Neonatal Heart Stem Cells May Help Mend Kids' Broken Hearts

Cardiac stem cells from newborns show stronger regenerative ability than adult stem cells

Tuesday, 11 September 2012

Researchers at the University of Maryland School of Medicine, who are exploring novel ways to treat serious heart problems in children, have conducted the first direct comparison of the regenerative abilities of neonatal and adult-derived human cardiac stem cells. Among their findings: cardiac stem cells (CSCs) from newborns have a three-fold ability to restore heart function to nearly normal levels compared with adult CSCs. Further, in animal models of heart attack, hearts treated with neonatal stem cells pumped stronger than those given adult cells. The study is published in the September 11, 2012, issue of Circulation.

"The surprising finding is that the cells from neonates are extremely regenerative and perform better than adult stem cells," says the study's senor author, Sunjay Kaushal, M.D., Ph.D., associate professor of surgery at the University of Maryland School of Medicine and director, paediatric cardiac surgery at the University of Maryland Medical Center.

"We are extremely excited and hopeful that this new cell-based therapy can play an important role in the treatment of children with congenital heart disease, many of whom don't have other options."

Dr. Kaushal envisions cellular therapy as either a stand-alone therapy for children with heart failure or an adjunct to medical and surgical treatments. While surgery can provide structural relief for some patients with congenital heart disease and medicine can boost heart function up to two percent, he says cellular therapy may improve heart function even more dramatically.

"We're looking at this type of therapy to improve heart function in children by 10, 12, or 15 percent. This will be a quantum leap in heart function improvement."

Heart failure in children, as in adults, has been on the rise in the past decade and the prognosis for patients hospitalized with heart failure remains poor. In contrast to adults, Dr. Kaushal says heart failure in children is typically the result of a constellation of problems: reduced cardiac blood flow; weakening and enlargement of the heart; and various congenital malformations. Recent research has shown that several types of cardiac stem cells can help the heart repair itself, essentially reversing the theory that a broken heart cannot be mended.

Stem cells are unspecialized cells that can become tissue- or organ-specific cells with a particular function. In a process called differentiation, cardiac stem cells may develop into rhythmically contracting muscle cells, smooth muscle cells or endothelial cells. Stem cells in the heart may also secrete growth factors conducive to forming heart muscle and keeping the muscle from dying.

To conduct the study, researchers obtained a small amount of heart tissue during normal cardiac surgery from 43 neonates and 13 adults. The cells were expanded in a growth medium yielding millions of cells. The researchers developed a consistent way to isolate and grow neonatal stem cells from as little as 20 milligrams of heart tissue. Adult and neonate stem cell activity was observed both in the laboratory and in animal models. In addition, the animal models were compared to controls that were not given the stem cells.

Dr. Kaushal says it is not clear why the neonatal stem cells performed so well. One explanation hinges on sheer numbers: there are many more stem cells in a baby's heart than in the adult heart. Another explanation: neonate-derived cells release more growth factors that trigger blood vessel development and/or preservation than adult cells.

"This research provides an important link in our quest to understand how stem cells function and how they can best be applied to cure disease and correct medical deficiencies," says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs, University of Maryland; the John Z. and Akiko K. Bowers Distinguished Professor; and dean, University of Maryland School of Medicine.

"Sometimes simple science is the best science. In this case, a basic, comparative study has revealed in stark terms the powerful regenerative qualities of neonatal cardiac stem cells, heretofore unknown."

Insights gained through this research may provide new treatment options for a life-threatening congenital heart syndrome called hypoplastic left heart syndrome (HLHS). Dr. Kaushal and his team will soon begin the first clinical trial in the United States to determine whether the damage to hearts of babies with HLHS can be reversed with stem cell therapy. HLHS limits the heart's ability to pump blood from the left side of the heart to the body. Current treatment options include either a heart transplant or a series of reconstructive surgical procedures. Nevertheless, only 50-60 percent of children who have had those procedures survive to age five.

According to the American Heart Association, congenital heart disease may affect approximately one in 100 children. In the United States, more than 1 million adults are living with congenital heart defects.

Source: University of Maryland Medical Center 

Contact: Bill Seiler

Reference:

A strong regenerative ability of cardiac stem cells derived from neonatal hearts

Simpson DL, Mishra R, Sharma S, Goh SK, Deshmukh S, Kaushal S.

Circulation. September 11, 2012

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How Many Genes in the Human Genome? Human Genome Far More Active than Thought

GENCODE Consortium discovers far more genes than previously thought

Friday, 07 September 2012

The GENCODE Consortium expects the human genome has twice as many genes than previously thought, many of which might have a role in cellular control and could be important in human disease. This remarkable discovery comes from the GENCODE Consortium, which has done a painstaking and skilled review of available data on gene activity.

Among their discoveries, the team describes more than 10,000 novel genes; identify genes that have 'died' and others that are being resurrected. The GENCODE Consortium reference gene catalogue has been one of the underpinnings of the larger ENCODE Project and will be essential for the full understanding of the role of our genes in disease.

The GENCODE Consortium is part of the ENCODE Project that, today, publishes 30 research papers describing findings from their nearly decade-long effort to describe comprehensively all the active regions of our human genome. ENCODE was launched in 2003 after the completion of the Human Genome Project, and brought together an international group of scientists tasked with identifying and describing all functional regions of the human genome sequence.

"We have uncovered a staggering array of genes in our genome, simply because we can examine many genomes in a detail that was not possible a decade ago," says Dr. Jennifer Harrow, GENCODE principle investigator from the Wellcome Sanger Institute. 

"As sequencing technology improves, so we have much more data to explore.

"But our work remains a skilled effort to annotate correctly our human genome - or, more precisely, our human genomes, for each of us differ. These vast texts of genetic information will not give up their secrets easily. GENCODE has made amazing strides to enable immediate access of its reference gene set by other researchers."

The team more accurately described the genes that contain the genetic code to make proteins: they found 20,687 such protein-coding genes, a value that has not changed greatly from previous work. The new set captures far more of the alternative forms of these genes found in different cell types.

More significant are their findings on genes that do not contain genetic code to make proteins - non-coding genes - and the graveyard of supposedly 'dead' genes from which some are emerging, resurrected from the catalogue of pseudogenes.

They mapped and described 9,277 long non-coding genes, a relatively new type that acts, not through producing a protein, but directly through its RNA messenger. Long non-coding RNAs derived from these genes can play a significant part in human biology and disease, but they remain only poorly understood.

"If the Human Genome Project was the baseline for genetics, ENCODE is the baseline for biology, and GENCODE are the parts that make the human biological machine work. Our list is essential to all those who would fix the human machine," said Dr. Tim Hubbard.

The new map of such genetic components gives researchers more avenues to explore in their quest to understand human biology and human disease. Remarkably, the team thinks their job is not complete and believes that there may be another 10,000 of these genes yet to be uncovered.

"Our initial work from the Human Genome Project suggested there were around 20,000 protein-coding genes and that value has not changed greatly," says Professor Roderic Guigo, GENCODE principle investigator from Centre for Genomic Regulation, Barcelona.

"However GENCODE has shown that long non-coding RNAs are far more numerous and important than previously thought"

"The limited knowledge we have of the class of long non-coding RNAs suggests they might play a major role in regulating the activity of other genes. If this is generally true of this group, we have much more to explore than we imagined."

As dramatic, GENCODE has catalogued for the first time a set of more than 11,000 pseudogenes by examining the entire human genome. There is some emerging evidence that many of these genes, too, might have some biological activity.

The GENCODE team predicts that at least 9% of pseudogenes may be active with some controlling the activity of other genes. Pseudogenes have been implicated in many biological activities, such as the prevention of certain elements known to be involved in the development of cancer.

"At the announcement of the Human Genome Project draft sequence, we emphasized this was the end of the beginning, that 'at present most genes - probably tens of thousands - remain a mystery'", says Dr. Tim Hubbard, lead principle investigator of GENCODE from the Wellcome Trust Sanger Institute. 

"Today, we describe many thousands of genes for the first time."

"If the Human Genome Project was the baseline for genetics, ENCODE is the baseline for biology, and GENCODE are the parts that make the human biological machine work. Our list is essential to all those who would fix the human machine."

The GENCODE human reference set will be updated every three months to ensure that models are continually refined and assessed based on new experimental data deposited in the public databases.

Source: Wellcome Trust Sanger Institute 

Contact: Don Powell

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ZenMaster

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Complexity of Human Genome Unravelled

ENCODE data describes function of human genome’s ‘dark matter’

Wednesday, 05 September 2012

The Human Genome Project produced an almost complete order of the 3 billion pairs of chemical letters in the DNA that embodies the human genetic code — but little about the way this blueprint works. Now, after a multi-year concerted effort by more than 440 researchers in 32 labs around the world, a more dynamic picture gives the first holistic view of how the human genome actually does its job.

During the new study, researchers linked more than 80 percent of the human genome sequence to a specific biological function and mapped more than 4 million regulatory regions where proteins specifically interact with the DNA. These findings represent a significant advance in understanding the precise and complex controls over the expression of genetic information within a cell. The findings bring into much sharper focus the continually active genome in which proteins routinely turn genes on and off using sites that are sometimes at great distances from the genes themselves. They also identify where chemical modifications of DNA influence gene expression and where various functional forms of RNA, a form of nucleic acid related to DNA, help regulate the whole system.

"During the early debates about the Human Genome Project, researchers had predicted that only a few percent of the human genome sequence encoded proteins, the workhorses of the cell, and that the rest was junk. We now know that this conclusion was wrong," said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), a part of the National Institutes of Health.

"ENCODE has revealed that most of the human genome is involved in the complex molecular choreography required for converting genetic information into living cells and organisms."

NHGRI organized the research project producing these results; it is called the Encyclopedia of DNA Elements or ENCODE. Launched in 2003, ENCODE's goal of identifying all of the genome's functional elements seemed just as daunting as sequencing that first human genome. ENCODE was launched as a pilot project to develop the methods and strategies needed to produce results and did so by focusing on only 1 percent of the human genome. By 2007, NHGRI concluded that the technology had sufficiently evolved for a full-scale project, in which the institute invested approximately $123 million over five years. In addition, NHGRI devoted about $40 million to the ENCODE pilot project, plus approximately $125 million to ENCODE-related technology development and model organism research since 2003.

William Noble, professor of genome sciences and computer
science, in the data centre at the William H. Foege Building, 

University of Washington, Seattle, Washington. Noble, an 

expert on machine learning, and his team designed artificial 

intelligence programs to analyse ENCODE data. These 

computer programs can learn from experience, recognize 

patterns, and organize information into categories 

understandable to scientists. The centre houses systems for a 

wide variety of genetic research. The computer centre has the 

capacity to store and analyse a tremendous amount of data, 

the equivalent of a 670-page autobiography of each person on 

earth, uncompressed. The computing resources analyse over 

4 pentabytes of genomic data a year. Credit: Clare McLean, 

courtesy of University of Washington. 

The scale of the effort has been remarkable. Hundreds of researchers across the United States, United Kingdom, Spain, Singapore and Japan performed more than 1,600 sets of experiments on 147 types of tissue with technologies standardized across the consortium. The experiments relied on innovative uses of next-generation DNA sequencing technologies, which had only become available around five years ago, due in large part to advances enabled by NHGRI's DNA sequencing technology development program. In total, ENCODE generated more than 15 trillion bytes of raw data and consumed the equivalent of more than 300 years of computer time to analyse.

"We've come a long way," said Ewan Birney, Ph.D., of the European Bioinformatics Institute, in the United Kingdom, and lead analysis coordinator for the ENCODE project.

"By carefully piecing together a simply staggering variety of data, we've shown that the human genome is simply alive with switches, turning our genes on and off and controlling when and where proteins are produced. ENCODE has taken our knowledge of the genome to the next level, and all of that knowledge is being shared openly."

The ENCODE Consortium placed the resulting data sets as soon as they were verified for accuracy, prior to publication, in several databases that can be freely accessed by anyone on the Internet. These data sets can be accessed through the ENCODE project portal as well as at the University of California, Santa Cruz genome browser, the National Center for Biotechnology Information, and the European Bioinformatics Institute.

"The ENCODE catalogue is like Google Maps for the human genome," said Elise Feingold, Ph.D., an NHGRI program director who helped start the ENCODE Project.

"Simply by selecting the magnification in Google Maps, you can see countries, states, cities, streets, even individual intersections, and by selecting different features, you can get directions, see street names and photos, and get information about traffic and even weather. The ENCODE maps allow researchers to inspect the chromosomes, genes, functional elements and individual nucleotides in the human genome in much the same way."

The coordinated publication set includes one main integrative paper and five related papers in the journal Nature; 18 papers in Genome Research; and six papers in Genome Biology. The ENCODE data are so complex that the three journals have developed a pioneering way to present the information in an integrated form that they call threads.

"Because ENCODE has generated so much data, we, together with the ENCODE Consortium, have introduced a new way to enable researchers to navigate through the data," said Magdalena Skipper, Ph.D., senior editor at Nature, which produced the freely available publishing platform on the Internet.

Since the same topics were addressed in different ways in different papers, the new website will allow anyone to follow a topic through all of the papers in the ENCODE publication set by clicking on the relevant thread at the Nature ENCODE explorer page. For example, thread number one compiles figures, tables, and text relevant to genetic variation and disease from several papers and displays them all on one page. ENCODE scientists believe this will illuminate many biological themes emerging from the analyses.

In addition to the threaded papers, six review articles are being published in the Journal of Biological Chemistry and two related papers in Science and one in Cell.

The ENCODE data are rapidly becoming a fundamental resource for researchers to help understand human biology and disease. More than 100 papers using ENCODE data have been published by investigators who were not part of the ENCODE Project, but who have used the data in disease research. For example, many regions of the human genome that do not contain protein-coding genes have been associated with disease. Instead, the disease-linked genetic changes appear to occur in vast tracts of sequence between genes where ENCODE has identified many regulatory sites. Further study will be needed to understand how specific variants in these genomic areas contribute to disease.

"We were surprised that disease-linked genetic variants are not in protein-coding regions," said Mike Pazin, Ph.D., an NHGRI program director working on ENCODE.

"We expect to find that many genetic changes causing a disorder are within regulatory regions, or switches, that affect how much protein is produced or when the protein is produced, rather than affecting the structure of the protein itself. The medical condition will occur because the gene is aberrantly turned on or turned off or abnormal amounts of the protein are made. Far from being junk DNA, this regulatory DNA clearly makes important contributions to human health and disease."

Identifying regulatory regions will also help researchers explain why different types of cells have different properties. For example why do muscle cells generate force while liver cells break down food? Scientists know that muscle cells turn on some genes that only work in muscle, but it has not been previously possible to examine the regulatory elements that control that process. ENCODE has laid a foundation for these kinds of studies by examining more than 140 of the hundreds of cell types found in the human body and identifying many of the cell type-specific control elements.

Despite the enormity of the dataset described in this historic collection of publications, it does not comprehensively describe all of the functional genomic elements in all of the different types of cells in the human body. NHGRI plans to invest in additional ENCODE-related research for at least another four years. During the next phase, ENCODE will increase the depth of the catalog with respect to the types of functional elements and cell types studied. It will also develop new tools for more sophisticated analyses of the data.

Source: National Human Genome Research Institute

Contact: Omar McCrimmon 

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