The Minnesota Gene Pool

The Complete Charles Darwin

2006-11-20T11:13:00.000-08:00

There is a new website dedicated to the collected writings of Charles Darwin. This announcement appeared in the Dec 2006 issue of Nature Reviews Genetics:

Research Highlight

Nature Reviews Genetics 7, 906 (December 2006) doi:10.1038/nrg2017

Webwatch: Complete Darwin on the web

Francesca Pentimalli

http://darwin-online.org.uk

From October 19th, anyone with an internet connection can now browse the entire body of work of Charles Darwin. The web site was the idea of a science historian, John van Wyhe, from the University of Cambridge, UK, who realized that the works of Darwin that were already on the web were scattered across different web sites with no obvious editorial standards. Many institutions and individuals have contributed to the project, which started in 2002. So far, over 50,000 searchable text pages and 40,000 images have been uploaded, making the web site the most comprehensive bibliography of Darwin's work ever published.

The repository contains all of Darwin's books, publications and manuscripts, as well as 'ancillary works' — a collection of reviews describing the naturalist's work. The web site also contains unpublished material, such as the notes that Darwin took on the ship the Beagle during his famous journey around the globe.

Alongside the fully searchable electronic text one can view original documents, including invaluable drawings. There are also links to freely accessible audio files and translations in several languages. By 2009, the bicentenary of Darwin's birth, the web site aims to host everything he wrote apart from his private letters, which are being collected on the web by the Darwin Correspondence Project.

And if a project in Wales goes according to plan, the Beagle will not only 'sail on the web', but on the ocean waves. The Beagle Project Pembrokeshire, which was founded by David Lort-Phillips (a descendant of one of the crew members of the Beagle), aims to build a replica of the ship, blending old-fashioned and modern technologies, to retrace its famous journey with a crew of scientists and students.

Having your cake and eating it, too

2006-11-03T07:37:00.000-08:00

The New York Times is reporting today on an interesting scientific finding related to diet and health. Scientists may have found a substance that is present in red wine that may ameliorate the effects of a high fat diet on the risk for cardiovascular disease and obesity. The substance, called resveratrol, was discovered by scientists at Harvard Medical School and the National Institute of Aging. So far, the observation has been only observed in mice. This may be part of the explanation for why drinking moderate amounts of red wine is associated with improved heart health and the French paradox, where the French have less cardiovascular disease than would be expected based on the amount of fat in their diet. Of course, more research needs to be done to test these hypotheses and also to see if humans respond to resveratrol the same way as the mice do. This could have a significant impact on health of the population if these observations are borne out in humans.

New Genomic Tests Guide Choice of Chemotherapy in Cancer Patients

2006-10-31T19:44:00.000-08:00

DURHAM, N.C. – Scientists at Duke University's Institute for Genome Sciences & Policy have developed a panel of genomic tests that analyzes the unique molecular traits of a cancerous tumor and determines which chemotherapy will most aggressively attack that patient's cancer.

In experiments reported in the November 2006 issue of the journal Nature Medicine, the researchers applied the genomic tests to cells derived from tumors of cancer patients. They found that the tests were 80 percent accurate in predicting which drugs would be most effective in killing the tumor.

The Duke team plans to begin a clinical trial of the genomic tests in breast cancer patients next year.

The new tests have the potential to save lives and reduce patients' exposure to the toxic side effects of chemotherapy, said Anil Potti, M.D., the study's lead investigator and an assistant professor of medicine in the Duke Institute for Genome Sciences & Policy. The tests are designed to help doctors select and initiate treatment with the best drug for a patient's tumor instead of trying various drugs in succession until the right one is found, Potti said.

"Over 400,000 patients in the United States are treated with chemotherapy each year, without a firm basis for which drug they receive," said Joseph Nevins, Ph.D., the study's senior investigator and a professor of genetics at the Duke Institute for Genome Sciences & Policy. "We believe these genomic tests have the potential to revolutionize cancer care by identifying the right drug for each individual patient."

The tests work by scanning thousands of genes from a patient's tumor to produce a "genomic" profile of the tumor's molecular makeup. Using the genomic tests in cancer cells in the laboratory, the scientists successfully matched the right chemotherapy for the patient's tumor type. The scientists were then able to validate their predictions against patients' actual clinical outcomes.

Doctors currently must use a trial-and-error approach to chemotherapy, trying various established drugs to see which has an effect. As a result, patients often undergo multiple toxic therapies in a process that places patients' lives at risk as their conditions worsen with each treatment.

"Chemotherapy will likely continue to be the backbone of many anticancer treatment strategies," said Potti. "With the new test, we think that physicians will be able to personalize chemotherapy in a way that should improve outcomes."

The first clinical trial will compare how well patients respond to chemotherapy when it is guided by the new genomic predictors versus when it is selected by physicians in the usual trial-and-error manner. The researchers anticipate that they will enroll approximately 120 patients with breast cancer in the study. Subsequent clinical trials will enroll hundreds of patients with lung and ovarian cancer, Potti said.

If proven effective, the tests could be applied to all cancers in which chemotherapy is given, not just breast, lung, and ovarian cancer, Potti said.

The researchers developed the new tests through a process that included analyzing the activity of thousands of genes in cells taken from the tumors of cancer patients.

In using the test, scientists extract the genetic molecule "messenger RNA" from a cancer patient's tumor cells. Messenger RNA translates a gene's DNA code into proteins that run the cell's activities. Hence, it is a barometer of a gene's activity level inside the cell.

The scientists then label the messenger RNA with fluorescent tags and place the labeled molecules on a tiny glass slide, called a gene chip, which binds to segments of DNA representing the tens of thousands of genes in the genome.

When scanned with special light, the fluorescent RNA emits a telltale luminescence that demonstrates how much RNA is present on the chip, and this reading indicates which genes are most active in a given tumor. The scientists use this signature of gene expression in the cancer cells to predict which chemotherapeutic agent will be most powerful in treating the specific tumor.

In the current study, funded by the National Institutes of Health, the researchers assessed the tests' ability to predict how patients with breast and ovarian cancer and leukemia responded to various anticancer drugs. They found that the tests predicted the clinical response to chemotherapy with 80 percent accuracy.

"Importantly, we believe this research can improve the efficiency of chemotherapy without changing the drugs currently used in standard practice," Nevins said. "Rather, the tests simply provide an approach to better selection, within a repertoire of available drugs."

Other researchers participating in the study included Holly K. Dressman, Andrea Bild, Jeffrey Marks, Andrew Berchuck, Geoffrey S. Ginsburg and Phillip Febbo of the Duke Institute for Genome Sciences & Policy; Richard F. Riedel, Robyn Sayer, Janiel Cragun, Michael J. Kelley, Rebecca Peterson, and David Harpole of Duke University Medical Center; and Gina Chan, Hope Cottrill and Johnathan Lancaster of the H. Lee Moffitt Cancer Center in Tampa, Fl.

Source: http://www.mc.duke.edu

Survivorship, Family History and Inherited Susceptibility for Cancer

2006-10-31T17:00:00.000-08:00

The New York Times has a moving and personal essay (In Breast Cancer, There Is a Single Agenda: Stay Alive, New York Times, October 31, 2006) by Aliyah Barukin today where she reflects on her journey through cancer diagnosis, treatment and survivorship. Last but not least, because of being half Ashkenazi Jewish, she describes the experience having and receiving genetic testing results for BRCA1 and BRCA2 mutations.

I will not be a spoiler and reveal how the story ends, but Ms. Barukin's reflections made me think of a conversation I had with a colleague who worked in the Cancer Control Division at CDC who made the connection between inherited susceptibility for cancer and survivorship. In all cases, the story starts with the person with cancer, but quickly radiates to other family members. In both cases, the threat of an untimely end of life heightens sensations, fears, and feelings of vulnerability in both the person with cancer and those closest to her. In both cases, the consequences of the disease cross generations, both in terms of guilt of passing on the increased risk for cancer and the guilt of leaving children behind without a parent. In both cases, there is the need to learn to live with the very real specter of cancer recurring (or occurring) and the real threat of untimely illness and death that family members share.

When it comes to our health and wellbeing, we all are only one step away from disaster at any time. One false step, one moment of inattention behind the wheel, one wrong move that results in serious injury can bring lifechanging circumstances for us and our families. However, for most of us, we learn to delude ourselves that the abyss is not really there, that these horrific events will only happen to someone else. For those who have had cancer or have an inherited predisposition to cancer, that comforting delusion is shattered and cannot be easily recovered and they must learn to live with the knowledge of the tenuous nature of good health. In these ways--and probably others--the knowledge of an inherited susceptiblity for cancer and surviving a cancer diagnosis are similar.

What are the ethical issues, needs and priorities regarding genomics in public health education?

2006-09-18T12:43:00.000-07:00

Question: What do we know about what public health workers think are priorities in ethics related to using genomics in research and practice? What are public health workers being taught during their training to deal with these questions? This question came to me when I read this press release report on a recent study on what medical residents believe what ethical and professional issues are important. I will look into this further and post more on this as I find it. If you have any ideas, opinions or facts regarding this question, feel free to post them in the comments section or e-mail me.

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A lesson in medical ethics: medical residents and faculty pinpoint priorities in ethics education

September 12, 2006 ANN ARBOR, MI – It sounds like a scene from Grey’s Anatomy: “I had to tell them that their dad had cancer, something that would change their life, and they would remember me telling them the news and how I said it and if I connected…but I felt like I couldn’t find the right words.”

So reports a resident when asked about training needs in ethics and professionalism.
There is no shortage of opinions on what physicians in training need to learn in ethics and professionalism; what has been lacking is data. In an article published in the most recent edition of The American Journal of Bioethics, researchers asked residents, faculty, ethic committee members and practicing physicians what residents need to learn to practice medicine ethically.

The authors identified several categories of needs:

Issues about individual ethics or actions, for example honesty in keeping medical records
Interprofessional relations, for example disagreements between residents and faculty
Issues related to individual patients, including how to break bad news (as in the opening example)

Issues arising from the work environment, for example working when sleep-deprived
Issues related to teaching and learning, for instance tension between efficiency and the responsibility to train future physicians

Issues arising due to external forces, such as insurance coverage and malpractice litigation.
“Commonly, a small group of educators decides what topics to cover for residency training in graduate medical education, or it is assumed they will learn by being around proper role models. This study asked residents what issues they confront, and faculty, practicing physicians and other in-the-know professionals what they think residents should learn,” says author Susan Dorr Goold, M.D., MHSA, MA, director of U-M’s Bioethics Program and an associate professor of medicine and health management and policy. “For ethics training to be useful, and used, it needs to be relevant to medical practice. This study is one of the few that collected data about what people think is relevant.”

Residents reported many of the same priorities in ethics and professional training as did faculty, practicing physicians, and other professionals. Still, there were differences. For example, practicing physicians, with their real-world experience, called for more training in the ethics of resource allocation for patients: should patients be just told how their doctor is going to treat their condition, or should patients be presented with alternatives that might be more expensive, or not covered by insurance? Residents raised concerns about conflicts between their need to learn and providing patients with the best care, and wondered how to handle situations in which they feel a supervising physician acts improperly.

Besides obtaining an overview of needs in ethics and professionalism education, the authors specifically looked for topics and issues common to many specialties.

“All residency programs are required to teach in this area,” says Goold “and some of the topics cross specialty boundaries. Learning about confidentiality, or how to obtain consent, is important for internists, surgeons, family practitioners, neurologists – just about every specialty. Why not develop and use the same tools to teach all of them instead of reinventing the wheel in each department?”

Goold and coauthor David Stern, M.D., Ph.D., a U-M associate professor of internal medicine and medical education, did just that at the University of Michigan, developing curricula in several topics that can be used across the institution. The study took place in 1999, prior to the launch of the Accreditation Council of Graduate Medical Ethics outcomes-based requirements for residency education, and portions of the curriculum have been emulated at many other institutions.

Written by Mary Beth Reilly

Source: http://www.med.umich.edu/

DHHS makes push for combining genetic data and electronic health records

2006-09-16T12:06:00.000-07:00

The Department of Health and Human Services has put together a team of experts working to integrate genomics into clinical information systems in an effort to better prevent, diagnose and treat disease using information on a patient's genetic makeup. HHS secretary Mike Leavitt said the genomics soon should play a much larger role in medicine and now is the time to begin incorporating genetic information in electronic health records.

Source: Government Health IT and The U.S. Department of Health and Human Services

The Wide, Wild World of Genetic Testing

2006-09-16T11:27:00.000-07:00

An article in the Tuesday, September 12, 2006 issue of the New York Times (free registration required) looks at the wild and largely unregulated world of direct-to-consumer genetic testing. Andrew Pollack details the history, companies, products and practices of this growing phenomenon. These tests promise to provide information relevant for all sorts of quasi-medical and non-medical concerns. As correspondent Andrew Pollack writes:

With a few mouse clicks, consumers can order tests that promise to tell them if they are at risk for particular diseases, to trace their ancestry back to the time of Genghis Khan, to help choose which antidepressant would be best for them, to identify the sex of their fetus as few as five weeks into pregnancy and to give advice on diet or exercise.

The trend to offer genetic tests directly to consumers is growing by leaps and bounds as the number of associations between specific forms of genes that vary between individuals are reported in the scientific literature.

Although vigorously opposed by most mainstream scientists, health care providers, policy makers, and public health officials, the process for accessing these tests online or in retail stores is completely legal. The burden of determining the value of and interpreting the test results is borne completely by the consumer and it is definitely true that in this arena, the "buyer must beware" if considering purchasing these products.

NICHD unveils its new, more user-friendly web portal

2006-09-16T11:05:00.000-07:00

The National Institute of Child Health and Human Development of the National Institutes of Health has re-designed its web portal to make information on child health and development more easily accessible. Information on health and human development, research projects funded by the agency and funding / grant proposal information and services for children with special needs is contained on the site.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

Source: The National Institutes of Health at www.nih.gov

Test Helps Identify Patients with Breast Cancer Who Will Likely Benefit from Chemotherapy, and Those Who Won’t

2006-09-16T10:25:00.000-07:00

September 15, 2006 -- CHICAGO -- A test that measures the amounts of two members of the same protein family - one of which appears to act as an oncogene, and the other as a tumor suppressor - helps identify patients with breast cancer who will likely benefit from chemotherapy and those who won’t, according to researchers.

The test, known as OncoPlan™, is already commercially available, and studies have shown that it can predict the aggressiveness of the patient’s tumor and the relative risk of disease recurrence following surgery in breast, colon and gastric cancers. Now, researchers in the U.S. and Canada have studied whether it also can help identify breast cancer patients who would benefit most from chemotherapy.

Results were presented at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.

OncoPlan measures two forms of Shc protein, which are known to drive the formation of protein complexes involved in signal transduction pathways and have been found to be involved in many of the pathways important to development of aggressive cancer. These two forms have a “push pull” relationship with each other: tyrosine-phosphorylated (PY)-Shc helps drive these dangerous cell pathways, but p66 Shc, after initial stimulation, works to inhibit the very growth pathway the other Shc proteins promote.

“This may be one mechanism whereby normal cells prevent runaway growth,” said the study’s lead author, A. Raymond Frackelton, Jr., Ph.D., a Brown University associate professor, staff scientist at Roger Williams Medical Center and Vice President of Research at Catalyst Oncology, which is marketing OncoPlan. “Perhaps more importantly, aggressive cancer cells must endure oxidative stress—stress that in normal cells triggers p66 Shc to cause cellular suicide,” he said. “Tumor cells, then, may have both growth and survival advantages if p66 Shc levels are low.”

Chemotherapy-mediated killing of tumor cells, however, does not require p66 Shc, Frackelton said, suggesting that patients whose tumor cells have low p66 Shc might respond well to chemotherapy. To test this idea, the researchers looked at the Shc proteins in tumors from 2,380 women from British Columbia who were diagnosed with invasive breast cancer, 717 of whom received chemotherapy as part of their initial treatment.

They found that, indeed, patients who had low levels of p66 Shc and did not receive chemotherapy had very poor outcomes. If similar patients received chemotherapy, however, their chances of relapsing and dying from their disease were reduced by two-fold or more, said Frackelton. Conversely, women with high levels of p66 Shc had a much higher likelihood of surviving their disease, but appeared to derive no benefit from chemotherapy, he said.

Possible additional associations between PY-Shc and chemotherapy benefit has not yet been fully explored, Frackelton said. “But even at this point, the results are very exciting because, with further validation in clinical trials, OncoPlan, which is already being used to predict disease aggressiveness, will help to ensure that individual patients receive the most beneficial therapies,” he said.

This work was supported in part by a grant from the Susan G. Komen Breast Cancer Foundation

Sources: The American Association for Cancer Research and Catalyst Oncology

Study Finds Distinct Genetic Profiles For Northern, Southern Europeans

2006-09-16T10:10:00.000-07:00

Results promise to improve genetic studies of human disease

September 14, 2006 -- (SACRAMENTO, Calif.) — An international team of scientists led by researchers at UC Davis Health System has found that, with respect to genetics, modern Europeans fall into two groups: a Northern group and a Southern, or Mediterranean one.

The findings, published in the Sept. 14 edition of Public Library of Science Genetics, are important because they provide a method for scientists to take into account European ancestry when looking for genes involved in diseases.

“Until now, little has been known about the distribution of genetic variation in European populations and how much that distribution matters in terms of doing genetic studies,” said Michael Seldin, chair of the Rowe Program in Genetics at UC Davis Health System. “Now we will be able to control for these differences in European populations in our efforts to find genes that cause common diseases.”

Seldin, who is also a professor of biochemistry and professor of medicine at UC Davis, worked with his colleagues to compare genetic data for 928 individuals. They looked at 5,700 single nucleotide polymorphisms, called SNPs or “snips.” SNPs are changes in which a single base in the DNA differs from the usual base at that position. Millions of SNP's have been cataloged in the human genome. Some SNPs cause diseases, like the one responsible for sickle cell anemia. Other SNPs are normal variations in the genome. People who share ancestry will have many SNPs in common.

Seldin and his group set out to discover which SNPs among Europeans could account for shared common ancestry. “We saw a clustering of individuals that come from either southern Europe or derived from populations that left southern Europe, or the Mediterranean, in the last 2,000 years,” Seldin said. This allowed the group to identify a set of 400 informative SNP markers that scientists could now use to control for European ancestry when conducting genetic studies of disease, response to drug treatment, or side effects from therapy.

In addition to future medical applications, the data are also of interest to anthropologists who study historical human migrations. The Southern grouping included individuals from Greece, Italy, Portugal and Spain, as well as Ashkenazi and Sephardic Jews. The Northern group included people with English, Irish, German, Swedish and Ukranian ancestry. These groups correspond to those historically divided by the Pyrenees and Alps mountain ranges.

With respect to population genetics, previous studies have shown that SNPs correlate broadly with continental ancestry, dividing modern humans into four large groups: Asia, Africa, Oceana, America and continental Europe. The new study gives scientists the evidence they need to further subdivide people with European ancestry into the Northern and Southern groups when looking for SNPs that may be involved in disease.

To prove this point, the researchers analyzed two sets of data. They looked at SNPs associated with rheumatoid arthritis and found that, when they corrected for ancestry, several of the genes that were previously believed to be good candidates for being involved in the disease were no longer candidates at all. They also corrected for ancestry in a data set looking at lactose intolerance.

“When we did not control for differences in population structure, we got a lot of false associations,” Seldin explained.

Seldin and his colleagues will soon be expanding the current European study by looking at 500,000 SNPs. They also have plans for similar studies of other continental populations and for further defining different subpopulations. Seldin said studies of other continents and ethnic groups are necessary if science is to get the most out of the advances made by the Human Genome Project.

“The ultimate aim of these studies is to be able to better define subgroups and use this information to eliminate false associations, giving us a better chance of finding true associations for disease genes,” Seldin said.

Other members of the research team include: Russell Shigeta from UC Davis Health System; Pablo Villoslada at the University of Navarra, Pamplone, Spain; Carlo Selmi at the San Paolo School of Medicine at the University of Milan; Jaakko Tuomilehto at the National Public Health Institute in Helsinki, Finland; Gabriel Silva at the Obras Sociales del Hermano Pedro in Antigua, Guatemala; John W. Belmont at Baylor College of Medicine; Lars Klareskog at Karolinska University Hospital in Stockholm, Sweden; and Peter K. Gregersen at the Feinstein Institute for Medical Research in Manhassett, New York.

This work was supported by grants from the National Institutes of Health.

Source: http://www.ucdmc.ucdavis.edu/newsroom/releases/index.html

The Intersection of Biotechnology and Pharmacogenomics: Health Policy Implications

2006-09-16T09:36:00.000-07:00

The Intersection Of Biotechnology And Pharmacogenomics: Health Policy Implications
Kathryn A. Phillips

Abstract: Increasing knowledge of the genetic basis of disease is changing the landscape of health care. Two critical aspects are growth in biotechnology and growth in personalized health care, particularly targeting medicines based on genetic information (pharmacogenomics). This paper provides an overview of the health policy implications of the integration of biotechnology and pharmacogenomics. I examine four factors that determine whether relevant technologies will be successfully adopted, using case studies for illustration. Key policy challenges include determining the appropriate role of policy in (1) providing incentives to develop socially beneficial interventions and (2) facilitating development of the evidence base.

Health Affairs, 25, no. 5 (2006): 1271-1280

Kathryn A. Phillips (PhillipsK@pharmacy.ucsf.edu is a professor of health economics and health services research at the School of Pharmacy, Institute for Health Policy Studies, and Comprehensive Cancer Center at the University of California, San Francisco.

Focusing in on Cancer's Complexity

2006-09-10T18:25:00.000-07:00

“Scientists who have seen these data have told us that it keeps them up all night thinking.”
Bert Vogelstein

September 08, 2006 -- In the first large-scale screen of genetic changes in cancer cells, researchers have found that a typical breast or colorectal tumor results from mutations in about 90 genes, with different sets of mutations producing the same type of cancer.

But the many different genetic routes to malignancy share common features that point toward new means of cancer prevention, diagnosis, and treatment.

Previous genetic studies of cancer have concentrated on specific genes or on chromosomal regions. In the September 8, 2006, issue of Science, Howard Hughes Medical Institute (HHMI) investigators Bert Vogelstein at Johns Hopkins University and Sanford D. Markowitz at Case Western Reserve University School of Medicine, together with a team of researchers from The Kimmel Cancer Center at Johns Hopkins and other institutions, report on a radically new way of identifying genes involved in cancer.

They screened the most well-annotated human genes, a total of more than 13,000 genes that all major genomic centers agree encode proteins. They first looked for mutations in 22 cancerous breast and colorectal tumors. From that list, 191 genes appeared to be particularly important. “Scientists who have seen these data have told us that it keeps them up all night thinking,” said Vogelstein. “It will hopefully open up a large number of opportunities in many areas of cancer research.”

The team found far more mutated genes in tumor cells than they had expected. The average breast or colorectal cancer cell was predicted to have an average of 90 mutations that alter protein structure. However, not all 90 were likely to contribute equally to the development of cancers. Through subsequent validation studies, the researchers identified an average of 11 genes in each cancer that were most likely to be directly responsible for its biologic properties. Extrapolating to the total number of genes in the human genome, an average of about 17 genes are expected to have critical involvement in the development of each cancer.

The researchers also were surprised by the heterogeneity of the cancers. Different genes were mutated in cancers of the same type, and the genes contributing to breast cancer were different from those mutated in colorectal cancers. “It presents a whole new view of the neoplastic process,” said Vogelstein, “and explains the heterogeneity that clinicians have long noted to exist among cancer patients.”

Despite the complexity of the results, a closer examination of the data has started to reveal an underlying order. Many of the genes that are mutated are involved in pathways thought to be important in cancer, such as cell adhesion, movement, and signaling. Each of these pathways relies on multiple genes, and flaws in any of the genes in a pathway may have similar consequences.

“By taking a systems biology approach to connect these genes, we suspect that the complexity will be less than it appears at first sight,” said Vogelstein. “The same 10 or 20 pathways may be altered in every cancer, though the particular mutated genes in these pathways will be different. The picture will become much clearer as the function of these genes and the ways they interact are better worked out.”

This kind of study could not have been done a few years ago, said Tobias Sjöblom, an HHMI research associate in Vogelstein's lab, who is the lead author of the Science article. But the availability of the human genome sequence and improvements in sequencing and bioinformatics technologies have made it possible to examine the genome of cancer cells in a comprehensive and unbiased manner, he said.

Still, a massive amount of work was involved. “It was a straightforward process once all the mechanistic details had been worked out and the bioinformatic infrastructure was in place,” said Sjöblom, “but very laborious.” The research team formulated 135,483 sets of DNA primers for the polymerase chain reactions needed to sequence the tumor cell genes. They then looked at 11 tumors for each type of cancer, along with two normal samples as a control. The result was almost a half billion letters of DNA sequence that had to be screened for suspicious mutations.
Successive rounds of computer analysis focused attention on smaller and smaller subsets of nucleotides. “The hard work was to remove all the junk so that you were left with the true mutations,” Sjöblom said. In the final stages, visual inspection of the sequences was required to confirm each mutation. According to Vogelstein, “the eye is better than a computer for some types of pattern recognition.”

Once the list of mutations was winnowed down, the chromosomal regions containing those mutations were resequenced in the tumors and matched to normal DNA samples to validate each mutation. This process resulted in 1,307 confirmed somatic mutations in 1,149 genes. These genes then were analyzed in 48 additional breast or colorectal tumors, which turned up an additional 365 mutations in 236 of the genes. Altogether, 921 and 751 somatic protein-altering mutations were identified in breast and colorectal cancers, respectively, most of which were changes in single nucleotides.

The researchers then used statistical techniques to identify the changes in a given gene that were more likely to contribute directly to the cancers' properties. This identified 122 genes in breast cancer tumor cells and 71 genes in colorectal cancers, which the researchers called CAN-genes (candidate cancer genes). Surprisingly, only two genes appeared on both lists.

Furthermore, even the types of mutations differed between breast cancer and colorectal cancer. For example, 59 percent of the colorectal cancer mutations went from a C:G base pair to an T:A pair, whereas this was the case for only 35 percent of the breast cancer mutations. “These differences may be due to different kinds of carcinogens, different types of repair mechanisms, or different exposures to endogenous mutagens,” said Vogelstein. “This is a very fertile area of epidemiologists.”

Even within each type of cancer, each tumor had its own distinct collection of mutated genes. No cancer had more than six mutated CAN-genes in common with any other cancer. This finding also was unexpected, “but it's consistent with clinical observations,” said Vogelstein, “because clinicians have observed for years that each cancer behaves in a unique way.”

The complexity of the results may seem discouraging, Vogelstein notes. “If anyone thought cancer was simple, they were wrong,” he said. “On the other hand, once you get the picture in focus, you can start to figure out what's going on.” Many of the genes they identified were not previously known to be involved in cancer, and each gene offers potential insights into the disease. “The first thing we'll probably delve into is diagnostics, as that's been one of the themes of our lab,” Vogelstein said. In particular, they will be looking to find evidence of the mutated genes in blood or other clinical specimens to help identify cancers before they cause symptoms.
Therapeutics based on the newly discovered genes are “a ways off,” in Vogelstein's estimation. But once the key pathways necessary for cancer are identified, researchers can look for ways to reverse the effects of the activated genes, said Vogelstein. "We now have a whole new set of targets to guide drug development."

Source: http://www.hhmi.org

Source: HealthOrbit Headlines on September 8, 2006

Closing In On Lethal Heart Rhythm In Young Athletes

2006-09-10T18:08:00.000-07:00

- New findings at Hopkins should improve screening and prevention

September 7, 2006 -- Johns Hopkins experts on the genetics of a potentially lethal heart rhythm defect that runs in families and targets young athletes report they have greatly narrowed the hunt for the specific genetic mutations that contribute to the problem.

Their new findings, described in the July issue of the American Journal of Human Genetics, should increase the accuracy of tests to identify those at risk for arrhythmogenic right ventricular dysplasia (ARVD), which is among the top causes of sudden cardiac death in the young and fit.
In February, the same team linked one-third of ARVD cases in their large database of patients to a dozen abnormal changes in a gene called plakophilin-2 (PKP2), which makes proteins involved in heart cell stickiness.

In the new study, confirming experiments elsewhere, the Hopkins team found four mutations in another sticky protein gene, Desmoglein-2 (DSG2), in five of 33 patients tested.

“This gene is highly expressed in the heart, where muscle tissue expands and contracts with the heartbeat,” says senior study author and cardiac geneticist Daniel P. Judge, M.D. “Our results confirm that altered genes in the desmosomal cellular complex are responsible for ARVD. And now that we know the genetic roots of this disease, we can also create better blood tests for their proteins to predict who is at risk for developing this condition.”

ARVD is characterized by weakness in the desmosome, or cell-to-cell binding structure. The inherited condition leads to the buildup of excess fatty and scar tissue in the heart’s right ventricle, causing irregular beats and – unless diagnosed and treated with drugs or implanted defibrillators – triggering a fatal heart rhythm disturbance.

Judge, an assistant professor at The Johns Hopkins University School of Medicine and its Heart Institute, says DSG2 mutations appear to account for at least 10 percent and possibly more of the estimated 25,000 deaths each year from ARVD.

“We expect a test for DSG2 mutations to be available to those with a family history of the condition before the end of the year,” he says. The same Hopkins team developed a blood test to screen for PKP2 mutations. That test became available in May and is currently the only one available for detecting those at greater risk of the disease.

More than 400 people have been screened at Hopkins so far and of these, two-thirds have had serious enough forms of the condition to warrant implantation of a defibrillator, an electrical device that corrects any disturbances in the heart’s rhythm.

The Hopkins researchers identified the DSG2 mutation through genetic analysis of blood taken from 60 men and women already diagnosed with ARVD. All were part of a patient database created at Hopkins in 1998. The researchers focused on cell-adhesion proteins because they had already been linked to Naxos syndrome, which produced symptoms in the right ventricle similar to those documented in ARVD.

When scientists excluded their ARVD patients with PKP2 mutations, they were left with 33 who had no known genetic explanation for their condition. Additional testing revealed the four mutations in DSG2.

“We knew right away that we had found something very significant,” says lead author Mark Awad, B.A., a medical and predoctoral sciences student at Hopkins. “The mutations were confined to a highly functional part of the gene and were highly conserved, meaning that evolution had not drastically changed the genetic sequence over time – the gene was kept the way it was because it was important to the heart’s normal function.”

According to Awad, not everyone with a genetic mutation develops ARVD. He adds that further analysis of the condition’s genetic roots will help researchers to calculate the precise increased risk from each mutation for developing symptoms and dying. Previous research by the Hopkins team showed that familial ARVD generally strikes after puberty and its symptoms – dizziness, fatigue and fainting after exercise – may appear up to 15 years before diagnosis.

Funding for this study was provided by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, the National Institutes of Health, the Donald W. Reynolds Foundation and the W.W. Smith Charitable Trust.

In addition to Judge and Awad, other researchers involved in this study, conducted solely at Hopkins, were Darshan Dalal, M.D., Ph.D., Eunpi Cho; Nuria Amat-Alarcon, M.S.; Cynthia James, Ph.D.; Crystal Tichnell, M.G.C, Sc.M.; April Tucker, M.G.C.; Stuart Russell, M.D.; David Bluemke, M.D., Ph.D.; Harry Dietz, M.D.; and Hugh Calkins, M.D. Calkins receives research support from device manufacturers Guidant, Medtronic and St. Jude. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Links: http://www.arvd.com

Source: HealthOrbit Headline News from September 9, 2006

Aging as the price for suppressing cancer?

2006-09-09T20:03:00.000-07:00

An article in the New York Times reports that a gene known for the suppression of tumor development also is responsible for the shutting down of the ability of stem cells to proliferate. This inhibition of stem cell function may be responsible for lowering the risk for cancer, but also may be related to many of the chronic degenerative conditions that are associated with aging. The finding is reported online by three research groups as advance online publications in Nature.

Live Long? Die Young? Answer Isn't Just in the Genes

2006-09-01T13:27:00.000-07:00

Gina Kolata's article in the August 31 New York Times reviews what we know about the contributions of nature and nurture to our lifespans. She correctly identifies that genetics plays a role, but that what happens to us in our lives is at least as--and likely is even more important than--the genes we inherit in most cases.

This is not a ground-shaking revelation. When you think about this, it isn't a huge stretch to see that genes, behavior and environment all contribute to the vast majority of components that contribute to the human condition, including lifespan. It is probably true that, as in the case of most other traits we possess, we do not exhaust what genetic potential that we inherently possess for a maximal lifespan in most cases. When you consider that genetic potential for longevity does not seem to be what is in short supply for most of us, but that how and where and with whom we spend our lives is more often the deciding factor in how many years we are around around this earth, then it is no great surprise that studies that look at the genetic component of longevity tend to find only very modest genetic contributions.

I really like this quote by Peter Parham when he wrote in the New England Journal of Medicine "The genome is a set of boundary conditions that limits the nature of the organism, not a blueprint that defines it." At first, you might think that this statement just negated everything I just argued in the previous paragraph. However, when you think of limits, think of them in the mathematical sense. What he means is that we can't develop beyond the boundaries that nature (read "genes") has given us, but within some very broad borders, the sky is the limit.

Ten Hot Jobs for 2007

2006-09-01T12:20:00.000-07:00

According to MSN and Careerbuilder.com, one of the hot jobs for 2007 will be genetic counseling!

Genetic Screening: Who should have it and when?

2006-09-01T11:49:00.000-07:00

I happened upon this video presentation on genetic screening, testing and counseling. It has information on when to refer for genetic counseling and what such a referral entails. Check it out!

A titan in the field of genetics has crossed over

2006-08-31T11:42:00.000-07:00

For those of you who knew Dr. Robert Gorlin, he passed away of complications of lymphoma on Tuesday morning, August 29, 2006. The following is from the School of Dentistry at the University of Minnesota.

Dr. Robert Gorlin:

Although Dr. Gorlin retired from his position at the dental school in 1993, he continued to lecture, write articles, edit text books, consult and, of course, to come to the dental school every day until only recently when his illness curtailed those visits. In addition to his faculty position at the dental school, Dr. Gorlin also held joint appointments in the University's Departments of Laboratory Medicine and Pathology, Obstetrics and Gynecology, Otolaryngology, Pediatrics, and Dermatology.

Dr. Gorlin was an internationally acclaimed expert on oral and maxillofacial pathology, as well as genetic defects and syndromes, craniofacial disorders and hereditary hearing loss. A lifelong observer of life's rarer forms of disease, he studied physical malformations for clues they provide about normal development and for the answers to some of biology's most basic questions. Over the course of his 50 years at the University, he studied and named more than 100 syndromes caused by genetic defects, discovering six in the process that were named for him. For several of those 100 syndromes, he and colleagues have been able to isolate the gene that causes the condition. His pioneering work has enabled physicians to assess and treat many genetic birth defects and is helping molecular biologists find ways to prevent or lessen their effects.

Internationally applauded across a variety of disciplines, he was the recipient of numerous awards, including five honorary doctorate degrees from universities as far away as Athens, Dublin and Copenhagen. In 1997, he was named a Senior Fellow in the Institute of Medicine of the National Academy of Sciences which serves as an advisor to the country in the conduct of studies and other activities on matters of significance to health. That same year, he also received the prestigious Premio Phoenix Anni Verdi Award, presented by the Italian Medical Genetics Society in recognition of his basic and applied research in genetically transmitted diseases, as well as the Goldhaber Award from Harvard University. In 2002, he received the University of Minnesota's highest honor, an honorary Doctor of Science Award, and in 2003 he was recognized by the American Dental Association with its Norton A. Ross Award. In 2004 he was the recipient of the American Society of Human Genetics Award for Excellence in Human Genetics Education and was the invited presenter on the topic of genetic signaling in development and disease at the Nobel Foundation conference in Stockholm. Committed always to sharing his knowledge and inspiring others, he mentored and helped launch the careers of more than 20 postdoctoral fellows and attracted the nation's scientific leaders to the University of Minnesota for conferences, guest lectures, and faculty positions. In 1967, he played a pivotal role in creating the Lasby Visiting Professorship program, which continues to this day as a vehicle for bringing distinguished international or American health sciences scholars to the U-M School of Dentistry to complement current research and education programs. For the last 13 years, he has been honored by an annual Robert J. Gorlin Dysmorphology Conference which attracts scientists and clinicians from all over the world to discuss their research.

Dr. Gorlin earned his doctor of dental surgery degree from Washington University School of Dentistry in 1947 and his master's in Oral Pathology from the State University of Iowa in 1956. The same year, he joined the faculty at the U-M School of Dentistry as associate professor and chair of the Divisions of Oral Histology and Oral Pathology. He was named a U-M Regents Professor in 1978.

Sciona Lab Responds to GAO Report

2006-08-16T10:13:00.000-07:00

Sciona Laboratory responded to the recent report by General Accounting Office that contained a negative assessment of nutrigenetic testing products through a press release dated July 27, 2006. In short, the company disputes the GAO's interpretation of the test results and offered to work with government entities to develop appropriate standards.

Genetics and Public Policy Center comments on DTC genetic testing

2006-08-15T19:24:00.000-07:00

The Genetic Public Policy at Johns Hopkins University announced today that it has published an issues brief on direct to consumer testing. The text of Director Kathy Hudson's testimony before the Senate Special Committee on Aging is also available.

Senate Hearings on Direct to Consumer Genetic Testing

2006-08-14T20:00:00.000-07:00

The Special Committee on Aging held hearings on direct-to-consumer genetic testing services on July 27, 2006. Testimony was heard from representatives from the Federal government, academia and the companies being investigated. The General Accounting Office (GAO) conducted an undercover investigation where samples of DNA from male and female test subjects were sent to four labs for nutrigenetic testing. The DNA samples were accompanied by varying profiles of age, physical activity, and diet information. According to the testimony of the Managing Director, Forensic Audits and Special Investigations (FSI), U.S. Government Accountability Office, the results of the undercover investigations report discrepancies in analysis of the DNA samples, health advice that is more consistent with reported lifestyle and diet than with the DNA test results, and the promise of personalized advice that actually was the same for all tested samples and profiles. The entire GAO report can be accessed here.

The results of this investigation are not surprising, though disappointing. The promise of personalized diet and other lifestyle advice based on a combination of genetic, demographic and lifestyle information is the anticipated promise of nutrigenomics. However, we are not there yet, not even close. With the negative publicity that is likely to be generated by these results, I hope that we do not throw the baby out with the bathwater. This type of testing, although clearly prematurely and inappropriately being applied in these situations, needs to have the type of regulatory structure that allows oversight without stifling innovation. Ironically, these intrepid entrepreneurs who are pushing the envelope by providing this technology to the public may actually end up triggering a regulatory reaction that makes future innovation in this area more difficult than it would have had to be.

Senator Barack Obama has introduced legislation to regulate direct to consumer testing. It will be interesting to see how this legislation is shaped as it wends its way through the legislative process in the US Congress. The legislation was introduced as S.3822 on August 3, 2006. So far, there are no co-sponsors. We will continue to follow this and report any new developments regarding this legislation.

Family history and Breast Cancer

2006-08-14T15:52:00.000-07:00

Check out the short article on family history and breast cancer in the July/August edition of the Sage Advice Newsletter. This piece succintly reviews the relevance of a family history of breast cancer and provides information for providers to confidently interpret a family history of breast cancer in their patients. The article is directed to the providers of cancer screening services who participate in the Minnesota Breast and Cervical Cancer Screening Program, otherwise known as the Sage Program. The Sage Program provides breast and cervical cancer screening services for women over age 40 who meet income guidelines and who are un- or under-insured. Women under forty years who have known risk factors (like a family history of cancer) may be eligible for screening through the Sage Program with a doctor's recommendation. This is a great program that has served almost 100,000 Minnesota women to date.

New Fact Sheets on Family History and Chronic Diseases

2006-08-14T15:24:00.000-07:00

Check out the new fact sheets on family history and chronic diseases at the Minnesota Chronic Disease Genomics Project's website. The conditions covered include cardiovascular disease, hypertension, breast cancer, prostate cancer, colorectal cancer, diabetes and depression. These materials cover screening and prevention recommendations for people with and without a family history of these conditions and give advice on what you can do to prevent these conditions.

I have it on good authority that other fact sheets are currently in the pipeline and that these will address prevention and screening for people who are concerned about a family history of asthma, obesity and ovarian cancer. I'll announce them here when they are available.

If you check these out, please provide feedback or comments via this blog and I will see that the comments get back to the program. The goal is to make these useful and accessible for everybody. Your feedback will help to make it so.

Family history as a tool for prevention in primary care

2006-08-14T11:18:00.000-07:00

The Oregon Chronic Disease Genomics Program has published a compact, information-filled article on using family health history for prevention of several chronic diseases in the July 11, 2006 edition of the CD Summary, an epidemiology publication of the Public Health Division, Oregon Department of Human Services. The good news is that knowing about your family history can give you and your healthcare provider the tools to keep you well. In most cases, a family history of something helps you either prevent or make a timely diagnosis of adult-onset diseases because you know to be watching for them. This contributes to better outcomes and health over the long term. Here are few fun facts from this piece:

* If your first degree relative (a parent, a brother or sister or child) has type 2 diabetes, your chances are doubled to develop type 2 diabetes, as well.

* Among people who were older than 45 years of age, were overweight and had a family history of type 2 diabetes, less than one third were worried about their risk to develop type 2 diabetes themselves.

* If you have a first degree relative (parent, brother, sister or child) who had cardiovascular disease before age 50, if male, or age 60, if female, you should have your blood checked for signs that you are also at risk for CVD.

* If you have a family tree that suggests that CVD is running in the family (more than one affected relative, showing up in more than one generation, onset early in at least some relatives), this may suggest you have a very strongly hereditary condition that results in CVD in your family.

* If you belong to one of these families that is strongly predisposed to develop CVD, there are very good options for prevention and treatment to greatly reduce your risk.

* 25% of people diagnosed with colorectal cancer have a relative who also has /had the disease.

* Colorectal cancer can be detected early and has a very high cure rate if diagnosed early.

* Family history of breast cancer is relevant to your risk, whether it comes from your mother or father's side.

* If you have concerns about your family history of ANY condition, talk to your healthcare provider about this and discuss being referred to consult with a genetic counselor, a medical geneticist, or other healthcare professional who specializes in assessing familial risk for adult-onset diseases.

50 best science blogs

2006-08-03T22:01:00.000-07:00

Nature has published their list of the 50 best science blogs written by scientists. Check it out.

Family history and coronary heart disease--common, actionable, under-appreciated

2006-07-31T14:44:00.000-07:00

A family history of coronary heart disease is an independent, common, actionable and perhaps under-appreciated risk factor for developing coronary heart disease in otherwise healthy people (1). In addition to shared genes, other factors such as blood lipid levels, blood pressure levels, body weight, type 2 diabetes, smoking habits, eating patterns, alcohol consumption, physical activity and socioeconomic status, also tend to cluster in families (2). Due to the fact that family health history captures the consequences of genetic, environmental and behavioral risk factors on cardiac health, it may be a better indicator of a person’s chances of developing CHD than many of the other risk factors that are more commonly relied upon for this purpose (1).

Familial coronary heart disease accounts for a significant fraction of the burden of CHD in the population. In a large study of over 122,000 families who were not selected for CHD and were ascertained through high school health classes, 72% of early-onset CHD and 48% of all CHD were clustered in 14% of the families studied (3). Community-based preventive interventions that included visits by public health nurses, were shown to be effective in educating families about their risks, assisting in making appropriate referrals and supportive for long term behavior changes (4). Preventive interventions that focus on families therefore may have a significant impact on reducing cardiovascular disease risk factors in the population as a whole. In addition, the populations with the greatest familial risk for CHD also show the greatest risk reduction in response to preventive interventions (5).

Family history of CHD is also very commonly encountered in the population. In a recent national mail survey (Healthstyles) that collected information on the health attitudes, behaviors, conditions and knowledge of a population that is representative of the U.S. population, almost 50% of the respondents reported a family history of CHD in a close relative (parent or sibling), suggesting at least a moderate familial risk (6).

Considering the prevalence, predictive power and actionable nature of family history of CHD, it is important for health practitioners to be able to confidently interpret the significance of a family history of CHD, to understand the potential consequences for their patient’s health, and to determine appropriate follow-up and screening (7). In general, the risk of CHD increases as the age of onset of heart disease in the family gets younger and the number of relatives who are affected increases, especially if the relatives are female. In addition, the risk increases as the relationship of affected relatives gets closer. Other characteristics of familial susceptibility include the presence of multiple CHD risk factors in affected relatives or the presence of related disorders (e.g. type 2 diabetes, hypertension or stroke) in family members (7). In families with moderate histories of CHD, the cardiac health history of siblings seems to be even more predictive of CHD than that of parents (8).

Although there are no universal screening or follow up guidelines that are recommended for all individuals with a family history of CHD, one or more of a range of options may be appropriate and effective in addressing a familial risk of CHD. Interventions may range from counseling on relatively minor changes in behavior or diet to referral for further evaluation to a cardiologist or medical geneticist. In general, the aggressiveness of intervention is determined by the degree of the family history of CHD encountered and the underlying etiologies that are responsible. More detailed information on risk stratification and appropriate interventions for patients at risk for familial CHD are collected in a recent review (7). For more information on familial CHD or assistance for appropriate referrals for familial CHD contact the Chronic Disease Genomics Project at the Minnesota Department of Health at 651-201-3609.

1. Kardia SLR, et al. Family-centered approaches to understanding and preventing coronary heart disease. Am J Prev Med 2003; 24(2):143-151

2. Higgins M. Epidemiology and prevention of coronary heart disease in families. Am J Med 2000; 108(5):387-395

3. Williams RR, et al. Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (The Health Family Tree Study and the NHLBI Family Heart Study). Am J Cardiol 2001; 87:129-135

4. Johnson J, et al. Utah’s Family High Risk Program: Bridging the gap between genomics and public health. Prev Chronic Dis [serial online] 2005 Apr.

5. Hunt SC, et al. Family history assessment: Strategies for prevention of cardiovascular disease. Am J Prev Med 2003; 24(2):136-142

6. McCusker ME, et al. Family history of heart disease and cardiovascular disease risk-reducing behaviors. Genet Med 2004; 6(3):153-158

7. Scheuner, MT. Clinical application of genetic risk assessment strategies for coronary artery disease: genotypes, phenotypes, and family history. Primary Care Clinics in Office Practice 2004; 31(3): 711-737

8. Nasir K, et al. Coronary artery calcification and family history of premature coronary heart disease: Sibling history is more strongly associated than parental history. Circulation 2004; 110:2150-2156

SACGHS seeks public comment on policy report

2006-07-30T12:42:00.000-07:00

The Secretary's Advisory Committee on Genetics Health and Society (SACGHS) advises the Secretary of Health and Human Services on selected issues related to genetic research and applications, including the ethical, social and legal implications. The SACGHS issued a draft report entitled "Policy Issues Associated with Undertaking a Large U.S. Population Cohort Project on Genes, Environment, and Disease." The SACGHS is seeking public comment on this draft until July 31, 2006.

The purpose of the report is to explore policy issues related to engaging in a very large study that is representative of the U.S. population to collect the necessary information for both biological and epidemiological studies that would help discern the relationship and interactions between genes and environmental factors that affect health. This would be a huge undertaking, so it is laudable that the SACGHS has begun to address this issue. They correctly observe that:

"A large population research project raises multiple policy issues because
1) it will involve an unprecedented number of participants and, thereby, will have a significant public profile and a direct impact on many people;
2) it requires a relatively large investment of public resources and, as such, warrants scrutiny of and deliberation about its relative value to science, society, and the Nation; and
3) the nature f the information that will be derived from it raises ethical, legal, social and public policy concerns that could be unique and/or significant, particularly in view of the number of potential participants”.

The SACGHS has identified five issue areas that need further exploration before a decision to engage in a large study of the U.S. population could even be made. These areas include issues related to:
1. Research policy
2. Research logistics
3. Regulatory and ethical considerations
4. Public health implications of the project
5. Social implications of the project

In the report, the SACGHS outlines the issues they have identified in each of these areas and some policy options for addressing each one. I will not re-cap the content further, but refer you to the report’s succinct executive summary. I will, however, offer a few brief observations on the report and its recommendations.

First of all, the report recognizes how important it will be that the public at large is and continues to be engaged in this project, should it occur. This is obviously very important, so it is good that the SACGHS clearly recognizes and addresses this.

Second, the report recognizes the existence of the many uses of this type of data and is sensitive to multiple perspectives of entities who may have interest in this information, including (but not limited to) the interests and concerns of racial groups, business interests, academia, ethicicists, policy makers, and public health.

Third, the areas related to issues on research policy and research logistics are especially detailed and well covered, offering very specific strategies for assuring that the project is multidisciplinary in nature and that the data generated is available for both public and private concerns, including issues related to protecting intellectual property.

Fourth, the sections on ethical issues and regulation, public health implications and social implications of the the project are, unfortunately, the least developed and the least specific. Although it is laudable that these issues were considered to be major enough to be considered part of the top five (all three are in the list detailed above), the recommendations provided by the SACGHS were vague and very nonspecific compared to the recommendations for the first two major issues, which were much better developed. Hopefully, in the next draft of this report, there will be a little more meat on the bones of this section.

The full report can be accessed here.

Dad's family history of breast cancer may get short shrift

2006-07-29T21:29:00.000-07:00

In families which have a familial tendency to develop breast cancer, this inherited susceptibility can come from either the mother's or the father's side of the family. In these families, the susceptibility comes through the paternal lineage about as often it does through the maternal side of the family. Many people (including some healthcare providers) are surprised that you can inherit a susceptiblity from your dad's side. After all, most men do not get breast cancer, even in families with a very strong tendency for developing this disease, so the idea that the susceptibility could pass through males to their female descendants seems counter-intuitive.

The main finding of a study that will be published in the September 2006 issue of the American Journal of Preventive Medicine by Dr. John Quillen and colleagues reports that women report fewer cases of breast cancer in their paternal relatives than would be expected. The consequences of this apparent under-reporting is that a woman's risk of breast cancer may be underestimated, potentially affecting her access to appropriate screening and/or cancer prevention strategies. Ultimately, her likelihood of having a poor health outcome due to breast cancer may be increased if the management of her risk is less aggressive than might be warranted if the true extent of her family history of cancer was considered.

The authors of the study report their results in the American Journal of Preventive Medicine. The full text of this article will be published in the September 2006 issue. The article cite is “Paternal Relatives and Family History of Breast Cancer” by John M. Quillin, PhD, Viswanathan Ramakrishnan, PhD, Joseph Borzelleca, MD, Joann Bodurtha, MD, Deborah Bowen, PhD, and Diane Baer Wilson, EdD. American Journal of Preventive Medicine, Volume 31, Issue 3 (September 2006).

An article by Eric Nagourney in the New York Times on July 25, 2006 also reports on this study. The full text of the article in the American Journal of Preventive Medicine is available here. A press release from the publisher that summarizes the findings is available here.

Beyond the Genome...Beyond the Individual: Genomics and Public Health

2006-07-29T20:24:00.000-07:00

The National Societies of Genetic Counselors (NSGC) is sponsoring a one and one half day long course on public health genomics in conjunction with the Annual Education Conference in Nashville, TN on November 9-10, 2006.

According the NSGC, the purpose of the course is to help genetic counselors to increase their capacity to be prepared to play an important role as genomics is increasingly used in public health activities aimed at health promotion and disease prevention. More specifically, the purpose of the course is stated to be:

"Innovations in genetics and genomic research are influencing health risk assessment, treatment options, and disease prevention strategies. New knowledge based on the interactions of genetics with environmental and behavioral risk factors has resulted in expanded opportunities to understand and prevent common conditions, such as cardiovascular disease, cancer, and diabetes. As genomics further permeates medicine and public health, there is a growing need for genetic counselors to have expertise in both genomics and public health to help consumers and practitioners comprehend the implications of genomics in practice.

The demand for genomics expertise in public health settings also provides new opportunities for expanding the practice of genetic counselors beyond individuals and families to the general population. For example, public health genomics is moving from the realm of newborn screening, education, and providing or funding care for vulnerable and underserved communities to dealing with family history as a population-based genomic tool, and incorporating genomics into chronic disease services and programs. Policies such as genetic nondiscrimination legislation and newborn screening expansion mandates are also affecting the practice of genetic counseling. Technological advances and elucidating their benefits and harms is another important part of public health genomics and genetic counseling.

To be maximally effective, genetic counselors must begin to strengthen their knowledge of public health principles, policy and practice. This short course will utilize plenary sessions and panel discussions to provide examples for using public health principles in genetic counseling, introduce the relevance of genomics to public health, discuss policy development, and explore ways in which genetic counselors can contribute to improving the health of populations. "

The course agenda is available. Online registration is available and you need not be a genetic counselor or a member of NSGC to participate.

National Office of Public Health Genomics at the CDC

2006-07-29T19:31:00.000-07:00

The Centers for Disease Control and Prevention has had an office working to integrate genetics and genomics into public health since 1998. At its inception, the office was known as the Office of Genetics and Disease Prevention to reflect this mission of using genetic tools to improve health. In 2002, the name was changed to the Office of Genomics and Disease Prevention to reflect the growing importance of genomics and other "omics" sciences in public health. On July 24, 2006, the name of the office was changed again, to the National Office of Public Health Genomics. According to the announcement on their website:

"Public health genomics is a multidisciplinary field concerned with the effective and responsible translation of genome-based knowledge and technologies to improve population health. Public health genomics uses population-based data on genetic variation and gene-environment interactions to develop evidence-based tools for improving health and preventing disease. Since 1998, our office has been at the leading edge of this development in the United States and internationally. Thus, the name change better reflects what we do."

New code in the DNA for nucleosome-wrapping

2006-07-27T16:58:00.000-07:00

The most obvious information contained in our DNA is the information contained in the genetic code which allows us to predict the amino acid sequence of protein products that are coded by genes. Although the complete catalogue of proteins in the proteome is still incomplete, other more subtle structural and sequence patterns are being uncovered that may affect the regulation of gene expression and other genomic activities. This fledging understanding of how and when genes are transcribed is vital to understanding the biology that underlies health and disease. This understanding may have been significantly advanced by recently published work by Drs. Eran Segal, Jonathan Widom and colleagues that suggests that there may be a subtle, degenerate code in the DNA that determines where the DNA is likely to be pliable enough to wind around the structural protein complexes called nucleosomes. Published online in Nature on July 19, 2006, the authors present data that supports the existence of this new, non-obvious code which may help to explain how DNA wraps itself around the nucleosomes. This secondary genomic structure not only helps DNA package itself more compactly, but it also has an effect on gene expression by regulating access to transcription factor binding sites. It is believed that this discovery could provide some important insights into how, why and when specific genes are--or are not-- accessed for expression. Paid registration is required to access this article.

Nicholas Wade also reports on this new finding in the New York Times on July 26, 2006. Access is via free registration.

Genes, Gender and Scientific Ability

2006-07-25T07:23:00.000-07:00

Nobody will ever say that males and females are exactly alike. At the level of the genome both males and females have 46 chromosomes in most cases, but males typically have an XY and females have an XX pair of chromosomes as part of the basic set. Phenotypically, male and female bodies have obvious physical differences. Some scientists are arguing that there are other constitutional differences between males and females that make females less able to compete and succeed at the highest levels of scientific endeavor due to a lack of innate ability and other "female" attributes.

A thoughtful essay in Nature (paid subscription required) by Dr. Ben Barres challenges some of these assertions. Dr. Barres is somewhat uniquely qualified to discuss these issues because, as a transgendered individual and an accomplished scientist, he has experienced life and career from both the perspectives of a woman and a man. Although he supplies his own experiences as anecdotes in this discussion, he does not consider them "data". Instead, he uses evidence from the published literature to support his argument that the differences between the observed levels of achievement between male and female scientists is due to a pervasive discrimination within academia that judges women as less competent than men.

Dr. Barres has also provided an interview to the New York Times, which was published on July 18, 2006, where he reviews and expands upon his comments in Nature. This article is available with free registration.

The Quest for the $1,000 Human Genome

2006-07-21T07:33:00.000-07:00

The goal of the $1000 Human Genome is almost certainly a little closer with the advent of a new generation of DNA sequencers. Nicholas Wade reports on some of these new developments in the July 18, 2006 issue of the New Yort Times article The Quest for the $1,000 Human Genome.

However, even as we get closer to this NIH-supported goal, the bigger question still remains: What impact will access to the complete genome sequence really have for most people's medical care? The developers of this new technology acknowledge that there is no real demand for this information, at least not yet. They are banking that access to complete genome sequence information will become routinely relevant in healthcare in the next few years. The jury is still out as to what the value of this information will be for most people.

So the question of whether the DNA sequence is likely to be so powerful and predictive that we all should have our genomes sequenced is a relevant one. By itself, the sequence is only potentially related to our health; it yields information about the probabilities of what our health is or will be, but not what our health actually is now or will be in the future. A prime example that illustrates this point are the hereditary cancer syndromes. Even in these families with inherited mutations in "cancer genes", many (if not most) of the individuals who inherit a cancer-predisposing mutation never get cancer. The probablilty that they will eventually develop cancer is higher, to be sure, but they are not sick simply because they inherited this strongly predisposing genetic element. This is even more true for the many less potent genetic elements that we all have that contribute to disease risk. The real story of health lies in the biological processes and interactions that are only partially due to the genome.

Our genes are only half (and sometimes significantly less than half) of our health story, both present and future. The other major players are all the extrinsic factors that make up our environment and the consequences of our behaviors. We are learning more and more about how our genome interacts with the myriad of elements within the genome itself and the almost infinite elements that are extrinsic to the genome. These interactions are more closely related to the health states we experience (both good and bad) than the sequence alone.

Of course, the DNA sequence obviously plays an important role--it is the foundation of our biology. However, the genome functions in an environmental context that regulates its activities at many levels. The technologies to elucidate the physiological consequences of these interactions between genes and environment are developing in parallel with the quest for the affordable genomic sequence. An understanding of how the genome is expressed and how non-genomic factors affect expression will ultimately be more directly relevant to managing the unique and dynamic physiological circumstances that contribute to a person's state of health or a particular disease process. As we close in on the quest for low-cost DNA sequencing, the genome sequence's greatest value may be in what it contributes to our understanding of the interactions between our genome and our environment, and thus, our health.

Family history and chronic diseases

2006-06-16T15:15:00.000-07:00

I am keeping a rolling list of conditions that have family history as a risk factor. Today's additions include urinary incontinence in women and heartburn. Interesting.

Obesity and genomics: A Public Health Perspective

2006-06-16T15:03:00.000-07:00

Obesity and overweight are at the root of several chronic diseases of public health significance. Diabetes, heart disease, hypertension, stroke and arthritis are just a few of conditions that count obesity as a significant risk factor. Trying to move our understanding of obesity beyond the obvious culprits of an environment that has an amazing abundance of easily accessible, calorie-rich and highly palatable food to the intrinsic factors that contribute to our desire for, consumption of and metabolism of our food is an area of active research. Genetics and genomics are helping scientists to better understand why some people seem to be more susceptible to obesity in this environment and why others aren't. Of course, the caveats is emphasized that genes are not deterministic for obesity or just about any other chronic disease, but they do tend to lean us in a particular direction. And if the environmental winds are going the same way, it is hard to resist.

The CDC's Office of Genomics and Disease Prevention and the CDC's Division of Nutrition and Physical have collaboratively published a webpage on genomics and obesity, seeking to look at it from a public health perspective. I include the link here for your review. Check it out. http://www.cdc.gov/genomics/training/perspectives/obesity.htm

Why do we do the things we do?

2006-06-15T19:36:00.000-07:00

Why do we do the things we do? Is it because of our upbringing? Where we are in the birth order? The way we are treated in our relationships with our siblings or parents? How society categorizes us due to our sex, attractiveness, sexual orientation or racial background? How our religious traditions shape us? Do we do what we do because we observe other people in our sphere doing similar things? Or do we each have an inborn personality that merely unfolds as time passes and we pass through a pre-determined developmental process with doors opening and closing in orchestrated and predictable ways? Do we do what we do because of the innate strength (or weakness) of an intangible set of traits we collectively call "character"? Are some of us just more "good" or "evil" than our peers? Do we truly have free will? Are we completely responsible for all of our actions? Why do we do the things we do?

These questions have intrigued and vexed human beings ever since we made the leap from an animal conciousness to self-awareness. I wouldn't be surprised if this question has caused many of the members of our species more anxiety and angst than any other because we simply cannot find a complete and satisfactory understanding of either our own or others' behavior. It has been examined and approached from multiple perspectives, including religious, philosophical, humanistic, and psychological ones, all contributing their ideas, theories, observations, data and beliefs to the effort to understand, but the picture is never complete. And what is worse, these perspectives often conflict with or contradict each other to greater or lesser extents.

Genetics has also weighed in on this question, attempting tease out what is intrinsic and what comes from the greater environment in which we develop. Using naturally occurring experiments in genetics such as studying how behaviors tend to run in families and how the behaviors of adoptees compare to their birth versus their adoptive families, we have tried to answer what aspects of our personalities and behaviors are inborn and which are not. These studies have suggested that at least part of behavior has genetic underpinnings, even while our ability to reason and choose, along with influences from our environment, are also variably influential in the actions we make.

With the completion of the Human Genome Project and the Haplotype Mapping Project, new tools are available to attempt to better define exactly what areas of the genome are associated with certain types of behaviors. These studies have focused on attempting to map regions across the human genome that contribute to behaviors and mental states that range from serious mental illnesses to tendencies to take risks, to believe in a higher being or to experience happiness. All of these studies challenge us for several reasons, not the least of which is the fact that a major underpinning of our social compact with each other is grounded in the premise that we have true choice in our actions and that we have the free will to exercise these choices. Suggesting that this may not be starkly true, or even true in the majority of cases, is challenging to us on many levels.

Amy Harmon in the New York Times has written a thought-provoking article that considers the contributions of genetics and environment to our behaviors and the choices we make. It is part of an ongoing series entitled The DNA Age: My Genes, Myself. In her thought provoking article, she discusses the tension that is caused by the intersection of the various conceptions of behavior as described by differing disciplines of study or thought. She also details some of the challenges that a growing genetic understanding of behavior will mount to the greater conception of behavior in our society. For examples, if our genes contribute greatly to what we do, should people be punished for these behaviors? Or, on the other hand, if some behaviors are largely intrinsic, does that make them immutable and resistant to change, suggesting that some people who violate the rules our society has codifed in law are more prone to rescidivism than others? Should this be true, what does our justice system do with this information? Do we treat these people differently? Do incarcerate them for their entire lives? Lots of hard questions and no easy answers, at least right now.

As another illustration, the genetic associations with the tendency to gain or lose weight are beginning to shape the perceptions of how we view overweight people in our society. Genetic underpinnings of our behavior may help to explain why some people tend to become overweight in our present environment of unprecedented plenty while other people seem blissfully immune to the multiple high-caloric temptations that plague their plump fellows many times aday. Ironically, it may be that at least some of us who battle the bulge on a chronic basis, along with the risk of the diseases associated with obesity, were the ones who were more likely to survive and reproduce in times past precisely because we could take advantage of sporadic opportunities to store away calories for the inevitable future when the times would not be so lush. The strategies that were so successful in eons past seem to have come back to bite a lot of us in the present day.

I am continuing to reflect on this subject because, obviously, it interests me. However, I will stop now and refer you to Ms. Harmon's article. She does a nice job of reviewing some of the issues, especially the ethical and social ones, that a growing understanding of how genetics contributes to behavior will challenge us with.

The Wild Streak? Maybe it runs in the family by Amy Harmon. The New York Times June 13, 2006 http://www.nytimes.com/2006/06/15/health/15gene.html?_r=1&oref=slogin

Heelstick test can cause unnecessary parental stress

2006-06-13T19:40:00.000-07:00

The rapid expansion of newborn screening has been a blessing to many babies and their famiies who have had early detection and intervention for inborn errors of metabolism that are amenable to treatment and improved outcomes. For these families, the results are the fulfillment of all the promise of newborn screening.

However, there are almost always some costs or downsides to even the most beneficial program and newborn screening is no exception to this rule. Some of the costs of newborn screening are born by the families who receive presumptive positive or indeterminate results that may take weeks or longer to reconcile as either frankly positive or truly negative, that is, normal and may involve considerable contact with the medical care system.

We in the business have tended to minimize this cost, suggesting that finding and saving lives and/or health of the kids with inborn errors is worth this cost. We have presumed (or hoped?) that families who go through the unsettling time when a diagnosis is not clear likely "get over it" once their child's health situation is resolved and found to be normal. These theoretical ramifications of false positives have been an unresolved issue for me for some time and I have wondered more than once whether there were any short and/or longterm consequences for the mental and psychological health of these families. So, it is with great interest that I noted this report by Waisbren and Gurien in the June 2006 issue of Pediatrics where the parents of babies who eventually were shown to not have a metabolic conditions were shown to have significant stress levels, even six months after testing. The authors suggest that this may be alleviated by better education of both parents and providers about newborn screening.

Money quote: "Although mothers in the false-positive group were interviewed at least six months after their child's diagnosis had been ruled out, they reported more worry about their child's future and rated themselves less healthy than mothers in the comparison group. Fifteen percent said their child needed extra parental care, versus 3 percent of mothers in the comparison group. After adjustment for socioeconomic factors, both mothers and fathers in the false-positive group had higher scores on the standardized Parenting Stress Index (PSI); 11 percent of mothers (versus no mothers in the comparison group) scored in the clinical range, in which treatment might be prescribed.

Waisbren and Gurian also found that false-positive tests affected the parent-child relationship: parents in the false-positive group scored more highly on two subscales of the PSI: a Parent-Child Dysfunctional Interaction scale and a Difficult Child scale. (The first asks parents to rate their agreement with statements like "I expected to have closer and warmer feelings for my child, and this bothers me"; the second has statements such as "My child makes more demands on me than most children.") "

This type of research is so important because we need to take into account these costs and work to address them. It is not fair that parents of kids who turn out to be healthy should be harmed in any way as a consequence of a program that exists to assure the health and wellbeing of all newborns and their families. By better understanding these unintended and unwelcome consequences, we can work to address and prevent them to the benefit of all.

A summary article can be accessed at: http://www.news-medical.net/?id=18240

Access to the article's abstract can be found via PubMed at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16740831&query_hl=2&itool=pubmed_docsum

Precise cite: Gurian EA, et al. Expanded newborn screening for biochemical disorders: the effect of a false-positive result. Pediatrics 2006 Jun;117(6):1915-21

Family health history and primary prevention

2006-06-12T19:01:00.000-07:00

For those of you who are versed in some of the more universal parlance of the public health set, the term "primary prevention" denotes a familiar concept. Primary prevention is all about preventing bad outcomes for people, to maintain or improve health and to anticipate and head off problems before they become manifest in people's lives. Here, we are trying to use the concept of family health history as another tool for keeping people well by informing them of their risk for chronic diseases.

Family health history is an independent risk factor for several conditions that contribute greatly to the morbidity and mortality of lots of people. Examples of conditions that can run in families include many types of cancer, including the biggies of breast, colorectal, and prostate cancers. There are also families in which other cancers can be very prevalent. For example, our former President, Jimmy Carter, has a remarkable family history of pancreatic cancer. He lost at least a couple of siblings and one parent to this disease. Thankfully for him (and for us), he has so far been spared from this disease.

Other conditions that tend to run in famlies include cardiovascular disease, hypertension and stroke and diabetes. Interestingly, we often talk about obesity as being a very potent risk factor for both cardiovascular disease and diabetes. Having a family history of these conditions--especially if the relatives are closely related--is comparable with obesity as a risk factor.

So, if your relatives have all keeled over from chronic diseases, does that mean that you are doomed to their fate? The really good news is that if your relatives have suffered from chronic diseases like cancer or diabetes, you can use your relative's experiences of poor health as a cautionary tale and avoid a similar fate. There is almost always something you can do to allay or greatly reduce your chances of repeating their history. It isn't just about genes, in most cases, but rather about an interaction between environmental and behavioral factors with a susceptible genetic makeup. In other words, there may be some genes that are necessary for disease to occur, but they certainly are not the whole story by any means. Remove any one of the predisposing elements and health is maintained, even if there is a considerable genetic predisposition. So, even though you can't change your genes, you can change your behaviors and your environment (including diet) and stay healthy. For most of us, the family health history of common chronic diseases that we have observed in our parents, grandparents, aunts and uncles, can be averted by following some pretty basic changes in habits and environments. So, if you can, raise of toast to the health (or lack thereof) to your relatives. By learning from what health conditions affected them, you can up your chances to have a long and happy life!

Best regards,

Genomics Gal

Newborn screening and informed consent

2006-06-11T20:04:00.000-07:00

The Minnesota Republican Party has added a plank to their party platform that would require parents to "opt in" to having newborn bloodspot screening for their newborn babies. This would be a major change from the current situation in Minnesota. Currently, parents can "opt out" of the program, but this very rarely happens. If the program is changed so that parents have to "opt in" to have their child screened, it is unclear what this would mean for the rates of participation. The concern is that many more kids would not be screened and that, sooner or later, a child with a treatable condition would be missed, resulting in permanent disability or death to the child. Also, if "opt in" becomes the standard, there will be a whole new informed consent process that will have to planned, developed and put into practice. Who would do this and what it would cost is unclear at this point. We will be watching this with great interest. Fee free to comment if you have any information or if you have perspectives on this. Best regards, Genomics Gal