Bizarre models for human diseases

Plants shed light on disfigured faces, and yeast and blood vessels find common ground.

• The search for models of human diseases might just have become easier, thanks to a data-mining technique that screens genetic databases to find subtle links to organisms as distant from humans as plants.
• The new tool integrates information from existing databases that associate gene mutations with observable traits in a range of species, including humans, mice, yeast, worms and plants. And the method identifies genes in the non-human species that are more likely than by chance to contribute to human disease.
• Mutations in the same gene can cause dramatically different effects in humans from those seen in other species. For instance, mutations in the RB1 gene are associated with eye cancer in humans but cause worm genitalia to develop in the wrong place. Although such genes remain conserved across species, they evolve different functions, says Edward Marcotte, a systems biologist at the University of Texas, Austin.
• On the basis of this principle, Marcotte and his colleagues set out to identify obscure gene candidates for human diseases. After screening a human database and identifying genes implicated in breast cancer, he searched for their function in the worm database and found that they were involved in producing male progeny. Moreover, he uncovered 13 genes in this worm network that might contribute to breast cancer in humans; nine of them had not previously been implicated in the disease. His findings are published today in Proceedings of the National Academy of Sciences.

• Marcotte found other unusual patterns. Genes responsible for sensing gravity in plants were linked to those associated with a developmental disorder in humans called Waardenburg syndrome, which causes abnormal pigmentation in the skin and hair, cleft palate and lip, and hearing loss. His analysis indicated that three genes in the plant 'gravity' network might be linked to the human syndrome. To investigate this further, he examined gene-expression patterns in frog embryos. One gene, sec23ip, was expressed in neural-crest cells, which are precursors of pigment cells and cranial tissue. Reducing the expression of the gene caused severe defects in the migration patterns of neural-crest cells. These results suggest that SEC23IP might be involved in Waardenburg syndrome.
• Marcotte also found that genes underlying blood-vessel growth in mice influence how well yeast grow in the presence of the cholesterol-lowering drug lovastatin. His analysis pulled out 62 genes associated with lovastatin sensitivity in yeast that may relate to angiogenesis — the formation of new blood vessels. Five out of 59 genes that had not previously been implicated in blood-vessel growth were expressed in the developing blood vessels of frogs. Reducing the expression of one gene, sox13, led to severe defects in vascular development in frogs and human cells. The findings suggest that yeast can be used to model the development of blood vessels in humans.
• "Yeast don't have blood or blood vessels, but they inform us about how the vasculature forms. And plants don't have heads, but they help us predict genes that are involved in the correct formation of the head," Marcotte says.
• "It's a nice illustration of how evolution completely co-opted entire genetic and molecular pathways," says Nipam Patel, an evolutionary developmental biologist at the University of California, Berkeley. "I was surprised how well it worked over that kind of evolutionary distance."
• The impact of the study comes from the scope of the data mining — the integration and analysis of existing data sets, which altogether encompass more than 200,000 associations between genes and observable traits.
• "I hope this study will encourage people to painstakingly annotate gene functions, which is not done universally," says Paul Sternberg, a molecular geneticist who studies worm development at the California Institute of Technology in Pasadena. He estimates that less than 5% of known gene functions are entered into databases.
• The approach will be most useful for identifying subtle associations related to complex diseases, Sternberg says. It might also speed up the identification of disease pathways and drug discovery, because carrying out experiments on organisms such as plants and yeast is cheaper and faster than studying mice and humans.
• But as the method relies entirely on statistics, there's no guarantee of accurate results. "It remains to be seen how well the technique will work for a range of diseases," Patel says. "It may not work for everything, but even if it works for a reasonable number of human diseases, it will still be exciting." 

References:-McGary, K. L. et al. Proc. Natl Acad. Sci. USA doi: 10.1073/pnas.0910200107 (2010).

US health bill promises changes for biomedical researchers

Translational work set to receive a boost.

• The historic health-care bill that passed the US House of Representatives on 21 March includes several lesser-known provisions that will significantly affect biomedical researchers, teaching hospitals and the biotechnology industry.
• The final legislation, which is expected to become law, would establish a new competitive grant programme at the National Institutes of Health (NIH). Called the Cures Acceleration Network (CAN), this provision was written into the law by Senator Arlen Specter (Democrat, Pennsylvania). It will authorize as much as US$500 million annually for speeding the translation of basic discoveries into treatments, through individual awards of up to $15 million per year. The CAN would be separate from an already existing NIH programme called Clinical and Translational Science Awards, which has a budget of roughly $483 million in 2010.
• The CAN programme comes without the guarantee of new money, and how it will be funded remains unclear. Advocates for basic research are worried that if Congress does not increase the NIH budget, funding might be pulled from its flagship, investigator-initiated R01 awards.
• "There has already been a long slide or stagnation in the funding of the gold standard: the R01," says Mark Lively, president of the Federation of American Societies for Experimental Biology in Bethesda, Maryland. "We would be concerned that any mandate that would require the NIH to move money to the CAN could very well come at the cost of losing still more R01s."
• Another provision in the bill will expose relationships between physician researchers and the medical industry. From 2013, companies will have to report to the Department of Health and Human Services every payment in cash, stock or kind of more than $10 they make to physicians and to teaching hospitals, in gifts, entertainment, and for services such as consulting and public speaking. The department will post the payments in a publicly accessible database.
• Companies that produce biologics — complicated and expensive protein-based drugs — do well out of the legislation. The new law will effectively guarantee 12 years of exclusive market access for makers of brand-name biologics before generic competitors can produce 'biosimilars', which mimic the original molecules.
• This provision is part of language that establishes a regulatory path by which makers of biosimilars can win marketing approval from the Food and Drug Administration (FDA). The European Union opened just such a regulatory path in 2005; the European Medicines Agency has since approved 14 such drugs.
• When Congress considered similar biologics legislation in 2008, the Congressional Budget Office estimated that its provisions for FDA approval of biosimilars would save about $25 billion over ten years by driving down prices of biologic drugs.
• Jim Greenwood, the president and chief executive of the Biotechnology Industry Organization, a lobby group based in Washington DC, said that the law "will lead to new and improved treatments, cures and cost-savings for patients, while driving job growth in our industry".
• But Kathleen Jaeger, president of the Generic Pharmaceutical Association, also based in Washington DC, lamented the pathway's "excessive and unprecedented market exclusivity protections for the brand industry". Generics makers and their congressional allies had sought to limit brand-name exclusivity to six years.

From Nature News

Cancer genes silenced in humans

Tiny particles carrying short strands of RNA can interfere with protein production in tumours.

• Short sequences of RNA that can effectively turn off specific genes have for the first time been used to treat skin cancer in people.The technique, called RNA interference (RNAi), gained its inventors a Nobel Prize in 2006, but researchers have struggled to get it to the clinic,partly because of problems in getting the molecules to their target.
• Now, Mark Davis from the California Institute of Technology in Pasadena and his colleagues have found a way to deliver particles containing such sequences to patients with the skin cancer melanoma. When analysing biopsies of the tumours after treatment, they found that the particles had inhibited expression of a key gene, called RRM2, needed for the cancer cells to multiply. Their research is published  in Nature¹.
• The researchers created the particles from two polymers plus a protein that binds to receptors on the surface of cancer cells and pieces of RNA called small-interfering RNA, or siRNA, designed to stop the RRM2 gene from being translated into protein. The siRNA works by sticking to the messenger RNA (mRNA) that carries the gene's code to the cell's protein-making machinery and ensuring that enzymes cut the mRNA at a specific spot.
• When the components are mixed together in water, they assemble into particles about 70 nanometres in diameter. The researchers can then administer the nanoparticles into the bloodstream of patients, where the particles circulate until they encounter 'leaky' blood vessels that supply the tumours with blood. The particles then pass through the vessels to the tumour, where they bind to the cell and are then absorbed.
• Once inside the cell, the nanoparticles fall apart, releasing the siRNA. The other parts of the nanoparticle are so small, they pass out of the body in urine. "It sneaks in, evades the immune system, delivers the siRNA, and the disassembled components exit out," Davis says.
• The study describes the science behind a phase I trial assessing the safety of the technique in 15 patients. When researchers analysed tumour samples from three of the patients who volunteered samples, they found fragments of the mRNA in exactly the length and sequence they would expect from the design of their siRNA. 
• And in at least one patient, the levels of the protein were lower than they were in samples of the tumours taken before treatment. They also found that patients who were given higher doses had higher levels of siRNA in their tumours. "The more we put in, the more ends up where they are supposed to be, in tumour cells," Davis says.
• Researchers will need more data from clinical trials to ensure that such therapies are safe to use in people. But Davis says that his study means there is now direct evidence that nanoparticles and RNAi can be used to attack harmful genes in humans — and not just in the test tube. "What's so exciting is that virtually any gene can be targeted now," he says. "Every protein now is druggable."
• Davis says that by targeting specific genes he hopes these treatments will not have major side effects. "My hope is to make tumours melt away while maintaining a high quality of life for the patients," he says. "We're moving another step closer to being able to do that now."
• But some researchers are concerned that the treatment has not been tested on more patients and that more samples were not taken from each patient. Molecular biologist Thomas Tuschl from Rockefeller University in New York says it is "exciting that such nanoparticles in multiple dosing schemes can reach the tissue and apparently have measurable effects". That is, he says, if one wants to believe the data from the single patient who had lower levels of the protein. "I hope these findings can be confirmed in the future," he adds.
• Biomedical engineer Daniel Anderson from Massachusetts Institute of Technology in Cambridge has also been trying to develop RNAi delivery systems, and he thinks the data are a great start. "Generally, people who worry about making therapeutics understand that animals are not people," he says. "There are a lot of really exciting data with animals, but ultimately, the usefulness of these types of drug-delivery systems must be evaluated in humans, and that's why this is an important study. But it's not like we're done." 

References:-Davis, M. E. et al. Nature advance online publication doi:10.1038/nature08956 (2010).

Writing an eye catching scientific resume

By May Li, PhD  in Bio Career Center:-

Format

Top
1-Put your Name, in bold, large print. If you have PhD, be sure to include this.
2-Include your present residential address (street, city, state, zip code)
3-Under your name, put your personal email address and home or cell phone number(s) for contact information.

Career Summary:
1-Using a few bullets, highlight your scientific profile. This helps the reviewer to get an idea if the candidate has the general background and level of experience that they need.
2-If you know the position description you are applying for, be sure to bring out the areas of your background that are relevant to this position.
3-Keep this general and brief.
4-Do not write an objective. It could screen you out of an opportunity if misinterpreted or if the position doesn't line up perfectly.

Professional Experience/Position Held:
1-List each company/ institution first, starting with most recent.
2-Under the company heading, include the city and state and the years you worked there.
3-List your position title, and years served in each position.
4-In as much detail as possible, describe your responsibilities, functions and skills used.
5-If you supervised people, include the number and levels.
6-Highlight and quantify all your accomplishments in this role.
7-Highlight problems that you solved.
8-This part should reflect your strengths and showcase your true skills
9-Be brief, but informative and use bullets with short sentence descriptions
10-Continue this for each position held, in chronological order.

Education:
1-List your degrees obtained from most advanced (most recent) to least advanced, BS or BA
2-Include the university where each degree was obtained and if there was a thesis you can include the dissertation topic.

Publications & Patents:
1-These can be listed in chronological order, starting with the most recent.
2-If a manuscript is in press or submitted for publication it is fine to list it this way
3-It is advisable to put your name in bold when listing authors

Technical Skills:
1-Many academic resumes list only their position titles and publications
2-Listing technical skills is advisable especially for people coming out of academic settings
3-Hiring managers need to know what skills were used and for how long, so, if you leave this out, you will hurt your chances of having a call back
4-Be specific and as detailed as possible but keep this brief and to the point.
5-In industry, hiring managers look for all transferable skill sets.
6-The topic of research is just as important as the techniques used to arrive at these results, so a breakdown is important to help the reviewer make the right match.
7- List the type of equipment used and the latest technology your research team was involved with.
8-Find ways to distinguish your background from the multitude of others with similar backgrounds and sell your skills  and expertise
9-For those of you who have begun to embark on managerial career track, your level of responsibilities, cross matrix management, supervising other junior scientists etc is important to include under each job title.

Cosmetics:
1-Make sure your resume is not too busy, and is eye catching
2-Use a font that distributes space evenly and is easy on the eyes
3-You may consider hiring a professional resume writing service but they will still ask you to list your skills and experience.

Length:
If you are an experienced professional with a long history of accomplishments your resume should reflect this.
1- Use more detail on the recent work you have done and be briefer with earlier work
2- Definitely include all the publications and patents, conferences where you presented an abstract or seminar.

http://www.linkedin.com/in/maykli

A vision for personalized medicine

Genomics Pioneer Leroy Hood says a coming revolution in medicine will bring enormous new opportunities:-

1-Leroy Hood had been at the center of a number of paradign shifts in biology. He helped in invent the first automated DNA sequencing machine in the 1980s along with several other technologies that have changed the face of molecular biology.
2-In 2000 he founded the Institute of Systems Biology, Seattle. Dedicated to examining the interactions between biological information at many different levesl and to moving forward a new perspective for studying biology.
3-He has founded a startup called Integrated Diagnostics to develop cheap diagnostics  that could be used to detect diseases at earlier more treatable stages.
4- He developed partnership between the institute of Systems Biology and Ohio State Medical School  to combine existing medical and genomics techonlogies can affect the practice of health care today.
 5- According to him, the personalized medicine  may be defined as P4 medicine- Powerfully predictive, Personalized, Preventative- meaning we shall shift the focus to wellness and Participatory.
6- Nanotechnology approaches to protein measurement- measuring 2,500 proteins from a drop of blood will also be important. We want to develop tests to asses 50 organ specific protein from 50 organs as way of interrogating health rather than disease.
7-We can analyze transcriptome and RNAomes, Proteomes and Metabolomes( the collection of transcribed genes or mRNA, Total RNA, Proteins and Metabolites respectively in the cell). That information will reveal quanti cellular states that will say lots about normal mechanisms and disease mechanisms.
8-Computational and Mathematical tools to deal with data dimensionality.

Credit to Technology Review