Posts Tagged ‘biomedical research’

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DTC Genomics: Opportunity Lost?

Monday, December 31st, 2012

Once I warmed up to the idea of startup companies offering to sequence the DNA of anyone capable of ordering from Amazon.com, I began to look forward to what might come of this nascent industry. Enabling individuals to have their DNA sequenced certainly seemed like an out-of-the-box idea at the time. I wondered if a so-called paradigm shift might arise from placing genetic information, unfiltered and unadvised, in the hands of those whose genes were being sequenced. Here were (and still are) two of my chief hopes for paradigm shifting that might come from throwing the genetics box wide open:

  • Will breaking the “chain of command” on health information change how we think about healthcare? The initial response from the medical world to the DTC genomics industry was less than enthusiastic, ostensibly because of the potential for harm when the uninformed masses got their hands on their gene sequences. This turns out not to be true—there is no evidence of harm from accessing one’s own DNA sequence information. Furthermore, there has been neither a flood of buyers nor a spate of lawsuits. The collective yawn over the availability of DNA sequencing (initial excitement not withstanding) suggests this might be more of a step along the way than a cannon shot.
  • Will putting this information in the hands of all who wish to know change how we think about genes? Over the last 60 years we have become quite genocentric in our view of biology. Genes are the “blueprints of life”, an identifiable “first cause” that drives everything else in the living world. For example, the term “oncogene” suggests that we have genes whose purpose is to cause cancer. That is possible, of course, but that suggests that there is some advantage to the organism to develop cancer, which doesn’t seem likely. As I think of it, genes are a part of a system we call an “organism” and they are no more or any less important than proteins, carbohydrates, etc that comprise that organism. It may be that not all of the diverse causes of cancer are genetic and we need to take a more holistic view of disease pathogenesis.

Essentially, what I am hoping for with the emergence of the DTC genomics industry is that the “hive mind” might provide new direction on genetics and its role in health and society. We might get really novel answers to thorny genetics questions like “what happens to missing heritability and is it important anyway?” Might it also be enough of a nudge to permanently put the paternalistic relationship between physicians and patients in the past? My hope for the DTC genomics industry is that it will help us reach a more balanced view of the role of DNA in living organisms.

However, for the moment at least, it appears that the wind is going out of the sails of the industry. As evidence, here are some recent developments:

  • Over the summer Navigenics was bought by Life Technologies, Inc. Gone was an industry pioneer.
  • This fall, deCODE was bought by Amgen. Not a surprising end to deCODE’s rocky road, but gone is another industry pioneer.
  • Recent developments announced by 23 and Me (patent received, grants funded, seeking FDA approval for products) sound suspiciously conventional. Has 23 and Me lost its will to break the mold?

Will there be a DTC genomics industry 2.0? The failure of pioneering companies in any new industry is not unusual. Yet, I am hopeful that these shifts will still happen. It seems likely, though, that it will be new companies that move the field forward and that (as usual) it will take longer than it initially seemed it would.

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Lessons learned from tumor heterogeneity

Tuesday, April 10th, 2012

My recent blog post, Tumor heterogeneity, revealed…, discussed the New England Journal of Medicine article by Gerlinger and colleagues describing the genetic heterogeneity found both within a patient’s individual tumor nodules and between spatially separate nodules.  There has been a substantial amount of discussion of this work and angst about how it might signal the end of personalized medicine even before it really got started.  I don’t believe that will be the case at all.  To the contrary, this paper made interesting contributions in three conceptual areas that may help pull the field forward.  These areas are the 1) relevance of prognostic gene expression profiles, 2) the nature of “driver” genetic mutations, and 3) the pathogenesis of cancer itself.  All of these areas are, in my opinion, very important to make headway in before personalized cancer medicine can become a truly effective tool in medicine.

Heterogeneity in gene expression profiles across the tumor specimen

The result that most seized on to proclaim the demise of personalized medicine was the finding that gene expression signature from spatially separated parts of a tumor nodule yielded different assessments of prognosis.  The implication is that a single biopsy specimen is inadequate to generate an accurate prediction of clinical course or response to treatment.  Most likely that is at least partially true.  However, the issue is with sampling, rather than the molecular biology.  We have known for decades that tumors have variable histology within their mass, with some regions reflecting poorer prognosis than others via their histologic grade.  Rather than reflecting a conceptual disconnect that dooms a new paradigm, it looks more like a technical problem to solve, which should be no surprise along this new path.

Convergent evolution

Both the Gerlinger paper, as well as others (e.g. Walter et al, NEJM), using NGS have now demonstrated that within a single patient the same gene can be found to be mutated multiple independent times, suggesting that this mutation creates a change in gene function that participates in the development of the cancer.  This had not been shown in humans before.  This finding will be useful for clinical diagnostics  and it may be game changing in basic research.  In clinical diagnostics identification of a multiply-mutated gene would give additional confidence that the damage it represents is causal and may help select targeted therapy.  In basic research, identification of such genes would represent novel evidence of the causality of specific genetic changes in the disease process.  This type of evidence is a smoking gun, a sign post saying “Needs to be mutated to reach this disease state”.  This type of evidence, which only deep sequencing can yield, is a new and useful application of NGS that was not previously available.

Pathogenesis

The picture that the Gerlinger paper, Walters paper, and others paints is one of clonal evolution of cancer.  This type of work paints this picture with clarity that has not been achievable before.  What is striking to me is that these results make it harder to ignore the concept that these molecular alterations, as important as they clearly are in the progression of cancer, may not be the cause of cancer.  They beg the question, “what initiated this evolutionary process?”.  Certainly, oncogenes, tumor suppressors, and the like are a part of cancer pathogenesis, carrying the developing disease along.  But it seems to me that there is still a “first cause” of some sort that we have not put our collective fingers on.  Genomic instability is certainly key, but then what is the genesis of the genomic instability?  What are the inputs that kick this process off?  Efforts to answer these questions will move us closer to effective treatments for cancer and other diseases that may share these pathogenic processes.

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Tumor Heterogeneity, Revealed…

Thursday, March 8th, 2012

A very interesting and timely article on tumor heterogeneity was published in the New England Journal of Medicine today.  Gerlinger and colleagues from the UK used next-generation sequencing to look for heterogeneity across various regions of renal tumors and metastases in four patients.  They report that indeed there is a great deal of heterogeneity within individual tumor nodules–in fact, most of the many alterations to the tumor genome were not shared across all nodules.  Further, analysis of the pattern of mutations revealed branching evolution of the primary tumor and its metastases, rather than a linear pattern of progression of the cancers.

A couple of important conclusions suggested by this work:

  • Single biopsies of the primary tumor may give you a very misleading understanding of the cancer.
  • Cancer stem cells may not be what we thought they were, if they exist.
  • Confirms the adaptability of cancers by demonstrating convergent evolution of functional gene alterations.

None of what was reported is inconsistent with evidence from previous decades of cancer research.  It was work that really needed to be done and I’m happy it appears to have been completed in a careful, thoughtful way.

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An Academic—Industry Partnership to Study DTC Genomics

Tuesday, March 6th, 2012

A GenomeWeb story today provides details of a study being performed by researchers at Brigham and Women’s Hospital and the University of Michigan on the motivations for getting and effects of DTC genomic testing. The study will look at the attitudes and motivations of 1000 people who order tests from 23 and Me or Pathway Genomics before testing. These results will be compared with the subjects’ attitudes toward their health and changes in their behaviors following testing to ascertain how people use genetic information.

Two interesting aspects to this study are the academic-industry collaboration and the window into social attitudes toward genetic information. The ability to complete this research will require the industry participants to cooperate, which in turn required give and take from both academia and industry to accommodate the needs of both parties during the planning process. These two groups are often at odds, so it is heartening to see a partnership that recognizes that both parties are motivated to make positive contributions to the greater health good. The road to this agreement is described in this paper by Lehmann and colleagues .

Clearly, the payoff for this study will be answers to questions around why people are interested in this type of testing anyway and what effect it has on their lives. A big concern from the health policy world has been that dispensing this type of information without expert interpretation might lead to a range of ill effects on the recipients. Happily, this so far has not been the case and for the most part I don’t believe ill effects will be observed in the future.

I am curious to see what the motivations for so-called “recreational” user are, if those can be identified in this study. Similarly, it will be interesting to infer from these results how seriously people take genetic information. My sense of it is that these results may reflect back in surprising ways on the usefulness of a variety of other genetic and genomic testing services, primarily involving the risks of disease. This study will hopefully provide a novel window into what we as a society really think of genomics.

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Testing DTC Genomic Testing I

Monday, November 14th, 2011

Now that we’ve all gotten over the shock of being able to order a genetic test through Amazon.com, we can begin to actually ask some useful questions about DTC genomic testing and its utility.  Not much is really known about how useful it is.  However, in the tradition of Hippocrates, the first question we must ask is “is it harmful?”

The medical research community was all over the task once the DTC genomic testing services emerged from the intellectual garages of Silicon Valley and elsewhere and hit the streets.  Two studies of note asked the question above, using Navigenics’ service as a model.  The first paper was published by Bloss and colleagues in the New England Journal of Medicine in February of this year.  Just last month, James and colleagues published another study of the effects of DTC genomic testing in the Proceedings of the Mayo Clinic.  Neither paper reported any untoward effects of genomic testing under these circumstances on the test population.

More studies of DTC genomic testing are in the offing, I’m sure, in addition to the commentary and other reports on the technology so far published.  Now might be a good time to take a longer look and ask some of the interesting questions about DTC genomic testing, what it means, and why it created such a commotion.  I am in the process of shifting through many of these reports and opinions and will write another post soon on the subject.

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Are most published research findings false?

Friday, October 7th, 2011

Many people are aware of the work of John Ioannidis regarding the analysis of research findings and the conclusions drawn from those analyses.  In particular, these concepts were described by him in a paper published in PLOS Medicine in 2005 is apparently the most downloaded article from that journal.

I’ve had this article on my mental favorites list for some time now.  I am finally putting a few words in print about it mostly to put a stake in the ground on this issue because I believe it is an important one in this era of high volume research reporting.  In short, I agree with the article’s main conclusions, although I might phrase it as “most published biomedical research conclusions are not true”.  This is not to say I think there is some conspiracy or that statistics are useless.  To the contrary:  statistics is an enormously useful field of applied mathematics.  I also think a great deal of very good research is being done in labs and clinics around the world by very dedicated and smart researchers.

My concern over the veracity of biomedical research and how these results are reported stems from the nature of statistical models and test versus how they are interpreted and reported.  Within that discussion is another around the unspoken assumptions underlying both our biological and statistical models.

Perhaps the stickiest issue for me is the use, or misuse, of p values in many published studies.  Without getting too long-winded about it, far too often the p value is used all by itself and given the status of a “stamp of approval”.  Using a p value in isolation (i.e. p=0.001 therefore I won!) is ignoring a lot of important information.  What type of test did you “win”?  What distribution of p values for this test did you assume?  Are your assumptions correct?  Did you keep testing data until you found the p value you were hoping for?

Fortunately, I think the wider scientific community is waking up to the deficiencies in the most commonly used statistical analysis scenarios.  This recent article from Genomeweb does a nice job describing the basic appropriate role for statistical analyses in biomedical research.  An important distinction pointed out in their article is that statistical significance and biological (or clinical) significance are two different things.  When we rely on statistics to identify important relationships within a vast ocean of information, it is all the more important to understand what these mathematical tools are telling us.

As the wise scientist once said, “Never assume anything other than a 4% mortgage.”  I mentioned assumptions above in the sense of statistical models; assumptions also come into play in experimental design.  My sense of it is that these assumptions are usually underappreciated or perhaps even ignored.  The danger, of course, is that incorrect assumptions, statistical or experimental, can invalidate the results and conclusions of any research.  Often these assumptions difficult to verify, which we might be able to cope with, if we knew what these assumptions were.  Unfortunately, they are not part of the standard scientific reporting paradigm.  This recent article in PLoS Computational Biology sheds some light on the issue of reporting experimental assumptions.  Again, by bringing the issue to light there is hope that we can begin to change our science reporting procedures to incorporate some discussion of assumptions.

I find it reassuring that these discussions about accurate analysis and reporting of scientific research are surfacing.  Opening up communication about these critical issues will greatly enhance our ability to navigate through the ocean of biomedical studies available to us.

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Failure of the Genome?

Thursday, May 19th, 2011

I recently read an article written by Jonathan Latham in the Guardian (UK) online with the title, “Failure of the Genome” (credit to Genome Web for pointing the post out to their readers).  Following the eye-grabbing headline, the article goes on to posit that the Human Genome Project has not turned up much of use.  Indeed, the author asserts that there is scant evidence supporting the genetic underpinnings of disease paradigm.  To a geneticist or one of the many others who have backed the various genome projects, this is provocative indeed.

So, why did this provocative headline catch my eye?  I have to admit, I am one of those who have become weary of seeing the “Gene For…” headlines ad nauseum over the last couple of decades, only to see those claims vanish into the twilight of yesterday’s news time and again.

The magically vanishing claims of genetic causation that show up daily certainly have jaded even a dedicated molecular biologist like me* to an extent.  As such, I can understand how this pattern of hype of research results followed by disillusion when the claims quietly die would dishearten others who see these stories.

So, maybe what grabbed me was the sense that we, as a society, have swallowed the genetic-cause-of-disease hype hook, line, and sinker—and this article is evidence of rising discontent the emptiness of those hyped promises that come in company and university press releases.  The real story about genes and disease is more complicated than will fit in the easy to digest news bits that are our common food in these information-intense times.

I hope that we scientists will recognize this backsplash as a signal to examine how we communicate our science.  What I most value in the scientific enterprise are the truthfulness and credibility that are a part of this culture.  I hope we will work to preserve these qualities.

 

*I come to this as a molecular biologist with a couple of decades of experience doing research in oncology, in particular, the role of oncogenes in the development and progression of cancer.  Based on my own hands-on experience in trying to understand the role of genes in a disease, I’d be hard pressed to simply dismiss genetic variation as a factor is disease causation, as Mr. Latham does.  It is pretty clear to me that variation in genetic makeup leads to variation in phenotype, some of those phenotypes being what we call “disease”.

 

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ESHG Chimes in on DTC Genetic Testing

Friday, September 3rd, 2010

The European Society of Human Genetics (ESHG) published a policy statement in the European Journal of Human Genetics on the Society’s position with respect to Direct to Consumer Genetic Testing services .  In this position paper the ESHG discusses its position with respect to DTC advertising, quality, supervision, counseling, consent, privacy, and more.

Overall, the authors present cogent arguments for their views about how to handle DTC genetic testing.  The authors open by affirming that individuals have the right to know information about their genetic makeup, a point that I have not seen argued yet.  Then the authors tackle advertising of DTC services and quality of DTC services.  In both cases I, like the ESHG, think the DTC companies leave much to be desired.

The following paragraphs of the position paper from the ESHG espouse supervision of all genetic testing by medical professionals, mandatory counseling, and a significantly more involved informed consent process.  These views from the ESHG seem pretty conservative to me, to the point of being paternalistic.  In fact, the authors state that the “right to know” needs to be balanced against “the need to protect the same individuals from inappropriate genetic information”.  Keep in mind that the ESHG has an interest in enhancing the public perception of genetic testing.

While their viewpoints are valid ones, they seem to me to reflect the current status quo and to lose the potential for discovering new uses for genetic information in healthcare that may result from “open horizon” creativity.  To be sure, the entrepreneurial attitude that characterizes the DTC genomics/genetics companies now comes with risks, but its exploratory character can result in quantum leaps in understanding.  The diminished quality and partial truthfulness of these young companies struggling in a new industry can be hazardous to society, but at some level we need to take risks like those in order to advance.  The secret, I believe, is to balance the liberty with restrictions in order to control the risk to society and its individuals as best as we can.

The good news is that this is exactly the kind of public conversation we should be having about how to handle this new area of medicine.

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UC vs NPG, continued…

Friday, August 27th, 2010

I have to confess that I agree with the excerpt quoted below from the UC rep.  Hopefully this saga portends future progress in the scientific publishing field.

From http://www.genomeweb.com//node/948284?hq_e=el&hq_m=798093&hq_l=3&hq_v=a2a10fac80:

“Laine Farley, who directs UC’s California Digital Library, tells USA Today that the current journal model, under which researchers ‘contribute the labor to produce the articles that go into these journals, they do the peer review, they often are editors, and then the institution has to buy back the access to the output of their research,’ is not acceptable, and ‘needs to change.’ “

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Is the Internet making us intellectually shallow?

Friday, June 25th, 2010

A colleague sent around an email a few days ago that pointed to a book review that asks this question:

Is the Internet making us intellectually shallow?  http://www.csmonitor.com/Books/Book-Reviews/2010/0621/The-Shallows?sms

For me, I’ve found the internet like drinking from a firehose–way too much material to take in.  Hence, I noticed initially that I was fairly shallow in how I read material online.  Now that this resource has become the dominant one for written material that I use for my work I have learned to discipline myself to better focus on what I have chosen to read.  While this requires some extra effort on my part, the upside is that there is an amazing amount of material within easy reach to chose from.

So, my answer to that question would be, “No, the internet does not necessarily make us intellectually shallow.”  Rather, my feeling is that the internet challenges us to choose wisely.

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