When Will Genomic Research Translate into Clinical Care - and at What Cost?

New study applies quantitative modelling to genomics

Saturday, 05 January 2013

Genomic research is widely expected to transform medicine, but progress has been slower than expected. While critics argue that the genomics "promise" has been broken – and that money might be better spent elsewhere – proponents say the deliberate pace underscores the complexity of the relationship between medicine and disease and, indeed, argues for more funding.

But thus far, these competing narratives have been based mostly on anecdotes. Ramy Arnaout, MD, DPhil, a founding member of the Genomic Medicine Initiative at Beth Israel Deaconess Medical Center (BIDMC), decided it was time to look at genomics from a new perspective. So he turned to quantitative modelling, a numerical forecasting approach used to predict everything from weather events to the outcomes of political elections, and an extremely useful way to both set expectations and assist in decision-making.

Arnaout and colleagues knew that drug-related adverse outcomes cost the health-care system upwards of $80 billion a year, and that many such cases should be avoidable by choosing and dosing drug prescriptions according to a person's genome. So they developed a quantitative model to estimate how much time and money would be required to use genomics, specifically pharmacogenomics, to cut these adverse outcomes in half. Their findings, currently published online in the journal Clinical Chemistry, provide one of the first examples of data-driven estimates being applied to genomic medicine and offer a template for the use of quantitative modelling in this field.

How do the numbers add up? After analysing their model for a range of situations, the research team found that the cost can be expected to be less than $10 billion, spread out over approximately 20 years.

"If you look across medicine, you can see specific places here and there where genomics is really starting to change things, but it's been hard to know how it all adds up in the big picture," explains Arnaout, who is also an Assistant Professor of Pathology at Harvard Medical School (HMS) and Associate Director of Clinical Microbiology at BIDMC.

"Quantitative modelling is a standard approach for forecasting and setting expectations in many fields as we all remember from the recent presidential election and from the hurricane season. Genomics is so important and is so often on the minds of our patients, students and staff, that it seemed like a good idea to use modelling to get some hard numbers on where we're headed."

The idea for the study originated nearly two years ago, while Arnaout (whose laboratory studies genomics) and Sukhatme, BIDMC's Chief Academic Officer, were attending a lecture, shortly after the 10-year anniversary of the sequencing of the genome.

"Vikas asked me, 'So when is genomics really going to change medicine?'" remembers Arnaout.

"I realized I didn't know. And that got me thinking."

Arnaout and Sukhatme, together with co-authors Thomas Buck, MD, and Paulvalery Roulette, MD, of BIDMC and HMS, decided to try and answer this question by applying forecasting methods to a big clinical problem – drug-related adverse outcomes.

"We know that preventable causes of these adverse outcomes -- patients' non-adherence, interactions between multiple drugs, and medical error, for example -- account for only a fraction of the millions of adverse outcomes that patients experience each year," explains Arnaout.

"This leaves a significant number that are currently considered non-preventable and are thought to be caused by genomic variation."

By way of example, Arnaout explains that 30 million Americans currently use the blood-thinning drug warfarin. But because, in some cases, patients' genomes contain variants that make the standard dose of warfarin too high for them, these individuals are likely to experience bleeding, an extremely dangerous side effect. In fact, researchers now estimate that three-quarters of the variability in warfarin dosing requirement is due to these genomic variants, and they have already identified a set of variants in six specific genes that explain two-thirds of the variability.

"This kind of progress suggested an interesting thought experiment," says Arnaout.

"What if we took existing examples in which there appears to be a carefully vetted, clinically useful connection between a specific adverse outcome and a specific genetic variant, found out how much it cost and how long it took to discover, and applied that model to all drugs? How much would it cost and how long would it take to cut adverse outcomes by 25 percent? How about by half?"

As data for the model, the authors selected eight associations involving six prescription drugs (clopidogrel, warfarin, escitalopram, carbamazepine, the nicotine-replacement patch and abacavir) and one drug class, the statin class of anti-cholesterol drugs.

Using an approach called Monte Carlo modelling, the team ran simulations to forecast the research investment required to learn how to cut adverse outcomes by meaningful amounts, and how long that research work would be expected to take. For statistical confidence, they ran their simulations thousands of times and explored a wide range of assumptions.

"The results were surprising," says Arnaout.

"Before we did this work, I couldn't have told you whether it would take a million dollars or a trillion dollars or whether it would take five years or a hundred years. But now, we've got a basis for thinking that we're looking at single-digit billions of dollars and a couple of decades. That may sound like a lot or a little, depending on your point of view. But with these numbers, we can now have a more informed conversation about planning for the future of genomic medicine."

The most important determinant of the numbers is the extent to which the examples used in the model will turn out to be representative of drugs as a whole.

"It's a broad set of drugs that were used, but we know how the genome can surprise us," says senior author Sukhatme.

"For example, you won't be able to use genomics to cut adverse outcomes in half if genomics turns out to explain less than half of the adverse outcomes. But even in that case, we found that pharmacogenomics will be able to make a significant dent in adverse outcomes – cutting them by a quarter – for multi-billion-dollar investments."

Also surprising, say the authors, was the timing.

"As a rule, the fruits of research come only after research dollars have already been spent," points out Arnaout. This means that, in this case, hundreds of millions of dollars will be spent for "pump-priming" long before the public can expect to see any meaningful clinical impact.

"It's one thing to say, 'Be patient,' based on just faith," he adds.

"It's another to be able to say so based on data and a model. We now have that. This enables the conversation to shift to which indicators of progress to look for, over the five or so years of pump-priming, to make sure we're on track."

Can we go faster?

"If we could enrol an ethnically diverse set of patients who are taking each of the 40 or 50 most commonly prescribed drugs, get their blood samples, and keep track of the adverse outcomes that some of them are bound to experience, we should be able to move faster, for less money," adds Arnaout, who describes this idea as a "50,000 Pharmacogenomes Project," a pursuit along the lines of the 1,000 Genomes Project, the UK10K or the Veteran's Association Million Veteran Program.

"This model provides the start of a provocative conversation and illustrates the value of quantitative modelling in this very practical and publically relevant aspect of genomics," adds BIDMC Chief of Pathology Jeffrey Saffitz, MD, PhD.

"Such models should help both decision makers and the public set expectations and priorities for translating genomic research into better patient care."

Source: Beth Israel Deaconess Medical Center 

Contact: Bonnie Prescott

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Researchers Print Live Cells with a Standard Inkjet Printer

Researchers Print Live Cells with a Standard Inkjet Printer
Monday, 19 March 2012

A fibroblast printed with the modified
inkjet printer. The interior of the cell
shows that the fluorescently tagged
actin monomers have been incorporated.

Credit: © The Journal of Visualized

Experiments. To watch the full video

article, please click here.

Researchers from Clemson University have found a way to create temporary holes in the membranes of live cells using a standard inkjet printer. The method will be published in JoVE, the Journal of Visualized Experiments, on March 16.

"We first had the idea for this method when we wanted to be able to visualize changes in the cytoskeleton arrangement due to applied forces on cells," said paper-author Dr. Delphine Dean.

She said other researchers have been using this method to print cells onto slides, but that they have only recently discovered that printing the cells causes the disruption in their membranes for a few hours. Creating temporary pores allow researchers to put molecules inside of cells that wouldn't otherwise fit, and study how the cells react.

"The authors have used an extremely innovative approach for bio-printing cells. Moreover, this approach can be used for applications other than cell printing," said JoVE Science Editor, Dr. Nandita Singh.

"Matrix proteins can be printed onto substrates with this technique for cell patterning. This JoVE publication will make this approach simple and approachable and enable other labs to replicate the procedure."

The printer is modified by removing the paper feed mechanism and adding a "stage" from which to feed the slides. The ink is replaced with a cell solution, and the cells are printed directly on to the slides.

Using this method, the researchers are able to process thousands of cells in a matter of minutes. Dr. Dean's team used the holes to introduce fluorescent molecules that illuminate the skeleton of the cell.

"We are actually interested in the cell mechanics of compressed cells. This method allows us to push on the cells and watch the response easily," said Dr. Dean.

"We are interested in cardiovascular cells, and how they respond to mechanical force."

Dr. Dean chose to submit her method to JoVE, the only peer reviewed, PubMed-indexed science journal to publish all of its content in both text and video format, because, according to her, "until you've seen it done, it's hard to understand the process."

Source: The Journal of Visualized Experiments

Contact: Katherine Scott

Reference:

Creating Transient Cell Membrane Pores Using a Standard Inkjet Printer
Owczarczak, A. B., Shuford, S. O., Wood, S. T., Deitch, S., Dean, D.
J. Vis. Exp. (61), e3681, DOI: 10.3791/3681 (2012)

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Artificial Life: First Self-replicating Synthetic Bacterial Cell Created

A fully synthesized genome transforms one species of bacterium into another
Thursday, May 20, 2010

Mycoplasma mycoides JCVI-syn1.0. Credit: J. Craig Venter Institute.

Researchers at the J. Craig Venter Institute (JCVI), a not-for-profit genomic research organization, published results today describing the successful construction of the first self-replicating, synthetic bacterial cell. The team synthesized the 1.08 million base pair chromosome of a modified Mycoplasma mycoides genome. The synthetic cell is called Mycoplasma mycoides JCVI-syn1.0 and is the proof of principle that genomes can be designed in the computer, chemically made in the laboratory and transplanted into a recipient cell to produce a new self-replicating cell controlled only by the synthetic genome.

This research will be published by Daniel Gibson et al in the May 20th edition of Science Express and will appear in an upcoming print issue of Science.

“For nearly 15 years Ham Smith, Clyde Hutchison and the rest of our team have been working toward this publication today – the successful completion of our work to construct a bacterial cell that is fully controlled by a synthetic genome,” said J. Craig Venter, Ph.D., founder and president, JCVI and senior author on the paper.

“We have been consumed by this research, but we have also been equally focused on addressing the societal implications of what we believe will be one of the most powerful technologies and industrial drivers for societal good. We look forward to continued review and dialogue about the important applications of this work to ensure that it is used for the benefit of all.”

According to Dr. Smith:

“With this first synthetic bacterial cell and the new tools and technologies we developed to successfully complete this project, we now have the means to dissect the genetic instruction set of a bacterial cell to see and understand how it really works."

To complete this final stage in the nearly 15 year process to construct and boot up a synthetic cell, JCVI scientists began with the accurate, digitized genome of the bacterium, M. mycoides. The team designed 1,078 specific cassettes of DNA that were 1,080 base pairs long. These cassettes were designed so that the ends of each DNA cassette overlapped each of its neighbours by 80bp. The cassettes were made according to JCVI’s specifications by the DNA synthesis company, Blue Heron Biotechnology.

The JCVI team employed a three stage process using their previously described yeast assembly system to build the genome using the 1,078 cassettes. The first stage involved taking 10 cassettes of DNA at a time to build 110, 10,000 bp segments. In the second stage, these 10,000 bp segments are taken 10 at a time to produce eleven, 100,000 bp segments. In the final step, all 11, 100 kb segments were assembled into the complete synthetic genome in yeast cells and grown as a yeast artificial chromosome.

The complete synthetic M. mycoides genome was isolated from the yeast cell and transplanted into Mycoplasma capricolum recipient cells that have had the genes for its restriction enzyme removed. The synthetic genome DNA was transcribed into messenger RNA, which in turn was translated into new proteins. The M. capricolum genome was either destroyed by M. mycoides restriction enzymes or was lost during cell replication. After two days viable M. mycoides cells, which contained only synthetic DNA, were clearly visible on Petri dishes containing bacterial growth medium.

The initial synthesis of the synthetic genome did not result in any viable cells so the JCVI team developed an error correction method to test that each cassette they constructed was biologically functional. They did this by using a combination of 100 kb natural and synthetic segments of DNA to produce semi-synthetic genomes. This approach allowed for the testing of each synthetic segment in combination with 10 natural segments for their capacity to be transplanted and form new cells. Ten out of 11 synthetic fragments resulted in viable cells; therefore the team narrowed the issue down to a single 100 kb cassette. DNA sequencing revealed that a single base pair deletion in an essential gene was responsible for the unsuccessful transplants. Once this one base pair error was corrected, the first viable synthetic cell was produced.

Dr. Gibson stated:

“To produce a synthetic cell, our group had to learn how to sequence, synthesize, and transplant genomes. Many hurdles had to be overcome, but we are now able to combine all of these steps to produce synthetic cells in the laboratory.”

“We can now begin working on our ultimate objective of synthesizing a minimal cell containing only the genes necessary to sustain life in its simplest form. This will help us better understand how cells work,” he added.

This publication represents the construction of the largest synthetic molecule of a defined structure; the genome is almost double the size of the previous Mycoplasma genitalium synthesis. With this successful proof of principle, the group will now work on creating a minimal genome, which has been a goal since 1995. They will do this by whittling away at the synthetic genome and repeating transplantation experiments until no more genes can be disrupted and the genome is as small as possible. This minimal cell will be a platform for analyzing the function of every essential gene in a cell.

According to Dr. Hutchison:

“To me the most remarkable thing about our synthetic cell is that its genome was designed in the computer and brought to life through chemical synthesis, without using any pieces of natural DNA. This involved developing many new and useful methods along the way. We have assembled an amazing group of scientists that have made this possible.”

As in the team’s 2008 publication in which they described the successful synthesis of the M. genitalium genome, they designed and inserted into the genome what they called watermarks. These are specifically designed segments of DNA that use the “alphabet” of genes and proteins that enable the researcher to spell out words and phrases. The watermarks are an essential means to prove that the genome is synthetic and not native, and to identify the laboratory of origin. Encoded in the watermarks is a new DNA code for writing words, sentences and numbers. In addition to the new code there is a web address to send emails to if you can successfully decode the new code, the names of 46 authors and other key contributors and three quotations: "To live, To err, To fall, To triumph, To recreate life out of life." – James Joyce; "See things not as they are, but as they might be.” – A quote from the book, “American Prometheus”; "What I cannot build, I cannot understand." – Richard Feynman. 

The JCVI scientists envision that the knowledge gained by constructing this first self-replicating synthetic cell, coupled with decreasing costs for DNA synthesis, will give rise to wider use of this powerful technology. This will undoubtedly lead to the development of many important applications and products including biofuels, vaccines, pharmaceuticals, clean water and food products. The group continues to drive and support ethical discussion and review to ensure a positive outcome for society.

Funding for this research came from Synthetic Genomics Inc., a company co-founded by Drs. Venter and Smith.

Background
The research published today was made possible by previous breakthroughs at JCVI. In 2007 the team published results from the transplantation of the native M. mycoides genome into the M. capricolum cell which resulted in the M. capricolum cell being transformed into M. mycoides. This work established the notion that DNA is the software of life and that DNA dictates the cell phenotype.

In 2008 the same team reported on the construction of the first synthetic bacterial genome by assembling DNA fragments made from the four chemicals of life — ACGT. The final assembly of DNA fragments into the whole genome was performed in yeast by making use of the yeast genetic systems. However, when the team attempted to transplant the synthetic bacterial genome out of yeast and into a recipient bacterial cell, viable transplants could not be recovered.

Ethical Considerations
Since the beginning of the quest to understand and build a synthetic genome, Dr. Venter and his team have been concerned with the societal issues surrounding the work. In 1995 while the team was doing the research on the minimal genome, the work underwent significant ethical review by a panel of experts at the University of Pennsylvania (Cho et al, Science December 1999:Vol. 286. no. 5447, pp. 2087 – 2090). The bioethical group's independent deliberations, published at the same time as the scientific minimal genome research, resulted in a unanimous decision that there were no strong ethical reasons why the work should not continue as long as the scientists involved continued to engage public discussion.

Dr. Venter and the team at JCVI continue to work with bioethicists, outside policy groups, legislative members and staff, and the public to encourage discussion and understanding about the societal implications of their work and the field of synthetic genomics generally. As such, the JCVI’s policy team, along with the Center for Strategic & International Studies (CSIS), and the Massachusetts Institute of Technology (MIT), were funded by a grant from the Alfred P. Sloan Foundation for a 20-month study that explored the risks and benefits of this emerging technology, as well as possible safeguards to prevent abuse, including bioterrorism. After several workshops and public sessions the group published a report in October 2007 outlining options for the field and its researchers.

Most recently in December of 2008, JCVI received funding from the Alfred P. Sloan Foundation to examine ethical and societal concerns that are associated with the developing science of synthetic genomics. The ongoing research is intended to inform the scientific community as well as educate our policymakers and journalists so that they may engage in informed discussions on the topic.

About the J. Craig Venter Institute
The JCVI is a not-for-profit research institute in Rockville, MD and La Jolla, CA dedicated to the advancement of the science of genomics; the understanding of its implications for society; and communication of those results to the scientific community, the public, and policymakers. Founded by J. Craig Venter, Ph.D., the JCVI is home to approximately 400 scientists and staff with expertise in human and evolutionary biology, genetics, bioinformatics/informatics, information technology, high-throughput DNA sequencing, genomic and environmental policy research, and public education in science and science policy. The legacy organizations of the JCVI are: The Institute for Genomic Research (TIGR), The Center for the Advancement of Genomics (TCAG), the Institute for Biological Energy Alternatives (IBEA), the Joint Technology Center (JTC), and the J. Craig Venter Science Foundation. The JCVI is a 501 (c) (3) organization.

Reference:
Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome
Daniel G. Gibson, John I. Glass, Carole Lartigue, Vladimir N. Noskov, Ray-Yuan Chuang, Mikkel A. Algire, Gwynedd A. Benders, Michael G. Montague, Li Ma, Monzia M. Moodie, Chuck Merryman, Sanjay Vashee, Radha Krishnakumar, Nacyra Assad-Garcia, Cynthia Andrews-Pfannkoch, Evgeniya A. Denisova, Lei Young, Zhi-Qing Qi, Thomas H. Segall-Shapiro, Christopher H. Calvey, Prashanth P. Parmar, Clyde A. Hutchison III, Hamilton O. Smith, and J. Craig Venter
Science, Published online May 20 2010; DOI: 10.1126/science.1190719
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China Stakes Claim as Global Centre for Scientific Research

China Stakes Claim as Global Centre for Scientific Research Thursday, 14 January 2010 Contrary to popular belief, China is doing much more than exporting clothing, toys, electronics, and other popular consumer goods. The country is on a scientific roll, to the point where it could conceivably be regarded as the emerging global centre for scientific research, a new report indicates. It describes an amazing growth in chemical patenting and publishing that could bring new and innovative products to the world market ranging from pharmaceuticals to microchips, according to an article in the current issue of Chemical & Engineering News, (C&EN) ACS' weekly newsmagazine. C&EN Senior Editor Sophie L. Rovner reports that China in 2009 became the world leader in the number of chemistry patent applications published annually. China published 67,000 patent applications in 2009, compared to 52,000 for Japan and 41,000 for the United States. Publication of scientific papers originating in China increased faster than any other nation during the last 10 years. The output of papers with Chinese authors more than quadrupled — from 20,000 papers in 1998 to more than 112,000 in 2008. The publication of U.S. scientific papers rose by barely 30 percent during that period. In achieving this growth, scientists in China are embracing collaborators in the U.S. and other countries. It is becoming increasingly clear that the country is changing the "world map of research," with China conceivably at its centre, the article suggests. This story is available at China Ascendant. ......... ZenMaster

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Superior Offspring without Genetic Modification

Superior Offspring without Genetic Modification Tuesday, 08 December 2009 We don't always turn out like our parents. Sometimes we become even better. How this happens is the subject of a new research project at the University of Gothenburg. When two gene pools combine, you might expect the characteristics of the offspring to end up somewhere in the middle between those of its parents. But children often have characteristics that are better or worse than that middle value, sometimes even better than both parents. Better horses, redder tomatoes This is not a newly-recognized phenomenon. Indeed, it has been exploited to breed better horses, redder tomatoes, more nutritious rice, and salmon that can thrive in fish farms, to mention but a few examples. New research project Heterosis is the scientific term for being better than your parents. Why does heterosis occur? What is the molecular mechanism? How common is it? How can we make it happen more often and to greater effect? Researchers at the Department of Cell and Molecular Biology at the University of Gothenburg and the Norwegian University of Life Sciences outside Oslo are aiming to find answers to these questions in a new research project. Baker´s yeast Using baker's yeast as a model, Jonas Warringer and his colleague Stig Omholt are mapping the incidence of heterosis for a large number of different characteristics. They hope to discover the mechanisms in human cells that govern the creation of children with characteristics sometimes superior to those of their parents. They are initially studying yeast cells - in which the mechanism has already been established. Brewer’s yeast In their first studies, Warringer and Omholt have shown how heterosis has enabled brewer's yeast to develop tolerance to copper, something that helps the yeast to survive in the large copper tanks used in the brewing industry. After some of the results where published in Nature in March this year, the interest in Warringers and Omholts research has increased. Life on Mars "Once we understand how heterosis occurs, breeding can be controlled so that we can selectively promote desirable characteristics in plants and animals more quickly and effectively. This could help in the fight against famine, help us develop new bio fuels for cars, and possibly, in the distant future, make it possible to create a functioning ecosystem on Mars - without having to resort to genetic modification," says Jonas Warringer. ......... ZenMaster

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Artificial Liver for Drug Tests

Artificial Liver for Drug Tests Thursday, 25 June 2009 If you have hay fever, headaches or a cold, it's only a short way to the nearest chemist. The drugs, on the other hand, can take eight to ten years to develop. Until now animal experiments have been an essential step, yet they continue to raise ethical issues. "Our artificial organ systems are aimed at offering an alternative to animal experiments," says Professor Heike Mertsching of the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB in Stuttgart. "Particularly as humans and animals have different metabolisms. 30 per cent of all side effects come to light in clinical trials." The test system, which Professor Mertsching has developed jointly with Dr. Johanna Schanz, should in future give pharmaceutical companies greater security and shorten the path to new drugs. Both researchers received the "Human-centered Technology" prize for their work. "The special feature, in our liver model for example, is a functioning system of blood vessels," says Dr. Schanz. "This creates a natural environment for cells." Traditional models do not have this, and the cells become inactive. "We don't build artificial blood vessels for this, but use existing ones – from a piece of pig's intestine." All of the pig cells are removed, but the blood vessels are preserved. Human cells are then seeded onto this structure – hepatocytes, which, as in the body, are responsible for transforming and breaking down drugs, and endothelial cells, which act as a barrier between blood and tissue cells. In order to simulate blood and circulation, the researchers put the model into a computer-controlled bioreactor with flexible tube pump, developed by the IGB. This enables the nutrient solution to be fed in and carried away in the same way as in veins and arteries in humans. "The cells were active for up to three weeks," says Dr. Schanz. "This time was sufficient to analyze and evaluate the functions. A longer period of activity is possible, however." The researchers established that the cells work in a similar way to those in the body. They detoxify, break down drugs and build up proteins. These are important pre-conditions for drug tests or transplants, as the effect of a substance can change when transformed or broken down – many drugs are only metabolized into their therapeutic active form in the liver, while others can develop poisonous substances. The researchers have demonstrated the basic possibilities for use of the tissue models – liver, skin, intestine and windpipe. At the moment, the test system is being examined. Within two years it could provide a safer alternative to animal experiments. ......... ZenMaster

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Stem Cell Innovation at Risk in UK

Survey of the Cell Therapy Industry and the Main Products in UK Monday, 06 April 2009 Despite great hopes for stem cell therapy, major structural and cultural changes within the NHS are needed if it is to succeed in the UK. Currently the chances of getting effective treatments into routine use in the short-term are small and the industry is at serious risk of 'market failure'.

These are the findings of two major studies into the commercialisation and adoption of stem cell therapy carried out by researchers at The

University of Nottingham. Dr Paul Martin, from the Institute of Science and Society said: "While the government has identified regenerative medicine as a national priority and the US has lifted its ban on stem cell therapy, urgent public policy action is needed if it is to become a reality. Although cell therapy is now established as an important branch of medicine, innovative firms struggle to make money, putting the UK industry in a very vulnerable position in the short term. Unless the situation changes the industry will contract and the progress needed to develop important cell therapies will be adversely affected." The research, funded by the Engineering and Physical Sciences Research Council (EPSRC) identified a number of important barriers to knowledge translation. It found that closer collaboration with clinicians was needed along with better funding for clinical studies, greater regulatory certainty and clearer reimbursement policies. There is also a need to develop enabling technologies to lower manufacturing costs. Commercial activity in cell therapy has grown very significantly since 2002. The industry now involves nearly 200 companies developing primary and secondary cell therapies, plus another 180 banking cord blood. In total the global cell therapy industry currently has sales of over $1 billion a year and a steady number of products are now reaching late stage clinical trials. However, the sector suffers from a high level of company turn over. As a consequence, the industry is dominated by small, young companies lacking the resources to bring products easily and successfully to market and those that do struggle to make sales. Dr Martin, whose expertise lies in the sociology of emerging medical technologies, said: "There are major structural barriers within the NHS that make it difficult to translate new scientific knowledge of stem cells into improved patient care. For a clinician to use a cell therapy routinely it needs to meet a number of strict criteria. They are also expensive and many are yet to have proven clinical outcomes." The reports are the result of a two-year study examining the UK regenerative medicine sector. They have been published ahead of the second National Stem Cell Network's Annual Scientific Conference, which is being held at Oxford University on Monday 6 April 2009 to Wednesday 8 April 2009. The conference attended by leading experts in the field is a celebration of the latest in UK stem cell science. References: The Commercial Development of Cell Therapy – Lessons for the Future? Survey of the Cell Therapy Industry and the Main Products in Use and Development Paul Martin, Ruth Hawksley and Andrew Turner, April 2009 Barriers to the Commercialisation & Utilisation of Regenerative Medicine in the UK Emma Rowley and Paul Martin, April 2009 ......... ZenMaster

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Bone Marrow Stem Cells Regenerate Skin

New study suggests that adult bone marrow stem cells can be used in the construction of artificial skin Thursday, 15 January 2009 A new study suggests that adult bone marrow stem cells can be used in the construction of artificial skin. The findings mark an advancement in wound healing and may be used to pioneer a method of organ reconstruction. The study is published in Artificial Organs, official journal of the International Federation for Artificial Organs (IFAO), the The International Faculty for Artificial Organs (INFA) and the International Society for Rotary Blood Pumps (ISRBP). To investigate the practicability of repairing burn wounds with tissue-engineered skin combined with bone marrow stem cells, the study established a burn wound model in the skin of pigs, which is known to be anatomically and physiologically similar to human skin. Engineering technology and biomedical theory methods were used to make artificial skin with natural materials and bone marrow derived stem cells. Once the artificial skin was attached to the patient and the dermal layer had begun to regenerate, stem cells were differentiated into skin cells. The cells are self-renewing and raise the quality of healing in wound healing therapy. When grafted to the burn wounds, the engineered skin containing stem cells showed better healing, less wound contraction and better development of blood vessels. Skin, the human body's largest organ, protects the body from disease and physical damage, and helps to regulate body temperature. When the skin has been seriously damaged through disease or burns, the body often cannot act fast enough to repair them. Burn victims may die from infection and the loss of plasma. Skin grafts were originally developed as a way to prevent such consequences. "We hope that this so-called 'engineered structural tissue' will someday replace plastic and metal prostheses currently used to replace damaged joints and bones by suitable materials and stem cells," says Yan Jin of the Fourth Military Medical University, lead author of the study. Yan Jin is a chair professor and director of the Department of Oral Histology and Pathology of the School of Stomatology, and director of the Center of Tissue Engineering at the Fourth Military Medical University, Xian, China. ......... ZenMaster

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GM Goats Make Anti-clotting Drug in Their Milk

FDA approval is pending Saturday, 10 January 2009 An anti-clotting drug made from the milk of genetically engineered goats moved closer to government approval Wednesday after experts at the Food and Drug Administration reported that the medication works and its safety is acceptable. Company data showed the drug was safe and effective, a majority of the Food and Drug Administration's 19-member panel voted. The FDA will consider the advice in making its decision, expected by February 7. Called ATryn, the drug is intended to help people with a rare hereditary disorder that makes them vulnerable to life-threatening blood clots. A Massachusetts biotechnology company, GTC Biotherapeutics, developed ATryn by altering the genes of goats so they would produce milk rich in human antithrombin, a protein that in humans acts as a natural blood thinner. Scientists at the GTC have made the drug by inserting the human antithrombin protein into single cell embryos of goats. These embryos were then put into the wombs of surrogate mothers who produced goats that possessed the new characteristics. The protein is gathered from the milk of the goat, which is then refined and purified. The scientific advisors at the FDA will see into the pros and cons of ATryn. They will then make a further recommendation for approval of the drug. “It's the first time we've held an advisory committee meeting on any product from a genetically engineered animal,” FDA spokeswoman Siobhan DeLancey said. If the drug is approved, then this would be a significant leap in the area of making medicines by altering genes of living organisms. GTC Biotherapeutics says that a single goat will produce more than six pounds of the protein in the course of a year, and also notes that the drug-producing trait will be naturally passed down to the next generation of goats. The company has a herd of about 200 at its Massachusetts facility, which are otherwise normal and screened for viruses, GTC said. “The real dramatic thing that is happening here is that we've been able to reduce some very clever science to the practical level of producing a drug that's safe and efficacious,” said Geoffrey Cox, Chairman GTC. The drug is licensed to Ovation Pharmaceuticals Inc in the United States. ......... ZenMaster

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Human Genomics in China

10-year endeavor: from planning to implementation Wednesday, 07 January 2009 By Chen Zhu and Zhao Guo-Ping Ten years ago, the Chinese National Human Genome Center at Shanghai (South Center, hereafter) was established in the Zhangjiang HiTech Park of Pudong District in Shanghai. To commemorate this important event, which marks the beginning of the Genomics Era in China, we specially organize a series of mini-reviews for this special issue. We hope that this effort may draw the attention of the Chinese life science research workers to collectively recall the short but fruitful history of human genome project and co-ordinately explore the trend and goal of the future development of this academic discipline in China. As early as in the late 1980s, the Chinese High Technology Research and Development Program, which is also known as the 863 Program, funded the scientists of Fudan University (in Shanghai) to construct DNA jumping library for human genetic disease related physical mapping. It was probably the very first human genome related research project supported by a national funding agency. After 1991, Fudan University, Ruijin Hospital and the Cancer Research Institute in Shanghai were all funded by the 863 Program in succession, to develop genomics technology by means of molecular genetics, and to study genetic diseases including cancer by means of medical genetics. Meanwhile, Beijing scientists such as those in the Institute of Basic Medicine, Chinese Academy of Medical Sciences also independently developed the rare cutter restriction enzymes such as Not I and Sfi I to facilitate the analysis of large DNA fragments of human genome, aiming at physical map construction. These early efforts and progress became truly "the spark of a fire" and the human genome research was thus initiated. In the early 1990s, focusing on the total sequencing and annotation of the complete human genome as its core mission, the Human Genome Project (HGP) was initiated under the leadership of the U.S.A. However, the initial response in China was, instead, to participate in the International Rice Genome Project led by Japan. The reasons behind were obvious. First of all, for China, the largest developing country of the world, food security is of the primary concern and rice is the major staple food for Chinese people. Second, rice, a diploid crop, with its relatively small genome size (about 400 Mb), is a nice model of the monocotyledon plants. Third, over the years, the Chinese scientists had accumulated a great deal of experiences in the basic and applied research of rice, and achieved significant progress in rice breeding and physiology studies, particularly, for the hybrid rice, a model of "Green Revolution". Inspired by these ideas, both the central and the Shanghai municipal governments supported the DNA sequencing expert HONG Guo-Fan, who just returned back to China from Sanger's laboratory, to initiate the rice genome project in 1992 and the Chinese efforts in rice genome sequencing and research were thus, set out on its long journey. Meanwhile, the far-sighted Chinese medical geneticists were still promoting the initiation of a human genome project in China. Academician WU Min, at that time, the director of the Department of Life Sciences, National Natural Science Foundation of China (NSFC), strongly recommended the NSFC committee to initiate some major projects for human genome research. The academician LIANG Dong-Cai, Deputy Director of the NSFC Committee and of the Department of Life Sciences, supported his efforts and thus, the first major human genome project in China was funded to study the genetic variations among the 56 Chinese nationalities. Meanwhile, the Chinese scientists working in the field of medical genetics gradually accepted the concept of genomics, and by applying the genomics technology, they carried out a series of research and made significant breakthroughs in the study and identification of disease associated genes, particularly the cloning and identification of genes related to leukaemia, solid tumours (including liver cancer, colorectal cancer and nasopharyngeal cancer) and genetic diseases (such as deafness). Furthermore, substantial progresses were made in the development of technologies for human genome genotyping and genetic polymorphism detection, as well as for expressed sequence tag (EST) and full-length cDNA cloning and sequencing. All these achievements greatly strengthened the Chinese scientists' confidence and encouraged them to further explore the human genome. On the other hand, they made people perceive and appreciate the Chinese human genetic resources, for their abundance in population (more than 1 billion) with 56 nationalities and numerous relatively isolated ethnic groups. If we actively collect and utilize the resources with intelligence in research, along with the HGP, we will be able to and obligatory to make great contributions to the course of human health, especially to the oriental people for the medical purpose. With this scientific and historical background, in July 1997, the academician TAN Jia-Zhen petitioned the central government, appealing for the protection of the Chinese genetic resources, and proposed to establish the national human genome centre to speed up the human genome research in China. This petition attracted great attention from the Party Central Committee and the State Council. JIANG Ze-Min, the General Secretary of the Party and the President of the People's Republic of China, wrote: "One, who did not think far enough ahead, inevitably may have trouble right-a-way. We have to cherish our genetic resources." Thus, the Shanghai Human Genome Research Center, co-sponsored by the Ministry of Science and Technology, Shanghai Municipal Government, Pudong District, Zhangjiang High-Tech Park, and six research institutions in Shanghai, was founded on March 4, 1998. On October 20, 1998, the centre was officially inaugurated as the Chinese National Human Genome Center at Shanghai (abbreviated as the South Center), thus becoming the first national research centre located in the Zhangjiang Hi-Tech Park of Pudong District. The academician CHEN Zhu has served as the director of the centre ever since, while ZHAO Guo-Ping acted as the executive director of the centre after 2002. At the same time, the National Human Genome Center at Beijing (the North Center) was established with the support of the Ministry of Science and Technology and Beijing Municipal Government, and the academician QIANG Bo-Qin served as the director. The "Huada" (Chinese Giant/Wash U) Genome Center, directed by YANG Huan-Ming, was also established by the Institute of Genetics, CAS. Together with the previously established National Gene Research Center, which was established by the joint efforts of both CAS and the Shanghai Municipality for rice genome research, a basic genomics sequencing and research framework formed in China, with Beijing and Shanghai each equipped with two genome centres. The connection between the human genome project and the rice genome project was greatly promoted, which eventually facilitated the success of the rice genome project. The 9th National Five-Year Plan (1996-2000) witnessed the rise, the struggle and the success of the Chinese genomic research. In the early stage of the 9th Five-Year Plan, the scientific committee of the 863 Program thoroughly assessed the international trend of research related to human health and diseases and promptly determined to set up a "key project" for human genome research, and soon upgraded it as a "major project". The committee set up a "two 1%" goal with respect to the genomic sequencing and the full-length cDNA identification, respectively, and coordinated the efforts of Shanghai and Beijing local government to set up the national human genome research centres for more efficient implementation. After acquiring the "one percent" share of human genome sequencing, the committee, together with CAS, promptly reinforced the support for the sequencing project. Co-ordinately, the National Key Basic Research Program, known as the 973 Program, started a disease genomics project in 1998 led by the academicians CHEN Zhu and QIANG Bo-Qin. The 973 Program continued to fund the project in 2004 under the title of "Systems Biology for the Multi-gene Complex Diseases" coordinated by CHEN Zhu. The Chinese human genome project fully exemplified the "Chinese characteristics". With respect to the project design, besides the above-mentioned "two one percent", it reinforced the research upon disease genomics and focused on the establishment of the disease sample/information collecting network along with the continuous efforts in cloning and identification of disease related genes by employing human genetic resources from China and abroad. The human health oriented functional genomics research, including bioinformatics, transcriptomics, proteomics, structural genomics and other technology platforms, such as model animals, biochip constructions, etc., were all developed along with the human genomic sequencing project in the late 1990s. Making full use of the technology and resource advantages of the human genome research helped to extend the genomic sequencing and related research to plants other than rice, microorganisms (pathogens for medicine and agriculture or important industry bacteria), insects (silkworm) and parasites (Schistosoma japonicum). In 2006, the original and assembled genomic sequence data of S. japonicum was registered in and released from a public bioinformatics database operated by the Shanghai Bioinformation Technology Development Center, for sharing with the international Schistosoma mansoni consortium. This action indicated that genomic information analysis technology had set out an important step forward in merging with the international GeneBank. In summary, although China started late in genomic sequencing, it has caught up with the international wave in functional genomics, and the achievements of which effectively enhanced the life science research and biotechnology development in China. With respect to funding policy and the establishment of platform centres, China adopted the international model initially — organizing grand scientific program/projects and establishing genome centres for implementation. On the other hand, based on the characteristics of funding and administration systems in China, various kinds of operation models for those genome centres were explored in order to encourage all sections of the governmental institutions to offer as much as possible funds through various channels. By adopting these multiple funding patterns under the guidance of the national projects, the Chinese scientists mobilized as much enthusiasm from the society as possible and efficiently integrated the national and local, the governmental and social resources and secured the development of the projects and centres. Take the South Center as an example. During the ten years period since its establishment, in the process of completing a series of international and national key genome projects, the original mixed research team of the centre was tempered, and the abilities of the team members were improved. Meanwhile, influenced by the centre, an array of "omics" and systems biomedicine research centres were gradually set up in the Zhangjiang HiTech Park of Shanghai. Collaborating with these research centres, the South Center has been accomplishing its transformation from a platform technology centre focusing on sequencing and genotyping services to a research centre engaged in the cutting-edge innovation on molecular targets identification and characterization for human health and diseases and the translational research on genomics, molecular genetics and systems biomedicine. Meanwhile, through the constant improvement of its comprehensive competitiveness in science and technology innovation, the service function of this systems biology research platform is becoming more substantial, and the centre continues to promote the formation and transformation of intellectual property based on the biomedicine research achievements. In fact, within the past ten years, the progress of genomics in China was a sort of frog leap development in terms of scale, quality, interdisciplinary, organization and international collaboration. The genomics research of human and rice, the two national major scientific projects, together with a series of genomic sequencing and functional genomics analyses, constitutes an unprecedented development in life science research and biotechnology development in China. For decades, particularly from the early 1950s to the 1970s, genetics and molecular genetics were sort of lagging in China, largely due to the influences of Lysenkonism in the 1950-1960s and then the hit by "cultural revolution" in the 1960-1970s. Fortunately, in this difficult period, with the cooperation of Chinese biologists and chemists, protein and nucleic acid chemistry gained a rapid development. The chemical synthesis and 3D structure determination of bovine insulin and the chemical synthesis of yeast alanine-tRNA were land marker achievements recorded in the scientific history. In contrast to the situation in China, from the 1960s to the 1980s, life science worldwide was led by genetics and molecular biology, i.e., studying DNA/RNA and the flow of genetic information (central dogma). In China, these disciplines were severely hampered, with few scientists such as Prof. TAN Jia-Zhen to be the only leading scientist to defend Morgan's theory for a long time. Therefore, China's life science was largely behind the world development trend for decades. However, in the early 1990s, with the incoming "scientific spring", Chinese life scientists grasped the historical opportunity of HGP to catch up with the world cutting-edge life science and realized a frog leap forward. For the first time, the concept of "big science" was introduced into the Chinese life science community thanks to HGP. The "big sciences" are grand scientific research programs guided with a comprehensive and long-term objective to tackle the major scientific problems related to the development of human and human society. They aimed to gather important scientific data and to make significant scientific discoveries with the aid of multi-disciplinary studies and integrated technologies. A strong link between big and small sciences was set up, in that in the genomic era, no body doing small science related to molecular biology, biochemistry and cell biology won't benefit from the dataset generated by human (and other) genomic studies. For instance, just in Shanghai, biologists engaging in molecular biology studies of mammalian reproductive system, signal transduction, immunology, microbiology, central nerve system, genetic evolution, leukaemia and pathogenesis, were all somehow involved in genomics work to certain extent. The rise of other molecular "omics" further strengthened the linkage of "big science" and "small science". For such a tremendous impact of this linkage upon life science research and the development of biotechnology, it is truly a revolution. Human genome study in China initiated a new phase of interdisciplinary in the history of life science in China. The rise of genomics relied on its integration with other academic disciplines, particularly in the following three areas. First, the integration with technology science has caused several rounds of revolution in DNA sequencing technology in the past 40 years, which directly led the first sequencing trial of 4 bases of the λ phage cosmid to the current program of sequencing the genomes of a thousand individuals. Second, the integration with computational science and computer technology brought about bioinformatics, which supported the system of data collection, administration, annotation, distribution, and services for genome researches; and the technology platform for data analysis, was also thus established. Third, the integration with mathematics and statistics led to the rise of computational biology, which makes full use of the genomic data and the data generated by other "omics" and then, analyzes them with various kinds of biological data. It provides experimental scientists with hypotheses/models for systems biology research. Actually, mainly promoted by bioinformatics and computational biology, laws of a complex life system can now be deciphered and understood. Human genomic research, with the magnitude of "big science "and "big project" and unprecedented dynamics of development, facilitated, in an extraordinary way, the domestic and international collaboration. HGP in China set a good example for "liberation of mind" in the life science fields. It makes the Chinese biologists to understand what the meaning of "leading the scientific frontier" is and what the "national strategic demand" is. It also inspired the Chinese biologists to challenge the important scientific problems and to participate in the international collaboration and competition. What's more, it teaches the Chinese biologists how to organize scientific teams for major scientific research projects and how to efficiently coordinate the nation-wide research efforts. In the early 1990s, in the mind of the leaders of Chinese human genome research, a consensus had been reached, that is: "In the next century, China will be one of the leading countries in genomics and life science. If we do not start the genomics program today, we are going to lose the right of voice in 10 years. Though we start from small, we shall harvest huge." With ten years of persistent struggle and hard working, we keep our words and have mostly realized these objectives. To recall the history is for a better development in the future. After the completion of the genomic sequencing and the HapMap project, the international HGP has entered an assault-fortified position aiming at studying the genetic mechanisms of human diseases and other phenotypes. The initiation of HGP is due to the lesson learnt from the failure of the cancer project in the Kennedy era of the 1960s, while the success of HGP also depends on its influence upon tackling cancer and other complex human diseases. Meanwhile, facilitated by the strategic plan of big sciences, the innovation of science and technology and their industrialization, as well as the fast progress in interdisciplinary studies such as bioinformatics, have prepared the ground for a new "great frog leap". Some of the mini-reviews published in this issue analyze the future trend of genomics research and its scientific impact based on the technical perspectives of genomic sequencing, genotyping and functional genomics. While the others present the significant change of research strategy and technology brought in by the HGP with respect to liver cancer (hepatocarcinoma), immunology, and medical, environmental and industrial microbiology. These reviews reflect the progress we have achieved, showing that, compared with the situation ten years ago, our research capability, technology experience, and academic intelligence have all been significantly improved. Meanwhile, we are confronted with more difficult challenges than ten years ago. If we can learn from the past experience, focus on a correct direction, move forward bravely but with caution, carefully organize and integrate the research teams, improve the management with both democracy and discipline, and work hard to explore the scientific truth, we shall be able to make faster and greater progress. On the other hand, if we arrogantly enjoy the past but ignore the new challenge, or underestimate our capabilities and feel afraid of innovation, it is possible that we may miss the good opportunities, as said in this old Chinese proverb, "Ninety miles is only half way of a hundred-mile journey". Confucius once said: "The passage of time is just like the flow of the River, which goes on day and night, for ever". The past glories are the momentum for our new journey, while the lessons of the past may teach us to be smarter. China, a developing socialist country rising from a hundred years of weakness and poverty, needs genomics to make historic contributions to the rejuvenation of the nation. Chen Zhu and Zhao Guo-Ping Shanghai Key Laboratory of Disease and Health Genomics The Chinese National Human Genome Center at Shanghai The People's Republic of China Reference: Sci China Ser C-Life Sci., Jan. 2008, vol. 52, no. 1, pp.2-6 doi: 10.1007/s11427-009-0016-5 See also: Science Key to China's Development CellNEWS - Thursday, 16 October 2008 Progress of China's Stem Cell Research CellNEWS - Tuesday, 05 August 2008 China Becoming Worlds Powerhouse in Science CellNEWS - Saturday, 02 August 2008 International Human Genome Project Launched CellNEWS - Wednesday, 23 January 2008 China's Biotech Industry CellNEWS - Monday, 07 January 2008 First Complete Asian Genome CellNEWS - Friday, 12 October 2007 ......... ZenMaster

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Tissue Engineering for Transplanting from Own Stem Cells II

Use of several types of adult stem cells grow new trachea Thursday, 20 November 2008 The first tissue-engineered trachea (windpipe), utilising the patient's own stem cells, has been successfully transplanted into a young woman with a failing airway. The bioengineered trachea immediately provided the patient with a normally functioning airway, thereby saving her life. These remarkable results provide crucial new evidence that adult stem cells, combined with biologically compatible materials, can offer genuine solutions to other serious illnesses. In particular, the successful outcome shows it is possible to produce a tissue-engineered airway with mechanical properties that permit normal breathing and which is free from the risks of rejection seen with conventional transplanted organs. The patient has not developed antibodies to her graft, despite not taking any immunosuppressive drugs. Lung function tests performed two months after the operation were all at the better end of the normal range for a young woman. The pan-European team from the universities of Barcelona, Bristol, Padua and Milan report on this pioneering work in an article published early online and in an upcoming edition of The Lancet. The loss of a normal airway is devastating, but previous attempts to replace large airways have met serious problems. The 30-year-old mother of two, suffering from collapsed airways following a severe case of TB, was hospitalised in March 2008 with acute shortness of breath rendering her unable to carry out simple domestic duties or care for her children. The only conventional option remaining was a major operation to remove her left lung, which carries a risk of complications and a high mortality rate. Based on successful laboratory work previously performed by the team, and given the urgency of the situation, it was proposed that the lower trachea and the tube to the patient's left lung (bronchus) should be replaced with a bioengineered airway based on the scaffold of a human trachea. A seven-centimetre tracheal segment was donated by a 51-year-old transplant donor who had died of cerebral haemorrhage. Spain has a policy of assumed consent for organ donation. Using a new technique developed in Padua University, the trachea was de-cellularised over a six-week period so that no donor cells remained. Stem cells were obtained from the recipient's own bone marrow, grown into a large population in Professor Martin Birchall's lab at the University of Bristol, and matured into cartilage cells (chondrocytes) using an adapted method originally devised for treating osteoarthritis by Professor Anthony Hollander at the University of Bristol. The donor trachea was then seeded with chondrocytes on the outside, using a novel bioreactor which incubates cells, developed at the Politecnico di Milano, Italy, allowing them to migrate into the tissue under conditions ideal for each individual cell type. In order to replicate the lining of the trachea, epithelial cells were seeded onto the inside of the trachea using the same bioreactor. Four days after seeding, the graft was used to replace the patient's left main bronchus. Professor Paolo Macchiarini of the University of Barcelona performed the operation in June 2008 at the Hospital Clínic, Barcelona. Professor Macchiarini, lead author on the paper, said: "We are terribly excited by these results. Just four days after transplantation the graft was almost indistinguishable from adjacent normal bronchi. After one month, a biopsy elicited local bleeding, indicating that the blood vessels had already grown back successfully". Martin Birchall, Professor of Surgery at the University of Bristol, added: "Surgeons can now start to see and understand the very real potential for adult stem cells and tissue engineering to radically improve their ability to treat patients with serious diseases. We believe this success has proved that we are on the verge of a new age in surgical care". Anthony Hollander, Arthritis Research Campaign Professor of Rheumatology and Tissue Engineering at the University of Bristol, concurred: "This successful treatment manifestly demonstrates the potential of adult stem cells to save lives". The patient, Claudia Castillo, a young woman from Colombia but now living in Spain, had no complications from the operation and was discharged from hospital on the tenth post-operative day. She has remained well since and has a normal quality of life. She is able to care for her children, walk up two flights of stairs and occasionally go out dancing in the evenings. She said: "Above all I would like to thank Dr. Macchiarini and his medical team who did the research, for the time and dedication they devoted to my case to make sure that everything turned out alright." Reference: Clinical transplantation of a tissue-engineered airway Paolo Macchiarini, Philipp Jungebluth, Tetsuhiko Go, M Adelaide Asnaghi, Louisa E Rees, Tristan A Cogan, Amanda Dodson, Jaume Martorell, Silvia Bellini, Pier Paolo Parnigotto, Sally C Dickinson, Anthony P Hollander, Sara Mantero, Maria Teresa Conconi, Martin A Birchall The Lancet, Early Online Publication, 19 November 2008, doi:10.1016/S0140-6736(08)61598-6 See also: Tissue Engineering for Transplanting from Own Stem Cells I CellNEWS - Thursday, 20 November 2008 ......... ZenMaster

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