity: The inbuilt immunity of an individual based on his or her genetic makeup is called as the innate immunity in contrast to the prior exposure to antigen to develop immunity. The innate immunity is seen either at species level or racial level or individual level. Species innate immunity as the name implies is the immunity shown by all individuals of the same species to the pathogens of different species. Racial immunity is the term applied to the difference in resistance shown by races or groups belonging to the same species. The individual innate immunity is the difference in resistance among individuals belonging to the same race or group.

The mechanism of defense in innate immunity is categorized into three types based on the type of protective barriers involved. They are the anatomical barrier, the physiological barrier and the phagocytic or endocytic barrier. The anatomical barriers protecting the body from various pathogens is the skin and the mucous membrane lining the respiratory tract, digestive tract etc. Skin, the large blanket covering all the organs of the body spread from head to toe is the first layer of defense. The hair follicles on the skin, the oil and sweat glands present in skin all forms the components of defensive mechanism of the skin. The mucous membrane lining the nasal area plays an important role in trapping the pathogens trying to enter the body. The mucous membrane lining the respiratory tract has cilial structure which pushes the foreign body out of the system, thus protecting the individual. Also the mucous membrane of the GI tract has similar function in tackling the pathogen. The tear, saliva and mucous are the secretions engaged in antibacterial and antiviral activity.

Looking into the physiological barrier they are the pH, temperature and chemical mediators. Temperature acts as an immunity agent by showing direct effect on the pathogen. For example chicks with high body temperature show resistance to anthrax. Likewise pH also contributes to immunity. The acidic nature of the stomach restricts and eliminates the growth of various pathogens. One example of chemical mediators as barriers is well indicated by the bacterial cell wall cleaving property of the hydrolytic enzyme, the lysozyme. The phagocytic or endocytic mode of defense involves the role of cells in forming structures to engulf and digest the pathogen, bacteria for example.

Acquired Immunity: Acquired immunity is the specific resistance developed by the body only on exposure to antigen (the foreign body). The four salient features of an acquired immunity are Antigen specificity, diversity of the immune system in recognition of molecule, the immunologic memory which stores the information of the type of antigen attacked and the type of immunity developed to the same and retrieve the information on the second attack by the same antigen and finally the ability to recognize the self and non-self antigens.

Acquired immunity is classified into active and passive acquired immunity each again falls into two categories called as the natural and artificial immunity. Active acquired immunity is the immunity developed by the body in response to an antigen, which once developed seems to exist in the individual forever and also it is stored in the memory of the immune system and exhibited on attack by the same antigen for the second time. Natural active immunity is the immunity developed naturally in response to any infection whereas artificial active immunity is induced in an individual with the help of vaccines.

Passive immunity is the induction of immunity in the immune deficient individual by introducing antibodies or immune cells as such to them. Unlike active immunity, passive immunity exists only for a short term and no immunological memory takes place. The transfer of immune particles from mother to fetus via placenta or breast milk is an example of natural passive immunity whereas the introduction of processed serum rich in antibodies to an immune deficient host is artificial passive immunity.

Though the immune system of our body challenges most of the pathogens, the evolution of new viruses challenges the immune system which can be explained by an example of the action of HIV on the immune system.
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Gene therapy for hair loss and baldness

November 19, 2012, 8:39 am
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Hair loss is one of the common problems faced by a large number of men and women. There are a number of remedies that are available in the market namely wigs, topical treatments, drugs, nutrient supplements like vitamin, hair transplant surgery, caps and hats or complete shaving of hair. Other than these treatments, there are a number of associations, support groups, counsellors, etc to help people cope with the mental agony caused due to hair loss. Since, no permanent cure has yet been devised for the baldness, constant research studies are being carried out to find out the reasons responsible for the development of baldness.

Research has shown that the development of hair follicles takes place in the womb and after birth; there is no appearance of new follicles. In the head of a person, there are about 100,000 follicles and if the follicles are severely damaged due to any reason, it results in its end of the follicles and there is no further formation of hair from those follicles. The follicles are limited in their ability for regeneration and as there is no new formation of follicles after birth, it causes severe hair loss resulting in baldness.

The scientists in the University of Pennsylvania have illustrated the role of a particular gene that is responsible for the hair follicle formation. They have performed successful studies in mice for the regeneration of hair follicles. They have found the role of a particular gene called Wnt, which on manipulation leads to hair follicle regeneration. This study provides an area of vast application for devising methods regarding hair re-growth.

The studies showed the role of Wnt gene in the process of wound healing and the formation of new hair follicles. Different experiments were performed, which illustrated the formation of new follicles in the wound healing process; hence, this could be manipulated for increasing the number of follicles to a great extent. The experiment involved the removal of small sections of skin from the mice that resulted in the formation of new skin in those regions due to stem cell activity. During the process of the wound healing, it was observed that the skin that formed during the healing process possessed the characteristics of the normal skin with the original glands, hair follicles and eventually the same appearance. It was seen that if the Wnt gene was active, the normal healing process was achieved, while in the Wnt gene knockout mice or the mice, in which the Wnt gene was blocked, there was no formation of hair follicles. Moreover, it was also observed that increasing the activity of Wnt gene resulted in an increase in hair growth. Hence, it was concluded that the creation of wounds caused the ‘waking up’ of the Wnt gene, which activated the wound healing process, thereby resulting in formation of hair follicles resulting in new hair growth.

Hence, it can be seen that the studies have created a new view among the scientists to look at the aspect of gene therapy for baldness instead of looking at hormones. Although, the regeneration ability of many animals is known like the re-growth of tail, limbs, etc, the ability of regeneration in mammals was thought to be quite limited. However, the successful studies of regeneration of hair follicles and surrounding area of skin in mice after the creation of wounds have generated interest for further in-depth studies in this area and for successful translation to human studies. The new possibilities in the treatment of wounds have shown great promise for reconsidering the regenerative capabilities of skin in mammals.

The studies on the Wnt gene may stimulate detailed analysis on the subject for finding new solutions and treatments for baldness. However, it fails to generate the same amount of enthusiasm in others as previous researches on the discovery of ‘hairless’ gene responsible for baldness by scientists in Columbia University in 1998 could not be translated into hair loss therapies due to various reasons. Hence, the development of permanent solutions for baldness using gene therapy is a dream for future as extensive studies are essential related to the subject. The role of inherited genes and stem cells in the development of baldness continue to excite the scientists for further detailed research on the subject.
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Find number of restriction fragment size in chromosome

November 19, 2012, 7:57 pm
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Hi all,
I am prepare in entrance exam. I need help.
A restriction endonuclease has the recognition sequence G/AATTC, where "/" indicate the cut side. This sequence is found, on average, once every 'X' residues in a chromosome. 'X' =
Options
a. 146 base - pairs
b. 200 base - pairs
c 256 base - pairs
d. 4096 base - pairs
advance thanks reply as soon as possible
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Issues in the production of Recombinant proteins in Plants

November 20, 2012, 7:51 pm
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The advance in the field of recombinant DNA technology and the techniques of plant transformation have helped in the creation of novel platforms for the production of proteins on the whole plants growing in soil or plant suspension cells that are grown in a bioreactor with fully defined synthetic media. Studies related to the use of plants as heterologous expression systems for the expression of recombinant proteins, both native as well as modified therapeutic ones from humans has gained importance in the past two decades with successful experiments related to the plant-based production of pharmaceutical proteins.

The scientists Barta et al. have established the ability of plants to express human genes. They have illustrated the expression of transcripts of human growth hormone fusion gene in the callus tissue of sunflower and undifferentiated tobacco, although there was no detection of any protein formation. Two potential therapeutic proteins have been successfully expressed in plant expression systems: human serum albumin that was expressed successfully in the potato and tobacco leaves and suspension cells and monoclonal antibody expressed in the leaves of tobacco. This process of using the plant-based systems for use as platforms for the effective production of molecules with industrial and pharmacological significance, is termed as ‘molecular farming’ (MF) with the pharmaceutically significant products obtained from them being termed as plant-derived pharmaceuticals (PDPs). A number of PDPs are being developed and commercialized that include antigens, blood substitutes, different enzymes, cytokines, antibodies and their fragments and many other important proteins.

The plant expression systems offer a number of advantages over other expression system platforms for the production of recombinant proteins such as being inexpensive, scaled highly as well as unsupportive of the growth of human pathogens. Due to the advantages offered, replacing the mammalian cell lines with plants for the expression and production of recombinant proteins was considered, though it had some technical drawbacks. The high investment involved with fermentation infrastructure, low grade performance of plants when compared to mammalian cell lines and the lack of regulation systems in plants for the production of biopharmaceutical products resulted in the lack of industrial interest.

Latest research has helped in overcoming the technical hurdles in the utility of plant expression systems.

a) Improvement of the intrinsic yields could be done by maximizing transcription by optimal expression construct designing, stability of mRNAs for translation, increasing the copy number of transgene and introduction of these transgenes within the germplasm. Reverse transition cycling is one of the methods employed for increasing yield and for convenient extraction. This process has been employed in some oil crops as well as seed storage proteins.

b) The downstream processing (DSP) of the yielded protein is very essential that requires the isolation of the expressed protein and involves the removal of fibers, by-products of metabolism as well as oil, based on the crops involved as in case of nicotine from tobacco leaves, etc.

c) One of the regulatory aspects of MF is the presence of plant glycans that may be necessary for the biological activity, stability, targeting, PK (Pharmacokinetic) as well as immunogenic properties of the therapeutic proteins that are glycoprotein. in nature.
However, the differences between plant and human glycans and the effect of the plant glycans on the protein structure, activity, etc have resulted in initiating research to abolish the plant-specific glycosylases by gene knockout and RNA interference as seen in tobacco, Arabidopsis, etc.

The absence of commercial pedigree of proteins was one of the hurdles faced by MF solved by the production of non-medical proteins by the plants for the commercial use. E.g. Maize was used as a platform for the production of avidin and β-glucoronidase (GUS) enzymes that have potential use in molecular biology. Both the proteins were similar to the natural ones in every aspect of activity, structure, etc. Although, there has not been much progress in the commercial production of such type of proteins for therapeutic use, it opens up new prospect for future research studies.

The regulatory perspective of the PDPs that involves the replacement of cell banks with seed banks, accounting natural variation in the plant organs by verifying batch to batch consistency, operating and processing techniques for various expression and production systems are some of the guidelines of FDA for the commercialization of plant-derived proteins.

The good manufacturing practice (GMP) strategy of the PDPs from whole plants is essential for the development of plant expression systems that includes

1) the selection of appropriate plants or crops as expression systems,
2) selection of proper cultivation method,
3) Knowledge of relative merits about the stable as well as transient expression systems and the DSP in plant systems compared to the other cell lines like mammalian, yeast, or bacterial.

The use of PDPs in near future can be foreseen in the development of various pharmaceutical products, vaccines, etc by solving the issues and adopting different strategies of GMP.
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Recombinant Cytokine therapy for immune and inflammatory disorders

November 21, 2012, 12:41 am
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Cytokines belong to a class of regulatory proteins that are produced in very minute amounts upon stimulation and are generally pleiotropic in nature i.e. have multiple actions on different target cells or organs. They are potent molecules and some distinct cytokines have functions that are redundant and overlapping. The cytokines may be autocrine or paracrine having important role in the cross talk between the cells within the body. The advance in RDT has helped in grouping the cytokines and their receptors based on their structure by the cloning of their genes. The cytokine molecules, their receptors and their signal transduction pathways have become promising targets for the study of therapeutic interference due to the multifunctional nature of the cytokines.

The role of cytokines in the immune and inflammatory disorders has led to the advancement of the cytokine-based therapies. Manipulating the functions of the cytokines with the aim of either blocking or restoring the activity of the specific cytokines is one of the approaches in the cytokine therapies. The coupling of the cytokines with the toxins, cloning of the cytokines, formation and fusion of recombinant cytokines and its receptors with the Fc portion of the human IgG1and albumin for stabilizing and thus increasing the serum half-life of the proteins, are being studied. The cloning of the natural and synthetic antagonists that interfere in the ligand-receptor interaction is being studied. The use of gene therapy and antisense oligonucleotides in delivering cytokines is also being assessed. The currently used approach for cytokine therapy is the use of monoclonal antibodies (mAbs) for blocking or neutralizing the action of cytokines. The use of completely human anticytokine mAbs for clinical purpose has been approved.

A novel approach in the treatment of inflammatory autoimmune diseases is the targeting of inflammatory cytokines. The drugs that block their action e.g. TNF (Tumor Necrosis Factor) are being used successfully in therapeutics of rheumatoid arthritis (RA). Apart from it, the fusion proteins of the sTNF receptor and Interleukin (IL) 1R antagonist are also major components in the RA therapeutics. The therapy involving the TNF α and IL-1 antagonists are now having wider scope and their use is being extended to other autoimmune inflammatory diseases. The use of TNF blockers are much more efficient than the therapy aimed at only the antagonism of the IL-1. The successful studies on IL-1 have led to the development of mAbs that target some of the cytokines and their receptors such as IL-6, IL-8, IL-18 and Interferon γ in different clinical conditions. The cytokine therapy using recombinant cytokines has been successful in different cases such as

a) IL-2 in cancer
b) IFN-α and its derivatives in various types of viral infections and cancer
c) IFN-β in multiple sclerosis
d) IFN-γ in cancer and osteoporosis
e) IL-11 in post chemotherapy induced thrombocytopenia
In some cases, recombinant cytokines have produced no effect as seen in case of recombinant IL-10 that is immunosuppressive, however further research is required to analyse any possible therapeutic application in future. In rare cases, adverse side effects have been produced as seen in IL-12.

Autovaccination has been developed as a novel strategy for the therapy of various chronic diseases that result due to excess production of certain factors. The physical association of the foreign proteins with the self-antigens has been used for overcoming the tolerance against self-antigens. Successful studies have been performed in mice using immunologic complexes by chemical coupling of cytokines IL-9 and IL-12 that lead to the complete inhibition of the function of cytokines. Resistance for cutaneous leishmaniasis was seen in IL-9 vaccinated mice and for the experimental autoimmune encephalomyelitis (EAE) in the IL-12 vaccinated mice.

Application of cytokine therapy in different allergic diseases and asthma has shown great promise. Th2-dependent mechanisms mediate most of the allergic reactions in the body with the involvement of almost all the Th2 cytokines such as IL-4, IL-5, IL-9, and IL-13 making them potential targets for the cytokine therapy against allergic diseases. The main promoter of Th2 development is IL-4 in in-vivo and in-vitro as seen in murine models using OVA as the allergen. The role of IL-5 in allergic asthma is also being studied, though much success has not been achieved. Three anti-asthmatic drug leads in clinical phase I trials that are related to IL-13 demonstrate IL-13 to be a potential target for allergic asthma. Further studies are being conducted in mice to define the roles of IL-4 and IL-13 in different infectious and allergic diseases by using knockout models.

The pleiotropic nature of the cytokines remains to be a drawback in the application of cytokine therapy for complex diseases. Hence, if experiments could be designed for the simultaneous inactivation or activation of multiple cytokines, then complex disorders could be treated with this therapy. RNA interference could help in achieving this goal in future due to the advancement in RNAi delivery studies.
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The pathway of Toxins in the body – Entry to Elimination

November 21, 2012, 2:27 am
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Toxicant is the name given to the substances that are potential to cause any undesirable effect in the living organism even causing death of the organism on exposure to such compounds. In simpler term a toxicant is called as poison. With wide variety of toxicants present in the environment one cannot escape from being exposed to it either intentionally or unintentionally. How does these toxic substances gain entry into our body on exposure and what happens to it in our system and how it is eliminated from the body is a quite interesting phenomenon very well defined under the area of science called as ‘Toxicology’.

The mode of exposure to the toxic substance determines the route of entry of the substance into the body. The mode of exposure is either by a physical contact like handling the substance or through inhaling the toxicant or through intake of the toxic substance. In case of physical contact with the substance the route of entry is skin and in case of inhalation the route of entry is lungs and gastrointestinal tract in the scenario of direct intake. Inspite of these multiple routes of entry the toxicant ultimately enters the blood stream. Besides all these routes the toxicant gains direct entry into the blood stream by injecting the substance either intravenously, intraperitoneal, subcutaneously or intramuscularly.

The skin which acts as the barrier between the body and the environment is a quite challenging route for the toxicants to enter the body. The epidermal layer of cells, the hair follicles, oil gland and sweat gland present on the skin are the possible route of entry for a toxicant to reach the blood stream. The entry through epidermal layer is difficult for the toxicants as it has to cross underlying layers such as the germinal layer and corium to reach the blood stream. The rate of diffusion of the toxicant is directly proportional to the permeable nature of the skin. Except for few toxics like acids and alkali makes the skin highly permeable by damaging the skin layer. The permeability of the skin is different for different species.

The toxic agents present in the air enter the body through respiratory tract upon inhalation. The toxic gases like carbon monoxide, sulphur dioxide and nitrogen dioxide and the volatile substances like benzene, the suspended particulate matter in the air enters the lungs through respiration. The absorption of these toxics in lungs is influenced by the larger area of the lungs and increased blood flow to the lungs. The quantity of the toxic gas in the air and the partial pressure of the same are the two factors governing the entry of the toxic gases through inhalation. The solubility nature of the toxic element decides the rate of diffusion of the substance from the lungs to the blood stream.

The next route of entry to be discussed is the gastrointestinal tract where the toxins make its entry via food chain. Also direct intake of toxic substance intentionally reaches the gastrointestinal tract. Thus the toxins reaching the GI tract is mostly harmless till the process of absorption of the toxin by the GI tract takes place. As the GI tract has several transport channels for the various nutrients, minerals and aminoacid present in the food, some of the toxins uses these transport system to reach the blood stream. The micro flora, acid and enzymes present in the GI tract are considered as important factors determining the fate of the toxin entering the GI tract. There is a possibility that the action of any of these factors on the toxic substance can reduce the toxicity of the substance. The rate of toxic element entering the blood stream from the GI tract depends upon the dissolution nature of the element.

Once entering the blood stream through different routes the toxicants either reaches their target organs or gets collected at various sites. The various such collection or storage units are the plasma proteins (albumin, globulin, and transferrin), the fat deposit of the body, the bone, the liver and the kidney. The toxicity of the element is organ specific and hence it need not be exhibited at the storage points.

Finally the distributed compounds are eliminated from the body by the proper functioning of the two vital organs, the liver and the kidney. The liver metabolizes the toxic element and releases into the bile for excretion and the kidney filters the blood and eliminates the toxins.

The amount of toxic substance, the length of exposure to the toxic substance, the age and health of the exposed individual are factors to be observed and analyzed to understand the effects of the toxin on the individual.
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Fewer Side Effects - Synthetic Enzyme Developed at Princeton University

November 21, 2012, 11:13 pm
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Scientists at Princeton University have developed a synthetic enzyme that will modulate ingested drug to prevent its metabolic degradation and reduce both toxicity and dose needed for expected medical effect.

Long and healthy life of the average man is dependent on the productive pharmaceutical industry. Thousands of drugs are available all over the globe. Despite having healing effect, drugs are associated with more or less severe adverse effects. Ingested chemicals are undergoing metabolic transformation before they are eliminated from the body. Metabolites (end products of drug degradation) could be reactive and inflict damage to the nearby healthy tissue. Liver is essential organ for drug transformation; it could be imagined as waste factory of the human body, where different chemicals are degraded thanks to numerous enzymatically enhanced biochemical processes.

Drug (xenobiotic) metabolism facilitates drug elimination from the organism by converting lipophilic compounds into hydrophilic metabolites. This process decreases pharmaceutical potential of the drug. Higher concentration of the drug is always applied to ensure desired medical effect. Enzymes responsible for drug metabolism are known as CYP enzymes (located mainly in the liver); they provoke either detoxification, when toxic compound is metabolized into less toxic metabolite, or toxication, when non-toxic compound is transformed into harmful metabolite. Xenobiotic metabolism is divided in couple of phases. In the first phase mixed function oxydases will eliminate hydrogen or add oxygen to create more polar compound that could be easily excreted from the body. Some drugs will be eliminated after this phase. Some other demand further transformation: endogenous substrate will bond to the newly added functional groups and increase polarity of the created conjugate. In the second phase, interaction of the polar functional groups of the phase I metabolites result in detoxified product. Conjugation reactions including methylation, acetylation, sulphation, glucuronidation on the carboxyl, hydroxyl, amino and sulfhydryl groups are turning reactive phase I conjugates into less active metabolites that could be excreted easily.

Scientists from the Chemical department of Princeton University and Caltech group of California Institute of Technology's Materials and Process Simulation Center teamed up to develop synthetic enzyme that will modulate ingested drug to prevent its metabolic degradation and reduce both toxicity and dose needed for expected medical effect. Created enzyme is acting like a catalyst that is replacing certain hydrogen with fluoride atoms. Altered drug molecule is stable and “safe” from the liver enzymes with the same (or even increased) pharmaceutical potential. Without metabolic degradation, level of available drug in the body is high and dose could be easily reduced. Addition of fluorine results in increased lipophilicity of a drug (essential for all in vivo acting molecules). It also increases fat solubility resulting in elevated drug bioavailability. Fluoride enhances binding of the drug to the enzymatic or receptor sites. Carbon and fluorine create strong bond with a higher oxidative and thermal stability compared to carbon – hydrogen bond. Some other functional groups could also make reversible electrostatic bonds with fluoride. This kind of substitution is useful when developing drugs where stable covalent bonds with molecular targets are needed.

Synthetic enzyme that is responsible for hydrogen – fluoride substitution is similar to cytochrome P450 that replaces hydrogen for oxygen atoms. However, unlike iron based cytochrome P450 enzyme, newly developed enzyme is manganese based. This enzyme is developed two years ago with a goal to increase drug reactivity by replacing hydrogen atoms with chlorine atoms. Scientists assumed that manganese based cytochrome P450 could also work properly if fluoride atoms are offered. They experimented with couple of fluoride materials and discovered that combination of silver fluoride and tetrabutylammonium fluoride trihydrate is the easiest and the safest way to incorporate fluoride into drug molecule. Computational methods are further used to test drug safety and pharmaceutical activity. Besides being effective in decreasing toxicity and dose applied, this method could be used in designing radioactive tracer drugs as easiest and less expensive method in medical imaging (to determine mechanism of action and exact reactive site of the drug in the organism). Already marketed drugs are currently under investigation for the potential improvement using fluorination method. Scientists are especially focused on steroid drugs because this class of drugs is widely used. All kind of hormone replacement therapy and/or birth control pills and various anti-inflammatory drugs are typical representatives of steroid drugs.

Further experiments will show if fluorination could alleviate unwanted side effects and provide safe and efficient drug treatment.
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Genetically Modified Milk, Carrot, Golden Rice and Tomato (Part 1)

November 22, 2012, 9:19 am
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Genetically modified food is becoming our reality and is possibly landing on our Thanksgiving dinner plate too.

Genetic engineering could increase nutritional value of the food, provide immunity against different microorganisms and resistance against pests or extreme weather conditions and enhance biomass production. A lot of plants were already modified and improved, but so far just few of them are approved for human use.

Thanksgiving dinner is prepared using the food native to the New World. In the near future, thanks to rapidly growing industry of genetically modified food, traditional Thanksgiving dinner could easily become genetically modified.

Here are traditional ingredients of Thanksgiving dinner and their genetic improvements:

Milk

2-3% of human babies are allergic to the cow’s milk. Genetic engineering improved milk formula by removing beta-lactoglobulin or BLG, protein that triggers allergic reaction. Cow needs to be genetically modified to produce BLG free milk. It is complicated procedure, but proved to be successful in the experiment conducted in the New Zealand. BLG gene in the cow’s egg was “silenced” (down-regulated) prior to fertilization. Not all attempts to down-regulate the gene were successful and just a small number of embryos survived long gestation period (290 days). Those that survived, grew-up in hypo-allergic milk producing cows. Besides being safe for use in people that are prone to milk allergy, BLG free milk is nutritionally valuable due to higher concentration of casein (another milk protein). Safety tests need to be performed before genetically modified milk become available for worldwide use.

Carrots

Carrots are rich in dietary fibers, minerals and vitamins. So far, they have been genetically modified to resist pests, fungi and to increase herbicide tolerance. With latest genetic improvements, carrots could become important source of another element essential for human health - calcium. Carrots are rich in calcium, but without proper calcium carriers it couldn’t be maximally absorbed. Increased level of proteins that act like carriers would increase calcium bioavailability. Experiments with mice showed that genetically altered carrots provide 50% more calcium than regular carrots. Test with human showed that genetically modified carrots offer 41% more calcium compared to unaltered plants. Calcium and vitamin D are necessary for the proper bone metabolism and adequate bone mineral density. Osteoporosis is famous and widespread disease resulting from lack of calcium in the bones; it is usually treated by various calcium containing pills. Genetically modified plants would simplify the procedure by providing calcium directly from the meal. Calcium “enriched” carrots are still not available.

Golden Rice

Rice is popular and often consumed plant (a staple food for more than 50% of the human population). It is estimated that rice provides 1/5 of the calories intake in the world. Besides high carbohydrate level, rice is rich in minerals and vitamin B group. Genetically modified rice became rich in another element - beta-carotene, a precursor of vitamin A. Endosperm (edible part of the rice) is site of beta-carotene production, thanks to newly incorporated psy (daffodil derived) and crtl (Erwinia uredovora derived) genes. Expression of both genes is under control of the endosperm specific promoter. Lycopene is the end product of genetically modified plant but enzymes located in the endosperm transform lycopene to beta-carotene that is responsible for the yellow color of the modified rice. Dose of vitamin A and its bioavailability is high. One cup of golden rice per day satisfies daily needs for vitamin A. A lot of organizations recognized the potential golden rice could have for the world regions that are struggling with vitamin A deficiency and supported financially whole project (Bill Gates and Hellen Keller International organization, for example). It’s estimated that golden rice could become available for worldwide use in 2013.

Tomatoes

Tomatoes can be consumed as a part of the salads, juices, in cooked meals…. With low caloric value and high level of different vitamins, minerals and pigments, regular intake of this plant is a guarantee for good health. Recently, scientists figured out the way to increase the value of tomatoes even more. Genetic engineering result in plant producing small peptide, 6F, that mimic the action of ApoA-1, responsible for lowering of the LDL (low density lipoprotein) or “bad” cholesterol level. Increased LDL level is responsible for atherosclerotic plaques and arterial inflammation, increasing the risk of cardiac attack and myocardial ischemia. Cardiovascular mortality is one of the leading causes of death in the modern society. Scientific community is focused on this issue, and modified tomatoes could be one of the promising solutions. Efficiency of the genetically altered tomatoes is tested on the mice. Animals were kept on the high fat diet until atherosclerotic plaques and arterial inflammation became detectable. Tomatoes producing 6F peptide helped reduce LDL level and level of arterial inflammation; 6F decreased both atherosclerotic plaques and level of lysophosphatidic acid (associated with plaque formation), and increased the level of paraoxonase enzyme responsible for good cholesterol level, with antioxidant activity that could prevent heart attack. Future experiments will show if modified plant could combat arterial disorders in humans.
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Genetically Modified Apples, Papayas, Potatoes, Corn (Part 2)

November 22, 2012, 9:22 am
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May be the food we are eating for Thanksgiving dinner is genetically modified, ex: Apples, Papayas, Potatoes and Corn.

Arctic Apples

Unique characteristic of each apple (no matter of the size, color or taste) is that slicing and peeling will change the color of the flesh. This characteristic does not make the apple inedible, but most people will find browning apples repulsive. Industry of food, dealing with sliced apples, is using different tricks to prevent apples from changing the color (like pouring vitamin C and calcium) and keep them desirable for the buyers. However, additives are not the perfect solution because they usually change the taste of the apple. Change of color is consequence of cell injury induced by cutting. Ruptured cells trigger reaction between polyphenol oxidase and chemicals in the apple that eventually alter the color of the slices. Scientists recently discovered four genes responsible for polyphenol oxidase production. Experiments showed that silencing of those 4 genes could prevent apple flesh from turning brown and soon enough, non-browning apple variety, known as arctic apple was developed. Golden Delicious and Granny Smith varieties are already modified in the “arctic apples” manner, but manufacturers are waiting for the regulatory approval before they become publically available.

Rainbow papayas

Just like any other living creature, plants are susceptible to different viral infections. ~30 years ago, Ringspot virus destroyed large portion of Hawaiian papaya fields. Only solution that could stop fast spreading of the virus was strenghtening of the plants by genetic engineering. Viral capsid proteins were inserted in the plant's genome. Similar to vaccination, this procedure boost plant’s immune system and ensure recovery of the papaya industry. Today, 80% of Hawaiian papaya is genetically modified. Tests showed that plant containing virus is not harmful for human health because viral particles undergo digestion as soon as they reach our stomach. Genetically modified papaya is available in most countries around the globe.

Potatoes

Potato is among the top 5 most cultivated plants on the planet. Roughly estimated, annual consumption of the potato is 33 kg per man. Although there are just 200 known potato species, long cultivation period and high popularity of the plant resulted in few thousand varieties available all over the world. Potato is rich in carbohydrates, vitamins, minerals, and carotenoids but conventional cooking methods destroy most of its nutritional value. Due to high carbohydrate level, excessive amount of potato in a diet can result in weight gain. Two years ago, group of Indian scientists genetically modified seven varieties of potato (that could be cultivated in different climates) by adding AmaA1 gene with the goal to increases protein content. Experiments showed that protein level could be increased up to 60% compared to non-modified plants. Also, this genetic modification increased crop yield. Nutritionally “improved” potato could help eradicate protein deficiency in the world. It is not marketed yet.

Transgenic corn

Corn (maize) is one of the oldest crops. Some evidence showed that corn was cultivated 2500 years BC. Due to widespread use, corn is genetically improved to become tolerant against insects and herbicides. In 2009, 85% of USA corn was genetically modified. Just like rice and potato, corn is staple food in the large portion of world and modifications that could increase its nutritional value are important. Vitamin E is acting like antioxidant and plays important role in pregnancy, it is recommended in cancer treatment and for prevention of the Alzheimer and Parkinson’s disease. Main sources of vitamin E are vegetable oils, nuts and seeds, but experiments showed that genetically modified corn could also be a good source of vitamin E. More complex experiment using South African variety resulted in transgenic corn rich in vitamin C, folate and beta carotene. It was shown that genetic modification could affect separate biosynthetic pathways and increase the level of three different nutrients beneficial for the human health. Vitamin enriched corn is still in experimental phase.

Whatever you are having for dinner, I hope you will spend a pleasant evening with your family and friends. Happy Thanksgiving! Smile
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What are Plastic Antibodies?

November 23, 2012, 2:45 am
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Researchers in Japan and California (Stanford, UC Irvine) have developed plastic antibodies capable of seizing and neutralizing dangerous materials in the body.

Immune system is complex set of cells, chemical signals and proteins united to target and eliminate the antigens (foreign molecules) after they enter the body. Antigens could be infective agents (like microorganisms), toxins or endogenous metabolites that should be cleared from the body. B-lymphocytes produce specifically shaped immunoglobulins (class of proteins) better known as antibodies that will bind to antigens and remove them from the organism. Bond between antigen and antibody is strong and specific: perfectly designed antibody will match antigen just like key will match certain lock. When organism is facing disease for the first time, it needs time before adequate antibody is created, but with each new infection (caused by the same pathogen) - immune response will be executed faster. Vaccination is mimicking naturally occurring pathogen attack; provoked immune system will produce antibodies against the pathogen and provide resistance against specific disease. A lot of severe infectious diseases were eradicated thanks to vaccination.

Besides vaccination, advanced technological methods allowed scientists to produce desired antibodies in laboratory using different animal species (by purifying their blood or through cellular cloning). Until recently, antibody production was exclusively associated with living creatures. Basic structure of the antibody is well known, but there is still a variable part of the protein that will change to fit each new antigen presented. In the body, one B cell lymphocyte could produce over billion different antibodies that will match and eliminate foreign substances successfully. Manually created antibodies were hard to produce without modern manufacturing techniques. Nanotechnology is already widely used and applied in various scientific fields. It proved to be useful even in the field of immunity, enabling scientists to develop first plastic antibody.

Dr. Ken Shea, Professor of the Chemistry at the University of California, designed and tested first nanotech derived antibody. Nanomaterials and nanoparticles are made out of polymers that will assemble in a predetermined way. To obtain a mold that will be used for the artificial antibody production, plastic material was placed around antigen. After antigen was removed, cavity that left behind served as pattern for plastic antibody production because it perfectly matches shape of the antigen that should be recognized and eliminated. When bigger pool of plastic antibodies was created, professor Shea start experiments with mice to test their efficacy in vivo. Mice were injected with lethal dose of bee venom. Animals that didn't receive plastic antibodies died, while 60% of immunized mice survived lethal dose of toxin. Important observation in this experiment was that plastic antibody managed to recognize circulating toxin (antigen) out of many other molecules in the blood and successfully eliminate it in 60% of animals. Besides proven selectivity, plastic antibodies have few more advantages compared to naturally derived antibodies. They are abiotic and manufacturing process doesn't require living organisms. Production is simple, faster and cheaper than conventionally applied procedure. Artificial molding of the antigen requires less time than naturally occurring recognition and response. Also, plastic antibodies could be applied in numerous ways. Dr. Shea’s laboratory is mainly focused on antidote production. Intoxication after snake or spider bite are often in the nature; some of them require fast and efficient treatment, and unfortunately, list of toxins without appropriate antidote is still long. Other promising application of plastic antibodies could be seen in protein purification and in a diagnostics field. Couple of issues needs to be solved before experiments on human start. Scientists still investigate clearance and metabolism (after binding to the antigens) of plastic antibodies. Main weak point: without naturally created antibodies, organisms will not “remember” antigen attack and it will be helpless when same antigen enters the body in the future (if artificially antibodies are not provided again). As mentioned before, adequate immune system response is dependent upon chemical signals and different type of cells that are playing complex roles while defending the body against foreign substances. Plastic antibodies couldn't communicate with the rest of the immune system and couldn't blend in cascade events typical for the immune response - they act on their own. But that doesn't mean that artificial antibodies should be rejected, they just need to be modified.

Plastic antibodies proved to have great potential and multiple applications and it is just a matter of time when they will be improved and approved for human use.
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Retinal devices and artificial cells

November 23, 2012, 9:24 am
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Thanks to the complex sensory system we can hear, smell, see, feel and taste the world around us. Each sense is important and has unique anatomy that can help us modify our behavior and adapt to the environmental changes. When one of the senses is damaged, remaining senses intensify their function (blind people hear better than people with normal vision). Sight can be impaired in numerous ways. Due to complicated anatomy of eye and associated neuronal connections, development of a device that could help restore damaged vision is truly a challenge. Luckily, advanced technology allowed scientists to design couple of prototypes that will soon become available for a worldwide use.

Eye is the central organ for the sense of vision. Retina is photosensitive part of the eye; it consists of the rods and cones (modified neuronal cell) that are responding to the light by generating action potential that is traveling through the optic nerve (formed by the retinal ganglion axons) to the visual cortex where image will finally be created. Blindness is usually associated with retinal damage, either as a consequence of an accident or as a result of diseases like macular degeneration, retinitis pigmentosa, cone-rod dystrophy…..

Two types of retinal devices are currently under investigation.

Epiretinal device consists of internal and external part. Silicon platinum electrode array (internal part) is placed on the inner surface of the retina. External part of the device consists of glasses containing miniature camera. Images captured by camera are wirelessly sent back to antenna in the inner electrode array. Electric impulses from the array will trigger remaining retinal cells and generate electric signal (visual information) that will travel to the brain via optic nerve. Patients need to learn how to interpret visual patterns. Disadvantage: external part of the device can be bulky and patient needs to move head to “update” visual information. Also, internal part needs to fit perfectly to prevent disturbance of the nearby axons (it can be fixed to the retina using miniature tacks). Epiretinal device finished clinical trials successfully; soon it will become available in couple of European countries.

Subretinal device is placed on the surface of the retina, between retinal photosensitive cells and retinal pigment layer. This prototype stimulates retinal cells directly. It consists of silicon pad containing light sensitive micro-photodiodes. Electric signal, generated by light, passes to the retinal cells and further to the brain. This device doesn’t need external apparatus, but it requires power supply to amplify up-coming light signals, which is the main disadvantage of the subretinal device. Problem could be solved using the artificial cells able to generate electricity. Experiments of that kind were conducted couple years ago, when group of scientists wanted to design artificial cell using eel’s electrocyte as a cell model. Eel use electrocytes to stun the prey, but they are also important for detection of various stimulus. Biochemistry behind the cell electricity is relatively simple. Cell voltage and electric current are associated with ion channels activity. Exchange of sodium and potassium currents over the cell membrane alter the cell voltage and trigger electric current. Electrocytes act like a nervous cells - initial signal travels fast and it is easily transferred to the next cell. Different types of ion channels will be more or less densely distributed along the cell membrane (depending on their function). Electric eel can generate up to 600 volts of electricity thanks to thousand of simultaneously firing electrocytes. Scientists wanted to investigate what are the main ion channels and find a way to increase produced electricity by altering their functions. Using the software, numerical design optimization method was applied to investigate which channels produce electricity under which circumstances. After main channels were detected, scientists enhanced their activity and ended up with the cell that could produce 40% more electricity than electrocyte in the natural environment. This type of cells could serve as bio-battery. Using 4 mm wide layer of electrocytes, 300 microwatts of electricity was generated. That amount of electricity would be enough for various implanted micro-devices, including retinal device. Artificial cell is still under investigation.

Although described devices are still not available (at least not everywhere), nor they are perfect, blind people are closer than ever to regain their sight.
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Ways to enrich ourselves with great knowledge

November 24, 2012, 8:47 am
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Hi,
I believe that becoming a mastery in a particular subjects of life science and Non-Life science subjects can help me acquire a great knowledge to become a successful researcher in the field of life science.
My Favourite inter-disciplines or life science studies are:

Genetic Engineering
Microbiology
Immunology
Pharmaceutical Biotechnology
Cell biology
Molecular biology
Biochemistry
Tissue culture studies
Nano biotechnology and
Ayurvedic/siddha/Indian traditional medicines.

I've a hope and confidence that i can surely become a master in biotechnology by doing M.Sc.Biotechnology and Phd in genetic engineering can give a mastery knowledge in GE.

But i don't know how to enrich myself in remaining subjects or don't know how to acquire a mastery in other disciplines..

My thought's may be stupid.But help me How to approach or to work to acquire broad knowledge in all those subjects..

Plz ..I'll be very helpful if any one can show a right path..
Plz..Help me by giving what ever suggestions,I'm ready to work hard..
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Dietary Benefits and the Industrial exposure hazards of the Essential metals

November 26, 2012, 3:41 am
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Metals possess wide range of applications from domestic to industrial use. Inspite of its toxic nature and effect on exposure of various metals few metals are very essential for the human body to carry out normal biological functions. The significant elements playing a vital role in influencing biological process are Chromium(III), cobalt, copper, Iron, Magnesium, Manganese, Molybdenum, selenium, vanadium, tantalum and zinc.

Chromium(III): The recommended daily intake of this element is 0.06mg and the dietary chromium(III) is involved in the metabolism of lipids and sugars. Chromium is widely used in paint industry, fabrication industries and in leather industry for tanning. The industrial exposure to compounds of chromium is found to cause skin ulcers, perforations in the nasal area and inflammation of liver and larynx. The target organ of chromium is the respiratory tract, central nervous system (CNS), liver, skin and kidney.

Cobalt: Key element of vitamin B12 and the recommended daily dietary intake is 0.3mg. Cobalt is generally obtained as a by product from different metals and is widely used in salt form as catalyst in paint industry to enhance the activities like drying of paints and to produce pigments. Excess intake of cobalt results in a condition called polycythemia and the target organs of cobalt are the GI tract, respiratory tract, CNS, cardio vascular system, skin and endocrine.

Copper: Plays a vital role in oxygen transport and influences the uptake of iron by the body and also involved in biological process by transporting electrons. The recommended daily dietary intake is 3.2mg. Copper is widely used metal in industries and its salts posses antibacterial and antifungal properties. The sensitivity to copper toxicity is less in humans but the oral intake of copper in its salt form may even be fatal. Blood and GI tract are the target sites of copper.

Iron: Significant element for the production of hemoglobin and also aides oxygen transport with daily dietary intake of 15mg. Iron as a metal is widely used in the steel industry for fabrication. Iron toxicity is either acute or chronic. Hemochromatosis is the condition arising as a result of chronic iron poisoning. The target systems of iron are the GI tract, respiratory tract, CNS, liver, blood and endocrine.

Manganese: Manganese is a significant element required for good bone health and structure. The recommended daily dietary intake of manganese is 5mg. Manganese as such and its derivatives are used in manufacturing steel alloys, batteries, coils, glass and many other applications. The target sites of manganese are the respiratory tract and CNS. The acute manganese poisoning as a result of inhalation affects the respiratory system whereas the chronic toxicity affects the central nervous system.

Magnesium: Being a co-factor for different enzymes catalyzing various biochemical reactions and important element in energy production the recommended daily dietary intake of magnesium is 500mg. The major industrial application of magnesium is in manufacturing alloys. Inhalation of the oxide form of magnesium causes metal fume fever. The target organ of magnesium is the central nervous system.

Molybdenum: The recommended daily intake of molybdenum is 0.35mg. The multiple functions of molybdenum involves energy production, maintaining the function of kidney by processing the water and participation in the biologic phenomenon of the nervous system. Molybdenum finds its way into industries producing lubricants and catalysts and it is also used in manufacturing temperature resistant steel alloys. Molybdenum toxicity in humans is not evident. The target organs of molybdenum are the liver, blood, kidney and bone.

Selenium: Selenium is considered as a good antioxidant protecting cells from free radicals and also important element for a good immune system. The recommended daily dietary intake of selenium is 0.06 to 0.15mg. Selenium finds its way into industries manufacturing electronic items, ceramic and steel industries and chemical industry. Acute toxicity of selenium causes damage to the central nervous system and chronic toxicity is exhibited by GI tract disorders, smell in the breath, anemia, damage to spleen and pain in the lumbar region. Selenium is also classified as teratogen. GI tract, CNS, skin and liver are the target sites of selenium.

Vanadium: Vanadium takes care of the blood vessels by protecting them by blocking or inhibiting the formation of cholesterol. It is involved in energy production and metabolism of fat as well. The recommended daily intake of vanadium is 2.5mg. Vanadium is used in the process of steel making, pigment production and also in the production of insecticides. Bronchitis and bronchopneumonia are the conditions upon exposure to vanadium. Also effects on GI tract, skin and tongue is noticed. The target organs of vanadium are the respiratory tract, CNS, skin and kidney.

Zinc: Zinc is the most important element participating in cell division and growth. Zinc is also considered as a vital factor in fertility. Zinc has an affinity for immune system, hair, nails and skin and enhances them. Zinc can also be mentioned as an elemental factor in gene expression. The recommended daily intake is about 12mg. Zinc is used in manufacturing various products like paint, rubber, preservatives of wood, paper and glass. The metal fume fever on inhaling zinc oxide and skin toxicity on exposure to zinc chloride are some of the effects of zinc compounds. Zinc targets the GI tract, blood and the bone.

Thus the significance of the dietary elements and the occupational hazards of the same elements has been explained.
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Gene therapy for Pancreatic cancer

November 26, 2012, 4:12 am
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Developments in the treatment of pancreatic cancer using gene therapy:

Among the different types of cancers, pancreatic cancer remains to be one of the most prevalent one that is difficult to treat due to its complex nature and poor prognosis. Various issues in the diagnosis of the disease in the early stages including location in the anatomy and improper symptoms; the rapid spread of the disease to the nearby crucial organs including the duct of bile, the blood vessels and nerves; the metastasis of the disease due to a minor primary focal point such as tumor; and the meagre disease response to different cancer-specific therapies, are responsible for the difficult prognosis of the disease. Since, the diagnosis of the disease in the early stages is difficult, hence in-depth research and clinical trials are necessary to discover a new method of treatment for the disease.

Gene therapy has shown great promise in the therapeutics for different diseases, especially cancer in the past few years. The main reason for the success of gene therapy lies in the fact that it targets the genes involved in the progress or development of a particular disease. In the therapy for cancer, the process mainly targets the different genes that may be responsible for the spread of cancer or those that prevent the killing of cancer cells. It may also help in the delivery of different specific devices that help in the killing of cancer cells.

The molecular abnormalities related to the pancreatic cancer is the typical occurrence of a point mutation in the K-ras gene associated with the K-ras signalling mechanism; apart from the presence of abnormal p53 gene, abnormalities leading to suppression or loss of expression in the DPC4 gene and DCC gene, different types of mutation mainly somatic in APC gene, the above-normal expression of the different fibroblast growth factors (acidic as well as basic) and the instability of the microsatellite. Since, the main role of K-ras was observed in the potent transformation of the activity of NIH3T3 cell line of mouse fibroblasts, hence was chosen as the main target for the pancreatic cancer.

The experimental studies of T.Yoshida et.al., involved the targeting of the K-ras by the transduction of the human pancreatic cancer cell lines such as AsPC-1, MIAPaCa-2, Panc-1, PSN-1 and BxPC-3 with the plasmids expressing the antisense K-ras RNA, which resulted in the tumor suppressive effect. Hence, it showed the validity of K-ras point mutation as a molecular target and the use of antisense K-ras RNA as a possible targeting tool for the same with the data from the studies showing the dependency of the pancreatic cancer cells on the K-ras protein for the growth mechanisms. However, the role of the K-ras protein may be mainly in the initiation of the cancer and not on the progression of the disease as was shown by the absence of significant difference in the number of mutations in the K-ras gene in the different stages of the disease.

They performed the targeting of the K-ras mutation in the intraperitoneal tumor nodules in the nude mice peritoneal dissemination model, as peritoneal dissemination was one of the major metastatic modes of pancreatic cancer. However, the lipofection or polyfection of the nodules with synthetic non-viral vectors using cationic lipids had low transduction efficiency. Hence, the use of viral vectors with tissue or cell specific promoters can prove to be a better method. However, the expression profiling data related to pancreatic cancer is insufficient and requires the accumulation of the data for the identification of unique tissue or cell specific promoters.

The use of immune system is another procedure for the targeting of the pancreatic cancer cell lines. The role of Interferon-α protein in the growth inhibition of cells and the presence of its antitumor activity in pancreatic cancer may help in the targeting of the immune system, although there is not much significance in the results observed. Hence, the cytokine gene therapy involving the introduction of cytokines directly to the tumor cells using vectors can be potent in the therapeutics for pancreatic cancer.

Thus, it is observed that the approach for the therapeutics for pancreatic cancer should be multidisciplinary for the development of probable protocols that may be utilised for the clinical trials associated with the disease. The significant progress observed in the studies of gene therapy, cytokine gene therapy combined with stem cell biology, vectorology, immunology, etc may help in the development of effective therapeutics for pancreatic cancer in future.
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Potential cure for Alzheimer's disorders

November 26, 2012, 5:07 am
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Treatment for Alzheimer disease:

Modern medicine and well established healthcare system prolonged the average length of the human life. Old age is associated with numerous neurodegenerative disorders; most typical is Alzheimer’s disease. Risk for developing Alzheimer’s disease is increasing with the age. It is estimated that 10% of people over the age of 65, and 50% of those over 85 suffers from Alzheimer’s disease. Most cases develop sporadically and just 1-5 % of Alzheimer’s cases are genetically inherited.

Alzheimer’s disorder is first described in 1906. Post mortem brain analysis and blood markers provided more information on this pathological brain disorder over the past 100 years, but exact trigger for the disease and successful treatment method are still lacking. Alzheimer’s disorder is characterized by brain shrinkage, loss of neuronal connections and disrupted blood brain barrier. Several theories about disorder genesis exist: cholinergic theory, where lack of acetylcholine triggers disorder, herpes simplex virus induced disorder, age related impaired myeline breakage or oxidative stress as a cause of neurodegeneration…Most probable are ones associated with altered metabolism of amyloid precursor protein and tau protein. Amyloid precursor protein is building part of neuronal synapses and essential ingredient of various cell membranes in the body. Proteolitic degradation of amyloid precursor protein results in formation of the fibrial protein - beta amiloid that is found in brain plaques, typical for Alzheimer’s disorder. Beta amiloid alters calcium ion homeostasis (resulting in apoptosis), inhibits enzymatic activity and prevents glucose utilization. Tau protein is essential for development of neuronal polarity; it promotes neuronal microtubule assembly and enhances axonal dynamics. When tau protein is hyperphosphorilated, it becomes insoluble and forms inclusions known as neurofibrillary tangles. Those tangles are associated with neuronal degeneration. Alzheimer’s disease can be diagnosed using couple of techniques: brain imaging (computed tomography or magnetic imaging), through neuropsychological tests or by blood analysis (couple known markers exist). Current treatments are focused on the main attributes of Alzheimer’s disease: dementia (memory loss), depression and cognitive impairments. Medication used is just slowing down the progression of neurodegeneration but it can’t prevent disease. Typical mechanism of action is focused on proteolysis of amyloid precursor protein; latest drugs could prevent proteolysis or bind to already formed beta amyloid prior its aggregation and eliminate it. Other drugs affect distribution of beta amiloid through the brain or decrease the rate of neuroinflammation. Alzheimer’s disease is one of the most common neurodegenerative disorders associated with old age and one of the most expensive to be treated because patients demand special care due to physically, physiologically and socially altered behavior.

Latest discoveries in the stem cells field could move Alzheimer’s treatment in completely new direction. Scientists from the University Of California, Irvine developed new line of stem cells - choroid plexus epithelial cells (CPECs) using human and mouse embryonic cells. Choroid plexus is part of the brain ventricles where cerebrospinal fluid is produced. This liquid is important for cleaning the waste products and metabolites that could damage the brain function. 500 milliliters of cerebrospinal fluid is produced each day, and it is renewed 4 times a day to ensure efficient detoxification of the neuronal tissue. CPECs are forming important blood - cerebrospinal fluid barrier. Neurodegenerative disorders are associated with dysfunctional CPECs and inefficient removal of the waste material (like beta amiloid) from the cerebrospinal fluid. Scientists were familiar with the role and importance of CPECs cells, but until now they couldn’t find the way to produce those cells in vitro. Embryonic cells are pluripotent and different transcription factors determine their cellular faith (direction of their differentiation). After discovering that brain morphogenic factor 4 (BMF4) is responsible for differentiation of the neuronal progenitor cells into CPECs, researchers applied BMF4 to produce sufficient amount of CPECs. Both human and mouse neuronal progenitor cells used in the experiment matured successfully into CPECs after BMF4 was applied. Developed CPECs act just like naturally produced cells; they could integrate in choroid plexus epithelium and form secretory vesicles. Neurological disorders associated with the accumulation of the peptides, proteins and other metabolites that alter normal function of the brain could be treated using CPECs. Scientists are hoping that this approach will be especially helpful in Alzheimer’s and Huntington’s disease as well in treatment of pediatric neurodegenerative disorders.
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What is personalized medicine and how does it work?

November 26, 2012, 9:44 am
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Recipe for every living creature is encoded in its DNA. Unique genetic combination inherited from parent determines phenotype of the newly created organism. DNA differences are smaller than expect. Out of 30.000 genes present in human genome, 99.9% is mutual for all humans and just 0.1% is unique and specific for each individual. That amount of genetic variability (genetic polymorphism) is responsible for wide range of phenotypical differences that exist in human population. Besides obvious physical differences, the way human body works is individual and specific. Metabolism, sensitivity toward one type of diseases and resistance toward others, effectiveness of given treatment or lack of its effect … are part of the genetic makeup that is unique for each person.

Medicine is developing faster than ever in the past couple of years. Slight genetic differences between people could provide useful information, accelerate treatment and reduce side effect of marketed drugs. Medical field focused on identification and utilization of the patient’s genetic and molecular background aiming to improve medical approach is known as personalized medicine.

Some disorders are genetically predisposed. Breast and ovarian cancers are associated with mutations in BRCA1 and BRCA2 genes. When family member is diagnosed with cancer, genetic testing could show whether altered gene is present (or not) in close relative. Specific mutations are associated with more or less aggressive type of the cancer. When genetic testing reveals “dangerous” form of gene, breasts or ovaries could be removed to prevent cancer development. Also, genetic testing could help determine which patients are suitable for chemotherapy, and which aren’t. It’s estimated that chemotherapy could be reduced by 34% if patients underwent genetic screening before treatment.

Pfizer has specially formed group focused on personalized medicine. Lung cancer statistics is not that bright. Recent experiments showed that life expectancy could be prolonged if genetic profiling is conducted prior therapy. Unselected cancer treatment (universal chemotherapy and radiation) during 5 years resulted in 6-15% survival rate (depending on the disease stage). Molecular targeting brought improvements in the field of lung carcinoma. Xalkori is non-small lung carcinoma selective drug that showed excellent results: partial or complete tumor response was noted in 60% of lung carcinoma cases and tumor shrinkage was noted in 90% of all non-small lung carcinoma cases. Also, life expectancy is prolonged.

Personal medicine provides useful information for physicians before prescribing the drug. Drug metabolism is controlled by various enzymes. Thanks to phenomenon known as single nucleotide polymorphism, expressed proteins could differ in one or more amino acids resulting in end product with different biochemical properties. When patient is familiar with its genetic polymorphism, doctor can prescribe certain dose or specific drugs that will be metabolized without serious side effects. Conventional approach of drug development (for the wide masses) is expensive and non-economic. Around 11 million dollars are spent every year for 15 new drugs that will induce more or less side effects (depending on the patient’s genetic profile) or prove to be ineffective for targeted disorder. Genetic identification of the patients would save money and time by pointing out the best therapeutic solution for each individual.

Number of drugs that are specifically tailored to fit patient’s genetic profile is increasing each year. From the 13 drugs marketed in 2006, number increased to 72 drugs of personalized medicine kind in 2011. 33 biomarkers are included in FDA's drug labels.

Personalized medicine is growing industry. Saliva is perfect source of DNA for the in-house testing. After delivering saliva to the specifically designed kit, it should be sent to a licensed laboratory for further processing. This method is not expensive and it is relatively fast (laboratory will send you results of genetic profiling in couple of weeks). Like every other medical innovation, this one couldn’t be implemented over the night. Not all doctors are thrilled that they will have to analyze another piece of paper prior prescribing the drug and some of them don’t find genetic profiling useful at all (16%). Electronic medicinal files are already in use in most hospitals over the world. By 2015, hospitals and healthcare professionals should collect as much molecular and genetic profiles as possible. Large (global) database could be used for targeted drug discovery and safer application of the already marketed drugs.
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Factors Governing the Expression of a Toxicant

November 26, 2012, 10:25 pm
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A study on toxicants and factor influencing the toxicity:

Any substance that is known to cause deleterious effect on a biological system upon interacting with the system is called as toxicant and the ability of the substance to bring about such change is described as Toxicity. A substance classified as a toxicant requires a medium or host to exhibit its toxicity and it is not as simple as that for the substance to bring about immediate effect. The expression of toxicity by a toxicant is governed by various factors like nature of the toxicant, the mode of exposure and the biologic system (individual coming in contact with the toxicant).

The chemical and physical nature of a toxicant, presence of any adulterant, stability of the toxicant when stored and in the biological system and the elements used for proper delivery of the toxicant are the factors influencing toxicity classified under the nature of the toxicant. In case of any impurities present along with the toxicant, the chances are that the impurity may itself be more toxic than the toxicant or the impurity may alter the toxicity of the toxicant. Same is the case with the additional compounds used in the formulation of a toxic agent. Also the media used to either dissolve the toxicant or suspend the toxicant for the better mobility influences toxicity which draws a closer observation while selecting the media.

The dose of the toxic agent, the concentration and the quantity of the toxicant, the route and site of administration, the rate of absorption, time of exposure and the frequency and length of exposure are all the exposure related factors governing the toxicity of the toxic agent.

Next factor influencing the toxicity is the biological system. Biological system refers to the animal or the individual who is coming in contact with the toxicant. The internal environment of the individual and the external environment which acts as the habitat for the individual have influence over the toxic agent entering the individual. The internal environment includes the type of species, genetic profile, immunologic profile, the dietary factors, age and gender and health and the existing disease if any. The ill effect produced by a toxin may not be same for all the species. A substance more toxic in one species may be less toxic or may not be toxic in the other.

The genetic profile influencing toxicity is explained by difference in response shown by the rabbits to the drug atropine. Few rabbits were found to have developed effects of the drug whereas few others showed resistance to the drug and the reason for the resistance was explained by the detection of the enzyme atropine esterase in the blood. This experiment validates the role of genetic profile in determining the toxicity. An altered toxic response to the same toxicant by an individual who developed sensitized reactions in response to the same toxicant earlier explains the role of immune system in influencing toxicity. As diet has direct influence over the health, metabolic process, biological function of the body ultimately it also has influence over the toxicity of the toxicant. Effect of toxicants in starved animals, toxicity of the substance in partially fed animals, expression of toxicity by the toxicant in response to altered diets are the various researches conducted on animals to understand the complete relationship between the diet of the animal and its effects on the toxicity of the test element. Though it is a very complex criteria to derive the relationship between different diets and different toxicants, it is understood that toxicity is influenced by diet.

Many experiments have been conducted to validate the effect of sex and hormones on the toxicity. One such experiment is that chloroform was found to be lethal for male mice of specific strain whereas the female mice of the same strain were found to be unaffected. Introducing estrogens to the male mice and introducing androgens to female mice before exposure to chloroform showed altered effects like male mice was protected to an extent and the female mice was found to be susceptible to the effects of chloroform.

Temperature, pressure and radiation are the factors related to external environment influencing the toxicity. Temperature is directly proportional to the toxicity and inversely proportional to the period to develop response. Next the change in pressure builds a stress in the body which may have effect on the toxicity. So it is advisable to consider pressure as a factor while studying the toxicity of an element. The known effects of radiation on the biologic system make it another factor influencing the toxicity.

The effect of one toxicant varies over the other under the above discussed influential parameters making it really a complex matter of subject to understand while studying toxicants.
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Genetically predisposed circadian rhythm and time of death

November 27, 2012, 2:01 am
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Living creatures adjust their biological activities according to the local environmental factors. Thanks to those factors, animals could determine perfect time to eat, sleep, mate, migrate… Pattern of behavior is changing during the day, week or season. Day light is the most important factor that affects biological activity on a daily basis. Established rhythm of behavior is known as circadian rhythm and it is driven by circadian clock. This “clock” is endogenous and it is unique for each individual. People are usually classified as early birds or night owls. No matter which category you belong, latest discoveries reveal genetic background behind this phenomenon.

Suprachiasmatic nucleus is located in the hypothalamus. This organ receives information about day light from retina via tight neuronal connection (retinohypothalamic track). After day light information is processed, it will be sent to a pineal gland that is responsible for melatonin production. Melatonin is hormone essential for sleeping. Level of melatonin is highest in the night and lowest in the morning. This hormone is important marker for sleep-wake rhythm screening. Electric light in the evening can affect normal circadian rhythm by delaying sleeping phase. Every man has its own rhythm and not all people demand 7 hours of sleep to achieve body refreshment and prepare themselves for the up-coming daily activities. Sleep duration is dropping down with age and old people usually sleep just few hours per day.

Scientists from the Neurological department of the University of Toronto investigated sleeping patterns of older people and discovered connection between genotypes and circadian rhythm. It was shown that genotype could even predispose time of person’s death. Original idea of the study was to investigate potential triggers of Alzheimer’s and Parkinson’s disease in the certain age group. Since all patients were genotyped, Dr. Lim (leader of the project) decided to expand study goals and explore connection between sleep-wake patterns and specific genotypes. This was large study conducted on the 1200 individuals having 65 years or more. It lasted over a decade and participants donated their brains for further post mortem analysis. Period 1 and Period 2 genes are well known genes, recognized as important for light entrapment and establishment of normal sleep-wake rhythm. When those genes were altered in experiment with mice, animals couldn’t respond normally to the light changes and sleeping pattern was disrupted. In this study, single nucleotide, located near Period 1 gene, showed slight alteration that correlated with differences in sleep-wake pattern observed between study participants. Adenosine (nucleotide) was found in 60% participants at the mention location while guanine was found in the remaining 40% cases. Since DNA is double helix, chances that adenine will be seen in other chain was 36% (resulting in A-A genotype), chances that guanine will be seen at exact same spot in the other chain was 16% (resulting in G-G genotype) and finally there was 48% chance of having a mixture of adenine and guanine (resulting in A-G genotype). Three described genotypes showed different sleeping patterns. A-A genotype wakes up one hour before G-G genotype and waking time of the A-G is in the middle of the A-A and G-G genotypes. Expression of the Period 1 gene is lower in the individual with G-G genotype during the day when the gene is normally expressed. Since every biological activity is driven by circadian rhythm, Dr. Lim wanted to discover if genes affecting sleep-wake pattern could also affect the time of death. Patients enrolled in the study participated over 15 years and a lot of them died during the study due to natural causes. Closer analysis of brain tissue and genetic material showed direct correlation between most likely time of a death (part of a day) and genotype. Participants with A-A and A-G genotypes passed away around 11 o’clock in the morning and participants with G-G genotype passed away around 6 o’clock in the evening. For the first time, one study showed that circadian rhythm could affect not just the time people will wake up or go to sleep, but the time when they will die.

Further experiments and even more information on this subject would be helpful for people working in shifts, changing time-zone often (and dealing with jet lag) or having trouble with daily tasks organization.
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Teratogen Effects and Evaluation - Are they Toxic?

November 27, 2012, 2:39 am
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Summary: All teratogens are toxins and not all toxins are teratogens

The drug or chemical with a potential to affect the fetus resulting in any malformation of the structure is called as teratogen. Teratogen is different from a toxicant as the former brings about any undesirable effect at the cellular level of the unborn fetus and during the organ formation and the later is known to affect at any stage of development. The effect of teratogen is not noticed once the organ formation of the fetus is completed. Hence Teratogen can be called as toxins of the fetus in the womb affecting the generative stage. The specialized subject to study the congenital malformation is called as Teratology and the substance responsible for causing malformation is called as teratogen.

There are various factors responsible for the congenital malformation. Heredity, presence of any particular infection in the pregnant women in early terms of pregnancy (Rubella infection is a good example), Nutritive deficit carrying mother, physical parameters like temperature and radiation and other environmental factors like pollutants present in air and water and chemicals are the factors to be considered while finding out the reason for either child born with defect or death of the fetus in the womb.

The teratogen acts in several ways. It affects the zygote resulting in the inhibition of further growth or cause mutation in the zygote. Teratogen is known to block any one of the steps in fertilization thus preventing the formation of the embryo. Also it has potential effect on the embryo, interferes in the cell division. The effect of teratogen is observed even at the time of implantation. Implantation is the process of embryo embedding in the endometrial lining of the uterus and exposure to teratogen at this stage may prevent the implantation resulting in the embryo leaving the uterus. Also teratogenic chemicals interfere in the organ development of the fetus causing malformation. Any undesirable effect on the fetus by a chemical after organ formation is completed is explained in the terms of toxicity and teratogen does not come into picture for the effects caused at this stage.

To identify and understand the teratogens affecting humans, the substance is initially experimented on laboratory animals. The selection of animal for this procedure is quite complicated as any animal tested should be closer to humans in the way that chemical is metabolized in humans, should have placenta similar to humans and the similar pregnancy term as that of humans and should be able to produce many offspring in order to understand the effects of the teratogen in subsequent generation. Also the size of the animal and the testing cost are other factors to be considered while selecting a test animal to study the effect of teratogens.

Also the route of administration of the drug under evaluation is important. The most preferred route of administration in the test animal is through peritoneal injection. As to evaluate the effect of different dosage of drug at different stages of gestation the time of injection of the drug to the test animal and the dosage selection are very crucial factors. After the full term the pups of the test animal are observed for three types of malformation like malformation seen visually, malformation in soft tissues and anomaly in the bone. The effects of teratogen are observed only in the stages of development whereas the effect of a toxicant is prenatal as well as postnatal.

Some of the drugs classified to be teratogenic to humans are Thalidomide, Vitamin D, androgen, estrogen, chemical agents used in chemotherapy and some of the antimetabolites and alkylating compounds. Few examples of compounds with teratogenic threats to humans are quinine, meclizine, phenmetrazine, tetracycline and cyclophosphamide. Examples of the beneficial teratogenic drug detected in animals are salicylates, Vitamin A, Vitamin D, adrenocorticoids, insulin and sulfonylureas.

It is not necessary that all the teratogens are chemicals/drugs, even radiation, some metals, minerals and pesticides are teratogens. X-ray is identified as a potential teratogen. Teratogenic effects of molybdenum, lead, zinc and manganese were identified in different animals. There is no evident of Teratogenic effect of pesticides in humans. The study by Green and team in 1967 reported the teratogenic effect of DDT, heptachlor, aldrin and endrin in eggs of chicken.

In simpler terms it can be explained as 'All teratogens are toxins and not all toxins are teratogens'.
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The most influential women in biotech industry

November 27, 2012, 7:21 am
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When you think about successful business and innovations in biotechnology field, first thing that comes to your mind is probably a clever man surrounded by the group of scientists. Women, especially those on the leading positions, are still minority in the biotech industry. Luckily, this trend is changing and number of intelligent and skillful women in biotech industry is increasing each year. Here’s the list of most influential women in biotech industry created by Ryan McBride and John Carroll of FierceBiotech.

Kathryn Biberstein, Alkermes

Kathryn is senior VP and chief compliance officer at Alkermes. Before joining Alkermes, she was working as a general counsel for Merck Serono in Switzerland. Kathryn is successful negotiator with long multinational experience in biotech industry. She speaks French, German and English fluently. One of the greatest achievements was doubling Alkermes business by acquiring Elan Drug Technologies for 1 billion dollars in 2011.

Abbie Celniker, Eleven Biotherapeutics

Abbie is CEO at Eleven Biotherapeutics. She holds a PhD in molecular biology. Her career started in Genentech and continued in a couple of respected pharmaceutical companies such as Wyeth, Millennium and Novartis during the next two decades. After improving Taligen Therapeutics business, she sold its key assets for 111 million dollars to Alexion Therapeutics. Besides dealing with business team and investors, Abbie is currently focused on protein engineering and immunotherapeutic development.

Kathleen Sereda Glaub, Plexxikon

Kathleen is president at Plexxikon. Prior Plexxikon, she was working at Genentech and Cell Genesys. Thanks to collaboration and partnering with various pharmaceutical companies, her group at Plexxikon managed to collect over 200 million dollars worth funding. Also, she helped conclude buyout pact with Daiichi Sankyo (for 1 billion dollars) and improved marketing and sales strategies for the newly approved melanoma drug Zelboraf.

Mary Lynne Hedley, Tesaro

Mary Lynnes is CSO and co-founder at Tesaro. After post-doctoral studies at Harvard, she started her own small pharmaceutical company, Zycos, focused on cancer and anti-viral drug development. Company was later sold to MGI Pharma where she continued working in the R&D sector. MGI was acquired by Eisai for 3,9 billion dollars in 2008. At Tesaro, Dr. Hedley is focused on cancer drug and supportive care development.

Bahija Jallal, MedImmune

Before joining MedImmune, Bahija served as VP of drug development at Chiron. Today, she is head of R&D at Medimmune, responsible for 2000 investigators working on 140 R&D programs in Gaithersburg, Maryland and Cambridge, UK.

Kiran Mazumdar-Shaw, Biocon

Kiran is founder and chief of Biocon, biggest Indian biotech company. They are focused on the insulin production and peptide drug development (anti-CD6 for psoriasis). Thanks to successful collaboration with USA pharmaceutical companies, drugs could reach market faster. Deal with Pfizer provides the company 200 million dollars for biosimilar insulin development.

Susan Molineaux, Calithera Biosciences

Susan is CEO at Calithera Biosciences. She started her career in Merck, New Jersey, followed by Rigel Pharmaceuticals, where she worked as VP of biology, focused on drug research. Soon after, she moved to Proteolix. From the drug development, she switched to biotech menagment working as CEO at Calithera. Also, she is implicated in mentoring the middle school students in the San Fransisco area in a program known as We Teach Science.

Julie Overbaugh, Fred Hutchinson Cancer Research Center

Julie is a scientist at Fred Hutchinson Cancer Research Center. She is graduated biochemist, focused on HIV/AIDS research. She collaborates closely with epidemiologist and scientists in Kenya (area severely hit by HIV virus). Julie runs a laboratory, where she trains and educates a lot of future scientists, beside regular research work.

Anna Protopapas, Takeda

Anna is executive VP at Takeda. She entered biotech industry with master degree in chemical engineering. Her career started in Morten Metal Technology and Proctor & Gamble, followed by Millennium pharmaceuticals. Takeda acquired Millennium for 8.9 billion dollars in 2008 (she remained at the position of the business executive after company was merged), and Nycomed for 13.7 billion dollars in 2011. Both acquisitions were successfully closed thanks to Anna's excellent negotiation skills.

Laura Shawver, Cleave Biosciences

Laura is CEO at Cleave Biosciences. She started career as a molecular biologist at Triton. Later she worked as president at Sugen. Laura was in charge for diabetes focused research at Phenomix that shut down after one of the financial partners went out. She continue further biotech career in Cleave Biosciences. After being diagnosed with ovarian cancer, she found non-profit charity organization focused on molecular screening and new therapeutics development to help women dealing with recurrent carcinoma to find a better treatment solution.

Hopefully, list of significant and valuable women in biotech industry will continue growing.

Reference: http://www.fiercebiotech.com
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