The Clarity "Challenge"

The Challenge sponsored by the Children's Hospital in Boston: "Competition participants will get de-identified genome sequences (from Life Technologies and Complete Genomics, which are sponsors of the challenge) and clinical summaries covering three children and their families. The children all have a rare disease with a suspected genetic component. The teams will aim to get from that [sequencing] data to the root cause of the disease, and to present their findings in a clinically meaningful report."

What is interesting is the amount of the award - it is only 25K. It suggests that the challenge isn't much of one.

Six Billion to One

Here is great depiction of the enormous task that is interpreting the human genome.

Roche to Buy Illumina?

Roche makes a hostile play for Illumina.

Word is they are holding out for $60/share.  Either they pony up the money or get out of gene sequencing technology altogether as their 454 technology, although good, is now dead thanks to Life's Ion Proton.

My bet is it will happen.

I'll Drink to That

Researchers to sequence Chardonnay genome

Same Day Genomes

Looks like the battle of over the delivery of both the same day genome and the $1000 price tag has been won with Life's introduction of the Ion Proton.

A Genomic Swiss Army Knife

Along with the ever-so-useful toothpick, a Swiss Army knife can also accommodate a genome (or 340 without annotation). Not exactly a game-changer in the genetics world, but an indicator of how easy it is becoming to accommodate a boat-load of information. But note the price: ~$2000 for 1TB.

Cost of the Human Genome

A decent graph (by Personalis, a start up by Standford researchers) depicting the decline in the cost of the human genome and the the number of genomes that have been sequencing. Note that it does not include Gnome's prices.

Lesson for the New Year: Don't Declare Your Goals.

Contrary to popular belief, the first step in achieving your goals is not telling anyone about them.

How to start a movement

A short lesson on the importance of being an early follower. 

A Passing Introduction of the Mendelianome

Because you can never have too many -omes!

Cracking the Bioelectric Code

“The hypothesis is that for every structure in the body there is a specific membrane voltage range that drives organogenesis,” said Pai. “By using a specific membrane voltage, we were able to generate normal eyes in regions that were never thought to be able to form eyes. This suggests that cells from anywhere in the body can be driven to form an eye.”

Roll Over DNA

Discover: Worms (specifically c. elegans) pass on a trait for 100 generation without DNA! Also see this study.

Ambry Now Offering "CLIA Exome" Sequencing

Yet another company getting on board.

Here is their recommended testing strategy:

Google and Your Memory

List of the Top 1000 Websites

Google gives us the top 1000 websites in the world. MayoClinic.com (#690) and Ancestry.com (#739) were the only two genetic testing related sites listed.

BCM launches Whole Exome Sequencing Clinical Testing

Baylor College of Medicine is now offering clinical whole exome sequencing analysis and interpretation for about $9000 with a TAT of 90 days.

The test will be conducted at Baylor's Whole Genome Laboratory - a name that clearly underlines their ultimate goal.

Blogging Your Genotype

Blogger Razib Khan publishes his 23andMe genotype data and puts it into the public domain in an effort to quell fears associated with exposing personal genomic information. The fear is seemingly irrational given that we now have GINA along with many state laws prohibiting genetic discrimination including California's new law.

Razib has noted that the test cost ~$300 in total and took about 4 weeks to get a result. Here is a list essentially everything he was tested for.

Bar-Coding Life

You can already identify animals with a DNA bar-code; now you can do it with plants too.

Trial and Error Rules!

A simple and brilliant perceptive by Tim Harford.

Fishy Business

The Boston Globe reports on fish fraud.

Specious Species

Fight against Seafood Fraud Enltists DNA Testing: Scientific American

Venter Speaks!

A great presentation by Venter at TEDMED 2010.

Hello and Goodbye to NGS Panel Tests

ØGeneDx adds CLIA Exome Sequencing to test menu.

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UK's NHS Report on NGS

Comprehensive recommendations for prompt and effective adoption of NGS - in the UK's National Health System's clinics.

New York's Genome Center

A little behind the curve, but a welcome event nonetheless:

Direct-to-Genomics Testing

It appears to be coming to a clinic near you.

Who has the majority of abortions in the US?

An article by Lauren Sandler of Slate.com shatters the teen, slut myth:

• According to the Guttmacher Institute (based on 2008 data) "...61% of women who terminate a pregnancy in this country already have at least one child." And 32% who had two or more children.
  
  
• "... a whopping 72%...looking to terminate a pregnancy were already mothers, up at least 10 percent from the years before the economy crashed."
  
  
• "...most women making this choice are contending with some combination of low income, unemployment, and a lack of health insurance, or are struggling to raise kids on their own."
  
  

The Bottom of the Backlog

(First published in The Journal of the Association of Genetic Technologists 2009;35(2):50-51)

Forensic DNA laboratories are overburdened and overextended to such a degree that the case backlog numbers in the hundreds of thousands. The last official government estimate of the state, local and national DNA backlog was in 2003. At that time the attorney general estimated the number of backlogged cases to be between 150,000 and 500,000. What is not clearly recognized or commonly known is that that much of backlogged samples are derived from rape victims. Human Rights Watch (a nonprofit, nongovernmental human rights organization) has estimated the number of untested rape cases to be nearly 400,000, nation wide and that “…evidence from homicides and other violent nonsexual crimes [are] regularly processed, while rape kits remain untested.”

Case in point: An official Los Angeles city audit issued late last year revealed that at least 7,000 rape kits remain “untouched” by the police department’s crime lab. Shockingly, more than 200 rape kits had been sitting so long, that the 10-year statute of limitations for bringing prosecutions had expired.

According to Human Rights Watch, Los Angeles City and County collectively comprise a total of at least 13,000 rape kits, sitting in storage – waiting to be analyzed.

Although this example is particularly egregious, history has proven that such situations are not confined to California. Until a few years ago, North Carolina reportedly suffered persistent DNA testing backlogs, including 6,000 untested rape kits that delayed arrests and prosecutions across the state.

The federal government does not require forensic laboratories to routinely count or categorize their DNA backlogs. Furthermore, most states are not required to notify victims if their evidence has not been processed. Consequently, many victims incorrectly assume that silence from the police means that their kit did not yield helpful information.

To its credit, Congress has made a number of significant legislative efforts to address the problem. The Debbie Smith DNA Backlog Grant Program (H.R.5057), first introduced in 2004 and reauthorized late last year as the Debbie Smith Reauthorization Act of 2008, allows appropriations for DNA analysis, the sexual assault forensic exam program, and includes forensic training and education for law enforcement, corrections personnel and court officers. Unfortunately, there are fundamental problems with this program that suggest that the DNA backlog may persist and that rape cases may once again find their way to the bottom, or remain there, as the case may be.

Since 2004, nearly half a billion dollars of federal funding have been appropriated under H.R. 5057 to process the thousands of unprocessed DNA evidence kits - including rape kits - across the country. Yet, in reports to the Justice Department from 2005 to 2007, half the states that received the grants did not spend all of the funds granted (for reasons that are not entirely clear). This situation has actually resulted in grant funding cuts to such states, and have been extended to intuitions that were involved (such as the Los Angles Police Department) – regardless of the need.

Although H.R. 5057 was originally designed to eliminate the rape kit backlog, states have used the grant for testing backlogged DNA evidence from any crime. States are not required to specify how many rape kits they process, and most reports say only how much DNA evidence was tested with the funding, not the types of cases to which the DNA was connected or whether they were even prioritizing backlogged rape kits at all.

Because Federal funding by the program is available only as a grant (spanning a period of usually 12 months), labs can only guarantee additional DNA analysts’ jobs for that allotted time – a factor that has reportedly stifled recruiting efforts.

Perhaps one of the most significant contributing factors is an ever-increasing influx of DNA samples that are over burdening and overextending forensic labs. As the technology has become more popular, police and prosecutors are relying on it in ever-increasing numbers. Compounding this problem is an attempt by the Federal, some state and local governments to expand the use of their DNA databases by mandating DNA testing of all felons and certain arrestees – who have not been convicted of a crime. In addition, there are attempts to also include familial testing data so that the DNA profile of a potential suspect can be deduced. Such expansions in collecting DNA profiles may contribute to the backlog by diverting money that could be used to pay for backlog testing.
Furthermore, new technologies are enabling DNA analysis of incredibly small or degraded samples – adding still more to the pending cases to be analyzed.

The apparent failure of previous congressional efforts to reduce the case backlog has led questions of how well the Justice Department supervises its backlog reduction program. Interestingly, according to government records, the Justice Department outsourced oversight of the program itself to a nonprofit company in Florida. Records indicate that an estimated amount $55 million of the department’s funds allocated for the DNA backlog problem is unaccounted for.
Hopefully, it is these contributing factors, among others, which are themselves due to legislative shortcomings and a lack of oversight, that are the reasons for the DNA backlog and not “…a failure to treat rape as seriously as other violent crimes” as suggested in a New York Times editorial. For the neglect and a lack of justice for those whose evidence comprise the DNA backlog, which are overwhelmingly rape victims, would be tantamount to criminal.

The Debbie Smith Reauthorization Act of 2008 mandates that The National Academy of Sciences, in consultation with forensic science practitioners from States and units of local government, conduct a study to determine the resources and other requirements necessary to eliminate the backlog and to prevent it from reoccurring. This new measure will likely shed some additional light on how best to eliminate the DNA backlog and the pending rape cases that account for much of it. Clearly, this provision should have been included in the original Act, which was passed nearly five ago. Given that sex offenders generally strike more than once, I wonder how many rapes could be prevented if there was no DNA backlog at all.

Sources:
Human Rights Watch, US: Soaring Rates of Rape and Violence Against Women, http://www.hrw.org/en/news/2008/12/18/us-soaring-rates-rape-and-violence-against-women, 2008

Katsanis, S., Reauthorization Of DNA Backlog Grant Program Could Expand Forensic DNA Collection, Medical News Today, http://www.medicalnewstoday.com/articles/118232.php, 2008.

Kirkpatrick, C.D., Charlotte's DNA backlog slows effort to solve crimes, The Charlotte Observer, http://www.charlotteobserver.com/local/story/356752.html, 2008.

Moore, S., DNA backlog stalling many criminal cases, Herald Tribune, http://www.iht.com/articles/2008/10/26/america/DNAweb.php?page=2, 2008.

Protess, B. and Rubin J., As DNA test backlogs soar, U.S. cuts funding, Los Angles Times, http://www.hrw.org/en/news/2008/12/18/us-soaring-rates-rape-and-violence-against-women, 2008.

The New York Times Editorial, A DNA Backlog, The New York Times, http://www.nytimes.com/2008/11/10/opinion/10mon2.html, 2008.

Tofte, S., A Test of Justice for Rape Victims, WashingtonPost.com, http://www.washingtonpost.com/wp-dyn/content/article/2008/07/21/AR2008072102359.html?sub=AR, 2008.

Willing, R., DNA backlog piles up for FBI, USAToday.com,
http://www.usatoday.com/news/nation/2007-09-03-dnabacklog_N.htm, 2007.

The Library of Congress – Thomas, Debbie Smith Reauthorization Act of 2008,
http://www.thomas.gov/cgi-bin/cpquery/T?&report=hr757&dbname=110&. 2008.

The Library of Congress - Thomas, Justice for All Act of 2004, http://www.thomas.gov/cgi-bin/cpquery/?&sid=cp108313am&refer=&r_n=hr711.108&db_id=108&item=&sel=TOC_31811&, 2004.

Kissing Cousins

(First published in The Journal of the Association of Genetic Technologists 2009;35(2):13)

Consanguinity is a state of being descended from a common ancestor. The term is often used as an indication of increased genetic risk to the offspring of such couples. However, the risk associated with, at least one type of consanguineous coupling - cousin couples - has been overstated. While the assumption that that offspring of cousins do have an increased risk of some deleterious genetic conditions is true, the actual risk has been found to be relatively low. Consequently, US laws governing marriage appear to be inconsistent with scientific evidence, the general North American sentiment towards cousin couples notwithstanding.

Cousins can be defined as remote ancestors by two or more steps and in a different line. The closer the biological relationship between partners, the greater the probability that their offspring will inherit identical copies of one or more detrimental recessive genes. According to Bennet et al. (2002), in the general population, the risk that a child will be born with a congenital birth defect is 3 percent to 4%. First cousins add another 1.7 to 2.8% to the background rate. Therefore, despite the doubling of the background rate, at worst, ~93% of the time there are no negative genetic health consequences.

As a result of these findings, Bennet et al. (a panel of genetic experts convened by the National Society of Genetic Counselors) concluded that no additional preconception screening was recommended for cousin couples.

In other words, the risk is similar if not lower than that of other relatively high risk groups such as mothers of advanced maternal age and even fathers of advanced paternal age among many others. For example, people with Huntington’s Disease or other dominant disorders have at least a 50% risk of transmitting the underlying genes to offspring. No laws exist to prevent genetic unions between Huntington’s carriers from taking place. Yet cousin couples (in the broadest sense of the term) appear to have been discriminated against within the United States – as reflected by marriage laws.

Thirty one states laws either bar the practice of cousin marriage (or marriage between a niece or nephew and their uncle or aunt) or allow it only if the couple has genetic counseling, is beyond reproductive age or if a partner is sterile. Of the 31 states, 6 states ban marriage between first cousins once removed (i.e. marrying the son or daughter of your first cousin). In addition, some of the laws do not distinguish biological kin from married kin.

Cousin marriage – and marriage between a niece or nephew and their uncle or aunt is legal in Canada – and has been at least since 1990. No countries in Western Europe have such prohibitions.

In contrast, in parts of the Middle East, Africa and Asia, marriages between first cousins are preferable, or less commonly between an uncle and niece or between double first cousins (when siblings from one family marry siblings from another family).

The reasons cousin coupling is addressed in the court of law, at least within America, are not entirely clear. Although anthropologist Martin Ottenheimer argues the prejudice is based on now-discredited 19th century research on birth defects among children born to first cousins, religious interpretation may have also played a role. In addition, common misunderstandings--such as overstating the role of consanguinity in the prevalence of Hemophilia in the royal families of Europe in the 18th and 19th centuries may serve as support for state laws. In fact, the mode of inheritance of this X linked recessive condition is independent on whether or not the union is consanguineous.

Arguably, if the risk to the offspring is significantly high, discrimination against couples may be warranted. However, eugenics quickly becomes the central theme when such an argument is posed. As William Saletan fo Slate.com suggested, “…why use a crude standard such as kinship? Why not test everybody for bad genes, ban marriage between carriers, and let cousins without bad genes marry each other?” He adds”…why not start with fertile women over 40? And what about ethnicity?” referring to ethnically predisposed diseases such as Tay Sachs and Sickle Cell Anemia.

Clearly, there is a stigma associated with cousin coupling within North American culture. The union is often referred to as incestuous. Interestingly, Bennet et al. made a point of stating that the term "incest" should not be applied to cousins but only to sexual relations between siblings or between parents and children.

Apart from discriminating state marriage laws and general societal views, perhaps the most disturbing result of the cousin coupling prejudice is that there are reports of counseling by physicians having urged unnecessary procedures such as tubal ligations and abortions.

Endogamy refers to a society in which mating partners are preferentially chosen from within the group, due to geographical, cultural, or religious factors among others. In addition to potential endogamous benefits to consanguineous couples, interestingly, Helgason et al. (2008), recently concluded that third and fourth cousin couples have the greatest number of offspring – the reasons for which are not yet understood.

There is a great need to disseminate information regarding consanguineous couples to medical professionals and the general public. Laws banning cousins from marrying are largely based on outdated assumptions with regard to risks to offspring of cousin couples. And it is the prejudice that allow such unjust laws to endure.

For a list of famous cousin couples see: http://en.wikipedia.org/wiki/List_of_coupled_cousins

Sources:

Bennett, et al., Genetic Counseling and Screening of Consanguineous Couples and Their Offspring: Recommendations of the National Society of Genetic Counselors, Journal of Genetic Counseling, Vol. 11, No. 2, April 2002.

CBC News, Repeal Laws Banning Cousins from Marrying: Geneticists, CBC, December 22, 2008.

Grady, D., Few Risks Seen to the Children of 1st Cousins, The New York Times, April 4, 2002.

Grossman, J.L., FindLaw Forum: A Genetic Report Should Cause a Rethinking of Incest Laws, CNN.com, April 10, 2002.

Helgason, A., Snæbjörn P. , Guðbjartsson D.F., Kristjánsson, þ., Stefánsson K., An Association Between the Kinship and Fertility of Human Couples, Science, , Vol. 319. no. 5864, pp. 813 – 816, February 8, 2008.

Keim, B., Cousin Mariage OK by Science, Wired.com, http://blog.wired.com/wiredscience/2008/12/cous
inmarriage.html, 2008.

Saletan, William, The Love That Dare Not Speak Its Surname: What’s wrong with marrying your cousin?, Slate.com, http://www.slate.com/id/2064227, 2002.

Direct To Consumer Genetic Testing: A Brief Overview

(First published in The Journal of the Association of Genetic Technologists 2008;35(2):195-196).

Direct to consumer (DTC) genetic testing is the practice of marketing and selling genetic testing services to private individuals, without any requirement for approval or guidance by a health care professional. Appealing as this development may be to some consumers, there is much controversy and concern regarding the testing claims, and resulting information from the genetic tests – not to mention the tests themselves.

DTC Genetic Testing Companies

There are at least two-dozen DTC genetic testing providers in the United States alone. These companies vary with regard to price, testing services and service packages. Some companies specialize in specific areas of genetics; Sciona, for example, specializes in nutrigenetic tests whereas Sorenson Genomics specializes in identity testing.

DTC Genetic Tests

Over 1400 DTC genetic tests are currently available to the general public; with both health- and non-health related evaluations offered. Some tests are designed to detect relatively common genetic diseases (such as Cystic Fibrosis, Thrombosis and Fragile X) whereas other tests claim to evaluate health risks (such as addiction, depression and cancer). Genome scans designed to identify potential predispositions are also offered.

Non-health related genetic evaluations can include testing for various bodily traits and specific forensics and genealogy studies. In one odd example, 23andMe provides results for the genetic determination of the subject’s ear wax type (wet or dry).

These tests can be ordered by the consumer via a home kit, which can involve the use of buccal swabs or mouthwash as the submitting specimen. The kits can even be found in supermarkets and drugstores. Identigene, for example, is a paternity test kit that is now available at many pharmacies across the country.

Going State-by-State and Beyond

According to The Genetics and Public Policy Center (GPPC),

“…whether health care provider authorization is required to obtain a genetic test is the province of state law. Some states explicitly authorize laboratories to accept samples from and deliver test results for specific tests (such as pregnancy tests) directly to patients without authorization from a health care provider. Other states categorically prohibit all DTC testing.”

As some states are silent on the issue, individual testing facilities are left to their own judgment as to whether to offer DTC testing. At the time of writing, 25 states and the District of Columbia permit DTC laboratory testing without restriction, whereas 13 categorically prohibit it. DTC testing for specified categories is permitted in 12 states, although the permission does not address genetic tests specifically (GPPC, 2008).

According to the American Society of Human Genetics, various countries have issued reports cautioning against its use of DTC genetic testing and several European countries have banned or are considering banning it. These efforts may prove useless, however, as any official ban of testing is easily circumvented with the use of direct mail.

Not All Labs are Created Equal

DTC genetic testing facilities are typically not certified by CLIA (or CAP)—a professional and legal standard that mandates federal regulatory compliance and or professional peer oversight in the effort to ensure quality laboratory testing. The Department of Health and Human Services, the Centers for Medicare and Medicaid Services work together to regulate the operation of clinical laboratories.

Not All the Tests or Claims Are Validated

While the Food and Drug Administration (FDA) has the power to regulate genetics tests as medical devices, it regulates only those sold as “test kits” and used by laboratories to perform testing. The FDA considers test kits to be medical devices and requires that they undergo pre-market review before they can be made commercially available.

Since the vast majority of genetic tests are developed by the laboratory, neither the tests, nor the claims made about them, are subject to FDA oversight. Consequently, many genetic tests currently offered have not been clinically validated. Furthermore, while most other home-use medical tests undergo FDA review to provide some assurance of their safety and effectiveness, no at-home genetic tests have been reviewed by the FDA.

As a result, DTC genetic testing companies can make claims that are unproven, ambiguous, false and/or misleading. In fact, according to the FDA and the Centers for Disease Control and Prevention (CDC), with regard to DTC genetic tests,
“…some of these tests lack scientific validity, and others provide medical results that are meaningful only in the context of a full medical evaluation (FTC, 2006).”

Furthermore, although some DTC genetic test results may provide a basis for choosing a particular diet, dietary supplement, lifestyle change, or medication, the FDA and CDC state that they know of no valid scientific studies showing that genetic tests can be used safely or effectively to recommend nutritional choices.

The Federal Trade Commission (FTC) polices advertising and marketing; thereby protecting consumers against unfair or deceptive trade practices such as false or misleading claims. However, according to the GPPC, the FTC has not been vigorous in preventing companies from making misleading claims.

In an apparent conclusion to the issue, both the FDA and FTC have recommended that consumers be skeptical regarding DTC genetic tests and their accompanying claims.

Considering the Ethics

According to a federal panel that convened in January 2008, the practice of bypassing doctors and marketing directly to consumers has raised a number of “significant ethical concerns” (Pear, 2008).

Consumers with little knowledge of genetics may have difficulty distinguishing between tests that are widely used and accepted by medical professionals and those whose validity is unproven in the scientific literature.

In addition, a company’s marketing literature and testing results may underemphasize the uncertainty of genetic testing results, or exaggerate the risk, thereby possibly increasing consumer anxiety and promoting unnecessary testing.

However, as Aaron Rowe of Wired magazine suggested, a healthcare professionals’ participation with genetic testing may not always serve to protect the patient.

“…regulators have a false notion that physicians are more familiar with genetics than educated consumers. Even clinicians who recently graduated from medical school have little training in personalized medicine or genetic counseling.”

Clearly, the Internet has made available a bewildering amount of information to virtually anyone on earth with access to a computer and a connection. Given this ongoing development, to question the intelligence of the general public may be, dare I say it, elitist.

Furthermore, as succinctly stated by Dr. Stefansson, the chief executive of Decode Genetics it would be wrongheaded to prevent people from obtaining information about themselves of their own free will and that [genetic professionals] “… cannot deprive people of the right of genetic self determination (Wade, 2008).”

It is also important to consider that increased competition, in part due to the advent of DTC genetic testing services, may force genetic testing prices down via commoditization (the transformation of the market for a unique, branded product into a market based on undifferentiated products through increased competition (Wikipedia, 2007)). If implemented appropriately, regulation can allow commoditization to occur readily. Consequently, with greater regulatory oversight of DTC genetic testing companies, consumers should benefit by the declining cost of genetic testing services – while ensuring quality testing.

Closing in on the Difference

Interestingly, some DTC genetic testing companies choose not to offer their customers anything more specific than suggestions towards disease predispositions and other equally vague advice precisely because of the lack of regulation. In fact, some providers have publicly requested specific federal guideless in an effort to expand their interpretations of tests results and the information they include in both marketing material and patient reports. Dr. Gill, the Chief Science officer of Sciona, for example, has publicly stated “…we would welcome more federal regulation” (Wade, 2008).

Some DTC genetic testing providers have also begun to adopt professional guidelines, acquire professional accreditation and or official recognition (along with the regulatory controls) equal to that of some clinical laboratories. For example, Sorenson Genomics is now AABB accredited and 23andMe utilizes a CLIA “high complexity” certified laboratory. DNA Direct claims to meet and exceed the recommendations listed by both the National Society of Genetic Counselors and the American College of Medical Genetics as guidelines for “direct-to-consumer” genetic testing companies and services.

Conclusion

Upon researching and writing this article, it seems to me that many of the technical concerns with regard to DTC genetic testing services may also apply to certified clinical laboratories. Certainly “home brew” kits are often utilized in certified clinical laboratories without direct regulatory oversight. And as new technologies—such as ever larger microarrays—become increasingly utilized, interpretation of tests becomes more complex. Even definitive claims of “testing negative” for a disorder or predisposition can be difficult to support, as exemplified by the accompanying statements within a report. The difference, however, is accountability. A clinical laboratory is subject to oversight and review and can be held accountable via the loss of specific accreditation, certification and or licensure. Without regulation, DTC companies have only their reputation and the threat of civil legal action as a measure of enforcing accountability.

It appears rather obvious that we need to regulate DTC genetic testing in an effort to address the ethical and technical concerns, yet provide greater accessibility, autonomy, empowerment and lower prices to the consumer—a regulatory prescription that will itself be very complex, but undeniably promising to the general public. Until then, it may be that professional groups will provide the necessary guidance to both general public and the DTC genetic testing service providers.

Sources:
Pear, R., Growth of Genetic Tests Concerns Federal Panel, New York Times, January 18, 2008.

The American Journal of Human Genetics, ASHG Statement* on Direct-to-Consumer Genetic Testing in the United States, Volume 81, Issue 3, 635-637, 1 September 2007.

Federal Trade Commission, At-Home Genetic Tests: A Healthy Dose of Skepticism May Be the Best Prescription, http://www.ftc.gov/bcp/edu/pubs/consumer/health/hea02.shtm, 2006.

The Genetic Public Policy Center (GPPC),
http://www.dnapolicy.org/policy.issue.php?action=detail&issuebrief_id=32, 2008.

Rowe, A., Wired.com, http://blog.wired.com/wiredscience/2008/06/top-10-reasons.html, 2008.

Wade, N., Company Offers Genome Assessments, The New York Times, November 16, 2007.

Wikipedia, Commodification, http://en.wikipedia.org/wiki/Commodification, 2007.

(For a compromise list of DTC genetic testing providers and corresponding test menus see: www.dnapolicy.org/resources/DTCcompanieslist.pdf)

Patently-Non-Patentable

(First published in The Journal of The Association of Genetic Technologists 2008;34(2):97-98).

Malcolm Simons had an idea. It was to patent the concept of analyzing all non-coding regions of DNA (promoters, SNPs, splice sites notwithstanding) for the purpose of making inferences about genes—any genes—of any species. According to Simons, his discovery was made during research he was doing between 1987 and 1988. He filed a patent application and assigned it to his employer in 1992. In 1997, the patent, known as “Intron sequence analysis method for detection of adjacent and remote locus alleles as haplotypes”, or US Patent 5,612,179, was granted.

It should be immediately apparent that US Patent 5,612,179 was—and is—invalid. Yet Genetic Technologies Limited (GTG), the patent holder, is pursuing the enforcement of this incredibly broad patent, in numerous countries throughout the world—with individual licensing fees that extend into the millions—with great success. This patent in particular, with its broad interpretation, will result in increased costs of (past and future) research and development, adversely affecting the availability of the developed product and services to the detriment of consumers and patients.

Patent Analysis Gone Wild

As discussed in a previous column, Patenting Policies As Applied To Genetics, it is not permissible to patent an abstract idea, nor any natural or physical phenomena.

Moreover, the idea in question was not "novel", one of the four criteria used to judge a patent application. In fact, the utility of non-coding regions was suggested as early as 1975 by Lin and Riggs where they stated "We propose that ‘junk’ DNA in [eukaryotes] functions to maintain total DNA at an optimum concentration" (Lin and Riggs, 1975).

It also seems that the idea was not "non-obvious"; yet another criterion used in judging the viability of a patent application. Certainly if Line and Riggs, independently—and publicly—surmised, in a top leading international scientific journal (Cell), that the analysis of non-coding regions may be of interest, then it is reasonable to assume that others in the field may have also suggested a similar idea, perhaps thereafter (within the twelve plus years prior to Simons research), or possibly even before the Lin et al.'s publication.

In fact, Francis Collins—the former director of the Human Genome Project—cites research dating back to 1978, by W.Y. Kahn, that disputes the novelty, and validity, of this particular patent. And of course, there is the DNA fingerprinting technology introduced by Alec Jeffries in the early eighties who, in fact, did discover a utility of non-coding sequences years prior to Simons patented realization. Extensive research may yield even more evidence proving that Simons’ patent was “non-obvious”.

Given that Simons’ idea did not satisfy the rules for patent approval, one can only conclude that the U.S. Patent and Trademark Office (USPTO) simply made a mistake in granting US Patent 5,612,179.

Standards Change

Clearly, the patent application would have been rejected under current rules, which have become more specific to the science of genetics. Under the new rules, one must be able to 1) Specify how the product functions in nature 2) Identify the genetic sequence 3) Specify the sequence's product 4) Enable one skilled in the field to use the sequence for its stated purpose. Note that Simons did not—could not—have provided this information to the USPTO.

Going Retro

Retroactive analysis of a patent would set precedence for a slew of other patents to be reevaluated and the entire process would require Congressional approval. This conundrum may be a factor in preventing attempts to reverse the mistake of granting this particularly ridiculous US patent.

Win or Lose, It Matters Not

To the credit of GTG's business acumen, the company brilliantly secured insurance that covers the costs of protecting the patent if it is legally challenged—a measure that seems to imply internal concern over the validity of the patent. The insurance, itself, may provide an incentive for the company to enforce the patent at essentially any cost.

Going to Collections

The patent has been approved in over 24 countries—almost solely due to the way in which international patent process is structured. This achievement enables GTG to collect licensing fees from a number of companies and institutions worldwide. Indeed, GTG appears to be wildly successful in collecting money from the "patent infringers".

Major biotech companies such as Applera, Monsanto, Myriad, Genzyme, LabCorp, Sequenom and Quest and even some governmental agencies—have already entered licensing agreements—thereby indirectly providing greater merit to the legality of the patent and directly supporting a pro patent paradigm. As a measure of how lucrative these licensing fees are, according to GTG, the company has generated over AU$53 million on this patent alone. Interestingly, Myriad, the company notorious for trying to monopolize breast cancer susceptibility testing of the genes BRCA1 and BRCA2, paid a million dollars in a non-exclusive (cross-licensing) deal for GTG’s questionable patent. Genzyme paid over 7.5 million, in cash and intellectual property, in addition to an annual payment of 1 million (until 2015) to secure a license for US Patent 5,612,179.

A patent is valid for approximately 20 years. Consequently, because of the age of the patent, their enforcement efforts (likened to blackmail by the CSO of Sequenom) are now focusing on smaller organizations, publicly funded institutions and non-profits, including universities and hospitals.

Conclusion

Given a description that is sufficiently abstract, I am nearly certain that any chromosome, whose sequence is publicly known, could be patented. Who knows: perhaps it has already been patented and the patent holder is just beginning the noble process of excessive fee collection. Or, better yet, perhaps this very idea could escape the qualifying rules of the patent process and be granted a US patent. You read it here first.

Sources

Coovadia, A., Patenting Policies As Applied To Genetics, J Assoc Genet Technol. 2007;33(1):17.

Four Corners, Interview with Dr. Francis Collins, http://www.abc.net.au/4corners/content/2003/20030811_patent/int_collins.htm, 2003.

Four Corners, Interview with Dr Malcolm Simons, http://www.abc.net.au/4corners/content/2003/20030811_patent/int_simons.htm, 2003.

Four Corners, Interview with Mervyn Jacobson,
http://www.abc.net.au/4corners/content/2003/20030811_patent/int_jacobson.htm, 2003.

Genetic Technologies Limited, http://www.gtg.com.au/index.asp?menuid=060.070.190.020, 2008.

Lin S, Riggs AD, The general affinity of lac repressor for E. coli DNA: implications for gene regulation in procaryotes and eukaryotes, Cell. 1975 Feb;4(2):107-11.

P. Scott, Casey Luskin and the junk DNA conspiracy,
http://all-too-common-dissent.blogspot.com/2007/07/creationist-lawyer-and-discovery.html, July 25, 2007.

Simons, M., Intron sequence analysis method for detection of adjacent and remote locus alleles as haplotypes, Google Patents,
http://www.google.com/patents?id=u2wjAAAAEBAJ&dq=us+5,612,179, 1997.

Message on the Bottle

(First published in The Journal of Association of Genetic Technologists 2008;34(2):61).

Pharmacogenomics is the study of variable drug response in individual patients. Personalized medicine refers to the use of an individual’s genetic information to tailor strategies for the detection, treatment, and prevention of disease (Collins, 2005). Until recently, these two complimentary studies have been akin to genetic therapy – promising areas of development with little practical achievement. With the relatively recent FDA approval of the re-labeling of a commonly prescribed drug, with clinically significant genotypic information, the promise of personalized medicine and the science of pharmoacogenomics is being officially realized and publicly recognized.

Note the Genotype

Warfarin (the generic version of Coumadin) is an anticoagulant and is one of the most widely prescribed drugs in the world, used for the prevention and treatment of thromboembolic disorders (cardiovascular disorders associated with thrombus and embolus formation in blood vessels). In the US, the drug is prescribed to over two million people annually.
Incorrect dosing of warfarin carries a high risk of either severe bleeding or failure to prevent thromboembolisms. In fact, according to the FDA, hemorrhage during warfarin therapy is a leading cause of death in Western countries and related adverse events account for 1 in 10 hospital admissions.

Two variable genes (CYP2C9 and VKORC1) play a key role in the metabolism and regulation of warfarin. Clinical studies have shown that patients with CYP2C9 and VKORC1 genetic variations require lower initial and maintenance dose to stay within the target INR (a measurement of the body’s ability to clot).

Healthcare professionals are not required to conduct CYP2C9 and VKORC1 testing before initiating warfarin therapy. However, the new label information may aid in prescribing the correct warfarin dose, and encourage increased attention to the drug response of the patients with these genetic variations.

Although dosing algorithms that take into account the genetic, clinical and demographic factors are available for this drug, the FDA has neither offered nor endorsed any dosing algorithm that factors in genotypic information.

Although warfarin is the first drug to have a recommendation for pharmacogenomic testing by the FDA, it is not the only drug to be labeled with genotypic information. In fact, the FDA has approved such labeling for all of the following: 6-Mercaptopurine (an immunomodulatory drug), Azathioprine (an immunosuppressant), Irinotecan (a topoisomerase 1 inhibitor), and Atomoxetine (a norepinephrine reuptake inhibitor).

Other candidates that may be approved for re-labeling with genetic information in the near future include cancer treatment related medications such as Methotrexate, Iressa, Tarceva and Gleevec, all which have been shown to have some degree of clinically significant correlation between the drug responses and genotypes.

Note the Regulator

The FDA is an agency within the United States Department of Health and Human Services (HHS) that, in accordance with the Federal Food, Drug, and Cosmetic Act (FD&C ), is responsible for protecting the public health by assuring the safety, efficacy, and security of a variety of items including human medication.

According to the FDA, personalized medicine is a component of the personalized health care initiative of the HHS. To meet this initiative, the FDA is charged with “1) re-labeling previously approved drugs with new genetic information when appropriate, 2) including genetic information in the labels of newly approved drugs when genetic tests can differentiate patients in advance with regard to predicting benefit, risk or doses, and 3) encouraging the pharmaceutical industry to include the study of genetics in new drug development” (FDA, 2007).

“The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health”(FDA, 2007).

Conclusion

The amount of new information generated by the genetic correlation studies is potentially enormous and requires genetic education for, and medical case coordination between, health professionals of nearly all types and the general public. It will also require additional continuing education for many health care professionals, including clinical geneticists, technologists and directors.

In much the same way that the science of nutrition and general biochemistry has, to some extent, been co-opted by the food processing industry, one can speculate that genetic variation information will also be utilized for marketing purposes. Food product labels may one day include genotypic information regarding potential consumers, along with the other numerous health claims often made. In addition, other products such as skins creams, herbs, and vitamins, etc., may also exploit genotypic relationships or correlations that will almost surely be discovered. Only time, and the FDA, will tell. Until then, the message from the FDA is clear: the age of personalized medicine and pharmacogenomics is here.


Sources

Collins, Francis S., Personalized medicine: A new approach to staying well, The Boston Globe, July 17, 2005.

Coleman, Howard, Genelex Corporation, http://www.healthanddna.com/WarfarinGenetics/WarfarinGenetics_viewlet_swf.html, 2006.

FDA, FDA's Mission Statement, http://www.fda.gov/opacom/morechoices/mission.html, 2008.

FDA, FDA News, http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html, August 16, 2007.
FDA, Questions and Answers on New Labeling for Warfarin (marketed as Coumadin), http://www.fda.gov/cder/drug/infopage/warfarin/qa.htm, August 16, 2007.
Genelex Corporation, Warfarin (Coumadin) and DNA, http://www.healthanddna.com/warfarin.html.

NPR.org, Day to Day, Genetic Testing Can Help with Drug Dosages October 24, 2007.

And the Helix May Set You Free

(First published in The Journal of The Association of Genetic Technologists 2008;34(1):11-12).

The first application of DNA forensics evidence was carried out by Dr. Alec Jefferies in 1983, in a British court case which sought to identify the relationship between an emigrant and her son. Since then, genotyping technology (also known as DNA fingerprinting and genetic profiling) has been developed and applied to identifying individuals for a wide variety of purposes including exonerating convicts.

Faulty forensic evidence is a common cause of wrongful convictions. And once convicted, access to the forensic evidence remains a clear barrier to possible exoneration. In fact, it is DNA exoneration that is driving state legislators to address some of the apparent legislative flaws that govern forensic evidence testing in the US.

Evidential Errors

As with clinical specimens, the identification, collection, testing, storage, handling and reporting of forensic evidence usually involves a number of people and it can be compromised at any stage of the process.The risk of compromising a forensic sample begins at the crime scene, where evidence can be mishandled, planted or destroyed. The evidence is then sent to a forensic lab, where it can be contaminated, poorly tested, unnecessarily exhausted or mislabeled. In any event, the final report can be misrepresented or incorrectly interpreted.

Conflicts of interest can exist between the crime lab and the prosecution and or police department. In fact, forensic misconduct by scientists, experts and prosecutors has lead to wrongful convictions in many states.
The former director of the West Virginia state crime lab, Fred Zain, testified for the prosecution in dozens of cases in twelve states over his career. DNA exonerations and new evidence in other cases have shown that Zain falsified his results, committed perjury, with regard to case results and his credentials, and willfully omitted evidence from numerous reports involving DNA and or serology.



An investigation of the Houston crime lab, completed in 2007, showed evidence of drylabbing - reporting results when no test was actually performed. In addition, it was discovered that there was 274 cases in which biological matter was detected but never tested. Moreover, final report test results were misreported in at least 43 of 135 DNA cases - 6 in which new tests have already discredited analysts' DNA work.


Pamela Fish, was a serologist in the Chicago Police Lab before she transferred to the Illinois State Police Lab and was later promoted to chief of the biochemistry section, which handled DNA testing. Fish has been accused in multiple lawsuits of presenting false or misleading testimony that helped to convict nine men, including three that have since been exonerated by DNA and four more defendants that have been cast in doubt.


Joyce Gilchrist, an Oklahoma City Police Department Forensic Chemist, falsely testified to matched hair and semen samples from a crime scene to a suspect. She also appears to have withheld evidence from the defense and failed to perform tests that could have cleared defendants in a number of cases. Hundreds of cases in which she has testified in have now come under review.


Of course, malfeasance and negligence (criminal or otherwise) are not confined to DNA (and serology testing). In the Houston Crime Lab investigation, errors have also been exposed in the lab divisions that test firearms and controlled substances. In fact, there is proof that the crime lab analysts skewed a variety of types of reports to fit police theories in a number of crime cases.


Missing Evidence

Only a fraction of criminal cases involve biological evidence that can be subjected to DNA testing. Even when such evidence exists at that time, it can be lost, depleted or destroyed after a conviction, making retesting impossible.

These poor forensic testing standards have contributed to the American Bar Association calling for a national moratorium on the death penalty in part due to the “…spotty collection and preservation of DNA evidence…”.

Access to Evidence

Once convicted, access to the forensic evidence remains a clear barrier to exoneration. Some states - namely Alabama, Alaska, Massachusetts, Mississippi, Oklahoma, South Carolina, South Dakota and Wyoming - deny any type of access to DNA evidence that may have not been available at the time of their convictions making possible proof of innocence much more difficult.

Evidential Legislative Flaws

Forensic laboratories are not subject to the same scrutiny and standards as clinical labs. Although, there are professional societies and an accreditation body for crime labs, namely, The American Society of Crime Laboratory Directors / Laboratory Accreditation Board (ASCLD/LAB), membership to such organizations are essentially voluntary.

Indeed, error and misconduct can occur regardless of standardization. Case in point, the Illinois Police Crime Lab had been consistently accredited by the ASCLD/LAB suggesting that perhaps, even more rigorous standards should be applied forensic testing facilities.

Fortunately, crime labs in many states are beginning to undergo greater scrutiny. Vermont and Maryland passed laws just over a year ago to improve crime lab oversight. In particular, Maryland recently passed a law that will hold its crime labs to the same standards as clinical laboratories, a much more rigorous requirement. At this time of writing, other similar legislative changes to crime lab oversight are pending in 21 states.

Conclusion

The first DNA exoneration took place in 1989. To date there have been 210 post-conviction DNA exonerations in the United States – of which 147 exonerations were since 2000. The average sentence served by a DNA exoneree is 12 years.

Consider the fact that of the 210 people exonerated through DNA evidence, 15 served time on death row. One can only conclude, with out any fundamental ethical concerns, that a state, or perhaps a federal moratorium on the death penalty should be implemented until legislation requires forensic crime labs (and forensic crime scene experts) to have rigorous mandatory standards, that are at least as high as those of clinical laboratories, so that we are not all, in the least, albeit indirectly, guilty of murdering of the innocent.

Of course, hindsight is 20/20, and when considering the possible advent of new technologies, not to mention the unearthing of legislative flaws such as those presented herein, perhaps the death penalty should be put to rest itself (pun intended). It would, in fact, be inline with all other Western countries.

Since 1973, over 125 people have been released from death row with evidence of their innocence. Certainly, the growing number of exonerations (via DNA or otherwise) provides evidence that such a moratorium or ban in the US is necessary.

DNA exonerations are yet another example of how the genetic technology we regulatory employ is forcing legislative changes that have the potential to be profound - and life saving.


Sources

Death Penalty Information Center,http://www.deathpenaltyinfo.org/article.php?did=412&scid=6, 2008.

Khanna, R. and McVicker, S., Police lab tailored tests to theories, report saysHouston Chronicle, May 12, 2006.

Khanna, R. and McVicker, S., `Troubling' cases surface in report on HPD crime lab, Houston Chronicle, June 17, 2007.

Luscombe, Belinda, When The Evidence Lies, Time.com, http://www.time.com/time/nation/article/0,8599,109568,00.html, May 13, 2001.

Moore, S., Exoneration Using DNA Brings Change in Legal System, New York Times, Oct. 1, 2007.

Sherman, M. and The Associated Press, The Denver Post.com, Lawyers say death-penalty systems undermine fairness, http://www.denverpost.com/nationworld/ci_7307794 10/28/2007.

The American Society of Crime Laboratory Directors (ASCLD), http://www.ascld.org/, 2008

The American Society of Crime Laboratory Directors / Laboratory Accreditation Board (ASCLD/LAB,), http://www.ascld-lab.org/, 2008.

The Innocence Project, http://www.innocenceproject.org/, 2008.
The President’s DNA Initiative, http://www.dna.gov/case_studies/convicted_exonerated/alejandro, 2008.

Westervelt Eric, Joyce Gilchrist, http://www.npr.org/templates/story/story.php?storyId=1122856, May 12 2001.

Symmetry, Information, Selection and Legislation: A Case for Universal Health Care

(First published in The Journal of The Assocation of Genetic Technologists 2007;33(4):191-92).

A number of articles published in newspapers, journals and magazines have predicted the inevitable demise of the US private health insurance industry, directly due to advancements in genetic technology.

With the upcoming DVD release of Michael Moore’s critically acclaimed film, "Sicko" and a forthcoming US federal election, where the issue of health care reform is beginning to take center stage, it seems appropriate to review this relatively common prediction of the direr implications of advancements in genetic testing with regard to the viability of the US private health insurance system.

The Insurance Model

The fundamental concept of insurance is that it balances risk across a large, random sample of
individuals. By pooling risk in this manner, health insurance companies rely on the model that the healthy will subsidize the sick. Therefore, by insuring enough people, “…on average, the payouts to the unexpectedly unhealthy policyholders should be [significantly – in a for profit model] offset by unnecessary premiums paid by the unexpectedly healthy policyholders” (The Economist, 2000).

Symmetry and Selection

According to economic theory, market failure (an inefficient market) can occur when asymmetrical information is available. Asymmetric information is exclusive information that confers an economic advantage to one party over another. Information asymmetry can lead to adverse selection (also known as anti-selection or negative selection), whereby the holder of the exclusive information takes advantage of it.

Adverse Selection

In practice, adverse selection refers to the tendency for only those who will benefit from insurance to buy it. As explained by Hall and Rich (2000) “…when this situation arises, it can be expected that high-risk individuals will purchase a disproportionate amount of insurance.” In this case, premiums set according to the average risk will not be sufficient to cover the claims that eventually arise. Consequently, health premium rates increase across the board, due to the inability of the insurer to identify [or discriminate towards] those that are at a higher risk. Raising health premiums “…compounds the problem by making insurance less attractive to lower risk individuals… If they [insurance companies] drop coverage, average rates go even higher. In the most extreme cases, adverse selection can cause rates to spiral so high that no one wants to purchase the insurance and so the market for that product entirely collapses (Hall and Rich. 2000)”.

Of course, it may be possible that “the market reaches an equilibrium in which insurers can earn a reasonable return even with higher risks in the pool, yet the price remains sufficiently attractive to keep medium or lower risks in the pool”(Hall and Rich, 2000). There is, however, at least one example in which an ever increasing, almost infinite amount of asymmetrical information is becoming readily available that can cause persistent market disruptions.

Genetic Discrimination

Information derived from genetic tests is not inherently (pardon the pun) asymmetric. Genetic test results can certainly be predictive and thus, reduce the uncertainty (or randomness) regarding predictions of an individual’s health, thereby requiring health insurers to pool a larger population; but the information is not necessarily exclusive. It is the laws that govern genetic discrimination at both the state and federal levels that can deem the information to be asymmetric, with regard to health insurance. As presented in the last JAGT issue, through a patchwork of current laws, personal genetic information can essentially be considered protected from insurance companies; thereby preventing a company from denying insurance, raising premiums, or exhibiting any other type of genetics-based discrimination. In addition, a comprehensive federal anti genetic discrimination bill has been approved and is pending final passage in the Senate, potentially sealing the deal by closing possible legal loopholes and specifying the particulars.

As genetic research and technology advance, a greater amount of asymmetric information will become available, enabling more precise predictions of future health outcomes for individuals and amplifying the problem of adverse selection.

The Model Solution

The only truly effective way to reduce adverse selection “…is to make the purchase of insurance compulsory, so that those for whom insurance priced for average risk is unattractive are not able to opt out” (The Economist.com, 2007).

And there you have it; Universal Health Care. Baring unforeseen political and legal maneuvers by health insurance companies, it appears that advancements in genetic testing will provide, as stated by Dr. Ashish Sureka (2000), an “impetus towards universal health care” within the US.

Conclusion

Universal health care is, by definition, health care granted to all citizens or residents of a country or territory. Many people, in fact, believe it is an essential human right. Indeed, it is proclaimed in the United Nation’s Universal Declaration of Human Rights, which applies to all member countries. Even the CEOs of major US companies such as Wall Mart and Safeway, considered to be notorious for their poor worker benefit programs, have aligned with labor groups to advocate for a universal healthcare system, albeit for economic reasons. There is considerable debate, however, over how to fund such a project. And therein lies the problem, by no means an insurmountable one.

The US currently spends 15.5% of GDP on private health care (more than any other nation) and yet is ranked poorly overall by international health standards by such organizations as the World Health Organization. More importantly, the fact that at least 45 million US citizens are uninsured (9 million of them children) suggests that market failure--defined as an inefficient allocation of scarce resources--appears to have occurred long ago.
Perhaps an improved system that is “uniquely American” as described by the American’s Health Insurance Plans, the industry’s main lobby group, can be implemented by incorporating both the much vaunted free market system and public funding and thereby satisfying all parities involved. Australia, for one, provides an example of how such as system can work; or perhaps the somewhat novel approach of non-profit or not for profit system as that found in Germany. Certainly, there are many types of systems to consider. Indeed, apart from the US, every industrial country, and many underdeveloped ones, offer some form of universal healthcare.

Among the literature I reviewed, one article dating back to 1996 suggested that it may be a great while before the behemoth of an admittedly troubled industry, at least with regard to ever increasing costs, is transformed into something new. In the meantime, regardless of the likely development of a universal health care system in the US, be aware that the genetic technology we regularly devise and employ is transforming our society in ways that relatively few are aware of. I, for one, welcome this change.

Sources:

Berry RM., The Human Genome Project and the end of insurance, Univ Fla J Law Public Policy. 1996 Spring;7(2):205-56.

Department of Health and Human Services Center for Medicare and Medicaid Expenditures, National Health Expenditures Projections 2006-2016, http://www.cms.hhs.gov/NationalHealthExpendData/downloads/proj2006.pdf, 2006.

Cecchetti, S., A future of public healthcare for all, Financial Times, http://my.brandeis.edu/news/item?news_item_id=10163, July 2, 2007.
Hall MA, Rich SS, Laws restricting health insurers' use of genetic information: impact on genetic discrimination, Am J Hum Genet. 2000 January; 66(1): 293–307.

NPR, Fresh Air from WHYY, Diagnosing U.S. Health Care — and 'Sicko,' Too , An Interview with Jonathan Oberlander, July 9, 2007.

Sureka, A., Improved genetic testing: a new impetus toward universal coverage, Princet J Bioeth. 2000 Spring;3(1):20-34.

The Economist, Do Not Ask or Do Not Answer?, Aug 25, 2007.

The Economist.com, Testing Times,
http://www.anderson.ucla.edu/faculty/bhagwan.chowdhry/genetic2.htm, Oct. 21, 2000.

The Economist.com,
http://www.economist.com/research/Economics/alphabetic.cfm?letter=A,
2007.

United Nations, The Universal Declaration of Human Rights, http://www.un.org/Overview/rights.html, 1948.

United Nations, The 2006 United Nations Human Development Report, http://hdr.undp.org/hdr2006, 2006.

Diversified Concerns: A Letter to My Employer

To Whom It May Concern:

I am concerned with the upcoming change in our 403b plan sponsor.

Could you please tell me, will Diversified offer a standard investment retirement savings account (as AIG Valic currently does) or will I be forced to participate in buying funds only? Assuming not, I would like to request that this option is added to the Diversified's plan.

As New York Times Economist David Leonhardt has reported, when adjusting for inflation in evaluating the period between March 2000-June 2007, the stock market has “…only marginally outperformed cash sitting in a bureau drawer” (http://www.nytimes.com/2007/07/18/business/18leonhardt.html?n=Top%2fReference%2fTimes%20Topics%2fPeople%2fL%2fLeonhardt%2c%20David). Consequnely, a 403b plan that does not provide a standard investment retirement savings account option (as AIG Valic currently does) would be sub optimal, to say the least.

Also, as a note of criticism, I find it ironic that although a key selection decision point for the change to Diversified is that it is suppose to provide greater transparency, the discussion and selection of a plan sponsor, and indeed the need for a change at all, was not made transparent to “general” All Children's employees. In fact, to my knowledge the discussion and final decision was exclusive to upper administration members only. I, as well as a number of my colleagues, find this fact disconcerting.

Furthermore, Diversified appears to be anything but. They appear to offer only their own mutual funds as opposed to AIG, for example, which offer a number of well-recognized funds, which are managed by different companies.

Could you please address these concerns for me?

Thank you for your time and attention to this matter.

Sincerely,

Adam Coovadia
Molecular Genetics
x8985

The New Laws of Genetics

(First published in The Journal of The Association of Genetic Technologists 2007;33(3):110-11).

Although the topic of genetics is commonly discussed in the media, apart from the topic of stem cell research, legislative issues pertaining to genetics are often unreported or simply overlooked. There are currently three U.S. congressional bills of considerable scientific consequence that, if passed will a great impact on science and healthcare and, in particular, on the science and practice of genetics within the United States.

The Genomic Research and Accessibility Act

The Genomic Research and Accessibility Act (H.R.977.IH) was introduced in the House of Representatives February 9th, 2007 by Mr. Becerra (D-Ca) and Mr. Weldon (R-Fla). The purpose of this bill is “…to prohibit the patenting of human genetic material”.

As most of us are aware, the patenting of genes is a controversial topic. A debate exists regarding the promotion of private research and development over the public interest. However, unlike conventional patented items, human genes, gene fragments, DNA sequences and corresponding proteins exist in essentially each and every one of us. This fact complicates the issue of who has the exclusive legal rights to govern and regulate the testing and analysis of human genetic material.

The key point of the Genomic Research and Accessibility Act is that it would include the banning of patents pertaining to “…nucleotide sequence, or its functions or correlations, or the naturally occurring products it specifics”. Furthermore, the bill would be non-retroactive, thereby allowing existing patents to run until their expiration approximately 20 years from their issuance. The bill has been referred to the Committee of the Judiciary (Library of Congress, 2007).

The Genomics and Personalized Medicine Act of 2007

The Genomics and Personalized Medicine Act of 2007 (S.976.IS), introduced in the Senate March 23, 2007 by Mr. Obama (D-IL) and Mr. Burr (D-IL) is essentially a relatively large research and development-spending bill.

The stated purpose of this bill is “To secure the promise of personalized medicine for all Americans by expanding and accelerating genomics research and initiatives to improve the accuracy of disease diagnosis, increase the safety of drugs, and identify novel treatments.”

In essence, the bill’s intended purpose is to spur development in pharmacogenomics via increased governmental communication, federal funding, and the creation of a National Biobank.

The key points of this bill include “$75,000,000 for fiscal year 2009, and such sums as may be necessary for each of fiscal years 2010 through 2014…” for the a national biobanking initiative. In addition, the bill makes a provision with “…$1,000,000 for fiscal years 2008 and 2009…” for developing a Genomics and personalized Medicine Interagency Working Group – a governmental advisory panel.

Furthermore, the bill allocates “…$5,000,000 for fiscal year 2008 and such sums as may be necessary for each of fiscal years 2009 through 2013…” for related educational grants and for the “integration of genetics and genomics into all aspects of clinical and public health practice by promoting genetics and genomics competency across all clinical, public health, and laboratory disciplines through the development and dissemination of health professional guidelines”.

Currently this bill has been referred to the Committee on Health, Education, Labor, and Pensions.

The Genetic Nondiscrimination Act of 2007 (GINA)

The Genetic Nondiscrimination Act of 2007 (GINA) (H.R. 493.EH), introduced by Rep. Louise Slaughter (D-NY) on January 16th, 2007 and passed by the House of Representatives on April 30th, 2007, is a comprehensive attempt to establish “…a national and uniform basic standard necessary to fully protect the public from discrimination and allay their concer[JS1] ns about the potential for discrimination, thereby allowing individuals to take advantage of genetic testing, technologies, research, and new therapies ”.

In essence, the bill prohibits health insurance companies from raising insurance premiums, excluding coverage, or denying insurance based on a preexisting genetic conditions. Employers would be prohibited from inquiring about one’s genetic condition except when workplace safety is a concern. In the event that personal genetic information is known, the employer would be required to keep it in a safe and separate place from other employee documents and would be barred from sharing the information. Furthermore, employee pay and working conditions could not be based on any genetic information.

Indeed, forty-one states have laws that protect the public from genetic discrimination by insurance companies, and 32 states have laws protecting their citizens from genetic discrimination in the workplace. In addition, an Executive Order was issued in 2000 that prohibits genetic discrimination in the workplace for federal employees (NIH, 2007). The Health Insurance Portability and Accountability Act of 1996 (HIPAA) also provides protection from genetic discrimination. However, HIPAA does not (1) prohibit the use of genetic information as a basis for charging a group more for health insurance or (2) limit the collection of genetic information by insurers and prohibit insurers from requiring an individual to take a genetic test or (3) limit the disclosure of genetic information by insurers or (4) apply to individual health insurers except if covered by the portability provision (NIH, 2007).

For over twelve years, Congress has officially considered legislation to ensure comprehensive genetic discrimination protection for all Americans. This particular incarnation of the bill was considered by three House committees - the Committee on Education and the Workforce, the Committee on Energy and Commerce, and the Committee on Ways and Means, and was passed in the U.S. House of Representatives by a vote of 420-3. However, it has been stalled for further consideration by one unidentified senator who has chosen to remain anonymous and who is capable, according to senate rules, of stalling the bill indefinitely, despite the wide bipartisan support in addition to White House support (Pollitz, 2007).


Conclusion
Whatever one’s political inclination, these three bills will, if passed, most certainly have a dramatic impact on genomic research and development and testing in both the public and private domains.

As highly educated specialized professionals it is our duty to get involved and express our professional opinions regarding these bills. For it is we genetic professionals, who understand the complexity and can see the practicality (or lack of same) of the laws that regulate what we do and how it impacts our patients.

Short statements are often more successful in conveying your political opinion when communicating with you representative. With this in mind, please take a moment to review the pending bills and call or write your congressional representative with your professional opinions and comments.

For more information concerning these and other U.S. congressional bills and to identify your congressional representatives please see: http://www.govtrack.us/.

Sources
Becerra, Weldon. The Genomic Research and Accessibility Act, 2007 (H.R.977.IH), 2007.

Library of Congress, http://www.loc.gov/index.html, 2007.

NIH, National Human Genome Research Institute - Legislation on Genetic Discrimination, http://www.genome.gov/10002077#2, March 2007.

Obama, Barack and Burr, Richard. The Genomics and Personalized Medicine Act of 2007 (S.976.IS), 2007.

Pollitz, Karen. NPR Talk of the Nation Science Friday - Genetic Discrimination Protection, http://www.npr.org/templates/story/story.php?storyId=10136888, May 11, 2007.

Slaughter, Louise. The Genetic Nondiscrimination Act of 2007 (GINA) (H.R. 493.EH), 2007.

Patenting Policies As Applied To Genetics

(First published in The Journal of The Association of Genetic Technologists 2008;33(1):17-19)

A patent (Latin, patere, meaning, to lay open) is a document issued by the federal government that grants to its owner a legally enforceable right to restrict others from practicing the invention described and claimed therein. Congress allows this right with the intention of encouraging public disclosure of technical advances and providing an incentive for investing in commercialization. As with other forms of property the rights symbolized by a patent can be inherited, sold, rented, mortgaged and even taxed. When a patent expires, the right to restriction ceases.

In recent history, the subject of what can be patented has been a focus of great concern, specifically with regard to the patenting of genes and related natural compounds. Although the surrounding controversial debate is beyond the scope of this article, the technical aspects of the patenting of genetic elements are reviewed herein in an effort to understand the policies and rules that govern the patenting process of them in the United States.

Note that even if someone holds a patent on a specific gene or protein, a second inventor can obtain a patent on a new use for that gene or protein. Consequently, patent stacking in conjunction with license royalty and fee stacking can result in very high costs associated with conducting research and clinical diagnostic genetic tests. The consequences can include lower health care standards, reduced availability and hindered future development of treatments and tests.

What is Patentable?
In accordance with the laws enacted by Congress, the U.S. Patent and Trademark Office (USPTO) in the Department of Commerce determines if something can be patented.

The following categories are subject to possible patent issuance by the USPTO:
• A process
• A machine
• An article of manufacture
• A composition of matter
• Any new and useful improvement to an invention
(that falls under any of these categories).

What Cannot be Patented?
Patents have been prohibited by Congress in only a few cases where the issuance of a patent was clearly contrary to the public interest such as certain medical and surgical procedures and nuclear weapons. In addition, a patent on a human being is strictly prohibited, regardless of circumstances.

Apart from these specific items, in accordance with USPTO
rules, it is not permissible to patent the following:
• Naturally occurring organisms
• Laws of nature
• Natural or physical phenomena
• Abstract ideas
• Natural compounds (except in their purified state)

Although one cannot patent a naturally occurring gene, protein or any other natural compound as it exists in the body, one can patent a gene, protein or other natural compound that has been isolated from the body and is useful in that form as a pharmaceutical drug, screening assay or other application.

Judging Criteria
A patent application is judged on four criteria:
1. Useful
2. Novel
3. Nonobvious
4. Enablement

With respect to this judging criteria, in terms of genetics, one
must be able to:
1. Specify how the product functions in nature
2. Identify the genetic sequences
3. Specify the sequence’s product
4. Enable one skilled in the field to use the sequence for its stated purpose

Categories of Gene Patents
Patents on Genes and Gene Fragments (ESTs)
Genes and gene fragments are considered patentable items. The full sequence and function of gene fragments and indeed, genes, are not always known. Consequently, the patent applications submitted often identify their utility with vague definitions such as acting as a scientific probe to help find a gene, another gene fragment or to map a chromosome.
The controversy revolving around vague utility definitions regarding gene and gene fragments culminated in 1999 when the USPTO released stiffer interim guidelines stating that "more usefulness"—specifically how the product functions in nature—must now be shown before gene fragments are considered patentable. The new rules call for "specific and substantial utility that is credible."

Interestingly, the same sequence can be patented more than once; e.g., both an expressed sequence tag (EST) and the full- length gene of the EST can be patented. In general, however, PTO guidelines allow EST applicants, if they come first, to claim "dominance" over the full gene, implicitly, through use of legal language.

Patents on SNPs
Single nucleotide polymorphisms (SNPs) occur every 100 to 1000 bases along the 3-billion-base human genome and can occur in both coding and noncoding regions. SNPs may predispose people to disease or influence their response to disease; environmental insults such as bacteria, viruses, toxins, and chemicals; and drugs and therapies. SNPs are considered patentable material by the USPTO.

In April 1999, a number of large pharmaceutical and electronic companies and the U.K. Wellcome Trust, the U.K.’s largest non governmental source of biomedical research funds, established a non-profit foundation to find and map 300,000 common SNPs. In fact, 1.8 million SNPs were identified. The consortium planned to patent all the SNPs identified in order to prevent others from patenting the same information. The information is freely accessible to the public on the World Wide Web. This was in hopes of allowing open access to the information rather than have it controlled by private corporations.

Patenting Stem Cells and Cell Lines
Cell lines and genetically modified single-cell organisms are considered patentable material. Patents for stem cells from monkeys and other organisms have already been issued. Consequently, human embryonic stem cells are technically patentable.

Patenting Gene Tests
Genetic tests are patentable and are usually patented and licensed by the owners of the disease gene patent.

The Patenting Process
Although a patent is based on the "first to invent" principle, inventors have a one-year grace period to file a patent after they publish. Normally the issuance of a patent can take anywhere from 18 months to three years.
In general, the patenting process for biologicals usually involves the following steps:

• File a provisional patent.
• File a utility patent application which includes:
• A transmittal form which identifies the name of the applicant, the type of application, the title of the invention and the contents of the application.
• A fee transmittal form which is used to calculate the appropriate fee.
• A specification which is a written description of the invention and the manner or process of making and using it.
• A drawing, if necessary, to describe the invention.
• An oath/declaration signed by all the inventors.
• A sequence listing, disclosing pertinent nucleotide/amino
acid sequences.
• A deposit of a sample of the new invention (in some
cases) into one of the 26 worldwide culture depositories.
Specimens must be capable of self-replication either
directly or indirectly, and must be viable for at least 30
years.

Fees
In general, patenting process fees are as follows:
• A provisional patent: $150.
• A utility patent application: ~$760.
• The fees due upon issue: $1,210.
• The maintenance fees for patents are $940 due at 3.5 years,
$1,900 at 7.5 years and $2,910 at 11.5 years.
• Other miscellaneous fees may apply.
• Professionally prepared patents can range from $2,000 to
$15,000, depending upon the complexity of the patent.

Patent Expiration
Patents are in effect for 20 years; 21 if a provisional patent is
filed and 20+ years if an extension is requested. Several new rules
have been implemented regarding patent expiration.
1. If a U.S. Patent Application was filed by June 7, 1995 and
if it was issued before June 8, 1978, then the patent expires
17 years from issuance.
2. If the patent was filed by June 7, 1995, and if the patent
issues after June 7, 1978, then the patent expires the later
of 17 years from issuance, or 20 years from filing of earliest
U.S. patent application.
3. If the patent was filed after June 7, 1995, then the patent
expires 20 years from filing of application.
It should be noted that these periods remain as long as the
maintenance fees are paid. Also, up to five years are added in
cases of marketing delay due to an FDA or Virus-Serum-Toxin
approval process.

Patent Infringement
In the event that a patent is infringed upon, an injuction is
issued to the patent infringer, which prohibits that party from
continuing a particular activity. In the event the infringer fails
to adhere to the injunction, that party faces civil or criminal
contempt of court and may have to pay damages or sanctions
for failing to follow the court’s order. Regardless, a civil lawsuit
can be filled immediately in a federal district court accusing the
potential infringer of infringing a U.S. patent and damages may
be awarded.

All genome sequences, in addition to information of other
genetic elements generated by the Human Genome Project, have
been deposited into GenBank, a public database freely accessible
by anyone with a connection to the Internet. Because patent
applications are confidential until a patent is issued, those who use
sequences from such public databases actually risk facing a future
injunction if those sequences turn out to be patented by a private
company on the basis of previously filed patent applications.
It appears that the highly profitable drug and biotech companies,
in particular, tend to engage in strict patent enforcement. This is
likely due to the amount of funds required to broadly enforce their
patent licenses, agreements or restrictions.

U.S. Patents Recognition
A U.S. patent is not recognized worldwide. As an interim
solution, the Patent Cooperation Treaty (PCT) application process
allows an inventor to file a single application simultaneously in
each of a number of industrialized countries. However, eventually
(within 18 months) the inventor must, through the PCT process,
obtain a patent in each country for which protection is sought.

Who Owns What?
Major holders of U.S. gene-based patents include the U.S.
government, public and private universities, pharmaceutical and
biotechnological companies.

A major patent holder of genetic tests is Athena Diagnostics
(Worcester, MA) which holds patents on the following tests,
among others:

• Autosomal Dominant Ataxia
• Complete DMD Evaluation
• Complete Myotonic Dystrophy Evaluation
• Friedreich Ataxia DNA Test
• Osteogenesis Imperfecta Evaluation
• Partial DMD Sequencing
• SCA1,2,3,6,7,8 DNA Test
• Spinal Muscular Atrophy Test
Roche (Nutley, NJ) holds an exceptionally large number of
genetic testing-related patents holdings. Although a number of
their patents recently expired, the following are some genetic
testing related processes that remain under patent protection:
• Methods for Generating ssDNA by PCR
• Methods for DNA Sequencing with Taq
• HLA Typing Method and DNA Probes Used Therein
• Reverse Transcription with Thermostable DNA
Polymerases – High Temp. Reverse Transcription
• Methods for HLA DP Typing
• Method for Determining the Relative Amount of Viral
Nucleic Acid Segment in a Sample by the PCR
• Reverse Transcription with Thermus thermophilus
Polymerase
• Method and Reagents for HLA Class 1A Locus DNA
Typing
• Process for Detecting Specific Nucleotide Variations and
Genetic Polymorphisms Present in Nucleic Acids
• Quantitation of Nucleic Acids Using PCR
• Methods for In-Solution Quenching of Fluorescently
Labeled Oligo Probes
• Method for HLA SP Typing
• Oligo Primers for HLA Class I B Locus DNA Typing
• Methods for coupled High Temperature Reverse
Transcription and PCR
• Detection of Nucleic Acids Using a Hairpin Forming
Oligonucleotide Primer and Energy Transfer Detection
System
• Process for Detecting Specific Nucleotide variations and
Genetic Polymorphisms Present in Nucleic Acids
• Unconventional Nucleotide Substitution in Temp.
Selective RT-PCR
• Characterization and Detection of Sequences Associated
with Autoimmune Diseases
• Methods and Reagents for HLA DR beta DNA Typing
• Amplification Using a Reversibly Inactivated
Thermostable Enzyme
• Reagents and Methods for Coupled High Temp. Reverse
Transcription and Polymerase Chain Reactions
• Amplification Using a Reversibly Inactivated
Thermostable Enzyme
• Reaction Mixture for Detection of Target Nucleic Acids
• Homogeneous Methods for Nucleic Acid Amplification
and Detection
• Stabilized Thermostable Nucleic Acids Polymerase
Compositions Containing Non-Ionic Polymeric Detergents
• Methods and Devices for Homogeneous Nucleic Acid
Amplification and Detection
Other biotech companies well known for their patenting
efforts included the following:
• Myriad Genetics (Salt Lake City, UT) – genetic testing of
breast/ovarian cancer genes (BRCA1, 2)
• Bio-Rad Laboratories (Hercules, CA) –genetic testing of
Hemochromatosis and Sickle Cell Anemia
Licenses, Royalties and Fees
Licenses usually involve an upfront fee, plus a royalty charge
per test. Usually 9-20% of the cost of genetic testing goes to
royalties fees. Examples of royalty charges are as follows:
• Hemochromotosis – $20/test
• Canavan Disease – $12.50/test
• Gaucher Disease – $5/test
• Cystic Fibrosis – ~$2/test (depending on volume)
• use of Roche Taqman (a DNA polymerase) – $10/test

Conclusion
As of the end of 2001, the PTO had issued over 6,500 patents
covering gene and open reading frame sequences (DNA sequences
that code for proteins). Of these, over 1,300 patents were for
human genes or open reading frames. To date more than 20,000
applications for genes, DNA fragments, SNPs and so forth have
been submitted for review. Currently over three million genome-
related patent applications have been filed.

Unlike the early 90s, where patenting was "in vogue" and
tended to lead to a high profile and/or high stock prices it has
been noted that institutions and companies now seldom release
information on the number of patent applications filed, in an
apparent effort to quell public discourse and concern for the
patenting of genetic elements.

Sources
American Intellectual Property Law Association, An Overview of
Intellectual Property, What is a Patent, a Trademark, and a Copyright?
1995.

Athena Diagnostics, http://www.athenadiagnostics.com, 2006.
BIO (Biotechnology Industry Organization), http://www.bio.org/ip/primer/, 2006.

Bio-Rad Laboratories, http://www.bio-rad.com, 2006.

Coverage and Reimbursement of Genetic Tests and Services, Report of
the Secretary Advisor Committee and Genetics, Health and Society,
Department of Health and Human Services USA, Feb. 2006.

Garber, Ken, Homestead 2000: The Genome, http://www.signalsmag.com/
signalsmag.nsf/0/FD168FB6C42ACF6E882568950015E2D0, Signals
Online Magazine, 2000.

The Human Genome Project – Genetics and Patenting, http://www.ornl.
gov/sci/techresources/Human_Genome/elsi/patents.shtml, 2006.
U.S. Patent and Trademark Office (USPTO), http://www.uspto.gov/, 2006.