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Phenomenon of Polyandry – Justified?
Besides having fun and frustration in the research, project could emerge from a random thought: Why female of most species, including many mammals mates with multiple male partners? – A term known as ‘Polyandry’. At first, some of us might call as a weird thought until it get published in Science magazine. Price, Wedell, et al. showed possible reasons of such behavior in one of drosophila species. Team showed increased behavior of female flies to mate with multiple male partners because many of male flies were carrying sex ration-distorting gene on chromosome X which lead to failure of male sex expression (on Chromosome Y) and producing sperm infertility and more and more female progeny. Hence, to avoid spreading such selfish gene (from male!) in the offspring and to balance sex ratio, female flies try to mate more often and thus, increasing her chance to mate with normal male to produce healthy offspring. Similar selfish genetic elements may exist in humans. Implications ?!?
Moral of story: Female > Male !
References:
Price TA, Wedell N, et al. Selfish Genetic Elements Promote Polyandry in a Fly, Science 2008:322(5905);1241-1243, DOI: 10.1126/science.1163766
Exactly three years from now, series of events put me (and I guess, to those linked) in the middle of nowhere and forced me to think what exactly I want to be and where I was driven till then. Many of us move on. I am not sure whether I moved on or not from then because I do not know what it means by moving away from one’s past. I just moved along with it and it worked very well. But certainly, things are changed a lot for & around me. Now when I see thorough my work space window facing HMS, I think: Gosh! I am in the middle of everything where anything is possible provided I put my commitment to be focused, thoughtful, persistent and consistent hard-working person (…again) not thinking much about rational path or being sheep-follower. It’s scary thought reflecting not being secured for future when one have a chance to follow the safe path. I am justifying it as 1. I’d same situation three years before and now I am very well over it. 2. It depends how one defines ‘being secured’. I define it in terms of happiness I see in me and around me. One of many examples contradicting such false sense of security is following line from Robin’s Reports: “When I see bald heads, I see a badge of courage. A badge of courage worn by a little girl to remind us all life is fragile.”
Looking at current research project, it seems like I am again in middle of nowhere having so much biological complexities and having least knowledgebase in genomics. Perhaps, biology itself is my best teacher prompting me to think off the track (and not rational). As I heard my mentor saying one day: “I sometimes do not believe in these gene nomenclature. It may mislead you by ignoring those gene names who are to you off the track, far away from hematology related gene names but might be the key regulators.” That is one of the core reason being glued to complex and illusive biology experiments – the Pandora’s box: We often get snakes out of it but sometimes it gives stars and flowers too. Wish I will be more in work than putting time in such writings. Hope continues…
PS: Pandora’s box line is taken from seminar speech given by one of the postdoc at DFCI.
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Disclosure: I don’t have any personality disorder for sure but I am falling into more than one ego defense levels. Your comments are welcome;-)
Exoplanets – Quest for the other life continues…..
Scientists at NASA just published first ever photographs of exoplanets – planets outside of our solar system, captured by the all-time great – Hubble Space Telescope!
Mark S. Marley, Exoplanets—Seeing Is Believing. Science DOI: 10.1126/science.1167569 (EPub-ahead of print) | 13-Nov-2008
Image reproduced from CNN.com article(Image copyright: NASA)
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The Next Lipitor
Following major setback of CETP (Cholesteryl ester transfer protein) inhibitor - torceptrapib by Pfizer in Dec 2006 and an ending era of Lipitor monopoly, the next LDL reducing agent is nearly stepping into phase 1 clinical trail as early as next year. Using RNAi phenomenon, research collaboration between UT Southwestern Medical Center and Alnylam pharmaceuticals team (Philip Sharp and team) 1 have come up with method to target gene named, proprotein convertase subtilisn/kexin type 9, or PCSK9 – mutation of which is responsible for third form of autosomal dominant familial hypercholesterolemia (HCHOLA3). Using similar RNAi targeted approach, company has shown (Nature magazine article) reduction of apolipoprotein B (apoB) protein and thus lowering of LDL by at least 60 % and total cholesterol reduction upto 85 % in a pre-clinical models. Company is expecting to launch phase 1 clinical trail by early 2009.2
Following are quotes from the president-elect Barack Obama in his pre-election interview to Nature magazine1 in September 2008.
“…hundreds of thousands of embryos stored in the United States in in vitro fertilization clinics will not be used for reproductive purposes, and will eventually be destroyed. I believe that it is ethical to use these extra embryos for research that could save lives when they are freely donated for that express purpose.”
“…Recent discoveries indicate that adult skin cells can be reprogrammed to behave like stem cells; these are exciting findings that might in the future lead to an alternate source of highly versatile stem cells. However, embryonic stem cells remain the 'gold standard', and studies of all types of stem cells should continue in parallel for the foreseeable future.”
Let’s all hope the change will come soon and so will be the translation from basic research to clinical cure.
1. Original article:
US election: Questioning the candidates. Nature 455, 446-449 (2008) | doi:10.1038/455446a
HOPE WINS FINALLY
Many congrats to the one who believed in the faith factor.
Best Regards & more success ahead Regards, Samir
PS: This message is sent via mobile device and may contain short text message format.
A little X ray machine inside (Scotch) tape
Researchers from UCLA have discovered something very amazing in particle physics. Dr Putterman’s lab have confirmed earlier (and mostly anecdotal) reports postulating emission of X rays while peeling off common adhesive tape (Scotch® branded) from its adhesive surface. Their custom made mechanical motor driven apparatus demonstrated burst of nearly 300, 000 X ray photons lasted for about a billionth of a second, which was sufficient enough to light up closed apparatus system (see video at Nature) and even to take an medical X ray of a finger! In an cover page article of Nature magazine, team explains this phenomenon as triboluminescence - Relative motion between two contacting surfaces can produce visible light (photons) and this concentration of diffuse mechanical energy into electromagnetic radiation, including X rays.
Is there a danger of radiation on keeping office desk tapes?
So far, scientists have showed X ray emission from Scotch tape in a moderate vacuum chamber and not in an open air system. Hence, it is safe for the time being!
Any potential future implications?
Good one: Possibility of research to develop tiny implantable medical device which can burst such electrons to target and destroy tumor cells.
Bad one: Possibility of developing ignition switch to power up nuclear fusion reaction driven by emitting electrons.
References:
1. Camara CG, Escobar JV, Hird JR, Putterman SJ. Correlation between nanosecond X-ray flashes and stick–slip friction in peeling tape. Nature 455, 1089-1092 doi:10.1038/nature07378
2. Chang K. From a Strip of Scotch Tape, X-Rays. The New York Times online (link)
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Tweaking Light in Cancer Signaling
Any idea how we can play around following keywords:
“….We haven’t learned anything that makes me think this is not a solvable problem”
- Douglas Melton, PhD
An astute, dedicated, daring and person driven by hope – Dr Douglas Melton of Harvard Stem Cell Institute is once again in media by making first successful direct cell reprogramming of adult mice exocrine pancreatic cells into cells resembling islet beta cells and producing insulin as well as improving local vasculature to control hyperglycemic state in-vivo. Unlike islet beta cells reprogrammed from embryonic stem cells or induced pluripotent cells (iPS), direct cell reprogramming technique bypass complete reversal of epigenetic code and instead, research lead by postdoc Qiao ‘Joe’ Zhou used combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) to yield induced beta cells. Further research, hopefully in coming months-years would focus on reproducibility, specificity, potency and important adverse effects of these transcription factors, if any.
Zhou Q, Melton DA, et al. | In vivo reprogramming of adult pancreatic exocrine cells to bold beta-cells | Nature advance online publication 27 August 2008 | doi:10.1038/nature07314
About Dr Melton: A person who once volunteered as a glass-washer in a wet lab to satisfy his bench work hunger, Doug Melton has a remarkable and inspirational story of his own which can be read at following links:
1. Driven – Fatherhood focuses Doug Melton's powerful intellect on cure for diabetes | Harvard News | 27-Aug-2008
With prevailing pessimism in HIV preventive research1, RNAi is sprouting as promising targeted therapy in coming years. Two papers indicating successful delivery of siRNA directed against HIV genes to halt HIV life cycle at one or more check points. In a first study performed at University of Amsterdam by Brake et al. demonstrated diminution of HIV-1 replication in human T-cells following lentiviral directed anti-HIV siRNA delivery in human hematopoietic stem cells engrafted in in-vivo mice model. Team first took Rag-2_/_ƴc_/_ mice and engrafted them with human fetal liver CD34+CD38- hematopoietic precursor cells to develop human immune system (HIS) mouse model. This model is capable of developing and maturing both myeloid and lymphoid cell lines and thus, better option to study in-vitro as well as in-vivo immune functions. Researchers first conducted in-vitro experiment by transducing mature CD4 T cells with a third-generation self-inactivating lentiviral vector - JS1-shNef, which contains an expression cassette for a shRNA against the HIV-1 nef gene. Then after, these cell lines were transfected with HIV-1 virus: wild type as well as mutant type having two-point mutations in Nef gene sequence to validate JS1-shNef sequence specificity. Results came out promising showing efficacy and specificity of JS1-shNef in significantly inhibiting HIV-1 replication ex-vivo. Team took an extra step to validate results in-vivo with use of HIS mouse model mentioned above. JS1-shNef transfected stem cells were engrafted in HIS mouse and subsequent infection with HIV-1 wild and mutant type was carried out. After 8-9 weeks of transplantation, lymphoid organs from sacrificed mice were taken out; both JS1-shNef transfected and untransfected CD4 T cells were isolated and HIV-1 replication was measured. Results showed significant inhibition of HIV-1 replication in-vivo in transfected cells. However, post-transplant count of JS1-shNef transfected stem cells were lower than untransfected cells because of unknown reason and may be deleterious effect of siRNA on immune system. “The advantage of this method is that only a single application of genetically modified cells is adequate to continually generate HIV-resistant cells in the body,” says Akkina in an interview to Nature magazine2. A pilot clinical study to evaluate efficacy of this research is currently active at Beckman Research Institute under chair of Amrita Krishnan, MD3
Brake T, et al. | Evaluation of safety and efficacy of RNAi against HIV-1 in the human immune system (Rag-2(-/-)(c)(-/ )) mouse model. | Gene Ther. 2008 Jul 31. [Epub ahead of print] | PMID: 18668146
In a second study performed by Shankar et al. at Harvard Medical School used antibody-directed delivery of siRNA targeting three different genes of HIV-1. Team favors antibody-directed delivery compare to viral vector delivery as later involves questions with consistent transgene expression and also risk of immune dysfunction secondary to lenti-/retro-viral integration in host genome. They also used different mice model, NOD/SCIDIL2rƴ_/_ having immunodeficient mice strain with common IL-2 receptor gamma chain mutation which is capable of sustaining long-term growth of transplanted human hematopoietic stem cells. Using a triple target approach, researchers delivered combination of siRNAs targeting CCR5 (to prevent viral spread) and conserved target sequences in the viral Vif and Tat genes (to block viral replications) using CD7-specific single-chain antibody conjugated to oligo-9-arginine peptide (scFvCD7-9R). Results showed significant decrease in viral entry in T-cell as well as decrease in viral replication for virus integrated within host genome. Such multi-target approach could provide shield against developing treatment resistant in HIV therapy.
Kumar, P et al. | T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice | Cell 2008 [Epub ahead of print] | doi:10.1016/j.cell.2008.06.034
References:
1. HIV vaccine trials discontinuation
2. Sands T | RNA tackles HIV; 7 August 2008 | Nature | doi:10.1038/news.2008.1018
3. A Pilot Study of Safety and Feasibility of Stem Cell Therapy for Aids Lymphoma Using Stem Cells Treated With a Lentivirus Vector-Encoding Multiple Anti-HIV RNAs | Clinicaltrials.gov ID: NCT00569985
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In memory of Randy Pausch
It's not about how to achieve your dreams, it's all about leading your life. If you lead your life in a right way, karma will take care of itself. And dreams will come to you.
Lodamin (TNP-470) – First oral, broad-spectrum, angiogenesis inhibitor
Researchers from the notable scientist, Late Dr Judah Folkman’s lab (aka Mr VEGF) have reformulated TNP-470 – a two decade old potent angiogenesis inhibitor into a new formulary using nanotechnology to deliver it orally. Newer compound named, Lodamin (In Hebrew: Lo dam means no blood) by the developer Ofra Benny, PhD. TNP-470 was originally developed from an accidental observation of potent anti-angiogenesis property of fumagillin, a mold by Donald Ingber, MD, PhD then fellow in the Children's laboratory of the late Judah Folkman, MD lab. Subsequent phase I and II clinical trails showed poor oral availability and short half-life, requiring frequent, continuous parenteral administration. Importantly, TNP-470 was found to have neurotoxic side-effects and trials were stopped prematurely. In 2005, Satchi-Fainaro, PhD from the same lab reformulated TNP-470 using polymer binding to prevent drug crossing through blood brain barrier (named, Caplostatin). Using the same concept, Benny took a step ahead and conjugated TNP-470 to monomethoxy-polyethylene glycol (PEG)–polylactic acid (PLA) to form nanopolymeric micelles and coined its name, Lodamin. Lodamin in pre-clinical trials showed very high oral bioavailability as well as significantly inhibited tumor growth without neurotoxicity. It is also found to prevent liver metastasis efficiently in mice as it passed through liver during oral administration. According to author, it seems to have powerful broad-spectrum activity in anti-angiogenesis and thereby, tumor growth suppression.
Further reading:
1. Original article: Folkman J, Ofra Benny et al., An orally delivered small-molecule formulation with antiangiogenic and anticancer activity, Published online: 29 June 2008 | doi:10.1038/nbt1415 | PMID: 18587385
PS: I feel lucky enough to work in a building next to where this as well as many other exciting things are happening every day (and night!). It’s a driving force….
Best citation of Phoenix (so far) to me
I never knew about Dr Sherwin Nuland until I saw his TED talk video where he describes his life following divorce and overcoming major depression to find the second chance of living. Interesting to me is when he ended his talk with the example of Phoenix as the most popular resurrection ever happened (Right! It’s mythological and may be delusional but it’s the symbol of faith and force and that’s the reason it inspires me every day)
In Dr Nuland’s words:
Perhaps the most popular resurrection theme outside of specifically religious ones is the one about the phoenix, the ancient story of the phoenix who, every 500 years, resurrects itself from its own ashes to go on to live a life that is even more beautiful than it was before. Richard, thanks very much.
You can see video here too. He cites Phoenix in the very end of a talk. Read transcript and Wikipedia entry on him. His book How We Die: Reflections on Life's Final Chapter (ISBN: 0679414614) remained NYT best seller for 34 weeks.
Working on Weekends…..
Professor Oliver Smithies lecture at Nobel Prize ceremony (2007) is worth watching for those beginning career in research. He aimed this lecture for lab researchers. At the age of 82, he still works on weekends, has preserved more than 100 of his lab notes right from the beginning of his research career and shows his home-made gel electrophoresis and PCR machines! In conclusion, he inspires to keep on working on ideas and especially on Sundays:-)
PS: For those who are color blind and worry about practical issues in lab (I was one of those an year before), FYI: Prof. Smithies is a color blind (Ref.: Wikipedia)
PS: For almost two months, I have not blogged and rather putting article links I go through in Medbuzz. Blogging the summary of article(s) takes time as I am not good at summarizing. I plan to restart by blogging 1-2 posts a week from now and see how it goes for me. Till then, please use Medbuzz or feed aggregator here and enjoy the DNA world (& Obama-Clinton finale tonight!) Thanks
Clinical Alert - 1 out of 4 teenage girls in US has STD
Today, 2008 National STD Prevention Conference (March 10-13, Chicago IL) by Center for Disease Control (CDC) is publishing a study report which estimates ONE IN FOUR(26 percent) young women between the ages of 14 and 19 in the United States (3.2 million teenage girls) is infected with at least one of the most common sexually transmitted diseases (human papillomavirus (HPV), chlamydia, herpes simplex virus, and trichomoniasis). This is the first to examine the combined national prevalence of common STDs among adolescent women in the United States, and provides the clearest picture to date of the overall STD burden in adolescent women. African-American teenage girls were most severely affected. Nearly half of the young African-American women (48 percent) were infected with an STD, compared to 20 percent of young white women. The two most common STDs overall were human papillomavirus, or HPV (18 percent), and chlamydia (4 percent).
[Text extracted from press release(11-March-2008), published by CDC, Atlanta. Details here]
Malaria vaccine: On the go.....
Something new is going to hit Malaria in next 2-3 years. Research in malaria and tuberculosis control hardly achieved much success in last two decades and global mortality because of these diseases is at peak now. In search of perfect vaccine for malaria, researchers have managed to bring a malarial vaccine named, FSV-1 (RTS,S) on the phase 3 clinical trial road map by this September. Although it is far away from named as perfect vaccine with vaccine efficacy of less than 50 % (and in some studies, around 10-20 %), it would surely be of potential benefit considering the fact that even with 50 % efficacy, we can save 1000-1500 live daily from dying of malaria. FYI: The World Health Organization (WHO) estimates that more than a million people in Africa die from malaria every year, including 3,000 children each day. 1,2 Developed by Ballou, et al at Walter Reed Army Institute of Research in Silver Spring MD and GlaxoSmithKline (GSK) team, RTS,S vaccine is a adjuvant vaccine with RTS,S/AS02A adjuvant system is studied extensively till date. It is a recombinant protein containing part of the circumsporozoite protein (CSP) sequence of Plasmodium falciparum, linked to the hepatitis B surface antigen (for better immune response) and formulated in the adjuvant system. 3,4,6
Related resources:
1. Nature News: Malaria: End of beginning Nature 451, 1042-1046 (2008) doi:10.1038/4511042a 2. Nature group: Malaria portal 3. Sacarlal J, et al. Safety of the RTS,S/AS02A malaria vaccine in Mozambican children during a Phase IIb trial Vaccine. 2008 Jan 10;26(2):174-184. Epub 2007 Nov 26 PMID: 18069097 4. Mettens P, et al. Improved T cell responses to Plasmodium falciparum circumsporozoite protein in mice and monkeys induced by a novel formulation of RTS,S vaccine antigen. Vaccine. 2008 Feb 20;26(8):1072-82. Epub 2008 Jan 7 PMID: 18258343 5. Malaria vaccine initiative: Articles 6. Enosse S, et al. RTS,S/AS02A Malaria Vaccine Does Not Induce Parasite CSP T Cell Epitope Selection and Reduces Multiplicity of Infection PLoS Clin Trials. 2006 May; 1(1): e5 PMID: 1488895
Towards erasing 'still'
I am following Randy Pausch since he delivered one of the most inspirational lecture, titled "Really Achieving Your Childhood Dreams" on Sept 18, 2007. To me, it's amazing and most respectful to observe tremendous amount of endurance such people have and yet finding a joyful way to live every remaining second. Unfortunately, miracles do no not happen so frequently in science but we all hope with scientists' continuing relentless efforts to control cancer juggernaut will able to erase 'still' from title of Randy's post.
Synthetic life in evolution: Mycoplasma JCVI-1.0 - the largest man-made DNA structure
Marching ahead (previous post) with the aim to develop controversial synthetic life form, Dr Craig Venter's team at J. Craig Venter Institute (JCVI) published report documenting largest man-made DNA structure by synthesizing and assembling the 582,970 base pair genome of a bacterium, Mycoplasma genitalium JCVI-1.0. Study lead by Dan Gibson, Ph.D., Nobel Laureate Hamilton Smith, et al. is the second of three key steps toward the team’s goal of creating a fully synthetic organism. In the next step, which is ongoing at the JCVI, the team will attempt to create a living bacterial cell based entirely on the synthetically made genome. Dr Venter believes application of such bacteria in producing hydrogen fuel and breathing greenhouse gases to keep environment green. 1, 2 Expecting heightened arguments on making of an artificial life, Dr Smith clarifies to media about difference between their synthetic life project versus making of an actual artificial life. The study focused on inserting custom made pieces of synthetic DNA blocks in the "living" bacteria to gain desired phenotype change. i.e. production of hydrogen fuel, taking up CO2 gas. As stated, this is like installing an entirely new operating system (genome) within the living cell and then rebooting the system to observe for desired cell functions mediated by new genome. This is more like large scale transplant of batch of genes in the parent genome. JCVI team have managed to successfully transplant synthetic genome of 582,970 base pairs using indigenous method to create series of "cassettes" of sythetic DNA blocks (each having 5000-7000 base pairs of code) and joining them in step-wise manner to build the ultimate 582,970 base pair code. This five step-wise manner involved use of in vitro recombination method using conventional DNA replication in E.coli and newer in vivo recombination application using homologous recombination property in S. cerevisiae as a cloning host for making larger and stable base pair code. Team is now working to transplant entire new synthetic chromosome in nucleotide of another mycoplasma bacterium, thereby rebooting its genome and creating synthetic life (proposed name: Mycoplasma laboratorium). Reports in press 2 suggest scientists from Japan have already created synthetic code which is 10 times larger than Mycoplasma JCVI-1.0
Study authors 3 quotes in conclusion: "Nothing in our methodology restricts its use to chemically synthesized DNA. It should be possible to assemble any combination of synthetic and natural DNA segments in any desired order by designing PCR primers to generate appropriate overlaps between them." Also, author's idea on changing function of universal stop codon UGA to synthesize tryptophan (or other proteins) in synthetic DNA could lead to endless possibilities. Hmmm! both - good and bad.....That choice is with us. 4
References: 1. Press release: Venter Institute Scientists Create First Synthetic Bacterial Genome | JCVI | Jan 24, 2008 2. Press report: Synthetic life 'advance' reported | BBC News 3.Gibson DG, et al. | Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome | Science DOI: 10.1126/science.1151721 [Epub ahead of print] 4. Synthetic genomics | Option for governance - Safety and security concerns report at JCVI website --
Team showed increased behavior of female flies to mate with multiple male partners because many of male flies were carrying sex ration-distorting gene on chromosome X which lead to failure of male sex expression (on Chromosome Y) and producing sperm infertility and more and more female progeny. Hence, to avoid spreading such selfish gene (from male!) in the offspring and to balance sex ratio, female flies try to mate more often and thus, increasing her chance to mate with normal male to produce healthy offspring. Similar selfish genetic elements may exist in humans. Implications ?!? 
