Quick quote:

“Medco, which already uses genetic testing to help guide usage of the blood thinner warfarin and the breast cancer drug tamoxifen, in February acquired the San Francisco-based genetic testing company DNA Direct. Now the company will expand its testing program to include the usage of the widely-prescribed blood thinner, Plavix, the HIV drugs Selzentry and Ziagen, and the use of Gleevec for patients being treated for chronic myelogenous leukemia.

Additionally, the company will counsel its clients for which genetic tests they should pay, and its member patients and their doctors about a variety of genetic and diagnostic tests including pharmacogenomic, fertility, and pre-natal testing, it says.”

Consider this case example of how genomics might be integrated into medical practice within the next 10 years:

Medical Practice Circa 2015

Li Fang , a 50-year-old woman, had her genome scanned 4 years ago, in 2011, by her physician and was found to have 5 genetic variants that increase her risk for heart disease threefold; Recommendations for her diet and medications have been made on the basis of her genetic profile for metabolizing nutrients and specific medication classes. During her last examination, she underwent a screening blood-based profile for coronary artery disease that not only showed that her atherosclerotic disease burden was high but also that her overall risk for developing an acute coronary syndrome in the next 5 years was high. When chest pain developed recently, a blood-based molecular biosignature confirmed ischemia caused by intermittent thrombosis without necrosis. Targeted specifically tailored anti-inflammatory and individualized dosing regimens for anticoagulant medications were prescribed and symptoms did not recur.

More on genes and genomics:

Rumor on the street is that the genomics trend will herald in a new era in designer “skin-tight” tailored therapy. The Human Genome Project, obtaining the DNA sequence of all human chromosomes followed by the identification of all human genes, was completed in 2003 and is being rapidly followed by studies to understand the functions of encoded proteins (functional genomics), and the mapping of the majority of sequence variants in the human population. Rapid advances in mapping variant genes have already changed clinical practice on several fronts raising the question of what impact genetic information will have once a majority of genetic variants is known for all major diseases.

From: Genomics Heralded as New Tool for Improving Public Health: Emerging Science by Teddi Dineley Johnson.

“Genomic advances are occurring rapidly. On March 30, for example, scientists from the National Human Genome Research Institute announced that they had identified six additional genetic variants that are involved in type 2 diabetes, raising to 16 the total number of genetic risk factors associated with increased risk of the disease. And new research published in Nature in April found that people who carry a certain gene may be particularly likely to get addicted to cigarettes and may consequently be at greater danger of lung cancer and other diseases.”

The cell’s brain center (nucleus) contains chromosomes. Chromosomes are composed of genes constructed from sequences of DNA. Genes are the blueprint for the body to create proteins.

Despite stunning advances in drug discovery, drug therapy is often purely palliative – improving disease symptoms or delaying poor outcomes but is not effective at curing the disease and may even cause serious harm especially in the chronic illness of the elderly. The search for “blockbuster” drugs with the implied suggestion that attempts to rectify a complex pathophysiologic process with a single agent (drug) of poorly defined characteristics obviously has limits. There is also an increasing awareness of genetic variability among individuals as a principal determinant of disease susceptibility and therapy outcome. Therefore, knowing the gene map of a patient might help improve drug efficacy and reduce toxicity — by selecting the right drug for the right patient.  

From: Company Sequences Whole Human Genome for $1,700

Want to know your entire DNA sequence? Privately held Complete Genomics says it can do a genome map for as little as $1,700 — compared with the $100 million the Human Genome Project spent to complete the first sequencing of the human genome in 2000.

Knowing a patient’s disease susceptibility may also permit early initiation of therapy or prevention and testing existing drugs against possible genetically susceptible patients in this fashion may potentially be as cost effective and as successful as the search for new drugs.

 For drug therapy, genetic information will have profound impact in a number of ways:

• Disease genotype (gene map) determines the optimal therapeutic approach.
• Genetic variants inform physicians in the selection of effective drug and proper dosage.
• Genetic variants affecting disease susceptibility serve to initiate early treatment or prevention.
• Genomics directs the design of novel drugs that avoid or exploit specific genetic variants.

The newly emerging fields of pharmacogenetics and pharmacogenomics deal specifically with genetic determinants of drug therapy. While pharmacogenetics largely focuses on a specific candidate gene, such as those for drug-metabolizing enzymes, pharmacogenomics broadens the scope of study to include all relevant disease or drug related genes. The latter approach takes into account that a patient’s response to any given drug depends on numerous proteins in the body, such as metabolizing enzymes, transporters, receptors, and entire signaling networks mediating the response. Furthermore, genetic defects that underlie the disease process could determine the drug’s effects even if they have no direct bearing on its mechanism of action.

Genome-wide scanning has become a priority and a hotly contested issue for the pharmaceutical industry in drug discovery and therapy. Several large pharmaceutical concerns have joined forces with the goal of making a genome-wide map publicly available for all to exploit equally — a generous altruistic gesture.

And what about Asia? Press release from the friendly folks at Big Pharma:

Lilly, Merck, And Pfizer Join Forces To Accelerate Research And Improve Treatment Of Lung And Gastric Cancers In Asia

NDIANAPOLIS, WHITEHOUSE STATION, N.J. & NEW YORK, Feb 23, 2010 (BUSINESS WIRE) — Eli Lilly and Company, Merck (also known as Merck Sharp & Dohme (MSD) outside the USA and Canada), and Pfizer Inc. today announced the formation of the Asian Cancer Research Group, Inc., (ACRG), an independent, not-for-profit company established to accelerate research and ultimately improve treatment for patients affected with the most commonly-diagnosed cancers in Asia.

The ACRG’s formation represents a prime example of a growing trend in pre-competitive collaboration in which large pharmaceutical companies combine their resources and expertise to rapidly increase knowledge of disease and disease processes. The goal of the ACRG is to improve the knowledge of cancers prevalent in Asia and to accelerate drug discovery efforts by freely sharing the resulting data with the scientific community.

“Through its work and the subsequent sharing of information, the ACRG hopes to empower researchers, foster innovation and improve the prognosis and treatment of patients with cancer,” said Gary Gilliland, M.D., Ph.D., senior vice president and franchise head, Oncology, Merck Research Laboratories.

Initially, the ACRG will focus on lung and gastric cancers, two of the most common forms of cancer in Asia. As many as 40 percent of patients with lung cancer in Asia demonstrate a mutation that is relatively rare in Western patients (EGFR mutation).1 This mutation has resulted in differences in response to some types of agents, suggesting that a different research approach is needed for developing treatments for certain patient populations.

Gastric cancer has reached near epidemic proportions in some countries in Asia. Despite its relatively low incidence in the West, gastric cancer is the second largest cause of cancer death in the world, killing more than 630,000 patients per year, more people than all cancers combined in the United States.

“Environmental and genetic factors are believed to underlie the dramatic differences in the molecular subtypes and incidence of cancers in Asia and other parts of the world,” said Neil Gibson, Ph.D., chief scientific officer of Pfizer’s Oncology Research Unit. “Although some progress has been achieved in the last few years in understanding and treating these cancers, they remain a huge unmet need and a disproportionate health burden to Asian patients.”

Over the next two years, Lilly, Merck and Pfizer have committed to create one of the most extensive pharmacogenomic cancer databases known to date. This database will be composed of data from approximately 2,000 tissue samples from patients with lung and gastric cancer that will be made publicly available to researchers and, over time, further populated with clinical data from a longitudinal analysis of patients. Comparison of the contrasting genomic signatures of these cancers could inform new approaches to treatment.

Today’s announcement marks the formation of the ACRG. The company is currently focused on establishing collaborative relationships throughout Asia to collect the tissue samples and data. All tissue samples and data will be collected and shared in accordance with good medical practices and local laws.

Lilly has assumed responsibility for ultimately providing the data to the research public through an open-source concept managed by Lilly’s Singapore research site. Moreover, Lilly, Merck and Pfizer will each provide technical and intellectual expertise.

“The ACRG is about sharing information for the common good,” said Kerry Blanchard, M.D., Ph.D., vice president and leader of drug development in China for Lilly and who represented Lilly in the ACRG’s formation. “This company will aid researchers around the world to develop diagnostics, tailor current treatments and develop novel therapies to improve outcomes for affected patients with lung, gastric and perhaps other forms of cancer.”

The future is now….almost.

Tej Deol M.D.

First, the International Society for Stem Cell Research (ISSCR) recently issued an excellent Patient Handbook on Stem Cell Therapies (attached below). This freely downloadable publication does not grapple with the complex regulatory differences between for example the USA, Europe and China, but does offer in layman’s terms some basic definitions and sound advice on how to evaluate the legitimacy of a stem cell therapy and on what questions to ask if you decide to participate in a clinical study. The ISSCR website is by far the best web portal for any and all information about stem cells, whether adult or embryonic, short summaries of recent experimental findings and ongoing ethical debates.

Second, learn by an exciting and as yet unproven example. Human embryonic stem cells (hESCs) are derived from the five-day old blastocyst-stage human embryo, a time before implantation into the uterine wall of the mother3. Each hESC line is derived from a single human embryo, and is thought to be able to, under the right experimental conditions, produce each and every cell type that comprises the adult human. That is to say that these cells are pluripotential—able to produce a retinal cell equally as well as a spinal cord neuron. Since their isolation in 1998 by Dr. James Thomson and colleagues at the University of Wisconsin-Madison, significant advances have been made in our understanding of their fundamental properties—what they are and what they really can do—and in their basic culture requirements in the laboratory. Today, hESCs can be grown by the billions and in conditions that meet current pharmaceutical-grade current Good Manufacturing Practice (or cGMP). Thus, there has been tremendous investment in places like Singapore and California to push stem cell research from the bench to the bedside. For those of us in the field, we consider hESCs as near inexhaustible source material for the future production of beta cells that secrete insulin for the treatment of type I diabetes or cardiomyocytes to restore heart function after myocardial infarct. Delivering on this promise of off-the-shelf stem cell therapies has, however, been frustratingly slow save one solid example: Geron, a biotech company based in Menlo Park, California, recently emerged as the first horse out of the gate, but the race to the clinic is still on.

The US FDA is responsible for promulgating all the regulatory requirements related to stem cell therapy, whether of embryonic or adult origin, and for addressing questions of safety and efficacy of cell preparations bound for transplantation. Excitingly, Geron received in January 2009 the green light from the FDA to launch the world’s first Phase I multi-center clinical trial of a product derived from hESC. (Phase I trials are coined “safety” trials as they enlist a small number of patients to evaluate the safety—pharmacovigilance—, kinetics and tolerance of a new drug.) In collaboration with scientists at the University of California Irvine, Geron established a bank of oligodendroglial precursor cells termed GRNOPC1 that were produced—often referred to in laboratory-speak as “differentiated”—from hESC. Oligodendroctyes are the cells that produce myelin, which ensheathes axons of the central nervous system to ensure the proper conduction of electrical impulses (the outside coating of our bodies nerve wiring). These cells are lost after spinal cord injury. In rodent studies, injection of GRNOPC1 into the site of spinal cord injury significantly improved the ability of the animal to move, although the molecular mechanism behind the observed recovery is unclear.

The announcement by Geron of the FDA’s approval of its GRNOPC1 Investigative New Drug (IND) application—purportedly, the largest single application ever—paved the way for transplantation of these cells into human patients with thoracic spinal cord injuries. This news was received with much excitement and trepidation by the stem cell community. If GRNOPC1 produced tumors—embryonic stem cells are inherently tumorigenic—or other dangerous side effects, the field of regenerative medicine would no doubt be dealt a crushing blow. If, however, GRNOPC1 were shown to be safe and hopefully efficacious, the field would experience renewed momentum. With the world’s eye on Geron, it was not altogether surprising that 8 months later, the FDA placed a clinical hold on Geron’s Phase I trail after it was revealed that in preclinical studies, some treated animals developed microcysts in the region of injury. To date, no patients have been transplanted with the GRNOPC1, and no other IND application concerning the transplant of hESC-derived material has received approval by the US FDA. According to Geron’s website, the company continues to evaluate the pathological significance, if any, of these microcysts in an effort to provide additional data supporting release of the FDA clinical hold.

Bearing in mind the protracted story of Geron’s highly anticipated clinical trial and the hundreds of millions of dollars and man and woman hours spent to propel a finding in an academic laboratory into the clinic, it is no surprise that rogue companies such as NuTech Mediworld, TheraVitae and Medra, Inc., which claim to treat diseases as diverse as epilepsy, muscular sclerosis, cerebral palsy and lupus with hESC or human fetal material or other assorted, poorly characterized stem cells, are subject to so much frustration and ire from the global scientific community. They operate outside of government regulation and local ethics boards and disregard the international norm of properly controlled clinical trials and publication in peer-reviewed journals. They prey upon the hope of desperate patients in “stem cell tourist traps”. Before booking your ticket to a renegade clinic for a purported magic bullet therapy, look to the example of the US FDA and Geron. Quite simply, do your homework.

Ray Dunn, Ph.D.
The views expressed in this piece are entirely the author’s own.

Begin forwarded message:

From: Chetan xxxxxxxx
Date: February 9, 2010 11:51:46 PM SST
To: Tej Deol
Subject: 2 cokes a day…

You were saying that there is no issue drinking several cokes a day… the study says you have an 87% chance higher risk…. take a look, made huge news a few days ago in the States.

My friend quoted 3 sources including WebMD, an article in Reuters, and the actual abstract from the Medical Journal, Cancer Epidemiology, Biomarkers & Prevention February 2010 19; 447 . Here is the actual abstract:

Soft Drink and Juice Consumption and Risk of Pancreatic Cancer: The Singapore Chinese Health Study

Abstract

Background: Sugar-sweetened carbonated beverages (called soft drinks) and juices, which have a high glycemic load relative to other foods and beverages, have been hypothesized as pancreatic cancer risk factors. However, data thus far are scarce, especially from non-European descent populations. We investigated whether higher consumption of soft drinks and juice increases the risk of pancreatic cancer in Chinese men and women.

Methods: A prospective cohort analysis was done to examine the association between soft drink and juice consumption and the risk of pancreatic cancer in 60,524 participants of the Singapore Chinese Health Study with up to 14 years of follow-up. Information on consumption of soft drinks, juice, and other dietary items, as well as lifestyle and environmental exposures, was collected through in-person interviews at recruitment. Pancreatic cancer cases and deaths were ascertained by record linkage of the cohort database with records of population-based Singapore Cancer Registry and the Singapore Registry of Births and Deaths.

Results: The first 14 years for the cohort resulted in cumulative 648,387 person-years and 140 incident pancreatic cancer cases. Individuals consuming ≥2 soft drinks/wk experienced a statistically significant increased risk of pancreatic cancer (hazard ratio, 1.87; 95% confidence interval, 1.10-3.15) compared with individuals who did not consume soft drinks after adjustment for potential confounders. There was no statistically significant association between juice consumption and risk of pancreatic cancer.

Conclusion: Regular consumption of soft drinks may play an independent role in the development of pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 19(2); 447–55

WOW. Look at that conclusion: “soft drinks may play an independent role”. It doesn’t get more definitive than that. Good reason to provoke public anxiety. Eating durians (despite the smell) “may” bring you wealth. “And in a “Look at Me!” article title published by WebMD:

Study Says 2 Sodas Per Week Raises Pancreatic Cancer Risk; Beverage Industry Says Study Is Flawed
By Kathleen Doheny
WebMD Health News
Reviewed by Louise Chang, MD

Feb. 8, 2010 — Drinking as little as two soft drinks a week appears to nearly double the risk of getting pancreatic cancer, according to a new study.

”People who drank two or more soft drinks a week had an 87% increased risk — or nearly twice the risk — of pancreatic cancer compared to individuals consuming no soft drinks,” says study lead author Noel T. Mueller, MPH, a research associate at the Cancer Control Program at Georgetown University Medical Center, Washington, D.C. The study is published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

The beverage industry took strong exception to the study, calling it flawed and pointing to other research that has found no association between soda consumption and pancreatic cancer.

etc etc…

Buried in the second page relative to attention-grabber:

The beverage industry protested the results. ”The study has a lot of weaknesses in it,” Richard Adamson, PhD, scientific consultant for the American Beverage Association in Washington, D.C., tells WebMD.

One example, he says, are the small numbers of pancreatic cancer cases. He points out that of the 140 cases, 110 of those people did not drink sodas, while 12 had less than two servings a week, and 18 had two or more servings a week.

”It has a small number of pancreatic cancer cases compared to the population studied,” he tells WebMD.

Other studies have found no link, he tells WebMD.

In a statement attributed to Adamson, the American Beverage Association points to a 2008 study finding no such link. It also takes exception to the focus on soft drinks rather than overall dietary patterns.

The Reuters article provided this message of caution as well:

But Susan Mayne of the Yale Cancer Center at Yale University in Connecticut was cautious.

“Although this study found a risk, the finding was based on a relatively small number of cases and it remains unclear whether it is a causal association or not,” said Mayne, who serves on the board of the journal, which is published by the American Association for Cancer Research.

“Soft drink consumption in Singapore was associated with several other adverse health behaviors such as smoking and red meat intake, which we can’t accurately control for.”

Other studies have linked pancreatic cancer to red meat, especially burned or charred meat.

As we can see, people pay a lot of attention to titles and sometimes skip the ‘meat and potatoes’. (Mis) Information is easily spread in the digital age and apparently sometimes accountability need not apply. This month, in the NY Times, we got this encouraging, but LONG OVERDUE, action by a highly respected British journal of medicine, the Lancet:

February 3, 2010
Journal Retracts 1998 Paper Linking Autism to Vaccines
By GARDINER HARRIS

A prominent British medical journal on Tuesday retracted a 1998 research paper that set off a sharp decline in vaccinations in Britain after the paper’s lead author suggested that vaccines could cause autism.

The retraction by The Lancet is part of a reassessment that has lasted for years of the scientific methods and financial conflicts of Dr. Andrew Wakefield, who contended that his research showed that the combined measles, mumps and rubella vaccine may be unsafe.

But the retraction may do little to tarnish Dr. Wakefield’s reputation among parents’ groups in the United States. Despite a wealth of scientific studies that have failed to find any link between vaccines and autism, the parents fervently believe that their children’s mental problems resulted from vaccinations.

Tom Skinner, a spokesman for the Centers for Disease Control and Prevention, called the retraction of Dr. Wakefield’s study “significant.”

“It builds on the overwhelming body of research by the world’s leading scientists that concludes there is no link between M.M.R. vaccine and autism,” Mr. Skinner wrote in an e-mail message.

A British medical panel concluded last week that Dr. Wakefield had been dishonest, violated basic research ethics rules and showed a “callous disregard” for the suffering of children involved in his research. Dr. Richard Horton, editor in chief of The Lancet, said that until that decision, he had no proof that Dr. Wakefield’s 1998 paper was deceptive.

“That was a damning indictment of Andrew Wakefield and his research,” Dr. Horton said.

With that decision, Dr. Horton said he could retract the 1998 paper. Dr. Wakefield could not be reached for comment.

Jim Moody, a director of SafeMinds, a parents’ group that advances the notion the vaccines cause autism, said the retraction would strengthen Dr. Wakefield’s credibility with many parents.

“Attacking scientists and attacking doctors is dangerous,” he said. “This is about suppressing research, and it will fuel the controversy by bringing it all up again.”….

….After Dr. Wakefield’s study, vaccination rates plunged in Britain and the number of measles cases soared. etc etc….

I wonder what is the responsibility of The Lancet in evaluating papers for publish. Can any Tom, Dick, or Andrew simply walk up and submit or are reasonable generally accepted principles of scientific research respected especially in news which the media may exploit. Dr. Horton, the editor in chief of The Lancet, claimed that “….until that decision, he had no proof that Dr. Wakefield’s 1998 paper was deceptive”. However, one year ago, this was published:

Times Online

From The Sunday Times
February 8, 2009
MMR doctor Andrew Wakefield fixed data on autism
Brian Deer

THE doctor who sparked the scare over the safety of the MMR vaccine for children changed and misreported results in his research, creating the appearance of a possible link with autism, a Sunday Times investigation has found.

Confidential medical documents and interviews with witnesses have established that Andrew Wakefield manipulated patients’ data, which triggered fears that the MMR triple vaccine to protect against measles, mumps and rubella was linked to the condition.

The research was published in February 1998 in an article in The Lancet medical journal. It claimed that the families of eight out of 12 children attending a routine clinic at the hospital had blamed MMR for their autism, and said that problems came on within days of the jab. The team also claimed to have discovered a new inflammatory bowel disease underlying the children’s conditions.

However, our investigation, confirmed by evidence presented to the General Medical Council (GMC), reveals that: In most of the 12 cases, the children’s ailments as described in The Lancet were different from their hospital and GP records. Although the research paper claimed that problems came on within days of the jab, in only one case did medical records suggest this was true, and in many of the cases medical concerns had been raised before the children were vaccinated. Hospital pathologists, looking for inflammatory bowel disease, reported in the majority of cases that the gut was normal. This was then reviewed and the Lancet paper showed them as abnormal.

Despite involving just a dozen children, the 1998 paper’s impact was extraordinary. After its publication, rates of inoculation fell from 92% to below 80%. Populations acquire “herd immunity” from measles when more than 95% of people have been vaccinated.

Last week official figures showed that 1,348 confirmed cases of measles in England and Wales were reported last year, compared with 56 in 1998. Two children have died of the disease.

And finally exposed…

The Shame of the Lancet’s Shoddy Autism Study Retraction
By Jim Edwards | Feb 3, 2010

The Lancet has published a retraction of a 1998 study by Andrew Wakefield that purported to show a link between vaccines and autism in children. The retraction is a full-scale reversal and denial of a key study that for years has been used as evidence by parents who believe (wrongly, as it turns out) that vaccines cause autism. But as Matthew Herper of Forbes points out, the wording of the Lancet’s retraction is virtually impossible to understand, and could muddy rather than clarify a debate which many parents of autistic children have tragically misunderstood. Herper:

… the Lancet uses language that is likely to be impenetrable to anyone not versed in the scientific literature. The retraction, as published, reads:

Following the judgment of the UK General Medical Council’s Fitness to Practise Panel on Jan 28, 2010, it has become clear that several elements of the 1998 paper by Wakefield et al* are incorrect, contrary to the findings of an earlier investigation. In particular, the claims in the original paper that children were “consecutively referred” and that investigations were “approved” by the local ethics committee have been proven to be false. Therefore we fully retract this paper from the published record.

(I’m quoting Herper’s version of the retraction because the Lancet has hidden its version in part behind a pay wall!)

That retraction gives you no idea of how bad Wakefield’s study actually was. Among its flaws, the kids were not picked at random. Wakefield (pictured) gathered them from parents who already believed vaccines may have triggered their autism. He also took £55,000 in fees from a legal aid society connected to a lawyer who wanted to sue vaccine makers. And, as The Guardian notes:

He was also found to have unethically arranged for his son’s friends to have blood samples taken from them during his birthday party – for which he paid them £5 each.

Even if you throw out the stuff about paying study participants and gathering data from a self-selecting population, and the financial conflict, the fact that there were only twelve children in the study ought to have indicated that its data was virtually worthless. (Gold-standard studies have hundreds or thousands of patients.)

Yet because it was published in the Lancet and concluded with a “link” between autism and vaccines, parents with autistic children have been searching and advocating a link between the two ever since.

etc etc …

So the media played both angles the way it usually does. First bringing on the panic with initial news release, then subsequently benefiting from exposing the reality. However, Medical Journals have reputations to protect and a responsibility to ensure the highest standards of scientific research are pursued before they publish. It is clear that in this case that was absent. People suffered and even died as a result of contracting measles due to the decline in immunization rates. The only question is will The Lancet be held accountable.

And then, from India, there is just the bizarre in accountability…

Tej Deol, M.D.