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a bio blog about genetics, genomics, and biotechnology
Josh: So while this research is very interesting, I would first like to call attention to biologists’ odd sense of humor. Apparently, SMAD4 stands for “Mothers against decapentaplegic homolog 4″. This is obviously some type of a joke made from MADD, but the bizarre sense of humor doesn’t stop here. Who can forget the signaling molecule Sonic Hedgehog (SHH), bride of sevenless (BOSS), frizzled, dishevelled, amongst many others that are escaping me at the moment.
Tumour suppressor genes do not necessarily require both alleles to be knocked out before disease phenotypes are expressed. Research published in BioMed Central’s new open access journal PathoGenetics reveals that only one allele of SMAD4 has to be damaged to put a person at risk of pancreatic and colorectal cancer.
Riccardo Fodde led a team of researchers from Erasmus MC, Rotterdam, who investigated SMAD4, a tumor suppressor gene implicated in pancreatic and colorectal cancer. They found that having one mutated SMAD4 allele was associated with the development of gastrointestinal polyps. This research is the first to address the molecular and cellular consequences of SMAD4 damage on a genome-wide scale.
This high quality research is typical of that which will be published in PathoGenetics, an open access journal created to meet the need for a resource focused solely on the pathogenesis of genetic diseases. The journal’s co-Editors in Chief are Professor Stylianos Antonarakis and Professor Andrea Ballabio. Ballabio said, “PathoGenetics will give scientists a unique opportunity to publish exciting research on the molecular mechanisms underlying the manifestations of disease phenotype”.
PathoGenetics will focus on both in vitro and in vivo studies on the cascade of events leading from gene mutations or genomic rearrangement to disease. The discovery of novel molecular and metabolic pathways relevant to disease pathogenesis will be given specific emphasis. The first issue includes a review by James Lupski and colleagues that deals with mechanisms for human genomic rearrangements and a groundbreaking piece on the methodology of knock-in vector construction by Nicholas Hastie and colleagues. According to Antonarakis, “Given its unique characteristics, PathoGenetics is likely to become the ideal journal for scientists from different backgrounds to publish and read exciting research on disease pathogenesis”.
Source: BioMed Central
Smad4 haploinsufficiency: a matter of dosage. Paola Alberici, Claudia Gaspar, Patrick Franken, Marcin M Gorski, Ingrid de Vries, Rodney J Scott, Ari Ristimäki, Lauri A Aaltonen, Riccardo Fodde. PathoGenetics 2008, 1:2 (3 November 2008)
Tip to Dr. Steven Murphy for bringing this article to my attention. He notably accompanied his email with much more profanity than I will use in this post.)
Note this excerpt from the deCODEyou blog October 20th: Customer Story: The Path To Prevention: (emphasis mine)
But because Jason’s mother had a history of strokes, Doneen wanted to dig deeper. She used deCODEme’s genetic test and searched Jason’s genome for a gene that medical studies have related to A-fibrillation. Jason was positive for the A-fib gene, so despite the fact that his heart-monitor test was negative Doneen put him on a heart monitor, but this time for a month in order to be more accurate. Sure enough, the month-long test showed that Jason was going into a-fib. Doneen immediately started treating Jason with a different course of medicine.
‘The test changed his course of treatment,’ she says enthusiastically.
Doneen cautions that just because a patient has an abnormal gene doesn’t mean that patient should be treated with medicine. In fact, she says there is no evidence to treat patients based on an abnormal gene. However, knowing that Jason had this abnormal gene, and had a family history of stroke, Doneen decided to take action, and put Jason on a heart monitor, which fundamentally altered his clinical course.
Why not just put everyone on a heart monitor for a month, instead of a week, and therefore make sure patients don’t have a false negative test?
‘Putting everyone on a monitor for a month is not feasible. But putting someone who has an abnormal gene on a monitor, that’s feasible.’
In other words, while putting everyone on a monitor for a month would catch more heart attacks, it’s not a “feasible” allocation of resources. So, the deCODEme test, which as stated has no evidence, is being used like a random number generator to justify picking some patients for additional care and not others. Why? They tested positive for the A-fib gene. Magic.
So, since there is no evidence, only “decision to take action,” you could replace the deCODEme test with a homeopathic test that produces the same ratio of positive results for the same clinical effect. I understand that people sometimes feel they need a special reason to pursue healthcare from which they could always hypothetically benefit, but there is no rational necessity to produce this impetuous prior to treatment other than the psychological comfort of rationalization.
I would like to see a study where one person gets the genetic test, and one person gets a random jibberish report recommending the same thing, and see if there is a clinical difference. Random jibberish is much cheaper to produce. Why not save your money and get a random jibberish test to help you “decide to take action?” I will put it in a leather case and have a doctor sign sign it on real parchment and read it to you in a very authoritative tone and use big words. You will be 238.8% as decided to take action as if I posted the result on your genomic Web 2.0 deCODEme profile. (there is no evidence to back this claim)
Non-casual risk testing at low-mid penetrance like deCODEme has great potential someday, but only to more optimally ration scare health resources for better net efficiacy that otherwise should be provided to everyone. However, there is no shortage of “eat healthier, reduce stress, exercise, and see a doctor if you have a problem” which is the best medical recommendation that can be produced by today’s DTC testing.
On an individual scope, one must ration personal wealth to pay for healthcare. It’s feasible that low-mid penetrance can aid in making more rational decisions. However, it’s much more likely that personal decisions to pursue which healthcare strategies are in no way rational or scientific and that “optimization” is a delusion. You can’t perform risk benefit assessment arithmetic on “your feelings.” 20% + you’re scared isn’t a number with a dollar sign.
On a social scope, low-mid penetrance risk assement can help better allocate a fixed amount of resources per person to purchase the most personally effective healthcare. However, this is assuming that the healthcare industry isn’t corrupt and would use the tests to justify whatever medically-arbitrary decision they’ve already made to benefit themselves. I don’t think that assumption is justified until the medical benefits of these tests are so obvious as to prevent such bureaucratic abuse excused as an “ongoing discussion.”
But, by all means, buy a deCODEme test. It’s the American way. But do it because you want it, not because of some magic you wish was medicine because you’re afraid of illness and death.
Adriano Squecco of DNA-forums.org is collecting Y Chromosome information from DTC consumers and compiling an open community ancestry database: Y-DNA-FORUMS [excel spreadsheet] (my results are under “Yates” on the 23andMe v1 page)
Interestingly, he is advertising his project on the 23andMe user boards, which is how I found Adriano and his project. Since users can download their 23andMe (or deCODEme) genomic test results as a text file, any 3rd-party service in a secondary genomic market can provide interpretation and collaboration services without ever handling biological samples over the internet.
This is the future.
The sequencing of the genome itself isn’t as interesting because we know what the end is: a cheap, accurate, complete genomic sequence. We may think of genomic testing today as an obscure luxury service, but the technology will bottom out and sequencing companies will consolidate, all offering the same undifferentiated sequence, all competing on price, economy of scale, and marketing.
Instead, what is interesting, what offers an unlimited potential for differentiation, competition, and innovation —is the secondary genomic market, services which accept biological test results and produce research and interpretation. And while genomic testing is the obvious start for a secondary medical information market, why not any medical test? We already send away blood and cultures to a lab and get back data at medical facilities, why not cut out the middle and do it directly through the mail and the Web?
Que Dr. Steven Murphy freaking out about involving doctors and irresponsibility… except, now we got smart. We’re going to beat the “hackers” at their own game, right Steve?
Introducing HelixGene
PS: obviously, this is just a quick proof of execution. Give us at least more than one night to build a prototype of a radical new model of health care, ok?
Introducing: HelixGene Foundation for Better Genomic Medicine. You email us your medical questions about genomics, our licensed medical genomic doctors email answers. This announcement is our soft-launch: we are accepting and answering emails and paid subscriptions, but we are still building the service and have not officially launched. Our genomic specialist physicians include:
Steven A. R. Murphy, MD (also known as The Gene Sherpa)
Clinical Genetics Fellow, Yale School of Medicine;
Managing Partner, Helix Health, PLLC
Adam J. Messenger, MD
Pharmacogenomics Specialist, Department of Pharmacology, New York
Medical College and Graduate School of Basic Medical Sciences
Matthew B. Lubin, MD
Jennifer Ibrahim, MD
Joy Samanich, MD
Our general subscription is $14.95 per month (FREE first month alpha accounts) to post medical genomic questions to HelixGene’s public forum by email. Private emails are $145 each and will be answered by a HelixGene health professional in 48 to 72 hours.
We DO discuss the medical validity and implications of all DTC genomic tests in a medical setting including: 23andMe, deCODEme, and Navigenics.
For the press, we provide expert opinion services for journalists and sell expert review subscriptions for mass media publications including medical genomic information. To enforce accountability we feel is lacking in medical reporting in the mass media today, HelixGene publishes medical genomic report cards for publications. Pre-submitting your publications and consulting with our experts helps us help you accurately and honestly report medical genomic information to the general public. Ask our about media medical consulting plans including those for bloggers, independent journalists, and major publications. Email us for pricing.
We also host a private, invitation-only genomic specialist forum which is free. If you are qualified, ask for an invitation to our expert forum. This is a forum for doctors and scientists to discuss academic issues, particularly to discuss the merits of new genomic services, academic issues, and troubling medical genomic reporting in the popular media. Email us for an invitation.
Secondary Market Database
I’ve started a database for secondary genomic market services. Please leave a comment here to report new services or send Think Gene an email.
October 20th, 2008
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Josh: This is a rather interesting study. It will certainly be at least 5 years before we could hope to see any drugs available that block this receptor (Gpr41). I would be more interested to see if there are variations in the gene encoding Gpr41, causing people to be more or less sensitive to the ligands, which in this case are fatty acids.
A single molecule in the intestinal wall, activated by the waste products from gut bacteria, plays a large role in controlling whether the host animals are lean or fatty, a research team, including scientists from UT Southwestern Medical Center, has found in a mouse study.
When activated, the molecule slows the movement of food through the intestine, allowing the animal to absorb more nutrients and thus gain weight. Without this signal, the animals weigh less.
The study shows that the host can use bacterial byproducts not only as a source of nutrients, but also as chemical signals to regulate body functions. It also points the way to a potential method of controlling weight, the researchers said.
“It’s quite possible that blocking this receptor molecule in the intestine might fight a certain kind of obesity by blocking absorption of energy from the gut,” said Dr. Masashi Yanagisawa, professor of molecular genetics at UT Southwestern and a senior co-author of the study, which appears online in Proceedings of the National Academy of Sciences.
Humans, like other animals, have a large and varied population of beneficial bacteria that live in the intestines. The bacteria break up large molecules that the host cannot digest. The host in turn absorbs many of the resulting small molecules for energy and nutrients.
“The number of bacteria in our gut far exceeds the total number of cells in our bodies,” said Dr. Yanagisawa.
“It’s truly a mutually beneficial relationship. We provide the bacteria with food, and in return they supply energy and nutrients,” he explained.
Using mice, the researchers focused on two species of bacteria that break up dietary fibers from food into small molecules called short-chain fatty acids. Dr. Yanagisawa’s team previously had found that short-chain fatty acids bind to and activate a receptor molecule in the gut wall called Gpr41, although little was known about the physiological outcome of Gpr41 activation.
The researchers disrupted communication between the bacteria and the hosts in two ways: raising normal mice under germ-free conditions so they lacked the bacteria, and genetically engineering other mice to lack Gpr41 so they were unable to respond to the bacteria.
In both cases, the mice weighed less and had a leaner build than their normal counterparts even though they all ate the same amount.
The researchers also found that in mice without Gpr41, the intestines passed food more quickly. They hypothesized that one action of Gpr41 is to slow down the motion that propels food forward, so that more nutrients can be absorbed. Thus, if the receptor cannot be activated, food is expelled more quickly, and the animal gets less energy from it.
Because mice totally lacking Gpr41 were still healthy and had intestinal function, the receptor may be a likely target for drugs that can slow, but not stop, energy intake, Dr. Yanagisawa said.
Source: UT Southwestern Medical Center
Buck S. Samuel, Abdullah Shaito, Toshiyuki Motoike, Federico E. Rey, Fredrik Backhed, Jill K. Manchester, Robert E. Hammer, S. Clay Williams, Jan Crowley, Masashi Yanagisawa, and Jeffrey I. Gordon. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. PNAS published October 17, 2008, doi:10.1073/pnas.0808567105
October 19th, 2008
posted
by admin
Kevin: Very cool. It’s going to be a while before this is ready for any sort of practical application, but it is another great tool for the cyborg scientists of the future to use.
Engineers from the California Institute of Technology have created a “plug-and-play” synthetic RNA device–a sort of eminently customizable biological computer–that is capable of taking in and responding to more than one biological or environmental signal at a time.
In the future, such devices could have a multitude of potential medical applications, including being used as sensors to sniff out tumor cells or determine when to turn modified genes on or off during cancer therapy.
A synthetic RNA device is a biological device that uses engineered modular components made of RNA nucleotides to perform a specific function–for instance, to detect and respond to biochemical signals inside a cell or in its immediate environment.
Created by Caltech’s Christina Smolke, assistant professor of chemical engineering, and Maung Nyan Win, postdoctoral scholar in chemical engineering, the device is made up of modules comprising the RNA-based biological equivalents of engineering’s sensors, actuators, and information transmitters. These individual components can be combined in a variety of different ways to create a device that can both detect and respond to what could conceivably be an almost infinite number of environmental and cellular signals.
This modular device processes these inputs in a manner almost identical to the logic gates used in computing; it can perform AND, NOR, NAND, and OR computations, and can perform signal filtering and signal gain operations. Smolke and Win’s creation is the first RNA device that can handle more than one incoming piece of biological information. “There’s been a lot of work done in single-input devices,” notes Smolke. “But this is the first demonstration that a multi-input RNA device is possible.”
Their work was published in the October 17 issue of the journal Science.
The modular–or plug-and-play–nature of the device’s design also means that it can be easily modified to suit almost any need. “Scientists won’t have to redesign their system every time they want the RNA device to take on a new function,” Smolke explains. “This modular framework allows you to quickly put a device together, then just as easily swap out the components for other ones and get a completely different kind of computation. We could generate huge libraries of well-defined sensors and assemble many different tailored devices from such component libraries.”
Although the work in the Science paper was done in yeast cells, Smolke says they have already shown that they can translate to mammalian cells as well. This makes it possible to consider using these devices in a wide variety of medical applications.
For instance, ongoing work in Smolke’s laboratory is looking at the packaging of these RNA devices–configured with the appropriate sensor modules–in human T cells. The synthetic device would literally be placed within the cell to detect certain signals–say, one or more particular biochemical markers that are given off by tumor cells. If those biomarkers were present, the RNA device would signal the T cell to spring into action against the putative tumor cell.
Similarly, an RNA device could be bundled alongside a modified gene as part of a targeted gene therapy package. One of the problems gene therapy faces today is its lack of specificity–it’s hard to make sure a modified gene meant to fix a problem in the liver reaches or is inserted in only liver cells. But an RNA device, Smolke says, could be customized to detect the unique biomarkers of a liver cell–or, better yet, of a diseased liver cell–and only then give the modified gene the go-ahead to do its stuff.
Source: California Institute of Technology
Maung Nyan Win and Christina D. Smolke
Science 17 October 2008:
Vol. 322. no. 5900, pp. 456 - 460
DOI: 10.1126/science.1160311
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