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OT: Dr Pandey is sitting on 2 million dollars worth of Paclitaxel which has not seen the light of day for a few years. Come the glorious day this guy is going to be the first up against the wall (after TonyTox of course)...
Jim, that sort of model would work. There are certain GAAP rules that have to be followed in pooled interest accounting (12 of them) but it is a good way to circumvent issues associated with purchasing another entity outright.
OT: Your choice of XKEM is not a good one IMO (I know you have posted on that board for a long time). I believe that XKEM is a sophisticated scam and that Dr. Pandey is essentially a crook. I know that opinions differ on this one, and that they have the sickle cell drug (Nisipran), they just did the Ceptor acquisition, etc, but...
Doug, one way to go about it is via a pooled interest merger...
Recording of Tony Frudakis on WGCU News talking about the work with Gavin Menzies:
http://www.wgcu.org/listen/wgcu_news_fullstory.asp?key=1087
A Sarasota scientific research company has teamed with a British author to try to prove his theory that the Chinese discovered America 70 years before Columbus. Yesterday we heard from author Gavin Menzies. Today we hear from Dr. Tony Frudakis – the chief scientific officer at DNA Print Genomics. The company conducts leading edge research on DNA testing for disease and drug responses as well as anthropology and genealogy. He’s about to begin groundbreaking DNA identification of Native Americans. He will be able to see if they have Chinese markers in their DNA and when those markers entered the culture.
Tony talks about being able to narrow down "admixture events" to 20-40 generations, which would give a high level resolution of population history.
OT: Not for the squeamish (you have been warned):
Looks like the Japanese Police could use DNAWitness 3.0
http://www.japantimes.co.jp/cgi-bin/getarticle.pl5?fl20040113zg.htm
By contrast Ovanome does a bit better than 75%. From the Paclitaxel response patent we know that: "When considered within the context of a complex (multifactorial) framework, about 98% of the variability in patient response is explained."
OT: Chris, well maybe a good gumming then!
Here's something for the doom and gloom merchants to get their teeth into:
http://www.sciencedaily.com/releases/2004/01/040112071137.htm
Source: University Of Texas M. D. Anderson Cancer Center
Date: 2004-01-12
Future Of Cancer Diagnosis, Treatment Lies In Tumor 'Barcode'
It has been said that a human being is a veritable encyclopedia of proteins. Proteins are the fabric of life – they provide the bricks and mortar of our cells, and run day-to-day operations. When these functions go awry – when too much or too little protein is produced, when a daisy-chain network of proteins working together is disrupted – illness can arise.
While an errant genetic code may underlie a disorder, biologists have estimated that 98 percent of disease is caused by something wrong in the proteins that genes produce.
So, in this era of molecular biology, oncology researchers are honing in on the proteins involved in the development and progression of cancer. Only by knowing the proteins altered, or responsible, for unrelenting cell growth can researchers control cancer. And turning cancer into a treatable, even preventable, disease is everyone's hope.
The hunt is on at The University of Texas M. D. Anderson Cancer Center to find such "markers" of cancer – a barcode of proteins or genes that identifies cells that have turned cancerous and gives hints as to how a patient's unique tumor can be treated.
These barcodes are expected to revolutionize cancer care, changing it from treatment based on a tumor's location in the body, to one that centers on an individual's unique cancer. A patient will not be just told that she has, say, breast cancer, but will be given a genetic/proteomic profile of her tumor, complete with a list of therapies shown to work with her subtype.
"In the next five to 10 years, proteins in a patient's tumor will tell us what is important to know about the nature of their cancer and how it should be treated, and gene and protein screens will be used to help direct therapy," says Gordon Mills, M.D., Ph.D., chair of the Department of Molecular Therapeutics.
"This truly will bring individualized treatment to oncology," he says, "and that will bring us closer to our ultimate goal – finding cancer early when it is most curable or making the disease one that can be chronically treated, manageable for many years."
The promise – and the problems
The idea that specific genes and proteins can be used to diagnose cancer and dictate treatment is an immensely exciting notion to cancer clinicians and researchers. Markers are "the apple pie and motherhood of molecular cancer research," says M. D. Anderson's top pathologist, Stanley Hamilton, M.D., head of the Division of Pathology and Laboratory Medicine. "And perhaps even more than genes, proteins are the ultimate participants in the molecular processes important to cancer."
But even as scientists work long and hard to find the specific genes and proteins that signify, say, prostate cancer that will spread, or breast tumors that will remain benign, they know they have a long row to hoe.
Although the 45,000 or so genes in a human cell have been catalogued, scientists do not know the function of most of the genes. The proteins that genes produce are even more mysterious: researchers estimate that each gene can give instructions for as many as 100 different proteins.
Worse still, investigators are finding that the biology of a cancer cell is changeable, so that genes and proteins found to be switched on in a cancer cell one day may not be active the next day. For example, when a chemotherapy drug shuts down one crucial molecular "pathway" of protein in a tumor, other redundant pathways may take over.
When Hamilton looked at what happened to genes in colon cancer cells after exposure to the common chemotherapy drug 5FU, he saw "an astounding change in gene response – 500 genes showed alterations, and 15 percent of all genes in the cell changed their response in a three-day period," he says. "Cancer cells don't sit by and let themselves be killed. They respond with an absolute ballet of protein molecules handing off functions to one another."
Hamilton says that despite the spate of studies being published that identify markers of interest, most have not been validated. "The markers are just not good enough yet," he says. "The studies may show they are highly biologically significant, but not clinically significant."
Scientists want something as effective as a pregnancy test to diagnose cancer, "but that is not happening yet, and it won't be anything we will have in the next two to five years," he says.
Still, the field is buoyed by success stories, such as the drug Gleevec, which is designed to shut down the crucial genetic/protein pathway involved in chronic myeloid leukemia and another rare cancer of the gastrointestinal tract, called gastrointestinal stromal tumor. Herceptin treats metastatic breast cancer that is driven by a gene known as HER2 that produces too much of a protein that tells cells to divide. Proteins found to be markers of these cancers also proved to be the switch that could turn the disease off.
So now researchers are using the most advanced techniques, such as DNA microarrays and proteomic technology, to find those genes and proteins that are specific to cancer, and that may offer a potential target for drug treatment.
At M. D. Anderson, those investigations are under way in many different types of cancer, and progress has been reported in some of the most common, as well as the most dangerous, types.
For example, the potential of proteins to flag disease made international news in 2002 when a team of researchers that included Mills showed that a palette of just five proteins could identify patients with known ovarian cancer.
Using a drop of blood from 116 women, the researchers correctly identified all of the 50 women who had ovarian cancer, as well as the lack of cancer in 63 of 66 healthy women.
The advance, reported in the British journal The Lancet, was exciting to researchers as well as the public because it offered a new future for one of the most deadly of cancers. Like lung cancer, ovarian cancer is unusually deadly because it is most often detected at a late, difficult to treat stage. If diagnosed before symptoms appear, perhaps by a blood test, however, the cancer is much more treatable.
But the researchers, who also hailed from the National Cancer Institute (NCI), the Food and Drug Administration (FDA), and Northwestern University in Chicago, say they don't yet know what the proteins are or how they even function in a tumor.
Still, the work is so suggestive that Mills and researchers at the NCI and Northwestern are using the protein combination to see if it can detect ovarian cancer patients at several institutions. That study, soon to be completed, will likely be followed by a prospective multicenter clinical trial to validate the proteomics approach to diagnosing ovarian cancer.
"Our goal is to find and classify patterns of protein changes that we can use to detect and predict cancer and other diseases," Mills says.
Subtypes of colon, lung cancer
As more and more subtypes of cancer are discovered, the need for biomolecular markers has become clearer and more urgent, M. D. Anderson researchers say.
Colon cancer is a good example of tumor diversity. It is not just one uniform disease; there are many subtypes that behave in biologically different ways, and some are more prone to spread than others.
Figuring out which colon cancer is more or less dangerous has been the research focus of Robert Bresalier, M.D., professor and chairman of the Department of Gastrointestinal Medicine and Nutrition in the Division of Internal Medicine.
Such knowledge, Bresalier believes, may pave the way to improved diagnosis and therapy. So far, the pursuit has resulted in "substantial progress in finding sensitive, clinically useful biomarkers," he says.
Bresalier and his colleagues have found several proteins associated with colon cancer metastasis, and early laboratory, tissue-based studies indicate they can use protein screens to correctly pick out cancers that have metastasized from those that have not.
One protein, galectin-3, known to act as a kind of biological glue that helps cells stick together, "looks quite good as a potential marker for colon cancer," Bresalier says. Another family of proteins, called mucins, are over produced in most colon cancers, but Bresalier has found that tumors in the colon that produce specific mucin subtypes are associated with a worse prognosis.
"Our department is working at a variety of levels to identify markers, including these two, to help us detect colon cancer earlier and to refine our ability to determine prognosis," he says. "Although the data we have so far are exciting, they are preliminary. There are no magic bullets yet."
Lung cancer may also be "100 different diseases" and the only way to determine which type of tumor a patient has is to use biomarkers, says Li Mao, M.D., an associate professor in Thoracic Head and Neck Medical Oncology Research.
Mao and his colleagues found molecular evidence that former smokers are still at high risk for developing lung cancer. In studying the genetic effects of tobacco smoke on the lung tissue of chronic smokers, researchers found genetic damage in the lungs of 82 percent of current smokers and 62 percent of former smokers. Such damage may lead to lung cancer.
Because it is difficult to take tissue from patients' lungs to determine their risk of developing lung cancer, Mao is working at pinpointing proteins in a simple blood sample that signify development of the disease from premalignant lesions.
"We have found that a single protein marker may not do the whole job," says Mao, "so now we are looking at a panel of molecules combined together that can give us more predictive powers." His team also is looking for markers of head and neck cancer, which also is strongly associated with smoking.
Eventually, a drop of blood from a smoker or former smoker could "predict lung and head and neck cancer risk as well as optimal treatment, possibly within a decade," says Mao. "To do a good biomarkers study, you must have a very strong clinical base, and that is the advantage we have at M. D. Anderson."
Proteins and genes involved in breast cancer
Breast cancer researchers at M. D. Anderson are using both proteins and genes to help determine which therapy will work best in patients – before they even begin any treatment.
In one landmark study, researchers demonstrated that they might be able to predict which women with early stage breast cancer could be cured by using a particular chemotherapy treatment before surgery.
The study, led by Lajos Pusztai, M.D., Ph.D., an assistant professor of Breast Medical Oncology, is one of the first to show that a genetic profile of a breast cancer tumor can help direct therapy.
This potentially represents a big step forward toward "personalized medicine," says Pusztai. "If these results continue to hold up in larger validation studies, they can fundamentally change the way that chemotherapy is selected for patients."
Using breast cancer cells taken from 24 early stage breast cancers, Pusztai and his colleagues discovered 74 genes associated with a cure when a common chemotherapy regimen known as Paclitaxel/FAC was used. From those genes, they created markers to predict the outcome in 21 newly diagnosed patients and found the test was 75 percent accurate in forecasting which women would respond to FAC. Now the investigators are testing the gene screen in a larger randomized study at M. D. Anderson. If this study validates the utility of the gene screen, a predictive test may be available for widespread use in two to three years, Pusztai says.
He adds that he expects the test to be over 80 percent accurate.
Eventually, the researchers want to develop a palette of tests that will predict outcomes from a number of different chemotherapy regimens, he says. "We want to be able to select from a large number of seemingly appropriate chemotherapy choices the regimen that is most likely to cure an individual at the time of diagnosis," he says.
A different team of M. D. Anderson researchers is studying the power of a protein to help doctors decide if breast cancer patients even need such chemotherapy – or if they need much more aggressive therapy.
In a study of about 400 patients reported in the New England Journal of Medicine, the scientists found those with high levels of a protein called cyclin E were significantly more likely to have an aggressive, invasive breast cancer. The protein, which is involved in regulation of a cell's living cycle, appears to be a much better predictor of patient outcome than any current predictive marker, says the study leader, Khandan Keyomarsi, Ph.D., associate professor in Experimental Radiation Oncology.
Currently, the prognosis for women diagnosed with breast cancer is determined by assessing whether tumor cells have spread to lymph nodes. But some women who have cancer cells in the lymph nodes never have a recurrence, while others whose cancer has not spread do have a recurrence. Yet many women undergo chemotherapy because of the uncertainty of their prognosis.
If an accurate predictive marker were available, many women could be spared chemotherapy, Keyomarsi says, but adds that the finding must be validated in larger clinical studies. She also is working on methods to prevent generation of excess cyclin E as a way to prevent a cancer from becoming aggressive.
"My hope is that this technique may help ease the burden of chemotherapy among breast cancer patients," she says.
Mills, who helped develop the ovarian protein test, is currently collaborating with Francisco Esteva, M.D., Ph.D., an assistant professor in Breast Medical Oncology, and Ryuji Kobayashi, Ph.D., a professor in Experimental Pathology, and colleagues at a number of other institutions, to look for novel breast cancer markers that could include proteins, lipids, genes and other molecules associated with tumor cells. Early results in an ongoing study suggest that a panel of proteins is at least as effective as mammography in determining whether women have a breast abnormality, but "these results need to be compared with other ongoing studies," says Mills.
"There is real excitement in the potential of these protein tests," he says. "For a number of diseases, I think we can expect to have powerful diagnostic and predictive tests within a decade."
"We are early in this field, and its history has been a little optimistic," says Experimental Therapeutics Professor Walter Hittelman, Ph.D., a basic researcher who studies the potential of biomarkers to help thwart even the initial development of cancer. "There will be different rates of discovery for different types of cancer, but we are getting there."
This story has been adapted from a news release issued by University Of Texas M. D. Anderson Cancer Center.
OT: frog, the problem is that you are apparently not really interested in the truth. Are NOT are NOT are NOT! eom and end of conversation with you...
There again, why bother? What could somebody with your intellect do with their life if they put their mind to it? We'll probably never know...
Frog, well that's funny because you didn't disagree 18 months ago, and yes you can count on me correcting you when you are wrong. Let's see when we were in agreement:
Frogdreaming said "I was trying to suggest that it was possible to interpret the contract in such a way that would preclude any imminent deals in regard to Retinome. Therefore, any recent changes in the stock price might not be the result of a previously negotiated deal with a third party, as the board was speculating." Yes, I agree with you.
I can always resurrect the post concerned, blah blah blah...
Before they point it out the 6 month expiry applies assuming that DNAP notified Orchid of "new" intellectual property such as Retinome as it was developed. An assumption which is highly likely to be correct!
gunnabeoneday, about to pump some iron so will have to be quick. Frog didn't give you any answers? I am surprised because I know for a fact that he is fully acquainted with the terms of the option from previous RB postings.
I believe that the option does not apply to Retinome because there is a 6 month expiry (see below). Frog's point 2 is wrong IMHO. Yes, to point 3. Any product that involves funding from a third party is exempt from the Option.
Here is my understanding of the option process from a previous RB post (where I agreed with frogdreaming of all things). The clauses referred to are the actual clauses in the Option agreement taken from the relevant 10K. It is complicated and this is my interpretation which may be wrong, but I think it works this way:
DNAP notify Orchid of some new intellectual property (IP). Orchid may decline to exercise its option there and then, otherwise DNAP negotiate with Orchid for the transfer of the IP (starting within 90 days of Orchid exercising its option) and may not negotiate with any third-party without first negotiating with Orchid. These negotiations can last for a total elapsed time of 6 months (this would be 9 months elapsed time if DNAP drag their heels for 90 days before starting negotiations but there is no point in them doing this so in practice it should be 6 months only). DNAP can force Orchid to exercise its option at any time after it has disclosed the IP by giving 90 days prior written notice to Orchid. This seems to be a long stop to prevent Orchid from just not responding to the initial IP notification and delaying indefinitely the start of the 6 month negotiating period (note in practice Orchid can drag their heels and extend the negotiation elapsed time by 90 days but I do not think that it is in their interests to do so). Orchid may exercise its option to any IP not previously sold, licensed or partnered, at any time during the term of the agreement and for 25 years after (a long stop for Orchid which should never apply in practice).
If Orchid declines to negotiate, or the parties fail to execute a license or other agreement after 6 months of negotiations, DNAP may negotiate with third parties. On receipt of an offer for IP from a third party, DNAP make the same offer to Orchid who have 20 business days to accept or reject the offer. Orchid have to include equivalent terms to those made by the third party in any acceptance, and the independent valuation process related to this (which can entail a further 10 day delay) is described. If Orchid reject the offer then DNAP can proceed with the third party. Note that I think that clauses 8.5 and 8.7 in the agreement are saying the same thing and that the 20 business days in 8.5 is the same as the 30 days in 8.7. It seems (clause 8.6) that DNAP may accept a third party offer outright without reference to Orchid if the consideration is not less than Orchid’s last offer plus 50% of the difference between the last amount offered by Orchid and DNAP during negotiations. I assume that this is the case.
Hope this helps!
W2P, yes that just about covers it! Did you know that emails from company officials are not public statements? Perhaps one day soon we will get public confirmation from the company e.g.
DNAPrint™ genomics, Inc. Announces Option Transfer to Beckman Coulter
SARASOTA, Fl, April 1, 2004, DNAPrint™ genomics, Inc. (DNAP) in a stunning surprise announcement today revealed that an Option agreement it had previously signed with Orchid Biosciences, Inc. (Orchid) has been transferred to Beckman Coulter following the acquisition in December 2002 by Beckman of certain assets of Orchid's including SNP (single nucleotide polymorphism) genotyping instruments, bioinformatic software and related consumables business.
DNAPrint™ had the rights to license, sell or partner its products exclusively within the United States and abroad, subject to the terms of the option with Orchid. Under the terms of the agreement, Orchid provided DNAPrint™ an up-front payment for the option to negotiate exclusively for a license to co-develop and/or co-commercialize certain DNAPrint™ products in the future. The agreement provided DNAPrint™ with a potential distribution channel and applied to products DNAPrint™ was currently developing and will develop in the near future.
"We are delighted that the Option has been transferred and are extremely excited about the prospects for DNAPrint™ now that this transfer has taken place," said Richard Gabriel, CEO and President of DNAPrint.
"This transfer marks the start of a new phase of development for the company. DNAPrint™ is now poised to make a significant contribution to the upcoming era of personalized medicine", said Hector J. Gomez, MD, PhD, and Chairman of the Company’s Board.
"This transaction recognizes the value of companies like DNAPrint – companies that are not afraid to take scientific risks, companies that develop technologies that are neglected or unforeseen by others, and companies that devote their efforts to rapidly commercializing products for underserved markets”, said Tony Frudakis, Founder and CSO.
Well maybe not, perhaps they have better things to do with their time...
gunnabeoneday, to get back to your excellent points which nearly got lost.
There are probably several reasons why large pharma's have not partnered with DNAP, different sets of reasons applying in different cases I would think. Candidate reasons have been discussed many times over the years and no doubt range from DNAP not wanting to give their technology away, and hence refusing lowball bids, to large pharma having a (mis)conception that it is not in their interests to segment the market for their products. The latter is probably a big factor, although we can see already that there will be pressure longer term for them to adopt pharmacogenomics, and several are already dipping their toes in the water (the people who run drug companies may be evil but they are not stupid). We do not know what discussions have taken place with third parties, or even whether deals have been struck and not yet anounced, and so can only speculate at this stage.
Other companies would typically not offer funding as such, but would rather look to acquire our technology. One probable reason that this has not happened is that any offer would again be in the lowball category. It is well known that big pharma tries to "steal" this sort of technology before acquiring it via a legitimate bid that is acceptable to shareholders of the company holding the intellectual property.
The option is indeed not applicable in the scenario that you mention.
mahastock thanks, I couldn't remember who posted it. So, the "fact" that you posted frog: "There has not been a public announcement from DNAP regarding the change of ownership of the option" is wrong is it not? This is not the only "fact" that I believe is wrong BTW. So, no, I do not agree with you.
Let's be quite clear about this. The only relationship I have with DNAP, and the only source of information that is not public domain, is by virtue of being one of the partcipants in the PP. Everybody else who is in the same category is, like myself, bound by the terms of the non-disclosure agreement that we signed. End of story.
Unless my memory fails me somebody posted an email from the company the other day in which they confirmed the fact that the option agreement had transferred to Beckman Coulter...
1USGrant, let's hope it's an opinion also shared by the moderators. Frogdreaming fits comfortably into the "disruptive" category IMO.
These are not the facts, as I suspect you know. The palpable desperation in your posts betrays an ulterior motive IMHO.
Not objective and unbiased? BS I refuse to rise to your bait Toad.
stakddek, I think what we are seeing here is illustrative of the fact that DNAP's technology is based on leading edge basic science, and that the people associated with the company (Shriver, Chakraborty, McKeigue, etc) are key players in the field. I also think that there is a misconception about just how far ahead we potentially are when NIH funded projects that have recently begun have as their objectives results that we have ostensibly already achieved. The issue I have is why we are not recipients of NIH funding - I think part of the reason for this is a bias against industry in favor of academia, which is in some ways understandable but also unfortunate in its ramifications. I am not sure to what extent, or if, we are involved in any of these projects; but I have my own views. I personally tend towards the view that our technology is increasingly integral to a lot of these efforts. Time will tell.
OT: Very familiar with ADZR. There seems to be a bit of a push on this one lately. Of course one view is that the big rise has already taken place...
66fan, we have looked at Julie before:
http://www.medicine.ufl.edu/cardio/research/biomarker/JulieBio.shtml
http://www.orchid.com/news/view_pr.asp?ID=231
http://pharmacy.ouhsc.edu/academics/lecture/ashby/jjohnson.asp
http://www.hum-molgen.de/meetings/meetings/1828.html
Johnson JA. Pharmacogenetics: potential for individualized drug therapy through genetics. Trends Genet. 2003 Nov;19(11):660-6.
Johnson JA, Evans WE. Molecular diagnostics as a predictive tool: genetics of drug efficacy and toxicity. Trends Mol Med. 2002 Jun;8(6):300-5. Review.
Evans WE, Johnson JA. Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu Rev Genomics Hum Genet. 2001;2:9-39. Review.
She has also been in the press recently:
http://www.ascpt.org/press/2004/2004Johnson.htm
Johnson's work focuses on cardiovascular disease-gene associations and the influence of race and ethnicity on drug responses. She investigates hypertension, heart failure, ischemic heart disease and obesity focusing on the proteins that drugs target and the impact of genetics on drug responses.
Wouldn't surprise me if there was a connection here...
And then of course there is:
Grant Number: 1R01HL074753-01
PI Name: SCHAEFER, ERNST J.
PI Email: ernst.schaefer@tufts.edu
PI Title: PROFESSOR
Project Title: Pharmacogenetics of the Statin Response
Abstract: DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is the leading cause of death and disability in our society. Most CHD deaths occur in subjects over 70 years of age. Significant independent CHD risk factors are age, gender, elevated low density lipoprotein (LDL) cholesterol (C), decreased high density lipoprotein (HDL) C, hypertension, smoking, diabetes, elevated lipoprotein (a) or Lp(a) (LDL C> 50% reduction), and elevated C-reactive protein. In this response to RFA HL-03-001 (ancillary pharmacogenetic studies), we propose to study 2804 male and 3000 female participants in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), who were selected for age 70-82 years, having vascular disease coronary, cerebral or peripheral) or increased CHD risk due to smoking, hypertension or diabetes and total cholesterol levels between 4.0 and 9.0 mml/L or 151 and 340 mg/dl. In this randomized controlled trial pravastatin decreased LDL C 34% and triglyceride 12% and raised HDL C 5%. C-reactive protein and Lp(a) values have already been measured. Fatal and nonfatal myocardial infarction (MI) were decreased by 19%, and fatal MI 24%, but increased risk of new cancer were noted in the pravastatin group over 3.2 years as compared to the placebo group (all p<0.01) (Lancet 360: 1623-30, 2002). Benefit was greatest in subjects with low HDL C (<1.1 lmml/L or 43 mg/dl). No benefit of pravastatin versus placebo on cognitive function or stroke was noted. We and others have shown that statins increase large alpha 1 migrating apolipoprotein A-I containing HDL, decrease plasma lathosterol, a marker of cholesterol synthesis, and increase plasma betasitosterol, a marker of cholesterol absorption as well as decrease cholesterol ester transfer protein (CETP) mass. We propose to measure HDL subspecies, CETP mass, lathosterol, and beta-sitosterol in the 292 subjects who developed CHD while on pravastatin and in a control group (n=292) who did not develop CHD on pravastatin. We propose to isolate DNA in all subjects, carry out sequencing for single nucleotide polymorphism detection in 5 male and 5 female hyper-responders and the same number of hypo-responders (LDL C <10% reduction) and then genotyping at all SNPs on the two 292 patients groups, and the informative SNP detection on the entire 5804 cohort at the following gene loci: ATP binding cassette transporters G5 and G8 (ABCG5, ABCG8), CETP; HMG CoA reductase, apolipoprotein E, lipoprotein and hepatic lipase, microsomal transfer protein, C-reactive protein, connexin, plasminogen activator type I inhibitor and stromelysin I. These genes have been selected because of our own preliminary studies, and their known key role in cholesterol absorption and lipoprotein metabolism or CHD. We hypothesize that response to pravastatin in terms of lowering of LDL C, triglycerides and C-reactive protein, and HDL C raising will be related to specific genotypes and haplotypes. We also hypothesize that subjects with the greatest LDL C- and C-reactive protein-lowering, the greatest increase in large alpha HDL particles, the greatest reduction in lathosterol and the least increase in beta-sitosterol will have the greatest benefit in CHD risk reduction, and that these changes will be related to specific genotypes and haplotypes of the candidate genes being examined. These results can be used to formulate guidelines for identifying elderly subjects for statin treatment to prevent future CHD.
Thesaurus Terms:
antihypercholesterolemic agent, coronary disorder, high density lipoprotein, naphthalene, pharmacogenetics
allele, apolipoprotein, cholesterol, gene frequency, genetic polymorphism, lipid metabolism, sitosterol
clinical research, genotype, human genetic material tag, nucleic acid purification, nucleic acid sequence, statistics /biometry, two dimensional gel electrophoresis
Institution: TUFTS UNIVERSITY BOSTON BOSTON, MA 02111
Fiscal Year: 2003
Department: NONE
Project Start: 29-SEP-2003
Project End: 31-AUG-2007
ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG: ZHL1
bag8ger, all of the projects are interesting in and of themselves. It would be interesting to know how many of them (if any) we are involved in, or what the implications of some of them are for our platform and some of our products. I do not know what prompted Mark Shriver to contact DNAP, only that (as per http://www.dnaprint.com/pr_7_10.htm ):
The impetus for the alliance was DNAPrint's recent success in developing complex genetics classifiers for the inference of human iris and hair color. "DNAPrint's work in the pigmentation field is innovative, and their results to date are compelling," said Mark Shriver, Assistant Professor of Anthropology and Genetics at PSU. "We have been conducting skin pigmentation research for some time at PSU, but we suggested an alliance because we felt a team effort would be the most efficient means by which to finally solve this fascinating puzzle."
BTW, does this picture correspond with the other view of "reality" that is propounded in some quarters?
Perhaps IFIDA can add something in this context, as he has had more historical contact with Mark Shriver than others...
I agree with you point about DNAP/Shriver holding a remarkable position. These projects are all current (even though some have been running for some time), and it seems that in some cases the work we have done is more advanced.
bag8ger, loathe as I am to discuss the LSHTM's ADMIXMAP PROGRAM (given the propensity of certain idiots to try to confuse people), the simple answer is that allele frequencies in the subpopulations under investigation is one of the inputs provided by the user of the program. The program itself is available via the web for anyone to download and use, although the LSHTM suggest that prospective users contact them first to discuss their requirements.
Some detail on the last project
http://www.cancer.mgh.harvard.edu/cancer_specialist_seiden.htm
http://www.genitrix.com/Website-PR%2010-15-03.html
Dr. Seiden serves as Chairman of the MGH Cancer Center Clinical Protocol Committee, as well as Chairman of the Dana Farber-Harvard Gynecologic Oncology Research Committee. He has published over 50 research articles and currently serves as Principal Investigator on 16 clinical and basic research projects. Dr. Seiden's administrative appointments have included Deputy Chief of Hematology/Oncology at MGH, Clinical Director of the MGH Center for Cancer Risk Analysis, Chairman of the Dana Farber Ovarian Carcinoma Immunotherapy Committee, and Director of the MGH/Brigham and Women's Oncology Fellowship Program. He serves as Assistant Professor of Medicine at Harvard Medical School. Dr. Seiden received his M.D. and Ph.D. degrees from Washington University, served as Chief Resident in Medicine at MGH, and completed fellowships at Dana Farber and the Brigham and Women's Hospital.
http://www.mgh.harvard.edu/pathology/pathology_services_SURGICAL_obstetric.htm
Dr. Esther Oliva has been appointed as a key co-investigator for an R01 NCI (R01-CA89150-01) (3 years) grant entitled “Identification of taxol resistance genes” collaborating with the Cancer Center, a consortium between the Massachusetts General Hospital, Dana Farber Cancer Institute and Brigham and Women’s Hospital, Dr. Michael Seiden being the principal investigator. In that study they are evaluating the potential role of the multi-drug resistance protein (MDAR-1) and other molecules known to be associated with drug resistance in predicting the clinical response of women with ovarian cancer to chemotherapy. They are studying paired tumor samples obtained from our tumor bank (Expression of multidrug resistance-1 (MDR-1) correlates with plalitaxel response in ovarian cancer patients. Penson RT, Oliva E, Skates SJ, Glyptis T, Fuller AF, Goodman AK, Nikrui N, Seiden MV. Cancer , in press.
From PubMed:
Duan Z, Duan Y, Lamendola DE, Yusuf RZ, Naeem R, Penson RT, Seiden MV. Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines. Clin Cancer Res. 2003 Jul;9(7):2778-85.
Lamendola DE, Duan Z, Yusuf RZ, Seiden MV. Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line. Cancer Res. 2003 May 1;63(9):2200-5.
Lamendola DE, Duan Z, Penson RT, Oliva E, Seiden MV. Beta tubulin mutations are rare in human ovarian carcinoma. Anticancer Res. 2003 Jan-Feb;23(1B):681-6.
Yusuf RZ, Duan Z, Lamendola DE, Penson RT, Seiden MV. Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets. 2003 Feb;3(1):1-19. Review.
Seiden MV, Swenerton KD, Matulonis U, Campos S, Rose P, Batist G, Ette E, Garg V, Fuller A, Harding MW, Charpentier D. A phase II study of the MDR inhibitor biricodar (INCEL, VX-710) and paclitaxel in women with advanced ovarian cancer refractory to paclitaxel therapy. Gynecol Oncol. 2002 Sep;86(3):302-10.
Duan Z, Lamendola DE, Yusuf RZ, Penson RT, Preffer FI, Seiden MV. Overexpression of human phosphoglycerate kinase 1 (PGK1) induces a multidrug resistance phenotype. Anticancer Res. 2002 Jul-Aug;22(4):1933-41.
Duan Z, Lamendola DE, Penson RT, Kronish KM, Seiden MV. Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells. Cytokine. 2002 Mar 7;17(5):234-42.
Penson RT, Kronish K, Duan Z, Feller AJ, Stark P, Cook SE, Duska LR, Fuller AF, Goodman AK, Nikrui N, MacNeill KM, Matulonis UA, Preffer FI, Seiden MV. Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. Int J Gynecol Cancer. 2000 Jan;10(1):33-41.
Duan Z, Feller AJ, Penson RT, Chabner BA, Seiden MV. Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype. Clin Cancer Res. 1999 Nov;5(11):3445-53.
Duan Z, Feller AJ, Toh HC, Makastorsis T, Seiden MV. TRAG-3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line. Gene. 1999 Mar 18;229(1-2):75-81.
What about this:
Grant Number: 5R01CA089150-03
PI Name: SEIDEN, MICHAEL V.
PI Email: mseiden@partners.org
PI Title: ASSOCIATE PHYSICIAN
Project Title: IDENTIFICATION OF PACLITAXEL RESISTANCE GENES
Abstract: The chemotherapeutic agent pacilitaxel (TaxolTM) plays an important role in the treatment of breast and ovarian carcinoma. Unfortunately acquired resistance to paclitaxel limits the clinical efficacy of this agent in both malignancies. The molecular mechanisms of acquired paclitaxel resistance are due in part to over expression of the multi -drug-resistance- 1 (MDR-1)-mediated drug export pump. Several laboratory and clinical studies support the hypothesis that there are additional mechanisms of acquired paclitaxel resistance in clinical cancers. Work in my laboratory has focused on identifying genes important in producing the paclitaxel resistance phenotype. Initial studies using the differential display technique and cDNA array technology identified several genes not previously associated with the paclitaxel resistance the functional role of these genes in directly inducing the paclitaxel resistant phenotype remained unclear. To increase the likelihood of identifying functionally important genes in the paclitaxel phenotype we have designed a functional cloning strategy to identify Taxol-Resistance-Inducing Genes or TRIGs. Specifically, cDNA from paclitaxel-resistant breast and ovarian cancer cell lines have been cloned into plasmids to form expression libraries designed to identify genes that are directly involved in the paclitaxel resistant phenotype. Care has been taken to select paclitaxel resistant lines that do not over express MDR-1. Preliminary functional cloning experiments have already identified one gene, TRIC-1, than when retransfected into a paclitaxel sensitive line generate not only a paclitaxel resistance, but also a multi-drug resistant phenotype that is independent of MDR-1 over expression. In addition, the principal investigator has accessed to a large ample set of both women with advance breast cancer and Taxol resistant ovarian cancer. The specific aims of this grant proposal will include: 1) the further characterization of genes identified through this functional cloning technique; 2) the further characterization of the TRIG-1 gene; 3) correlation of TRIC and MDR-1 expression with clinical, this will include correlation of response to neoadjuvant paclitaxel with TRIC/MDR-1 expression in locally advanced breast cancer and response to paclitaxel (with or without vx-710 (an MDR-1 inhibitor)) in women with recurrent ovarian cancer. When completed this analysis should both expand the list of molecules directly involved in the paclitaxel resistance phenotype and, most importantly, focus attention on those molecules directly involved in paclitaxel resistance in the clinical setting.
Thesaurus Terms:
breast neoplasm, multidrug resistance, ovary neoplasm, paclitaxel, phosphoglycerate kinase
complementary DNA, enzyme activity, recombinant protein
clinical research, expression cloning, female, human subject, in situ hybridization, patient oriented research, polymerase chain reaction, women's health
Institution: MASSACHUSETTS GENERAL HOSPITAL 55 FRUIT ST BOSTON, MA 02114
Fiscal Year: 2003
Department:
Project Start: 14-MAR-2001
Project End: 28-FEB-2004
ICD: NATIONAL CANCER INSTITUTE
IRG: ZRG1
How about this one:
Grant Number: 5R01MH060343-03
PI Name: MCKEIGUE, PAUL M.
PI Email: paul.mckeigue@ucd.ie
PI Title:
Project Title: GENES UNDERLYING ETHNIC DIFFERENCES IN DISEASE RISK
Abstract: The objective of this project is to develop statistical methods and markers for mapping genes that underlie ethnic differences in disease risk, based on a novel approach that exploits the autocorrelation of ancestry on chromosomes of mixed descent in a manner analogous to linkage analysis of an experimental cross. This has obvious applications to investigating the genetic basis of conditions such as hypertension, Type 2 diabetes and systemic lupus erythematosus in the USA and other countries where there has been recent admixture between ethnic groups that have different risks of disease for genetic reasons. The development of the statistical analysis program will rely on methods developed for "missing data" problems, using Markov chain simulation to generate the posterior distribution of ancestry at each locus given the observed marker data at all loci. A score test for linkage will be obtained by averaging over this posterior distribution. Extensive tuning of the algorithms will be required to ensure that the the statistical methods are robust over all models and data structures that are likely to arise in practice. The development of the marker sets will extend the work already in progress in Shriver's lab, based on screening SNP libraries and using subtractive hybridization to identify population-specific alleles. As the marker set is developed, the multipoint analysis program will be used to plot the information content for ancestry extracted by the marker set and to identify areas where additional markers are required to meet the target of extracting 80 percent information about ancestry in an initial genome searches. The program and the markers will be beta-tested on data from studies in admixed populations now under way in the USA, the Caribbean, and Australia The program will be made publicly available via the web.
Thesaurus Terms:
genetic marker, genetic susceptibility, human population genetics, linkage mapping, racial /ethnic difference
Internet, data collection methodology /evaluation, family genetics, genetic screening
Australia, Caribbean island, clinical research, human data, human genetic material tag, single nucleotide polymorphism
Institution: U OF L LONDON SCH/HYGIENE & TROPICAL MED HYGIENE & TROPICAL MED LONDON,
Fiscal Year: 2002
Department:
Project Start: 01-JUN-2000
Project End: 31-MAY-2004
ICD: NATIONAL INSTITUTE OF MENTAL HEALTH
IRG: GNM
BTW, I highlighted the piece above mainly for the benefit of those who (wilfully) fail to understand the relationship between Shriver and McKeigue.
But this one does:
Grant Number: 2R01GM041399-13
PI Name: CHAKRABORTY, RANAJIT
PI Email: ranajit.chakraborty@uc.edu
PI Title: ROBERT A KEHOE PROFESSOR AND DIRECTOR
Project Title: Population Mixture Effects on Genetic Variation
Abstract: DESCRIPTION (provided by applicant): As this project enters in its 14th year, the over-all objectives still remain the characterization of the effects of population mixtures on genetic variation, and differentiation of this from that of genetic linkage and past demographic changes. With introduction of newer laboratory and computational methods in genomic studies, it is now widely accepted that mapping of genes and their interactions with environmental/life style risk factors can be successfully conducted using population-based association study designs, with appropriate considerations of evolutionary factors that may affect association of genes at population level. Based on the past work done in this project and by other investigators, we propose to address the issues of effects of population mixtures on: (i) haploblock size and pattern; (ii) strategies for efficient choice of markers and marker densities; and (iii) methods of adjustments for cryptic differences of cases and controls, so as to make the association study designs cost-effective, and less prone to false positive results. Using analytical as well as computer simulations methods based on the theory of coalescence and diffusion models, we will examine the effects of SNP based studies on the inferences of the above issues. Finally, using the anonymous DNA repositories of our study team from five selected populations (two admixed - US African-Americans, and Mexican Mestizo from Nuevo Leon; two cosmopolitans - US Caucasians, and Chinese; and one small isolated population from Adriatic Islands of Croatia), we will generate empirical data on similarities/dissimilarities of the characteristics of haplotype/haploblocks and choice of markers for 2 to 3 selected regions of the genome, using both microsatellite and SNP a series of theoretical and empirical studies to investigate the effects of population admixture of properties of linkage disequilibrium and to develop better strategies for association mapping through LD. markers. Such data, in addition to the analytical and simulation work, will prescribe bounds for parameters under which mixed and/or non-equilibrium populations can be used for complex disease studies. The results of this project will aid (a) in developing strategies of mapping genes using repeat as well as SNP markers in populations of different mixture histories, and (b) in understanding the history and global spread of mutations underlying complex phenotypes.
Thesaurus Terms:
There are no thesaurus terms on file for this project.
Institution: UNIVERSITY OF CINCINNATI 2624 CLIFTON AVE CINCINNATI, OH 45221
Fiscal Year: 2004
Department: ENVIRONMENTAL HEALTH
Project Start: 01-APR-1990
Project End: 30-NOV-2007
ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
IRG: MGN
This one has no abstract unfortunately:
Grant Number: 5R01HG002154-03
PI Name: SHRIVER, MARK D.
PI Email: mds17@psu.edu
PI Title: ASSISTANT PROFESSOR
Project Title: CONSTRUCTION AND APPLICATION OF A US ADMIXTURE MAP
Abstract:
This abstract is not available.
Thesaurus Terms:
United States, gene expression, genetic disorder, genetic polymorphism, human population genetics, linkage mapping, phenotype, African American, Hispanic American, allele, gene frequency, genetic marker, linkage disequilibrium, quantitative trait loci, genotype, human data, human genetic material tag, polymerase chain reaction, restriction fragment length polymorphism, statistics /biometry
Institution: PENNSYLVANIA STATE UNIVERSITY-UNIV PARK 201 OLD MAIN UNIVERSITY PARK, PA 16802
Fiscal Year: 2001
Department: ANTHROPOLOGY
Project Start: 24-SEP-1999
Project End: 31-MAY-2004
ICD: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
IRG: GNM
Here's an interesting NIH grant:
Grant Number: 1R01HL074730-01
PI Name: JOHNSON, JULIE A.
PI Email: johnson@cop.ufl.edu
PI Title: PROFESSOR OF PHARMACY PRACTICE & MEDICIN
Project Title: Hypertension Pharmacogenetics
Abstract: DESCRIPTION (provided by applicant): Hypertension (HTN) is the most common chronic disease in the United States, and is a leading cause of stroke, acute myocardial infarction (MI), heart failure and kidney failure. There are numerous effective antihypertensive drug classes, but only about half of patients have a good response to any given drug. Pharmacogenetics might significantly improve BP control and outcomes, as genetically-guided drug therapy selection could dramatically increase the number of patients who receive the best drug for their HTN. We propose to test pharmacogenetic hypotheses that center on BP response and outcomes (death, MI, stroke) in HTN, using 5,871 genomic DNA samples we have collected from participants in INVEST, a large, international trial in patients with HTN and ischemic heart disease. We propose to test the following hypotheses: Hypothesis 1: Genetic variability in the proteins important to verapamil's pharmacologic action contribute to interpatient variability in verapamil's antihypertensive effect. Specific Aim 1A. Identify sequence variability in the genes for the major L-type Ca channel (LTCC) subunits alpha1C and beta, the sarcoplasmlc retlculum Ca2+-ATPase 2, the Ca2+-activated K channel, and critical portions of the ryanodine receptor by resequencing the genes in Corriel DNA from 60 individuals. Predict those polymorphisms most likely to be functionally significant using various bioinformatics techniques. Specific Aim lB. Perform in vitro functional studies, including ion channel patch-clamp studies, to test for functional significance of polymorphisms in the LTCC a1C subunit. Specific Aim 1C. Determine the association between verapamil's antihypertensive effect and genetic polymorphisms of interest, as identified in Aim 1A. Hypothesis 2: Antihypertensives that target the underlying molecular/genetic basis of a patient's HTN will result in better outcomes than antihypertensives that do not target the underlying pathophysiology. Specific Aim 2. Determine whether drug therapy that is targeted at a "drug response" polymorphism or haplotype results in better patient outcomes (specifically fewer deaths, strokes, MIs) than therapy that does not target the "drug response" polymorphism(s). This hypothesis will be tested for all four study drugs: atenolol, verapamil, hydrochlorothiazide and trandolapril. Because of the diversity of the INVEST genetics sample (47% Hispanic (mostly Puerto Ricans), 38% Caucasian and 11% African American), we will test Hypothesis 3: Use of molecular markers to define genetic heterogeneity in the study population is superior to race/ethnicity information in genetic associations with drug response. Specific Aim 3A. Determine whether models of genetic association with drug response perform better with use of genetic marker-defined population cluster and individual ancestral proportion information than with clinician-defined information on race/ethnicity. Specific Aim 3B. Document that any positive associations between drug response and genotype are not the result of population stratification or admixture. These aims will be accomplished by genotyping patients for at least 50 Ancestral Informative Markers. The proposed studies will provide considerable new evidence regarding the pharmacogenetics of verapamil, and will significantly further our understanding of the pharmacogenetics of p-blockers, thiazide diuretics, and ACE inhibitors. They will substantially enhance our understanding of the genetic variability in proteins important to Ca ++ regulation and response to CCBs and other drugs, and the functional significance of this genetic variability. Finally, the proposed studies will increase our understanding of the role of molecular markers for defining population stratification and admixture in pharmacogenetic studies. The proposed studies should add substantial new information about antihypertensive pharmacogenetics, and could influence how antihypertensive medications are prescribed in the future.
Thesaurus Terms:
blood pressure, cardiovascular disorder chemotherapy, human therapy evaluation, hypertension, pharmacogenetics, pharmacokinetics, antihypertensive agent, biomarker, calcium channel, cardiovascular pharmacology, gene frequency, genetic polymorphism, genetic susceptibility, linkage disequilibrium, mathematics, outcomes research, potassium channel, clinical research, genetic mapping, genotype, high throughput technology, human genetic material tag, informatics, nucleic acid sequence, site directed mutagenesis, voltage /patch clamp
Institution: UNIVERSITY OF FLORIDA GAINESVILLE, FL 32611
Fiscal Year: 2003
Department: PHARMACY PRACTICE
Project Start: 26-SEP-2003
Project End: 31-AUG-2007
ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG: ZHL1
Ancestral Informative Markers eh?
Mark Shriver
Mark is one of the External Faculty for this Short Course on Statistical Genetics for Obesity and Nutrition Researchers:
http://www.soph.uab.edu/ssg_content.asp?id=1227
Tentative Schedule:
April 20, 2004 8:00 a.m. to 12:00 noon
Nancy Cox, Varghese George
Introduction to Biostatistical Methods in Genetic Analysis
April 20, 2004 1:30 p.m. to 5:00 p.m.
Robert Elston, Carl Langefeld
Linkage Analysis, Allele Sharing & Haplotype Methods
April 21, 2004 8:00 a.m. to 12:00 noon
Warren Ewens, Kathryn Roeder, Mark Shriver
TDT, Genomic Control, Admixture Mapping
April 21, 2004 1:30 p.m. to 5:00 p.m.
David Allison, Susan Hilsenbeck, Grier Page
Microarray, Proteomics and High Dimensional Analysis
Some interesting people. BTW, David Allison was one of the authors of this paper:
Fernandez JR, Shriver MD, Beasley TM, Rafla-Demetrious N, Parra E, Albu J, Nicklas B, Ryan AS, McKeigue PM, Hoggart CL, Weinsier RL, Allison DB. Association of African genetic admixture with resting metabolic rate and obesity among women. Obes Res. 2003 Jul;11(7):904-11.
Here is the Full List of External Rotating Faculty for these annual courses:
http://www.soph.uab.edu/ssg_content.asp?id=1175
A couple of names stand out here: Paul McKeigue and DC Rao (not to mention the DNA Forensics expert Bruce Weir). The point is that if some of these people are strongly connected to Mark Shriver (if not DNAP) then perhaps some of the other names have some connection as well?
bag8ger I cannot profess to having more than a passing acquaintance with project 6, which seems to be related to assays tangentially connected to project 3. The project 6 initiatives though seem to have run into some difficulties:
"...however the results obtained were not as reliable as the visual score in cytokinesis-blocked lymphocytes. For this reason the patent was allowed to lapse."
"Novel chromophores were produced and provisional patents filed. The chromophores that were produced had some useful spectral characteristics and are useful for research purposes, however they were unable to compete with novel products that are now available in the market. Therefore the project has now been discontinued."
bag8ger, we will have to see who is doing what with whom!
A reminder of a similar initiative
http://www.vu.edu.au/library/pdf/default/Biomed_Postgrad_Projects_03.pdf
FORENSIC SCIENCE: CAN DNA BE MADE TO SERVE AS AN “EYE-WITNESS”?
Dr Swati Baindur Hudson Dr. Roland van Oorschot,(Victorian Forensic Science Centre)
Forensic science is used to investigate violent crimes such as assault, murder and rape as well as for other crimes such as smuggling and embezzling. It encompasses a broad range of sciences including pathology, fingerprinting, ballistics and DNA profiling or typing. DNA typing profiles from samples at a crime scene are compared with genetic profiles of suspects or of convicted criminals. The majority of DNA typing uses short tandem repeats (STRs) that constitute certain non-coding regions of the human genome. These typing results do not reveal any information regarding the physical characteristics of a person (except for gender). If there are no eye-witnesses to a crime, or other clues about the identity of the suspect, what sort of person should the police start looking for?
The long-term aims of this project arise from the question, “Can DNA from samples left at the scene of a crime be used to create an “identikit”? We are investigating this possibility through use of known genetic information about certain characteristics. These characteristics necessarily have to be related to the physical appearance of a person. Characteristics such as height, weight, age, colour of the hair and eyes, attached earlobes, right or left-handedness, etc, would be useful to look at. However, not all these traits can be predicted from DNA alone, as they may either be multi-gene determined or strongly influenced by environmental conditions. One area of our investigations has focused on genes determining hair colour. The red hair phenotype has been linked to variations in the melanosome stimulating hormone receptor (MSHR) gene, and these studies are being extended to find links to eye and skin colour, and to another gene called the P-gene. However, the melanin synthesis pathway is complex and there are other candidate genes that may contribute to the various phenotypes, such as the microphthalmia and cKit genes. A company in the USA has been investigating the use of Single Nucleotide Polymorphisms (SNPs) inseveral genes to predict hair, eye and skin colour. We are in the process of establishing an international collaboration with them, which will lead to several research projects being available, of direct application to forensic investigations.
In addition, a pilot study has been carried out to investigate the use of telomere length variations to predict age. Telomeres are repeated DNA sequences that are added onto ends of chromosomes in humans with the help of the enzyme telomerase. As a person grows older, the length of these telomeres becomes shorter. At this stage, we do not know whether there is sufficient variation between age groups and not too much variation within age groups to allow us to use this phenomenon to predict age from DNA samples left at the scene of a crime. Mitochondrial DNA also accumulates mutations with age. These phenomena need further investigation. Other traits could be selected for study, provided there is enough starting genetic information about these traits and they are not strongly influenced by the environment. Several projects are possible in this area at honours, Masters or PhD levels.
Skills/knowledge required: Knowledge of biochemistry & molecular biology, some knowledge of human genetics, basic skills in PCR and gel electrophoresis techniques. Familiarity/ease with the use of computer databases in general would be useful.
Skills/knowledge acquired: Molecular techniques such as the Polymerase Chain Reaction (PCR), RealTime PCR, agarose & polyacrylamide gel electrophoresis, Southern blotting, probing with radioactive &non-radioactive labeled probes, DNA sequencing, searching and analysis of sequences using databases such as GenBank and EMBL, use and analysis of information from the Human Genome Project.
More detail on CRC projects
http://diagnosticscrc.org/CDxAdmin/AnnRep2003.pdf
HUMAN IDENTIFICATION MARKERS
PROJECT LEADER
QUT: Dr Angela van Daal and A/Prof Phillip Morris
RESEARCH STAFF
QML: Ms Sue White and Dr Lorraine Westacott
QUT: Drs Andrea Crampton, Richard Hodgson and Joanne Voisey; Mr Steven Brigg
The project also will involve other key collaborations outside the CDx: CRC-CHGD, QIMR, Queensland Department of Health, FBI and Royal Canadian Mounted Police. Diatech will also play a significant role through seeking the best partner for commercialisation.
BACKGROUND
The ability to DNA type evidence samples has revolutionised forensic science. Current methods utilise highly polymorphic, anonymous DNA markers and require a suspect to be identified for comparison. Knowledge of the molecular basis of human physical characteristics (such as hair colour, eye colour, height) would allow DNA analysis of an unknown scene sample to provide useful descriptive information about the perpetrator of a crime. With significant experience in DNA forensics and excellent access to samples, CDx is in a strong position to identify new forensically-useful SNP targets and this project also will provide SNP detection technologies for this purpose.
SUMMARY OF OBJECTIVES
The aim of this project is be to determine the genetic basis of the genes for physical characteristics such as pigmentation (skin, hair and eye colour) and to identify the polymorphisms that determine these traits in an individual. This will allow a physical description to be provided from a DNA sample in instances where there is no such information on the perpetrator of a crime. It also can be used to assist in the process of identification of skeletal remains of unknown origin. We therefore will generate a profile of useful SNPs involved in physical traits for development of forensic identification assays.
The short-term objectives of this project are to identify SNPs responsible for characteristics such as pigmentation by comparison of DNA sequences in population samples of differing phenotypes. This will be achieved by a combination of database mining and comparative genomics to investigate candidate genes for SNPs associated with particular phenotypes (eg hair colour). This will constitute a patentable ID profile with enormous value to the forensics industry where such information would greatly simplify and better direct forensic investigations.
MILESTONES FOR 2002-2003
Recruitment of volunteers to establish DNA database for human identification
• Volunteers have been recruited by public media advertising and QUT staff and students.
Ongoing collection of samples from study subjects
• Approximately 250 venipuncture blood samples have been collected from volunteers to date.
Identification of further pigmentation gene SNPs by database mining
• Approximately ten additional pigmentation genes have been identified by database mining.
Identification of candidate pigmentation gene SNPs and analyse in the population samples
• Approximately 250 SNPs (100 coding, 100 5’- and 50 3’- untranslated) have been identified in 25 genes by database mining.
• Twelve SNPs have been analysed in population samples.
Identification of candidate genes for facial morphology
• Approximately 20 genes have been identified as potential genes involved in facial morphology based on animal models.
PLANNED ACTIVITIES
Milestones for 2003-2004
• Identification of pigmentation, height and facial morphology gene SNPs by database mining.
• Identification candidate pigmentation, height and facial morphology gene SNPs.
• Analysis of SNPs in the population samples.
• Integrate these activities with Project 6 in a combined ‘Genome Diagnostics’ project.
Milestones for the period after 30 June 2004
• Analysis of subset of population samples using SNP chip technology.
• Analysis of the SNP chip data.
• Screening of SNPs significantly associated with phenotype in a larger population group.
http://diagnosticscrc.org/education/students.html
Genetic basis of human pigmentation variation
Levi CARROLL
Location: School of Life Sciences, Queensland University of Technology (QUT), Brisbane
Supervisors: A. van Daal, P. Morris (QUT)
Start date: 20 January, 2003
Scholarship: QUTAPA + CDxPRA Top-up expires 19 January, 2006
Thesis: Max submission date 19 January, 2007
Contact information: Tel: 07 3864 1793 Fax: 07 3864 1534 Email: l.carroll@qut.edu.au
Genetic basis of human height variation
Shea CARTER
Location: School of Life Sciences, Queensland University of Technology (QUT), Brisbane
Supervisors: A. van Daal, P. Morris (QUT)
Start date: March 18, 2002
Scholarship: QUTPRA plus CDx Top-up expires March 17, 2005
Thesis: Max submission date 17 March, 2006
Contact information: Tel: 07 3864 1434 Fax: 07 3864 1534 Email: sl.carter@student.qut.edu.au
The role of TWIST and RGFR1 pathways in calvarial suture fusion and their influence on skull vault morphology
Anna COUSSENS
Location: School of Life Sciences, Queensland University of Technology (QUT), Brisbane
Supervisors: A. van Daal, A. Crampton (QUT)
Start date: 31 March, 2003
Scholarship: QUTPRA plus QUT VC'sInitiative expires 30 March, 2006
Thesis: Max submission date 30 March, 2007
Contact information: Tel: 07 3864 1793 Fax: 07 3864 1534 Email: a.coussens@student.qut.edu.au
Genetic basis of human age
Justin GRAF
Location: School of Life Sciences, Queensland University of Technology (QUT), Brisbane
Supervisors: A. van Daal (QUT); M. Fenech (CSIRO)
Industry contact: M. Fenech (CSIRO)
Start date: 24 February, 2003
Scholarship: QUT PRA + CDx Top-up expires 23 Feb 2006
Thesis: Max submission date 23 Feb 2007
Contact information: Tel: 07 3864 1793 Fax: 07 3864 1534 Email: j.graf@student.qut.edu.au
Utility of Whole Genome Amplification (WGA) for sample archiving, forensics and diagnostics
Firman (Iman) MUHARAM
Location: School of Life Sciences, Queensland University of Technology (QUT), Brisbane
Supervisors: A. van Daal, R. Hodgson (QUT)
Industry contact: L. Westacott (QML)
Start date: March 3, 2003
Scholarship: Nil
Thesis: Max submission date March 2, 2005
Contact information: Tel: 07 3864 1793 Fax: 07 3864 1534 Email: f.muharam@student.qut.edu.au
Molecular markers of obesity
Chris SWAGELL
Location: School of Life Sciences, Queensland University of Technology (QUT), Brisbane
Supervisors: P. Morris, A. van Daal (QUT); D. Henly (UQ)
Start date: April 1, 2000
Scholarship: PhD - full CDxPRA expires 30 September, 2003
Thesis: Max submission date 31 March, 2004
Contact information: Tel: 07 3864 1793 Fax: 07 3864 1534 Email: c.swagell@student.qut.edu.au
Miss Scarlet, here you go:
http://archiver.rootsweb.com/th/read/GENEALOGY-DNA/2004-01/1073420735
Cooperative Research Centre for Diagnostics
This Center has an interesting annual report. This link is not currently working:
http://diagnosticscrc.org/CDxadmin/AnnRep2003.pdf
However, you can get an HTML version of it here:
http://216.239.53.104/search?q=cache:XMrFgoZqXwIJ:diagnosticscrc.org/CDxadmin/AnnRep2003.pdf+%22rana....
The Human Identification Markers section of Project 3 on page 21 is particularly interesting.