New Mexico Human Services Secretary Pam Hyde on Monday presented state legislators with “drastically reduced” cost estimates of a universal health coverage plan introduced by Gov. Bill Richardson (D), the AP/Santa Fe New Mexican reports. According to the new estimate, state health care spending would increase by less than $30 million in fiscal year 2010, and projected additional costs over five years would be about $72 million under the governor’s plan (Baker, AP/Santa Fe New Mexican, 12/17).

Hyde on Dec. 4 told the state Legislative Finance Committee that, based on a cost analysis prepared by the Mathematica Policy Research Group, state health care spending under the proposal would increase by about $75 million in FY 2010 and by $333 million over five years (Kaiser Daily Health Policy Report, 12/7). However, Mathematica officials said a computer error led to inflated cost estimates for Richardson’s plan and all other reform plans the company was reviewing for the state Legislature, according to the AP/New Mexican.

The new figures are still preliminary and will be reviewed by Mathematica ahead of its final report to the state Legislature in February 2008.

Mathematica also revised its estimate of what percentage of the state’s population younger than age 65 does not have health care from 25% to 18%, according to Deborah Chollet, the company’s project director. Chollet said the new figure was based on new data from FY 2007 that showed a considerable increase in the number of residents who are enrolled in Medicaid and other health care programs for low-income people (AP/Santa Fe New Mexican, 12/17).

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation© 2007 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

New Jersey Gov. Jon Corzine (D) on Wednesday announced an agreement with Horizon Blue Cross Blue Shield of New Jersey that will allow families with incomes greater than 350% of the federal poverty level to purchase health insurance for their children at significantly lower rates, the New York Times reports.

Under the program, families would pay monthly health insurance premiums to Horizon at the same rate paid by those who qualify for FamilyCare, the state’s version of SCHIP (Chen, New York Times, 12/20). Families with one child would pay $137 per month, families with two children would pay $274 per month and those with three or more children would pay $411 per month. By comparison, a parent would pay $400 per month per child for coverage under the Small Employer Health Insurance administered through the state Department of Banking and Insurance, according to state Sen. Joseph Vitale (D). The program would not provide health coverage for adults (Livio, Newark Star-Ledger, 12/19).

The program requires that families with more than one child enroll all of their children in the plan. In addition, families must provide proof that their children were uninsured during the previous six months (New York Times, 12/19). Between 50,000 and 60,000 children would be eligible for the program, according to Vitale. A Rutgers University study indicated that about 15,000 children would enroll, according to state Department of Human Services Commissioner Jennifer Velez (Tamari, Gannett/Asbury Park Press, 12/20).

Horizon President and CEO Karen Clark said the company will absorb the cost of the program, which she estimated to be up to $1 million in the first year (New York Times, 12/20). Horizon spokesperson Tom Rubino said, “We’ve gone into this to work with the state to reduce the number of the uninsured. We’re going to be meeting with the state about the progress of the plan, and the ultimate goal is to make it break even” (McCoy, Philadelphia Inquirer, 12/20). Horizon will begin accepting applications in January 2008 (Newark Star-Ledger, 12/19).

According to the Times, the program “sets the stage” for a universal health coverage plan for all state residents that would be phased in over several years, which Corzine and Vitale said could be unveiled as early as next month (New York Times, 12/20).

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation© 2007 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Senior Senate Republicans “finessing their election-year message” are calling on the Senate Republican Conference to stress health care issues to help win over independent voters in their attempt to regain a majority in 2008, The Hill reports. Sen. Bob Bennett (R-Utah), a close adviser to Minority Leader Mitch McConnell (R-Ky.), said health care “has replaced Iraq as the No. 1 item of anxiety and concern.”

Sen. Lamar Alexander (R-Tenn.), the incoming conference leader, said, “From a Republican point of view, we want to put together four words that don’t usually go together — universal access and private sector.”

The issue of health care — on which voters trust Democrats more than Republicans, according to polls — is “particularly sensitive” for the GOP following President Bush’s vetoes of two bills to renew and expand SCHIP, The Hill reports. “I think Democrats will use that as an issue,” Sen. Orrin Hatch (R-Utah) said, adding, “I think most Republicans want SCHIP, but they wanted it to work right.”

Legislation
Bennett and Sen. Ron Wyden (D-Ore.) are trying to build support for the Healthy Americans Act (S 334), which would require individuals to enroll in private health plans. Under the bill, the government would subsidize premiums for lower-income families, and insurance companies would be prohibited from denying coverage or raising premiums because of pre-existing conditions. Bennett said, “Republicans don’t use the language of universal health care because it’s code for a single-payer government-run system.” He continued, “Now, I’m perfectly willing to embrace universal coverage as long as it’s understood that it’s not a single-payer government-run system, because I do endorse the goal of every American (being) insured.”

“Wyden says [the bill] appears to be more politically palatable next year than SCHIP for Republicans,” The Hill reports. He said, “It gives Republicans the private-sector role for health care they are looking for, at the same time allowing Democrats to say everybody is going to be covered.”

Sen. Jim DeMint (R-S.C.) last week proposed an expansion of access to low-cost health care without a government mandate (Raju, The Hill, 12/20).

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation© 2007 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

A mechanism which can lead to hay fever and other allergic reactions, by preventing the immune system from regulating itself properly, has been discovered by scientists. Researchers hope their finding, published (Thursday 27 December 2007) in the journal PLoS Biology, will allow therapies to be developed that treat allergies by stopping this mechanism.

The new research shows that a gene known as GATA-3 can block the development of regulatory T-cells in the immune system by locking another gene. This gene, FOXP3, is key to regulatory T cells and when it is blocked new regulatory T cells stop being produced.

The scientists, from Imperial College London, the Swiss Institute of Allergy and Asthma Research in Davos, Switzerland, and other international institutions, hope that if they can develop therapies to stop FOXP3 being blocked, they can ensure that regulatory T cells are free to work normally.

Regulatory T cells are believed to be vital for averting allergic reactions in healthy individuals because they keep the other cells in check, suppressing pro-allergic cells known as Th2 cells and stopping the immune system from needlessly attacking the body.

In people with allergies, some types of cells in the immune system, particularly the Th2 cells, wrongly identify a particular allergen, such as pollen, as being dangerous. Whenever the person encounters this allergen again, these cells promote the production of antibodies to attack it, causing an allergic reaction.

Dr Carsten Schmidt-Weber, the principal investigator on the research from the National Heart and Lung Institute at Imperial College London, said: “This finding will help us to understand how healthy individuals are able to tolerate allergens and what we need to do to re-induce tolerance in the immune systems of patients with allergies. We hope that we will soon be able to help not only patients suffering from single allergies, but also those with multiple ones - the atopic patients.”

The researchers reached their conclusions by analysing the genes related to regulatory T-cells and analysing how they interacted. They confirmed their findings by using mouse models to show that mice which were genetically engineered to express the GATA-3 gene in all T cells showed dramatic defects in the production of regulatory T-cells.

Dr Schmidt-Weber and his colleague Professor Stephen Durham, also from the National Heart and Lung Institute at Imperial College, hope the new findings will eventually lead to new, more effective treatments for hayfever and other allergies, to be used in combination with existing immunotherapies. They hope such treatments could help prevent hay fever and allergic asthma from reaching epidemic proportions.

This research was funded by the Swiss National Science Foundation, the Ehmann Foundation Chur, the Saurer Foundation Zurich and Swiss Life Zurich.

Imperial College London
http://www.imperial.ac.uk

Scientists at the Institute for Systems Biology (ISB), in collaboration with researchers from New York University (NYU), have developed a model which rapidly characterizes and accurately predicts the molecular-level, mechanistic response of a free-living cell to genetic and environmental changes. The paper describing the EGRIN model was published today in the online edition of the journal Cell.

The knowledge gained through the Environmental and Gene Regulatory Influence (EGRIN) model demonstrates that it is possible to discover how complex biological systems work and opens the door to more complex genetic engineering that produces fewer unintended consequences.

Mechanics can fix cars because they know all the parts of a vehicle, what each part is supposed to do, how the parts are supposed to work together and what happens when parts wear out over time or stop functioning due to outside influences. Biologists, on the other hand, have trouble fixing and/or reengineering cells because they don’t have a comprehensive molecular parts list, let alone an understanding of how those parts work together to facilitate healthy functioning.

“Unraveling complex biological networks is why I came to ISB,” said Nitin Baliga, Ph.D., an associate professor at ISB. “The genomes of more than 500 organisms have been sequenced, yet we as a scientific community know very little about how their biological networks function.”

“The systems approach to biology, of which the founders of ISB were early champions, has proven to be a spectacular success in achieving a molecular level understanding of complex biology, which is necessary if we are to engineer cells back to health or reengineer organisms to improve bioenergy production or bioremediation, for example,” Baliga said.

The EGRIN model linked biological processes with previously unknown molecular relationships and accurately predicted both new regulation of know biological processes and the transcriptional responses of more than 1,900 genes to completely novel genetic and environmental experiments.

Baliga and colleagues used Halobacterium salinarum NRC-1, a member of the Archaea family of organisms, because it has been the subject of relatively little scientific study. Archael organisms are evolutionarily distinct from the two other forms of life, Eukaryotes and Prokaryotes. They have evolved to thrive in harsh environments that would be lethal to most other organisms. As a result, their unique biology could provide new solutions to challenges in environmental contamination, energy production and healthcare.

Working with an organism about which relatively little is known allowed the Baliga lab to demonstrate the value of taking a systems approach, which can lead to the rapid discovery of structure and function in unstudied biological networks.

“The ability to gather this level of information regarding a poorly characterized organism from a single study is significant and unprecedented,” Baliga said. “In addition, the nature of the EGRIN model is such that it’s applicable to many complex biological networks.”

The process of discovery involved perturbing cells (e.g. altering, individually and in combination, 10 environmental factors and 32 genes), characterizing growth and/or survival phenotype, quantitatively measuring steady state and dynamic changes in mRNA, assimilating the changes into a network model able to repeat the observations and experimentally validating hypotheses formulated through the model. More than 230 out of 413 microarray experiments used were collected and/or conducted specifically for this study. In addition, researchers used data from genome-wide binding location analysis for eight transcription factors, mass spectrometry-based proteomic analysis, protein structure predictions, computational analysis of genome structure and protein evolution as well as data from public sources.

The vast array of approaches to data gathering and validation required a systems biology approach, in which scientists of varied disciplines (e.g. biochemistry, physics, mathematics, computation, statistics, genetics and more) collaborate and contribute their skill sets to the achievement of a single scientific objective.

The researchers’ next steps involve applying the EGRIN model to more complicated organisms and/or networks, and actually reengineering organisms based on knowledge obtained through the EGRIN model.

“It will take a lot more effort before the EGRIN model can be applied in a practical fashion,” Baliga said. “At this point we’ve basically proven that we can develop a comprehensive understanding of how complex biological systems work, which has been an open question to this point.”

About the Institute for Systems Biology

The Institute for Systems Biology (ISB) is an internationally renowned, non-profit research institute headquartered in Seattle and dedicated to the study and application of systems biology. Founded by Leroy Hood, Alan Aderem and Ruedi Aebersold, ISB seeks to unravel the mysteries of human biology and identify strategies for predicting and preventing diseases such as cancer, diabetes and AIDS. ISB′s systems approach integrates biology, computation and technological development, enabling scientists to analyze all elements in a biological system rather than one gene or protein at a time. Founded in 2000, the Institute has grown to 12 faculty and more than 200 staff members; an annual budget of more than $25 million; and an extensive network of academic and industrial partners. For more information about ISB, visit http://www.systemsbiology.org.

Genome rearrangements, resulting in variations in the numbers of copies of genes, occur when the cellular process that copies DNA during cell division stalls and then switches to a different genetic “template,” said researchers at Baylor College of Medicine in Houston in a report that appears today in the journal Cell.

The new mechanism is called replication “Fork Stalling and Template Switching,” said Dr. James R. Lupski, Cullen professor of molecular and human genetics and vice chair of the department at BCM. He is also professor of pediatrics. It not only represents a new way in which the genome generates DNA copy number variation, but it also demonstrates that copy number variation can occur at a different time point in the life of a cell. DNA replication takes place as the cell is dividing and becoming two.

Copy number variation involves structural changes in the human genome that result in the deletion or extra copies of genes (or parts of them). Often, this process is associated with disease, and also with evolution of the genome itself.

DNA (deoxyribonucleic acid) exists as two complementary strands that remain together because of the attraction between nucleotides. A or adenosine is always attracted to T (thymidine). C or cytosine is always attracted to G or guanine.

When a cell divides, it must reproduce its DNA so that each cell that results from the division has the same genetic code. That means it must replicate its DNA. During this process, an enzyme called a helicase separates the two strands, breaking the hydrogen bonds between the A - T and G - C base pairs holding the strands together. The two separating strands become the replication fork. On one strand, an enzyme called DNA polymerase reads the genetic material in the strand as a template and makes a strand (leading strand) of complementary DNA to pair to it. Again, the code is A to T and C to G. This process is continuous. On the other strand that comprises the fork, the complementary strand (lagging strand) is made in short, separated segments by a process that involves RNA and a series of enzymes.

Until the 1990s, researchers studying reasons for genetic mutations or changes looked at molecular “typos” in this process, tiny changes in the As, Ts, Cs or Gs called single nucleotide polymorphisms (SNPs). These SNPs changed the message of the gene. However, in the early 1990s, Lupski was one of the pioneers to elucidate a new mechanism in which the structure of the DNA itself was grossly duplicated or deleted, which changed numbers of copies of a gene that occurred in this genetic material. This “copy number variation” wrote a new chapter in the understanding of genetic variation.

Lupski and his former graduate student Dr. Jennifer Lee (now a postdoctoral fellow at BCM) found in their experiments that this process stalls when there is a problem with the DNA. In that case, the process switches to a different template, copying another similar but significantly different stretch of DNA, before it switches back to the appropriate area. Dr. Claudia M. B. Carvalho, also of BCM, took part in this research.

Previously, Lupski and colleagues had identified two different ways in which recombinations of genetic material resulted in copy number variation. However, when Lee was studying an inherited disease called Pelizaeus-Merzbacher disease, she found changes in the genome that the previous theories about DNA recombination did not explain.

Structural changes in the genome in people with the disease, a neurodevelopmental disorder, vary from person to person. In some places, genetic material that was duplicated was similar to that nearby but it was thrust into the middle of another duplication of material. The question was how they got there, Lee said.

The fork stalling, template switching mechanism explained the oddities, said Lupski.

“It stalls and rather than restart at the position where it is, it switches to a different template,” said Lupski. Usually this occurs in an area of the genome where there are many repeats of the nucleotides that form an unusual structure. This can actually aid in the template switching, he said.

“One could envision that it could happen anywhere in the genome and would be a way to make copy number changes in any gene you want,” he said. It might even play a role in evolution, allowing organisms to change. Some of the changes might make it easier for that organism to live in particular environment or survive in a stressed situation.

Funding for this research came from the Charcot Marie Tooth Association, the National Institute of Child Health and Development and the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center.

To learn more about Lupski’s research, go to http://www.bcm.edu/genetics/faculty/index.html

Baylor College of Medicine
http://www.bcm.edu

Cells keep a close watch over the transcriptome the totality of all parts of the genome that are expressed in any given cell at any given time. Researchers at the Salk Institute for Biological Studies and the University of Missouri-Kansas City teamed up to peel back another layer of transcriptional regulation and gain new insight into how genomes work.

Converting the “genetic blueprint” into molecular building blocks requires two basic processes: transcription, which copies the information from DNA into RNA transcripts and takes place in the cell’s nucleus, and translation, where the RNA serves as a template to manufacture proteins outside the nucleus.

But before transcripts can guide protein synthesis or take on regulatory functions, they have to undergo a strict mRNA surveillance system that degrades defective, obsolete, and surplus transcripts. In their study, published in the Dec. 28 issue of Cell, the scientists zoomed in on a specific subclass of transcripts that are under the control of the exosome, a molecular machine in charge of controlled RNA degradation.

“We found evidence for widespread exosome-mediated RNA quality control in plants and a ‘deeply hidden’ layer of the transcriptome that is tightly regulated by exosome activity,” says Joseph R. Ecker, Ph.D., professor in the Plant Biology Laboratory and director of the Salk Institute Genomic Analysis Laboratory.

Since the exosome is in the business of chewing things up, the scientists inactivated the multi-unit complex to bring its otherwise invisible substrates to the fore. Then they combed the transcriptional landscape for hitherto unseen peaks of transcripts that now were untouched by the degrading force of the exosome complex and came up with a genome-wide atlas of Arabidopsis exosome targets.

“Our careful design and rigorous validation of the system for conditionally and quickly inactivating the exosome turned out to be really crucial for homing in on its RNA targets,” explains Dmitry A. Belostotsky of the University of Missouri-Kansas City. “On the other hand, genome-wide analyses of permanent genetic mutations often produce a complex mixture of direct and indirect effects, making it very hard to untangle. Thus, we think our strategy has a broadly-applicable value.”

“From a genomics perspective it really allowed us to visualize what information from the genome is actually expressed,” adds co-first author Brian D. Gregory, Ph.D., a postdoctoral researcher in Ecker’s lab. “When you knock down exosome activity, you see changes in the transcriptome that are not visible under any other circumstance.”

Since the common notion is that the exosome plays a central role in bulk RNA turnover, the researchers say, they expected to find the levels of all transcripts increasing when they inactivated the exosome complex. “But not everything is going up, instead the exosome mechanism seems to be very tightly regulated,” says Ecker. “We didn’t see regions that are known to be silenced to go up, instead we found a very specific group of transcripts that are regulated in this way.”

Among them are regular protein-coding RNAs, RNA processing intermediates and hundreds of non-coding RNAs, the vast majority of which hadn’t been described before. “These strange transcripts are associated with small RNA-producing loci as well as with repetitive sequence elements,” says Gregory. “They are under very tight regulation by the exosome, but we still don’t know exactly what this means.”

“It is likely that these RNAs that are usually ‘deeply hidden’ become important for genome function or stability under some circumstances”, adds co-first author Julia Chekanova, an assistant at the University of Missouri-Kansas City. “We need to do more work to figure out what these circumstances are.”

Researchers who also contributed to the study include post-doctoral researchers Ravi Kumar, Ph.D. and Tanya Hooker, Ph.D. at the University of Missouri - Kansas City, post-doctoral researchers Sergei V. Reverdatto and Pinghua Li at the State University of New York at Albany, graduate student Qian Peng, bioinformaticist Huaming Chen, postdoctoral researchers Junshi Yazaki, Ph.D and Jose Alonso, Ph.D., all at the Salk Institute, post-doctoral researcher Nikola Skiba, Ph.D., at Havard Medical School, and post-doctoral researcher Vladimir Brukhin and professor Ueli Grossniklaus, Ph.D., at the University of Zürich, Switzerland.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Salk Institute
http://www.salk.edu

A team of biologists have developed a model mapping the control circuit governing a whole free living organism. This is an important milestone for the new field of systems biology and will allow the researchers to model how the organism adapts over time in response to its environment. This study marks the first time researchers have accurately predicted a cell’s dynamics at the genome scale (for most of the thousands of components in the cell). The findings, which are based on a study of Halobacterium salinarum, a free-living microbe that lives in hyper-extreme environments, appear in the latest issue of the journal Cell.

The study’s lead authors are New York University Assistant Biology Professor Richard Bonneau, who holds appointments at NYU’s Center for Genomics & Systems Biology and the university’s Courant Institute for Mathematical Sciences, and Nitin Baliga of the Institute for Systems Biology in Seattle, WA. The study also included researchers at the University of Maryland, Vanderbilt University, and the University of Washington.

The researchers focused on a little studied organism that can survive high salt, radiation, and other stresses that would be deadly to most other organisms. By focusing on such an organism the researchers were able to show definitively that they could understand and model the circuit controlling the cell directly from experiments designed to measure all genes in the genome simultaneously. These are called systems-biology experiments. This scholarship is part of a new scientific field, systems biology, which examines how genes influence each other via extremely large networks of interaction and how these networks respond to stimuli, adapting over time to new environments and cell states. The field has blossomed over the past 10 years, spurred by successful mapping of genomic systems.

By a combination of experimental and algorithmic advances studies in this area have shown that scientific knowledge can go from genome to a functional and dynamical draft-model of the whole organism in a relatively short time. Important previous studies in this area identified cell components (genome sequencing) and how cell components are connected. But the study in Cell went beyond previous scholarship and accurately modeled how Halobacterium, an important organism in high-salt environments such as the Dead Sea or Utah’s Great Salt Lake, functioned over time and responded to changing environmental conditions. The researchers were, for the first time, able to predict how over 80 percent of the total genome (several thousand genes) responded to stimuli over time, dynamically rearranging the cell’s makeup to meet environmental stresses.

“This organism is amazingly versatile and tolerates lots of different extreme environmental stresses,” said Bonneau. “It does this by making decisions and dynamically changing the levels of genes and proteins; if it makes incorrect decisions it dies. Our model shows how these decisions get made, how the bug responds.”

“This is also a good model to explain how, in general, cells make stable decisions as they move through time scales,” added Bonneau, who is part of an NYU research group that handled the analysis of this genome. “If you want to understand how cells respond to their environments, the model offers a clearer window than previously existed for this domain of life.”

The collaboration between Baliga’s and Bonneau’s research groups represents a type of partnership becoming more essential to biological and biomedical research: biologists and computer scientists teaming up to design experiments and analysis that synergize to decipher living systems, resulting in ever more complex and accurate models of the cell. The result is more comprehensive, reaching genome-scale levels, more accurate, and more relevant to biologists and biomedical researchers hoping to understand the whole system.

Bonneau added that by understanding how biological systems function, researchers can then turn their attention to engineering the biosynthesis of biofuels and pharmaceuticals.

“We are now gearing up to try this sort of analysis on several other organisms,” he noted. “In addition, because this study examined the dynamics of a key environmental microbe it offers a window into understanding life in extreme environments, in some cases created by human activities, such as the concentration of pollution by evaporation or high salt marine environments.”

The study was sponsored by the National Science Foundation and the U.S. Department of Energy.

New York University
http://www.nyu.edu

Researchers from Japan’s RIKEN SNP Research Center, collaborating with a team at the University of California, San Diego (UCSD), have discovered a new genetic variation that affects a child’s risk of getting Kawasaki disease (KD), an illness characterized by acute inflammation of the arteries throughout the body. The genetic variation influences immune activation and the response to standard treatment, as well as the risk of developing coronary artery aneurysms - a swelling of the artery that can result in blood clots and heart attack - as a complication of KD.

Lead author, Yoshi Onouchi, M.D., Ph.D., SNP Research Center, RIKEN, Yokohama, Japan, used DNA from hundreds of U.S. children and their parents, collected through the Kawasaki Disease Research Center at Rady Children’s Hospital San Diego (RCHSD), Department of Pediatrics, UCSD School of Medicine.

“This was a wonderful collaboration,” said co-author, Jane Burns, M.D., professor and chief, Division of Allergy, Immunology, and Rheumatology, UCSD Department of Pediatrics. “Dr. Onouchi used our DNA to make this observation. Now we are building on that observation.”

Kawasaki Disease, a pediatric illness characterized by fever and rash, is not a rare illness but it is most prevalent in Japan. In San Diego County, 20 to 30 children per 100,000 children less than five years of age are affected each year. More than 50 new patients are treated annually at RCHSD. The illness is four to five times more common than some more publicly recognized diseases of children such as tuberculosis or bacterial meningitis.

If untreated, KD can lead to lethal coronary artery aneurysms. KD tends to run in families, suggesting that there are genetic components to disease risk. It is also 10 to 20 times more common in Japanese and Japanese American children than in children of European descent.

Researchers identified a region on chromosome 19 linked with the disease. In particular, a series of variants across four genes in the region appeared more frequently in individuals with the disease than those in the healthy control group.

The team focused on one of these genes, ITPKC, which appeared to be the most likely candidate. The gene lies in a signaling pathway that affects the activation of T cells, one arm of the body’s immune response system. ITPKC encodes an enzyme that is part of a signaling pathway with a critical role in T cell activation. The authors showed that one of the risk variants reduces the expression of ITPKC, and that lower levels of ITPKC lead to over-activation of T cells.

“This single gene jumped out as an obvious candidate because it is involved in immune activation, and KD is a disease of immune over-activation,” said Burns. “This was great detective work to decipher the function of this variant.”

Study authors suggest that the association of ITPKC with Kawasaki disease may have immediate clinical implications. Up to 20% of children who have KD are resistant to the standard treatment with intravenous immunoglobulin. This therapy is more likely to fail in individuals with the ITPKC risk variant. If these individuals could be identified with a genetic test, they could be offered alternative, more intensive therapies.

Further studies will identify additional sites of genetic variation and may capture enough of the genetic influence that a diagnostic test can be devised to identify children at increased risk. These children with KD would be candidates for more aggressive therapy.

“A significant number of KD patients suffer irreversible coronary artery damage, which can lead to heart attack, heart failure, or require transplant,” noted Burns. “Our goal at RCHSD is to create a genetic test for KD patients that will indicate whether the patient is at increased risk. If that’s the case, we can use additional treatments and potentially reduce future complications.”

In addition, the finding may have implications for understanding the genetic thermostat that regulates the intensity of a person’s immune response to inflammation. Investigators are now looking at what impact this genetic variation might have on initiating other inflammatory conditions, such as atherosclerosis and myocarditis, an inflammation of the heart muscle often caused by a viral infection.

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The Kawasaki Disease Research Program is a joint collaboration between the Departments of Pediatrics and Sociology at University of California, San Diego (UCSD), the Climate Center at Scripps Institution of Oceanography, and Rady Children’s Hospital San Diego. The Program was created to help foster excellence in care for patients with Kawasaki Disease (KD) and to support clinical, laboratory, and epidemiologic investigation into the etiology, pathophysiology, and natural history of the disease. The program brings together investigators from more than 15 countries with diverse research interests and expertise to work together to further our understanding of this enigmatic disease.

Kawasaki Disease is often accompanied by the following symptoms: high fever and irritability; rash; swelling and redness of the hands and feet; bloodshot eyes; red mouth, lips, and throat; and swollen lymph nodes in the neck. It affects children almost exclusively; most patients are under 5 years of age. For reasons still unknown, males acquire the illness almost twice as often as females.

Source: Kimberly Edwards
University of California - San Diego

When humans began to migrate out of Africa about 100,000 years ago, their skin color gradually changed to adapt to their new environments. And when the last Ice Age ended about 10,000 years ago, marine ancestors of ocean-dwelling stickleback fish experienced dramatic changes in skin coloring as they colonized newly formed lakes and streams. New research shows that despite the vast evolutionary gulf between humans and the three-spined stickleback fish, the two species have adopted a common genetic strategy to acquire the skin pigmentation that would help each species thrive in their new environments.

The researchers, led by Howard Hughes Medical Institute investigator David Kingsley, published their findings in the journal Cell. Kingsley and first author Craig Miller are at the Stanford University School of Medicine, and other co-authors are from the University of Porto in Portugal, the University of British Columbia, the University of Chicago, and the Pennsylvania State University Further studies of stickleback, they say, may reveal other malleable pieces of genetic machinery both fish and humans have used for adaptation.

The stickleback has become a premier model organism for studying evolution because of its extraordinary evolutionary history, said Kingsley. “Sticklebacks have undergone one of the most recent and dramatic evolutionary radiations on earth,” he said. When the last Ice Age ended, giant glaciers melted and created thousands of lakes and streams in North America, Europe, and Asia. These waters were colonized by the stickleback’s marine ancestors, which subsequently adapted to life in freshwater. “This created a multitude of little evolutionary experiments, in which these isolated populations of fish adapted to the new food sources, predators, water color, and water temperature that they found in these new environments,” Kingsley explained.

Among those adaptations were new colorations that helped the fish camouflage themselves, distinguish species, and attract mates in their new environments. Until now, however, scientists had not understood what genetic factors drove the changes in skin pigmentation.

Human populations have also undergone pigmentation changes as they have adapted to life in new environments. The ecological reasons for those changes may be quite different from the forces driving the evolution of pigmentation in sticklebacks, said Kingsley. As human populations migrated out of Africa into northern climates, the need for darker pigmentation necessary to protect against the intense tropical sun diminished. With skin that was more transparent to sunlight, humans were better able to produce sufficient vitamin D in their new climate.

To begin to understand the genetic basis of skin pigmentation changes in fish, Kingsley and his colleagues crossed stickleback species that had different pigmentation patterns and used genetic markers and the recently completed sequence map of the fish’s genome to search for the mechanism regulating stickleback pigmentation. They searched for chromosome segments in the offspring that were always associated with inheritance of dark or light gills and skin. Through detailed mapping of one such segment, Kingsley and his colleagues found that a gene called Kitlg (short for “Kit ligand”) was associated with pigmentation inheritance. Kitlg was an excellent candidate for regulating pigmentation because mutant forms of the corresponding gene in mice produce changes in fur color, said Kingsley.

The Kitlg gene is involved in a variety of biological processes, including germ cell development, pigment cell development, and hematopoiesis. Light-colored fish have regulatory mutations that reduce expression of the Kitlg gene in gills and skin, but that do not reduce the gene’s function in other tissues. “By altering expression of this gene in one particular place in the body, the fish can fine tune the level of expression of that factor in some tissues but not others,” said Kingsley. “That lets evolution produce a big local effect on a trait like color while preserving the other functions of the gene.”

Humans also have a Kitlg gene, and Kingsley and his colleagues wondered if it played a role in regulating the pigmentation of human skin. One clue they had came from previous research by other groups that had revealed that the human Kitlg gene has undergone different changes among different human populations, suggesting that it is evolutionarily significant.

Kingsley and his colleagues tested whether the different human versions of the Kitlg gene are associated with changes in skin color. Humans with two copies of the African form of the Kitlg gene had darker skin color than people with one or two copies of the new Kitlg variant that is common in Europe and Asia.

“Although multiple chromosomal regions contribute to the complex trait of pigmentation in both fish and humans, we have identified one gene that plays a central role in color changes in both species,” said Kingsley.

“Since fish and humans look so different, people are often surprised that common mechanisms may extend across both organisms,” he said. “But there are real parallels between the evolutionary history of sticklebacks and humans. Sticklebacks migrated out of the ocean into new environments about ten thousand years ago. And they breed about once every one or two years, giving them five thousand to ten thousand generations to adapt to new environments.”

Although modern humans arose in Africa, they are thought to have migrated out of Africa in the last 100,000 years. “Humans breed about once every 20 years, giving them about 5,000 generations or so to emerge from an ancestral environment and colonize and adapt to new environments around the world,” Kingsley added. “So despite the difference in total years, the underlying process is actually quite similar. Whether it be fish or humans, there were small migrating populations encountering new environments and evolving significant changes in some traits in a relatively short time. And the genetic mechanisms that can produce these changes may be so constrained that evolution will tend to use the same sorts of genes in different organisms.”

Kingsley and his colleagues are now exploring the genetic basis of other evolved traits in the stickleback that could find a parallel in humans. “And given the degree to which evolutionary mechanisms appear to be shared between populations and organisms, we’re optimistic about finding the particular genes that underlie other recent adaptations to changing environments in both fish and humans,” he said.

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Source: Jennifer Michalowski
Howard Hughes Medical Institute