VATIS Update Biotechnology . Jul-Aug 2010

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Biotechnology Jul-Aug 2010

ISSN: 0971-5622

VATIS Update Biotechnology is published 4 times a year to keep the readers up to date of most of the relevant and latest technological developments and events in the field of Biotechnology. The Update is tailored to policy-makers, industries and technology transfer intermediaries.

Co-publisher: Biotech Consortium India Ltd
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Capacity expansion on the cards for Indian biotechnology

The Government of India plans to spend around Rs 7 billion (approximately US$150 million) in the next two years to boost production at biopharmaceutical firms, even as the local industry gears up for a global boom. This is the first time the government is focusing on developing infrastructure in the sector, a top official said. “We feel that it requires large investments in manufacturing as well as scaling up its operations to cater to the emerging generic opportunity in the global markets,” Said Mr. M.K. Bhan, Secretary, Department of Biotechnology (DBT) of the Ministry of Science and Technology.

DBT, responsible for formulating policy and promoting biotechnology, has been spending around US$27.8 million a year to support research, development and innovation. “The country’s biotech sector is still not that huge to absorb large research and development funding as it is projected by the industry associations and the players,” Mr. Bhan said. The Association of Biotechnology Led Enterprises (ABLE) and the consultancy firm Pricewaterhouse Coopers had recently submitted a report titled A BioPharma Strategy for India: Vision 2020 to the government. The report projected a rapid growth in the US$137 billion global biopharmaceutical market. It is expected that the local industry could capture at least 10 per cent of the estimated US$319 billion market by 2020.

Some 48 biopharmaceuticals with a combined sales of US$73 billion in 2009 are going off-patent in the next 10 years, which provides a competitive opportunity for Indian firms, though production of biopharmaceuticals is more complicated compared with drugs based on conventional chemistry. “The immediate need that we have now realized is in the field of scaling up the industry’s capacity to tap the generic or off-patent product opportunity in the global markets,” Mr. Bhan said.

DBT’s current estimate is that the biopharmaceutical industry has a funding requirement of about US$150-171 million for capacity building. It currently operates three funding schemes – small business innovation research initiative, biotechnology industry partnership programme, and biotechnology industry research and assistance programme. In the fiscal year that ended 31 March 2010, the three schemes together granted just about US$25.6 million.

Japan contributes US$10 million for AIDS vaccine development

The Government of Japan has pledged US$10 million grant to support Acquired Immunodeficiency Syndrome (AIDS) vaccine research and development over the next five years, according to International AIDS Vaccine Initiative (IAVI). The grant, which will be channelled through a newly established World Bank trust fund, is the first of its kind from the Japanese government to IAVI. IAVI will use the funds from Japan to continue developing, together with its Japanese partners, an AIDS vaccine candidate that is constructed using a paramyxovirus known as the Sendai virus. Viral vectors based on the Sendai family have the potential to elicit a durable and highly targeted immune response in mucosal tissues, where HIV often establishes infection before it spreads.

IAVI has been working with Japan since 2001 to muster scientific, political and financial resources to support AIDS vaccine development. This has led to a collaborative development of a Sendai virus vector-based AIDS vaccine candidate, which is expected to enter Phase I testing in humans in two to three years. A vaccine offers the best hope of ending the AIDS pandemic and improving millions of lives around the world.

IAVI is a global not-for-profit organization with a mission to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996 and operational in 25 countries, IAVI and its network of collaborators research and develop vaccine candidates.

Funding for synthetic biology in Europe and the United States

The United States government has spent around US$430 million on research related to synthetic biology since 2005, according to the Synthetic Biology Project at the Woodrow Wilson Centre, the United States. By comparison, the European Union and three individual European countries – The Netherlands, United Kingdom and Germany – together spent only about US$160 million during that same period. Approximately 4 per cent of the United States funding and 2 per cent of the European funding was being spent to explore ethical, social and legal implications (ELSI) of synthetic biology. The analysis uncovered no projects dedicated to risk assessment.

In 2005, the European Union and the three afore-mentioned European countries were ahead of the United States in terms of funding, with about US $20 million and about US$5 million, respectively. While European government investment stayed about the same for the next couple of years, the United States government’s spending grew, almost catching up with the European level by 2007. In the following year, United States funding skyrocketed to over US$140 million, while European funding was just above US$40 million. In 2009, United States funding increased to about US$150 million, and this year it is down to roughly US$ 130 million. European funding levels for 2009 and 2010 were approximately US$70 million and US$ 20 million, respectively.

“These figures are preliminary and based on best-effort attempts to gather data from multiple government sources in the United States and Europe,” the authors write in their report. “It is hoped that this report will stimulate a broad discussion of funding levels that will lead to better estimates over time.” The report points out that the United States Department of Energy is far outspending any other government agency in funding synthetic biology, although the report has taken a conservative approach, and considered only half the numbers quoted because of lack of project-by-project funding details.

Funding of synthetic biology in the United Kingdom is estimated at between US$30 million and US$53 million since 2005. Research funding is divided among three programmes: Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, and the Wellcome Trust. In 2008, three Dutch universities announced that over the following five to ten years, they would invest a total of US$90 million in centres for synthetic biology research. As for Germany, the Deutsche Forschungsgemeinschaft (German Research Foundation) is planning to invest approximately US$3.5 million in synthetic biology.

Fast-track approval for international patent applications

In the United Kingdom, Prime Minister Mr. David Cameron announced a new scheme that sets out his vision for transforming the country’s economy. The new fast-track scheme of the Intellectual Property Office (IPO) would help tackle the worldwide backlog of patent applications, which costs the global economy an estimated £7.6 billion a year.

Welcoming the Prime Minister’s announcement, the Intellectual Property Minister Baroness Wilcox said: “Innovation is one of the main driving forces for Britain’s economic recovery. Delays in dealing with patent applications prevent firms from expanding and creating new jobs.” She hoped “The new fast-track procedure will make it quicker for business to turn innovation and ideas into products and jobs.”

The new procedure will apply to applications filed under the international Patent Cooperation Treaty (PCT). The United Kingdom is one of 142 countries that have signed the Treaty. Under PCT, applications undergo a preliminary assessment of their patentability before being passed to individual nations to consider the details. The Treaty aims to stop duplication of work when an applicant wants patent protection for the same invention in several countries. Now businesses and individuals can apply for their application to be dealt with under the PCT (UK) Fast-Track when it has been approved in the international phase.

Applicants requesting the fast-track service will receive an examination report within two months. Under current timescales this could take more than 18 months. The examination report will either approve the application or detail any changes needed before a United Kingdom patent can be granted. Any substantial issues will have been addressed in the international phase. The new scheme will work in the same way as the IPO’s existing fast-track procedures, which include the ‘Green Channel’ for inventions with environmental benefits.

Indian biotech industry records three-fold growth

The Indian Biotech industry has grown three-fold in the last five years to touch revenues of US$3 billion in 2009-2010. The country’s biotech industry registered a growth of 17 per cent over the previous year, according to a joint study conducted by the Association of Biotechnology Led Enterprises (ABLE) and the trade publication Biospectrum. Biocon, based in Bangalore, regained top position among the domestic biotech companies after four years, notching up a revenue of Rs. 11.80 billion (US$253.76 million). The company registered a year-on-year growth rate of 29.3 per cent to reclaim its lost position. Pune-based Serum Institute of India Ltd. with a revenue of Rs 8.5 billion (US$ 182.80 million) and Delhi-based Panacea Biotec with Rs 7.03 billion (US$151.18 million) in revenues have emerged as the second and third largest companies in the country, respectively. The study projects a future slowing down of growth for the domestic biotech industry, which, it says, would grow only at 20 per cent annually in the next few years.

Within the biotechnology industry sector, the biopharma segment contributed nearly three-fifths to the industry’s total revenues at Rs 88.29 billion (US$1.90 billion), recording a growth of 12 per cent. This is followed by revenues clocked by bioservices that stands at Rs 26.39 billion (US$567.53 million) and bio-agriculture that raked in Rs 19.36 billion (US$416.34 million). The remaining revenue came from the bio-industrials segment with a contribution of Rs 5.64 billion (US$121.29 million) and bioinformatics at Rs 2.31 billion (US$49.68 million).

With revenues totalling Rs 66.31 billion (US$1.43 billion), the western part of the country emerged the biggest contributor to India’s biotech sector revenues, followed by the southern biocluster contributing Rs 55.38 billion (US$1.19 billion) to the total biotech kitty. The state of Gujarat alone contributed approximately 8 per cent of the total revenues at Rs 11 billion (US$236.56 million), by registering a growth of about 50 per cent. The Northern biocluster trailed behind by contributing just about one-seventh of the total revenues at Rs 20.30 billion (US$436.56 million).


Mayo and University of Illinois form research alliance

In the United States, the Mayo Clinic and the University of Illinois have formed a strategic alliance to promote a “broad spectrum of collaborative research, development of new technologies and clinical tools, and design and implementation of novel education programmes,” the Mayo Clinic announced. A formal agreement was recently signed to provide a framework for broad cooperation in personalized medicine. Integration efforts will focus on three areas – basic, translational and clinical research; bioengineering, particularly for point-of-care diagnostics; and development of tools and methods in computational biology and medicine.

Initially, the alliance’s projects will focus on the microbiome, genomics, bioinformatics and other computational sciences, including the use of petascale computing, imaging, nanotechnology and tissue engineering, the Mayo Clinic said. It added that several research projects are already under way. Bilateral educational programmes in engineering, computational medicine, nanotechnology, genomics innovation, and entrepreneurship are also being planned. A steering committee is being formed to oversee the alliance and its projects.

Japan all set for a wave of new drug launches

A dozen new drugs, including seven new molecular entities, are set for launch in Japan shortly, following their listing on the National Health Insurance (NHI) formulary. Japan’s Central Social Insurance Medical Council (Chuikyo) has given its formal approval for the drugs’ listings. Five products from Takeda are included among the 12 set for market roll-out, including Nesina, a dipeptidyl peptidase-4 (DPP4) inhibitor alogliptan formulation for the treatment of type 2 diabetes, the launch of which in Japan will mark its first introduction worldwide. The drug is expected to earn 63.3 billion yen (US$747.34 million) in its tenth year based on treating 185,000 patients.

The other four Takeda products newly listed on the NHI formulary are Metact (pioglitazone/metformin), another drug for the treatment of type 2 diabetes, plus Rozerem (ramelteon) for insomnia treatment, Unisia (candesartan/amlodipine) for hypertension, and Vectibix (panitumumab) for treating a type of advanced or recurrent colorectal cancer. Altogether, the five Takeda drugs are reported to see combined sales in their peak years totalling 197.30 billion yen (US$2.33 billion).

The other seven newly listed products are: Pfizer’s Lyrica (pregabalin) for post-herpetic neuralgia; Novo Nordisk’s type 2 diabetes treatment Victoza (liraglutide); Kyowa Hakko Kirin’s Nesp (recombinant darbepoetin alpha) for renal anaemia; Soliris (eculizumab) from Alexion for paroxysmal nocturnal haemoglobinuria; Santen/Merck & Co.’s Cosopt (dorzolamide/timolol) for glaucoma and ocular hypertention; Alcon’s DuoTrav (timolol/travoprost) for glaucoma and ocular hypertension; and Hisamitsu’s Fentos Tape (fentanyl citrate) for the treatment of cancer pain. Among these, the product with the largest annual peak sales is tipped to be Nesp, at 66.4 billion yen (US$783.72 million).

Tekmira expands relationship with global pharmaceutical firm

Tekmira Pharmaceuticals Corp., Canada, has signed a multi-year agreement with Bristol-Myers Squibb Company, based in the United States, to expand work on its therapeutic research. Under the agreement, Bristol-Myers Squibb will conduct preclinical work using small interfering RNA molecules formulated by Tekmira in stable nucleic acid-lipid particles (SNALP) and share the data with the company.

Tekmira will receive US$3 million with the signing of the agreement. Over the agreement’s four-year term, Tekmira will be responsible for providing the SNALP molecules to Bristol-Myers Squibb, who will have a first right to negotiate a licensing agreement on certain RNA interference products developed by Tekmira that evolve from gene targets validated by Bristol-Myers Squibb. Tekmira had reported a 23 per cent jump in revenue last year, mostly from its R&D collaborations with pharmaceutical firms and from licensing fees and milestone payments.

Gilead offers US$120 million for CGI Pharma

In the United States, therapeutics giant Gilead Sciences Inc. is offering up to US$120 million for CGI Pharmaceuticals, a development-stage drug company. Most of the price for CGI Pharmaceuticals, in which Connecticut State is a stakeholder, will be paid upfront, with the remainder based on clinical development progress, Gilead said. Gilead is one of the world’s fastest-growing bioscience companies, with 2009 sales totalling US$7 billion and earnings of US$2.6 billion.

Gilead said CGI’s lead preclinical compound could have applications for treating serious inflammatory diseases like rheumatoid arthritis. The state’s technology investment arm, Connecticut Innovations Inc., invested US$4.7 million in CGI from 2000 to date, said its President Mr. Peter Longo. The exact percentage of the state’s stake in CGI is still being determined, Mr. Longo said.
Once the deal is through, CGI, which focuses on small-molecule chemistry and kinase biology, will become a wholly owned subsidiary of Gilead. CGI, which was formerly Cellular Genomics Inc., sprang from research at Yale University.

Bayer CropScience supports research at Texas Tech

Bayer CropScience, one of the world’s leading innovative crop science companies with headquarters in Germany, has announced a US$7.5 million contribution to the Department of Plant and Soil Sciences of Texas Tech University, Lubbock, the United States. The contribution in support of new research initiatives and facilities development is eligible for a full funding match through the Texas Research Incentive Programme (TRIP), creating a US$15 million total contribution to the university.

Of this, US$10 million will be allocated to support research and development collaboration between Bayer CropScience and Texas Tech, and US$5 million will go towards a planned Plant and Soil Sciences Building. The collaborative research project will be focused on developing cotton with improved fibre properties. The project includes scientists affiliated with the Fibre and Biopolymer Research Institute within the Department of Plant and Soil Science.

“Texas Tech is a leading agricultural research institution with which Bayer CropScience has enjoyed a close relationship,” said Mr. Joachim Schneider, Head of the BioScience Business Unit of Bayer CropScience. “This contribution from Bayer CropScience will enhance our already formidable research and academics in the Department of Plant and Soil Sciences,” said Texas Tech President Mr. Guy Bailey. “It also continues a longstanding and productive research relationship between Texas Tech and Bayer CropScience.”

Japan accepts Critical Path’s biomarkers for drug toxicity tests

The Critical Path Institute, the United States, said that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has accepted its seven-biomarker panel for use in detecting drug-induced kidney injury. The acceptance, the first ever regulatory biomarker qualification decision by PMDA, means data generated using the panel can be submitted to the agency as part of the drug approval process in Japan, Critical Path said in a statement.

The biomarkers were developed by the Predictive Safety Testing Consortium, an initiative led by the Critical Path Institute that was initiated in 2006. PMDA’s decision follows similar ones by the United States Food and Drug Administration and the European Medicines Agency in 2008.

The seven biomarkers are KIM-1, albumin, total protein, ß2-microglobulin, cystatin C, clusterin and trefoil factor-3. According to Critical Path, PMDA decided that the panel can provide additional information for detecting drug-induced kidney injury in preclinical rat safety studies when used along with current standard biomarkers, serum creatinine and blood-urea nitrogen.
PMDA said that the novel biomarkers in early clinical trials in Japan and elsewhere “may be accepted on a case-by-case basis in order to gather further data that PMDA considers necessary to qualify their usefulness in monitoring drug-induced renal toxicity” in humans.


New genes identified in variation of human eye colour

Three new genetic loci have been identified with involvement in subtle and quantitative variation of human eye colour in a study led by Dr. Manfred Kayser of the Erasmus University Medical Centre Rotterdam, The Netherlands. In this genome-wide association study, the eye colour of about 6,000 Dutch Europeans from the Rotterdam Study was digitally quantified using high-resolution full-eye photographs. This quantitative approach, which is cost-effective, portable and time-efficient, showed that human eye colour varies along more dimensions than represented by the colour categories used previously. Previous studies on the genetics of human eye colour used broadly categorized trait information such as ‘blue’, ‘green’, and ‘brown’.

The researchers identified three new loci significantly associated with quantitative eye colour. One of these, the LYST gene, was previously considered a pigmentation gene in mice and cattle, whereas the other two had no earlier association with pigmentation. These three genes, together with previously identified ones, explained over 50 per cent of eye colour variance, representing the highest accuracy achieved so far in genomic prediction of complex and quantitative human traits.

UV light helps form ‘missing G’ of RNA building blocks

Guanine – the G in the four-letter code of life – has proven to be a particular challenge for scientists attempting to understand how the building blocks of RNA originated on Earth. While the other three bases of RNA – adenine (A), cytosine (C) and uracil (U) – could be created by heating formamide to 160°C in the presence of mineral catalysts, guanine had not been produced by those reactions.

By the addition of ultraviolet (UV) light to a model prebiotic reaction, researchers from the Georgia Institute of Technology, the United States, and the University of Roma La Sapienza, Italy, have discovered a route by which the missing guanine could have been formed. They also found that the RNA bases may have been easier to form than previously thought – suggesting that starting life on Earth might not have been so difficult after all.

The researchers showed for the first time that guanine can be produced by subjecting a solution of formamide to UV radiation during heating. The trace gaunine yield was greatly enhanced when minerals and photons were used together. In addition, production of adenine and a related molecule called hypoxanthine increased when UV light was added to the heating process (130°C) – a 15-fold increase was seen in adenine yield. The study demonstrated that guanine, adenine and hypoxanthine can be produced at lower temperatures than previously reported, even in the absence of minerals, as long as photons are added. “These results potentially relax some of the requirements and reactions necessary to get life started, because formamide molecules would not have had to be in contact with a particular type of rock when heated on the prebiotic Earth, if the formamide was exposed to direct sunlight during heating,” said Prof. Nicholas Hud from the Georgia Tech School of Chemistry and Biochemistry.

The researchers suggest that aqueous pools containing small amounts of formamide may have existed on the early Earth. During hot and dry periods, water evaporation could have given rise to concentrated solutions of formamide and exposed mineral surfaces coated with formamide. By conducting additional experiments at 100°C with solutions of formamide and water, the researchers confirmed that this “drying pool” model could give rise to solutions of formamide capable of producing the compounds found in their earlier experiments.

Scientists create world’s first synthetic cell

At the J. Craig Venter Institute, the United States, a team of researchers was able to take a bacterium and replace its genome with synthetic DNA they had developed using computer code. To make the synthetic cell, a team of 25 researchers led by bioengineer Dr. Daniel Gibson and Dr. J. Craig Venter essentially turned computer code into a new life form. They started with a species of bacteria called Mycoplasma capricolum and, by replacing its genome with one they themselves wrote, turned it into a customized variant of an existing species, called Mycoplasma mycoides.

To begin, the researchers wrote out the entire genetic code of the microbe as a digital computer file, documenting more than one million base pairs of DNA in a biochemical alphabet of adenine, cytosine, guanine and thymine. They edited that file, adding new code, and then sent that electronic data to a DNA sequencing company, where it was transformed into hundreds of small pieces of chemical DNA, they reported.

To assemble the strips of DNA, the researchers said they took advantage of the natural capacities of yeast and other bacteria to meld genes and chromosomes to stitch those short sequences into ever-longer fragments until they had assembled the complete genome. They transplanted that master set of genes into an emptied cell, where it converted the cell into a different species.
This new synthetic cell has no commercial use, but now that the team has accomplished this proof-of-concept work, Dr. Craig Venter – who has worked towards this moment for the past 15 years – is already working at new organisms that can be used to make petrol. Dr. Venter and his colleagues signed their work, writing their names into the DNA of the new cell. This new bacterium, and all of the ones to follow, will also be similarly stamped. All new life forms will be owned by their creators.

How the wrong genes get repressed to keep cell identity

Researchers at University College London (UCL), the United Kingdom, have identified a mechanism by which ‘polycomb’ proteins, which are critical for embryonic stem cell function and fate, are directed to DNA. The discovery has implications for the fields of stem cell and tissue engineering.

A key feature of stem cells is the suppression of genes that, when later switched on, lead to the differentiation of the cells into specific mature cell types, such as neurons or immune cells. Polycomb proteins, first discovered in fruit flies, are known to play a critical role in the suppression of these developmental genes. Polycomb repressive complex-2 (PRC2) is present in all multicellular organisms and is important in stem cell differentiation and early embryonic development.

The UCL scientists found that PRC2 is brought to its target genes though binding to a new class of short RNAs transcribed by RNA polymerase II. PRC2 can then methylate chromatin, preventing the activation of developmental regulator genes that would otherwise act to alter the identity of the cell. Dr. Richard Jenner from UCL Infection & Immunity Department said: “Discovering that polycomb also binds to these RNAs shows how polycomb might be recruited to genes, which are then repressed to maintain the identities of different cell types. This has been a key question in the field for some time and has important implications for how we might be able to control cell fate in tissue engineering”.

Chromosome ‘glue’ springs some surprises

Proteins called cohesins ensure that newly copied chromosomes bind together, separate correctly during cell division and are repaired efficiently after DNA damage. Scientists at the Carnegie Institution, the United States, have found for the first time that cohesins are needed in different concentrations for their different functions. This discovery helps to explain how certain developmental disorders, such as Cornelia de Lange and Roberts Syndrome, arise without affecting cell division essential to development. The study was made possible by a new technique developed for membrane-bound cells (eukaryotes), which enables scientists to gradually reduce the concentration of a protein in living cells.

One of the biggest surprises is that only a small amount of cohesin is needed for the cell division process, which is thought to be cohesin’s primary role, revealed Dr. Jill Heidinger-Pauli at Carnegie’s Department of Embryology and lead author of the study. A cell has a four-phase life cycle: growth, synthesis, growth, and mitosis. During the synthesis phase, DNA inside the cell’s nucleus is duplicated and two identical daughter chromosomes called sister chromatids result. These twins must remain connected until the cell is ready to divide. This moment occurs in the last step of the cell cycle, the mitosis phase, where chromosomes condense, and fibrous structures called spindles form. Cohesin keeps the sisters glued together until it is time for the spindles to pull the them to opposite sides of the cell. The cell then separates into two genetically identical cells.

Cohesin is also important for other processes, such as in DNA condensation and the repair of DNA damage. To determine how much cohesin is needed for these different processes, the researchers used a genetic trick that lets a stop codon occasionally code for an amino acid. A codon is a set of three DNA bases that either codes for an amino acid or stops the translation (the reading) of the DNA sequence. “We found that DNA repair, chromosome condensation and the stability of repeat sequences of DNA were all compromised by decreasing cohesion to 30 per cent of normal levels,” said Dr. Heidinger-Pauli. Interestingly, the sister-chromatid cohesion and chromosome segregation were not affected even with levels at only 13 per cent of normal.

Camel genome sequenced

Scientists from Beijing Genomics Institute (BGI), China, and King Abdulaziz City for Science & Technology (KACST), Saudi Arabia, have sequenced and analysed the genome of the Arabian camel, Camelus dromedarius. So far, the team’s analyses of the roughly 2.2 billion base Arabian camel genome suggest that the animal shares genetic similarities with cattle. The genome of C. dromedarius also appears to house some 57 per cent of genes found in the human genome. With the camel genome in hand, the team hopes to gain clues about the animal’s ability to survive the harsh desert environment as well as genetic insights that may help improve camel health and facilitate selective breeding programmes to enhance desirable traits such as speed and strength and milk, meat, and wool production. The findings may also have implications for human health, especially since camel milk is thought to contain compounds that may combat a range of human disease. “We look forward to further expand our understanding of the camel physiological and biochemical characteristics and to bring it to application for the benefit of mankind,” said BGI President Dr. Jian Wang in a statement.


Molecular strategy to fight cancer drug resistance

Scientists at Dana-Farber Cancer Institute, the United States, have found a way to incapacitate a common protein that often thwarts chemotherapy treatment of several major forms of cancer. They discovered, surprisingly, that they could exploit a small portion of this anti-death protein, called MCL-1, to make a molecular tool that specifically blocked MCL-1’s “pro-survival” action, allowing standard cancer drugs to kill the tumour cells by apoptosis, or programmed cell death.

“We think this is a very important step towards developing an inhibitor of MCL-1, which is emerging as a critical survival factor in a broad range of human cancers,” said Dr. Loren D. Walensky, a paediatric oncologist and chemical biologist at Dana-Farber, and the senior author of the study. The lab experiments showed that combining the MCL-1 inhibitor with a class of conventional agents that can be rendered ineffective by MCL-1 resensitized the cancer cells to the drugs. The MCL-blocking compound is now being advanced to testing in animal models.

MCL-1 belongs to the BCL-2 family of proteins that control the process of apoptosis. The “pro-death” BCL-2 members form a pathway that triggers cellular self-destruction, while “pro-survival” members such as MCL-1 establish blockades in the death pathway, often by binding to pro-death proteins and disabling them. Cancer cells exploit the pro-survival pathway by over-expressing anti-apoptotic proteins such as MCL-1, which makes chemotherapy drugs less effective.

A small, coiled peptide unit called BH3 is a key interaction point between pro- and anti-apoptosis proteins. BH3 domains differ in important though subtle ways from one another, like a set of keys for different locks. The researchers searched through BH3 domains in cells hoping to find one that could bind to only MCL-1 and serve as a specific inhibitor of this formidable cancer protein. After combing a collection of BH3 domains, it turned out that the one they were looking for was the BH3 domain of MCL-1 itself.

The helical BH3 domain of MCL-1 is located within a small “pocket” in the protein structure, and acts as a dock to enable binding of other proteins. It is by means of this docking unit that MCL-1 traps pro-death proteins and keeps them from triggering apoptosis in cancer cells. The researchers were also able to analyse the three-dimensional structure of the key parts of the MCL-1 docking mechanism and discover why it binds so specifically to its target, opening up the potential for the development of novel therapeutics to diseases driven by pathologic MCL-1-mediated cell survival and chemoresistance.

Water-free liquid from blood protein

Scientists at the University of Bristol, the United Kingdom, have discovered a way to make a highly concentrated water-free liquid of myoglobin, a key blood protein, opening up the possibility of new types of biomedical materials. They use a chemical procedure, in which surfactant molecules are attached to the protein surface, to remove the water by freeze-drying at low temperature and produce a solid powder. When warmed to room temperature, the powder melts to produce a viscous liquid containing a very high concentration of myoglobin molecules, while the protein structure remains unchanged even though no water is present.

The experiments, carried out by Prof. Stephen Mann, Dr. Adam Perriman and colleagues in the School of Chemistry at the University of Bristol, found that the ability of the liquid protein to reversibly bind oxygen remains unchanged. This means that the potency of the oxygen molecules can be varied in response to the pressure applied. The resulting liquid is a simplified form of “artificial blood” that might be used as a smart solvent-less fluid of highly concentrated protein for oxygen storage and delivery.

The findings represent a major scientific breakthrough given that it has been previously thought that the structure and properties of proteins require water molecules to operate correctly. A water-less liquid protein with high chemical potency could therefore lead to a re-evaluation of the importance of water molecules in protein folding in general.

Architecture of the protein complex of cellular respiration

Scientists in Germany have elucidated the architecture of mitochondrial complex I, the largest protein complex of the cellular respiratory chain. They found in this molecular complex an unknown mechanism of energy conversion, which is required to utilize the energy contained in food.

Dysfunction of complex I is implicated in several neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, and with the general physiological processes of biological aging. The work of Prof. Carola Hunte of the Freiburg Institute for Biochemistry and Molecular Biology, in cooperation with Prof. Ulrich Brandt, Professor for Molecular Bioenergetics at the Frankfurt Centre for Biological Chemistry and Dr. Volker Zickermann of Prof. Brandt’s research group, is a major step forward to this understanding.

The structural model provides important and unexpected insights for the function of complex I. A special type of “transmission element”, which is not known in any other protein, appears to be responsible for the energy transduction within the complex through mechanical nanoscale coupling. This could be described as a power transmission by a coupling rod that connects, for instance, the wheels of a steam train. This nano-mechanical principle will now be analysed by additional functional studies and a refined structural analysis.

New method to identify glycosylated proteins

Scientists of the Max Planck Institute of Biochemistry (MPIB) in Germany have now made a crucial contribution to the identification of protein modifications that take place in human body. Using a new method, they have identified more than 6,000 glycosylated protein sites in different tissues and have thus established an important basis for the better understanding of all life processes.

Until now, the identification of modified proteins was only possible with limitations. Particularly, the transformation of proteins by glycosylation – carbohydrates binding to single amino acids – has been mostly unexplored. But this is one of the most important mechanisms for the transformation of proteins and plays an important role in the formation of organs and organisms. When errors occur during the protein modification or in case it takes place in an unregulated way, this can contribute to diseases like Alzheimer’s disease or Creutzfeldt-Jakob disease.

In the MPIB Department of Proteomics and Signal Transduction, scientists headed by Dr. Matthias Mann have developed a method based on mass spectrometry that allows the identification of N-glycosylated protein sites in different tissues in a highly efficient way. N-glycosylation is a specific type of glycosylation in which the carbohydrates bind on a certain component of a protein, the amino acid asparagine (N). The new method is based on a filter technique that offers the possibility to extract also poorly accessible proteins from biological samples. The scientists combined this method with high-resolution mass spectrometry to identify 6,367 N-glycosylated protein sites. They also derived novel recognition sequence patterns for N-glycosylation.

A key protein controls T-cell proliferation

New research in the United States has found that a key protein called PEA-15 stops T-cell proliferation by blocking the cell’s ability to reproduce. The control of T-cell proliferation is essential in preventing certain blood cancers and autoimmune diseases, as well as the orchestration of the immune response to infection. A research team from the University of Hawaii Cancer Research Centre, Rutgers University and Washington University in St. Louis examined the normal function of PEA-15, which acts as a tumour suppressor in some cancers including brain, ovarian and breast cancers. They found that PEA-15 normally controls lymphocyte (white blood cell) proliferation.

To determine the normal role of this protein, researchers examined mice lacking PEA-15. They found that the mice without the protein had both spatial learning disabilities and a pronounced increase in lymphocyte proliferation. A closer inspection revealed that loss of PEA-15 particularly affected a group of lymphocytes called T-cells. T-cells are involved in killing invading pathogens as well as stimulating more long-term immunity.

The PEA-15 protein works by acting as a brake on a group of proteins that activate cell cycling and proliferation when they recognize a signal from an invading organism. Lymphocytes without PEA-15 continue proliferating beyond the normal response levels. “Understanding how T-cell expansion is controlled at the molecular level should lead to new methods to control immune response during infection, as well as perhaps helping the development of novel ways to utilize these cells to attack tumours,” said Dr. Joe Ramos, an assistant professor in natural products and cancer biology at the University of Hawaii. “Dysregulation of PEA-15 function might also play a role in the development or progression of lymphomas or leukaemias,” he added.

A protein complex that leads a double life

Researchers have identified a protein complex, which seems to be one of the major regulatory complexes both in Drosophila (fruit fly) and in mammals. “Without it, flies die early in embryonic development,” says Dr. Asifa Akhtar at the Max-Planck Institute of Immunobiology, Germany.
Because the absence of the newly found complex causes early embryonic death of both males and females, Dr. Akhtar and colleagues named it Non-Specific Lethal (NSL), in contrast to a previously known complex Male-Specific Lethal (MSL). The MSL complex enables males to double the expression of the genes in their single X chromosome – a process known as dosage compensation – by binding to the body of those genes together with a protein called MOF. Thus, male flies are able to compensate for the fact that they only have one X chromosome, while females have two.

But MOF leads a double life: it also binds to the promoter regions of genes on all chromosomes, in both sexes. The NSL complex helps MOF to bind to promoters and thereby plays a key role in determining the life MOF will lead. If it partners up with NSL, MOF turns on genes in all chromosomes. If it interacts with MSL, it binds to genes on the males’ X chromosome, playing its role in dosage compensation. NSL indirectly drives this MOF function too, by acting with it to turn on the genes whose output will then be raised by dosage compensation.


Micro RNA study unlocks secret of immune cells

Scientists at the National Institutes of Health (NIH) in the United States are closer to understanding how activity outside of the nucleus determines a cell’s behaviour. They looked at mouse immune cells and examined the types, amount and activity of microRNAs (miRNAs) to get a map to the variety of miRNAs contained within mouse immune cells and reveal the complexity of cellular protein regulation.

Protein levels impact a plethora of cellular functions, ranging from development, differentiation and metabolism to host defence, said Dr. Rafael Casellas, the study’s principal investigator from the Genomics and Immunity Group of the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases. The research focus is on discovering how miRNAs contribute to the regulation of those functions.

The NIH scientists used a new microsequencing technology to comprehensively identify all of the different miRNAs existing in mouse immune cells. They also discovered several cellular mechanisms that regulate miRNA abundance. The study found that some miRNA constructs exist in a dormant state within the nucleus until they receive signals from the epigenome to become active. The epigenome regulates transcription and comprises all of the non-genetic material in the nucleus. These epigenetic mechanisms do not hamper other miRNAs, which are controlled simply through transcription.

‘Junk’ DNA behind cancer cell growth

Researchers from the University of Leeds in the United Kingdom and the Charite University Medical School and the Max Delbruck Centre for Molecular Medicine (MDC) in Germany have identified how ‘junk’ DNA promotes the growth of cancer cells in patients with Hodgkin’s lymphoma. Prof. Constanze Bonifer from the University of Leeds and Dr. Stephan Mathas from Charite and MDC co-led the study which suggests that these pieces of ‘junk’ DNA, called long terminal repeats (LTRs), can play a role in other forms of cancer as well. The researchers uncovered the process by which this ‘junk DNA’ is made active. “This would have implications for diagnosis, prognosis and therapy of these diseases,” said Prof. Bonifer. Although LTRs originate from viruses and are potentially harmful, they are usually made inactive when embryos are developing in the womb. If this process of inactivation doesn’t work, then the LTRs could activate cancer genes, a possibility that was suggested in previous animal studies.

This latest study has now demonstrated that these ‘rogue’ active LTRs can drive cancer growth in humans. The work focused on cancerous cells of Hodgkin’s lymphoma that originate from white blood cells (antibody-producing B cells). Unusually, this type of lymphoma cell does not contain a so-called ‘growth factor receptor’ that controls the growth of other B-cells. The scientists found that the lymphoma cells’ growth was dependent on a receptor that normally regulates the growth of other immune cells, but it is not usually found in B-cells. However, in this case, the Hodgkin/Reed Sternberg cells ‘hijacked’ this receptor for their own purposes by activating several LTRs.

The researchers found evidence of the same LTRs activating the same growth receptor also in anaplastic large cell lymphoma, another blood cancer. The consequences of such widespread LTR activation are currently still unclear, said the researchers. Such processes could activate other genes involved in tumour development. It could also affect the stability of chromosomes of lymphoma cells, which may explain why Hodgkin/Reed Sternberg cells gain many chromosomal abnormalities over time and become more and more malignant.

Simulator to test blood platelets in virtual heart attacks

Bioengineers from the University of Pennsylvania Institute for Medicine and Engineering, the United States, have trained a computer neural network model to accurately predict how blood platelets would respond to complex conditions found during a heart attack or a stroke. Using an automated system, they exposed human blood platelets to hundreds of different combinations of biological stimuli such as those experienced during a heart attack. This was done by fingerprinting each platelet sample with 34,000 data points obtained in response to all possible pairs of stimuli.

The researchers applied the system to predict intracellular calcium signalling responses of human platelets to any combination of up to six different agonists used at different dosages, and even applied at different times. The model predicted platelet responses accurately, even distinguishing between 10 blood donors, demonstrating an efficient approach for predicting complex chemical responses in a patient-specific disease milieu.

The strategy involves selecting molecules that react with blood platelets in high-risk situations, such as a heart attack, measuring the cellular responses to all pair-wise combinations of stimuli and then training a two-layer, non-linear, neural network with the measured cellular responses. For platelets, it was found that the complexity of integrating numerous signals can be built up from the responses to simpler conditions involving only two stimuli. The researchers developed Pairwise Agonist Scanning, an experimental/computational technique, to define platelet response to combinations of agonists – chemicals that bind to platelet cells – initiating a cellular response. “With patient-specific computer models, it is now possible to predict how an individual’s platelets would respond to thousands of ‘in silico’ heart-attack scenarios,” said Dr. Scott L. Diamond, a professor of chemical and biomolecular engineering and Director of the Penn Centre for Molecular Discovery.

Breakthrough in stem cell culturing

Embryonic stem (ES) cells are currently cultured with the help of proteins from animals, which rules out their use in the treatment of humans. Alternatively, stem cells can be cultured on other human cells, known as feeder cells, but these release thousands of uncontrolled proteins and therefore lead to unreliable research results. A research team at Karolinska Institute, Sweden, has now cultured human ES cells without using of other cells or substances from animals. Instead they were cultured on a matrix of a single human protein – laminin-511 – which the researchers produced using recombinant techniques. Together with scientists at the Harvard Stem Cell Institute, the United States, the research team led by Prof. Karl Tryggvason has also shown that in the same way they can culture reprogrammed stem cells, which have been converted “back” from tissue cells to stem cells.

Laminin-511 is part of the connective tissue and acts in the body as a matrix to which cells can attach. In a newly formed embryo, it is also needed to keep stem cells as stem cells. Once the embryo begins to develop different types of tissue, other types of laminin will be needed. Until now, different types of laminin have not been available to researchers, because they are very difficult to extract from tissues or to produce. The team of Prof. Tryggvason has cloned the genes for most human laminins, and even managed to produce several types of laminin using gene technology.

Living human lung on a chip

In the United States, researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard Medical School and Children’s Hospital Boston have created a device that mimics a living, breathing human lung on a microchip. The device, about the size of a rubber eraser, acts like a lung in a human body and is made using human lung and blood vessel cells. Because the lung device is translucent, it provides a window into the inner workings of the human lung without having to invade a living body. It has the potential to be a valuable tool for testing the effects of environmental toxins, absorption of aerosolized medicines and the effect of new drugs.

“The ability of the lung-on-a-chip device to predict absorption of airborne nanoparticles and mimic the inflammatory response triggered by microbial pathogens, provides proof-of-principle for the concept that organs-on-chips could replace many animal studies in the future,” says Dr. Donald Ingber, senior author of the study and the Founding Director of Wyss Institute. Tissue-engineered microsystems have been limited mechanically or biologically and one can’t understand how biology works unless it is in the physical context of real living cells, tissues and organs, he adds.

The lung-on-a-chip microdevice has two layers of living tissues – the lining of the lung’s air sacs and the blood vessels that surround them – across a porous, flexible boundary. Air is delivered to the lung lining cells, a rich culture medium flows in the capillary channel to mimic blood and cyclic mechanical stretching mimics breathing. The device was created using clear rubbery materials, in a new microfabrication strategy pioneered by Dr. George Whitesides, the Woodford L. and Ann A. Flowers University Professor at Harvard.

To determine how well the device replicates the natural responses of living lungs to stimuli, the scientists tested its response to inhaled living Escherichia coli bacteria. They introduced E. coli into the air channel on the lung side of the device and at the same time flowed white blood cells through the channel on the blood vessel side. The lung cells detected the bacteria and, through the porous membrane, activated the blood vessel cells, which triggered an immune response that then caused the white blood cells to move to the air chamber and destroy the bacteria.

New cancer detection technology

Pacific Edge Biotechnology, New Zealand, has received clearance to market its new technology that helps detect and predict cancer. The technology allows doctors to find aggressive cancer in patients already diagnosed with colorectal or cancer of the bowel. “The prognostic test enables physicians to predict colorectal cancer and its progression, providing patients with more specific treatment following surgery,” says Pacific Edge Chief Executive Mr. David Darling.

Pacific Edge has done extensive research and developed a gene expression database (or profile of the gene) from a range of human tumours. Along with a patient’s clinical data, this forms the discovery platform for diagnostic and prognostic testing. Colorectal cancer is reported as the fourth most common cancer, and in 2007, there were 1 million cases of this cancer diagnosed worldwide, with 520,000 people dying of the disease. The Pacific Edge’s new prognostic test provides doctors with a valuable tool to help identify those patients at greatest risk and adopt a treatment regime well in time.


A novel tool for the biofuel industry

Auxin is a powerful plant growth hormone that tells plants how to grow, where to lay down roots, how to make tissues, and how to respond to light and gravity. Knowing how to manipulate auxin could thus have enormous implications for the production of biofuel, making plants grow faster and better. Prof. Shaul Yalovsky from the Molecular Biology and Ecology of Plants Department of Tel Aviv University, Israel, describes ICR1, a special protein found to control the way auxin moves throughout a plant affecting its development. When ICR1 is genetically engineered into valuable biofuel crops, farmers can expect to get far higher yields than otherwise possible.

“We have found a mechanism that helps the shoot and root talk to each other,” says Prof. Yalovsky. “The plant’s shoots need to respond to its environment. We have discovered the mechanism that helps auxin do its job.” ICR1 works with a group of proteins called ROPs. Together, this system works in harmony to manipulate the composition and vascular tissues of plant cell walls. The researchers found specifically that ICR1 can be manipulated to influence auxin distribution in plants, with the possibility of manipulating plant into having a cell wall composition needed in making biofuel.

Plant cells have a tough cell wall composed of cellulose, a polysaccharide, and lignin, the woody material. Current methods for removing lignin – which must be removed to produce biofuel – cause the loss of about 50 per cent of cellulosic material that could be used for biofuel. Ideally, the crop growers want to maximize the amount of plant cellulose, which can be broken down to make sugar for ethanol.

Rust resistance genes added to common beans

In the United States, new cultivars of common bean developed by scientists from the Agricultural Research Service (ARS) of the United States Department of Agriculture (USDA) and two universities could shore up the crop’s defences against the fungal disease common bean rust. According to Dr. Talo Pastor-Corrales, an ARS plant pathologist, the new cultivars possess two or more genes for resistance to the rust fungi. Most of the cultivars also have Ur-11, which is considered the most effective rust-resistance gene in the world.


Working with scientists at the University of Nebraska and Colorado State University, Dr. Pastor-Corrales resorted to this multi-gene strategy in response to the high diversity of strains of the bean rust pathogen. Lately, virulent new races of rust have overcome the Ur-3 resistance gene in crops in Michigan and North Dakota. The battle against rust is complicated by the fact that races present in crop fields can vary from one year to the next, says Dr. Pastor-Corrales, who leads a bean breeding project at the ARS Soybean Genomics and Improvement Research Unit.

‘Cisgenics’ offers new biotechnology tools

Forestry scientists at Oregon State University (OSU), the United States, have demonstrated for the first time that characteristics of trees such as the growth rate can be changed using “cisgenics”, a type of genetic engineering that is conceptually similar to traditional plant breeding. Cisgenics employs genes from closely related species that usually are sexually compatible. The researchers used cisgenic manipulation to affect the actions of gibberellic acid, a plant hormone, in poplar trees. This had significant effects on the growth rate, morphology and wood properties of seedling trees. The advance is important for forestry research, but perhaps even more significant in demonstrating the general value and success of cisgenics.

“Until now, most applications of biotechnology have been done with transgenics, in which you take genetic traits from one plant or animal and transfer them into an unrelated species,” said Dr. Steven Strauss, a distinguished professor of forest biotechnology at OSU. “By contrast, cisgenics uses whole genes from the same plant or a very closely related species. We may be able to improve on the slow and uncertain process of plant breeding with greater speed and certainty of effect.”

Cisgenics “is a process that is similar to what happens naturally during crop breeding and evolution,” Dr. Strauss says. “We are not trying to insert genes from a fish into a strawberry here,” Dr. Strauss explains. “We are taking a gene from a poplar tree and putting it back into a poplar tree.” That would be more acceptable than transgenics to most people and regulatory agencies.
In any group of plants, some might grow taller or better resist disease than others. Once the researchers know what genes are controlling growth and disease resistance, they can take them from one plant and put them back into the same or closely related species, and amplify or attenuate the desired characteristic. “That is conceptually the same thing we have been doing in conventional plant breeding for two centuries,” remarked Dr. Strauss.

Fern’s gene may help clean up contaminated land

Researchers at Purdue University, the United States, have isolated a gene that allows a type of fern to tolerate high levels of arsenic, and hope to use the finding to create plants that can clean up soils and waters contaminated by the toxic metal. The fern Pteris vittata can tolerate 100 to 1,000 times more arsenic than other plants. Dr. Jody Banks, a professor of botany and plant pathology, and Dr. David Salt, a horticulture professor, uncovered what may have been an evolutionary genetic event that creates an arsenic pump in the fern. “It actually sucks the arsenic out of the soil and puts it in the fronds,” Dr. Banks said. “It is the only multi-cellular organism that can do this.”

Without a sequenced genome for P. vittata, the scientists used yeast functional complementation for gene identification. Thousands of different P. vittata genes were combined with thousands of yeast cells that were missing a gene that makes them tolerant to arsenic. The yeast was exposed to arsenic; those strains that lived had picked up the genes from P. vittata for arsenic resistance. The researchers found that the protein encoded by this gene ends up in the membrane of the plant cell’s vacuole. Dr. Salt said the protein acts as a pump, moving arsenic away from the cytoplasm so that it can’t have an effect on the plant.

Heat-tolerant bean varieties

New bean germplasm lines containing drought, heat and disease tolerance are being released by scientists at the Agricultural Research Service (ARS) of the United States Department of Agriculture and their co-operators. ARS geneticist Dr. Tim Porch, at the Tropical Agricultural Research Station in Puerto Rico, recently released two new kidney bean germplasm lines, called TARS HT-1 and TARS HT-2, that tolerate very hot conditions. The new releases are part of collaborative breeding efforts of ARS with Cornell University and the University of Tennessee in the United States, and the University of Puerto Rico, Puerto Rico. TARS HT-1 yields well under high day and high night temperature stress, and TARS HT-2 works well under high day and moderate night temperature stress. These germplasm lines can improve yields under hot summer conditions. Dr. Porch and colleagues are also developing new black bean germplasm lines with tolerance to drought and heat, and resistance to root rot and common bacterial blight, caused by the bacterium Xanthomonas axonopodis pv. Phaseoli. Field as well as greenhouse trials have shown that the lines yield well, and possess drought tolerance, disease resistance and adaptation to both short and long days

Enzyme that increases yields in the biofuel industry

Novozymes A/S of Denmark has launched a new enzyme that makes it possible to produce more ethanol from corn. The product, Spirizyme Excel, converts more starch in corn, wheat and other feedstock into sugars for fermentation to ethanol, thereby increasing yields by more than one per cent. Compared with other available solutions, a typical ethanol plant can gain US$1 million or more per year using the enzyme, the company claims. Spirizyme Excel breaks down the most difficult starch fractions in the feedstock to maximize biofuel production yields. Increased efficiency in crop production, ethanol conversion and co-product use also means ethanol made from corn can reduce carbon dioxide emissions by up to 70 per cent compared with gasoline, claims Mr. Poul Ruben Andersen, Biofuel Marketing Director of Novozymes.


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