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Precision Medicine: The Coolest Part of Medicine

QuellosOne size rarely fits all. Most medical knowledge is derived from studying groups of subjects, subjects who may be different in some way from the individual who walks into the doctor’s office. Basing medicine only on randomized controlled studies can lead to over-simplified “cookbook” medicine. A good clinician interprets study results and puts them into context, considering the whole patient and using clinical judgment to apply current scientific knowledge appropriately to the individual.

CAM practitioners claim to be providing individualized treatments. Homeopaths look up symptoms like “dreams of robbers,” “sensation of coldness in the heart,” and “chills between 9 and 11 AM” in their books, and naturopaths quiz patients in great depth about their habits and preferences; but they don’t have a plausible rationale for interpreting the information they gather. And they have not been able to demonstrate better patient outcomes from using that information.

A new concept, “precision medicine,” was recently featured in UW Medicine, the alumni magazine of my alma mater, the University of Washington School of Medicine. Precision medicine strives to provide truly individualized care based on good science. It identifies the individual variations in people that make a difference in our ability to diagnose and treat accurately. Peter Byers, MD, director of the new Center for Precision Diagnostics at the University of Washington, calls it “the coolest part of medicine.”

The “omic” tool set

It’s not enough to map the DNA; knowing that a patient has a gene doesn’t tell us whether that gene will be active, how it will interact with other genes or the environment, or what effects it will have. We need to understand how genes are expressed, what controls gene expression (what turns a gene on or off, or modifies its rate of function), and how RNA transcription molecules, proteins, and metabolic processes are involved. The 4-part “omic” tool set consists of:

  • Genomics: DNA sequencing and analysis. We have gone far beyond the methods of the Human Genome Project and can now sequence all the genes at the same time.
  • Transcriptomics: study of RNA transcript molecules.
  • Proteomics: study of the complete array of proteins produced by genes.
  • Metabolomics: study of small-molecule metabolites that fingerprint cellular processes resulting from gene expression.

The UW-Oncoplex cancer gene panel

Want personalized information about your cancer? Your surgeon can submit a sample of your tumor for a UW-Oncoplex cancer gene panel. It uses genetic sequencing to detect mutations in tumor tissue and identifies 194 cancer-related genes. It looks for “actionable” mutations, those we can do something about, for instance those that tell us one drug will work better than another. Potentially, it might some day be able to pick out cancers that are slow-growing and unlikely to metastasize, identifying patients who can safely avoid the risks and discomforts of radiation and chemotherapy.

Oncoplex uses next-generation “deep sequencing.” I don’t understand what that means, but apparently it can identify more kinds of mutations – not just single nucleotide variants, but also small insertions and deletions, gene amplifications, and selected gene-fusions. In an example given by Dr. Byers, a patient with metastatic lung cancer was found to have a gene fusion that had been missed by other genetic testing panels. Based on this new information, the patient was switched to crizotinib and had a complete symptomatic and radiographic response.

Quellos High-Throughput Screening Core

Researchers used to work with single test tubes. The process has been automated and miniaturized (see the picture above). Scientists can now work with plates that have as many as 1,536 compartments (“wells,” essentially tiny test tubes) that a machine automatically fills with as little as 50 nanoliters from tiny dispensing nozzles. The Quellos High-throughput Screening Core has a library of 120,000 compounds, including FDA-approved drugs, drugs in the testing stage, and candidates for future testing. Diseased cell samples can be simultaneously exposed to a multitude of compounds in various concentrations to see which ones damage or kill the cells, identifying drugs that merit further study. The system has both clinical uses (guiding treatment) and basic science applications like studying what happens downstream in cell metabolic processes when a specific gene is knocked out.

Precision medicine research at UW

Cancer researcher Pam Becker has been testing cells donated by her acute myeloid leukemia patients, and in almost every case the screening has suggested an alternate treatment that would not have been next in line.

Tony Blau, director of the UW Medicine Center for Cancer Innovation, and his wife, oncologist Sibel Blau, are using these techniques to test biopsy samples from women with metastatic triple-negative breast cancer, investigating how the tumor cells respond to 180 compounds and trying to incorporate the positive responses into the patient’s treatment regime.

Ophthalmologist Jennifer Chao is using Quellos to study macular degeneration. Stem cells are prodded into transforming into retinal pigment epithelium and the resulting cells are bombarded with factors that are thought to cause macular degeneration (the death of retinal cells), then they are exposed to 2,000 different medical compounds to see if any of them prevent cell death.

Neuropathologist Tom Montine is using precision medicine tools to study Alzheimer’s disease, which he compares to arthritis of the brain. A damaged joint can be further damaged by the body’s immune response, and immune regulation in the brain seems to play a key role in Alzheimer’s disease. He is attempting not just to identify the genetic drivers of the disease but to track the molecular pathways that provide the mechanisms for genetic influence.

The Act Smart initiative at the Institute for Prostate Cancer Research is a multi-million-dollar effort to understand and target prostate cancer tumors in ways specific to each patient, using the new tools of precision medicine.

Conclusion

This is an exciting time in medical science. We are just beginning to see authentic science-based individualized medical care. Accept no substitutes.

Posted in: Basic Science, Cancer, technology

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44 thoughts on “Precision Medicine: The Coolest Part of Medicine

  1. rork says:

    Demand evidence as you usually would.
    Person’s tumor has mutant gene G1 in tumor type T. What’s the evidence that drug D against G1 works better than other treatments?
    The presence of the mutation alone does not demonstrate that drug D has been shown to work better. Might be true.
    The docs are swooning, without always thinking through what kinds of studies will be needed.

    1. Ed Whitney says:

      Harriet: with respect to rork’s point about demanding evidence, do you happen to know what kinds of clinical trials are being contemplated at UW for these precision-based interventions? Are there designs more sophisticated than classical randomization which would be better to use? One challenge seems to be that for each patient entered into a trial, you would be testing at least two hypotheses. One is rork’s example of drug D being superior to other drugs for tumor type G1; the other is that precision medicine can correctly identify the gene variant most relevant to the clinical course of the tumor. Considerable ingenuity will be required to come up with good ways to test these approaches to disease with the requisite nuance for which randomization may be inadequately adapted.

      Today, May 20, happens to be International Clinical Trials Day, and one of the topics being discussed today in Denmark is adaptive designs. Do you think that precision medicine lends itself to being tested by these designs? Oncologists seem to be interested in adaptive designs for drugs, and it would be interesting to ask the pioneers of precision medicine whether they think that such trials would be useful.

      1. Harriet Hall says:

        I don’t understand your and Rork’s comments. I described several ongoing research projects at UW. I explained that a patient’s individual cancer cells can be directly tested for response to various drugs in a microarray. I don’t understand what you are asking for.

        1. qetzal says:

          Just because a patient’s individual cancer cells respond to a given chemotherapeutic in vitro doesn’t mean that drug will work in the patient. Even if the patient does show a response after receiving that drug, it doesn’t prove that the in vitro test was actually useful.

          I think rork & Ed are absolutely right. We will somehow need to conduct trials to more rigorously determine if such methods are actually beneficial.

          After all, Burzynski claims he can do personalized treatments based on testing tumor tissue, too. We need ways to verify which of these methods really work, and which do not.

          1. Harriet Hall says:

            “Just because a patient’s individual cancer cells respond to a given chemotherapeutic in vitro doesn’t mean that drug will work in the patient.”
            Maybe not, but when you have no better way to choose between two chemotherapeutic agents, it is certainly reasonable to be guided by these tests. Of course, they will need to compare survival with and without such testing, but the plausibility is high enough to use the tests while waiting for the research. I wonder what IRBs would have to say about doing a prospective study and denying the control group access to these tests.

          2. MadisonMD says:

            Just because a patient’s individual cancer cells respond to a given chemotherapeutic in vitro doesn’t mean that drug will work in the patient.

            Exactly. In fact, in vitro chemotherapy sensitivity assays do not predict of chemotherapy benefit in patients. They are not used in clinical practice for this reason. The possible reasons for the failure of a Kirby-Bauer type assay for cancer include:
            (a) cell clones that happen to grow in the lab are not representative of the population that grow in a patient; and
            (b) the tumor stroma and microenvironment play key roles in chemotherapy sensitivity that are not reproduced with isolated cancer cells.

            Distinct from this failure of in vitro sensitivity tests, success has been achieved by identifying a mutated oncogene and using a drug that inactivates that oncogene (e.g. erlotinib-EGFR, vemurafenib-BRAF, imatinib-ABL).

        2. Ed Whitney says:

          Rork appeared to be asking for evidence that these advanced diagnostic techniques translate from bench to bedside. It is reasonable to assume that some folks at UW are starting to plan studies to accomplish exactly that.

          Randomized trials are rather blunt instruments and there are very smart people out there working to develop more nuanced ways to come up with unbiased estimates of the effects of clinical interventions. I am wondering if UW has arrived at the planning stage to conduct clinical trials, and what kinds of plans they may be contemplating.

      2. MadisonMD says:

        Harriet: with respect to rork’s point about demanding evidence, do you happen to know what kinds of clinical trials are being contemplated at UW for these precision-based interventions?

        Many individual trials have been developed for specific drug-biomarker pairs just along what Rork is requesting (e.g. melanoma with mutant BRAF ->vemurafenib). Hopefully UW folk will be enrolling on these. I should point out that many many cancer centers are getting into the genomic sequencing business. However, those with some experience are having trouble finding “actionable mutations” and matching patients to clinical trials and sometimes struggle on whether to put patients on off-label therapies outside of trials.

        However, a master study is in the works called NCI MATCH This is designed to be a series of parallel single-arm phase II trial where each tumor will be matched to a drug based on genotype, as determined by central testing at NCI (b/c you have to have validated tissue testing methodology). NCI-MATCH is planned to begin later this year, and can be opened at any NCI-cooperative group sites around the country. [BTW most such trials will not single institution, Ed, because each genotype is expected to be relatively uncommon.]

        The success of the study hinges largely on the strength of the hypothesized matches between drug and biomarker. In some cases there is strong preclinical evidence and precedent (chemical inhibitors of mutant oncogenes). In other cases, the preclinical evidence is less strong (synthetic-lethal approaches and targeting tumor suppressors). Existing experience among academic oncologists suggests that many patients may not have a matched drug at all. Another limitation of NCI-MATCH is it will depend on which companies provide drug to NCI on a CRADA. The advantage to them is NCI bears the cost of the study. Disadvantage is that they will not control the study.

        Rork:

        The docs are swooning, without always thinking through what kinds of studies will be needed.

        Yes, scientists and doctors often run away with excitement– we really really want to cure cancer. A decade ago it was bevacizumab (Avastin) which was thought to be panacea. Two decades ago, high-dose chemotherapy. This sequencing excitement, too, shall pass, and it will certainly not reach the sanguine expectations of its most fervent proponents. However, there will hopefully be some modest success its wake. I have heard many notes of caution among academic cancer researchers.

        1. Harriet Hall says:

          “do you happen to know what kinds of clinical trials are being contemplated at UW for these precision-based interventions?”
          The only trials I know about are the ones I mentioned. I have no access to “contemplations” and contemplated trials may not have access to funding. Too bad we can’t use some of the money being wasted by NCCAM.

    2. Dave says:

      Rork, over the past decade genomics has taken some criticism on being full of promise but empty of results. I think this is changing. I would refer you to an article in the March 27 issue of the NEJM as an example of the type of studies that are coming out. I am posting a few paragraphs from the abstract:

      “Approximately 4 to 15% of lung adenocarcinomas harbor a genomic rearrangement in the anaplastic lymphoma kinase gene (ALK) that creates a gene fusion activating the tyrosine kinase ALK.1-4 Treatment of patients with ALK-rearranged lung cancer with the MET and ALK inhibitor crizotinib induces responses5 and confers a benefit in progression-free survival.6 In a nonrandomized registry study, crizotinib also improved overall survival.4

      Unfortunately, all patients who have ALK-rearranged lung cancer will have a relapse eventually, after a response that typically lasts for 8 months.6 Thus, drugs that are capable of suppressing the growth of recurrent tumors are urgently needed. In the phase 1 trial by Shaw and colleagues7 reported in this issue of the Journal, one of these drugs, ceritinib, induced remissions in almost 60% of patients with ALK-rearranged lung cancer. More striking, however, is the fact that responses were independent of whether patients had been treated with crizotinib previously. Thus, patients appear to have a second chance of response after relapse occurs following crizotinib treatment.

      Thus far, data suggest that acquired resistance to crizotinib may emerge by means of second-site mutations affecting the binding of the drug in the kinase domain or by means of the activation of pathways that bypass the original oncogenic kinase signal.8 Since ceritinib is several times as potent as crizotinib,9 interindividual variations of drug levels in plasma, which may cause insufficient inhibition of the target by crizotinib in some patients, could be less of a problem with ceritinib, which may still be able to shut down the oncogenic kinase. Moreover, the higher potency of ceritinib may often be sufficient to inhibit the mutant ALK causing crizotinib resistance.10 Of note, one of the mutations that led to crizotinib resistance, but was overcome by ceritinib, was the mutation at the so-called gatekeeper position of the kinase domain, L1196M. Mutations of the gatekeeper in ABL or epidermal growth factor receptor (EGFR) cause resistance to ABL inhibitors in chronic myeloid leukemia and to EGFR inhibitors in lung cancer and are among the most difficult to overcome.”

      Just an example…

      1. Ed Whitney says:

        Dave: The brand new JAMA appears to be describing a multicenter study of oncogenic drivers in the setting of lung cancer. Looks pretty exciting, though the authors seem to consider it a proof-of-concept study which needs randomized trials to confirm. I assume that this is a further example of what you are describing.

        Above question about whether there could be alternatives to randomized trials still applies. Supposedly adaptive designs can reduce the number of patients deprived of effective therapy compared to fixed designs; this seems like a topic for further exploration on this site.

      2. rork says:

        That’s a good example of how I want it to work: They are actually doing a trial, in a single tumor type, trying a drug on tumors with a particular kind of mutation. We have much work to do.
        What I was warning people about is docs may just go out and decide extra ERBB2 copies means you get trastuzumab even if it’s a glioblastoma, without it being part of a clinical trial. It’s what some quacks would do, and perhaps are doing now. There are quacks testing drugs on tumor cells too, and it can sound super-cool.

        PS: I know how it works – I do basic genetic and cancer research as a statistician. I am not knocking knowing the mutations a tumor has at all – I am wildly enthusiastic. But we gotta watch out or an army of Burzynski’s will appear.

        1. MadisonMD says:

          They are actually doing a trial, in a single tumor type, trying a drug on tumors with a particular kind of mutation.

          Why do you think it is so important to separately investigate in each tumor type? We categorize carcinomas by organ of origin. Why? Because for decades, cancer was primarily a surgical disease. Surgery on lung and liver are completely different. However, certain carcinomas of lung and liver might harbor very similar genetic characteristics.

          Do we have to accept the current classification scheme of lung versus colon carcinoma as set in stone, forevermore? Might it be better and more predictive to rebuild cancer phylogeny, to some extent, based on genetics rather than site of origin?

    3. swbarnes2 says:

      “Person’s tumor has mutant gene G1 in tumor type T. What’s the evidence that drug D against G1 works better than other treatments?”

      Well, if drug D came out of the process “Gene G is important in T cancer, let’s find a chemical that will bind to it and stop it”, then the odds are pretty good.

      And that’s how a lot of drug discovery works…figure out a good target gene, throw chemicals at it till you find one that sticks, see if you can tweak it to make it behave like a good drug, see if it’s not horribly toxic, then that’s your potential drug.

  2. Jen Phillips says:

    “The presence of the mutation alone does not demonstrate that drug D has been shown to work better. Might be true. the docs are swooning, without always thinking through what kinds of studies will be needed.”

    Actually, there are really clever ways of screening potential therapies in vitro, using the patient derived cell lines mentioned in the OP. Fibroblasts from skin biopsies are induced to form stem cells, which are then induced to specialize into the tissue of choice. Said differentiated tissue can then be tested for responsiveness to different small molecules, gene therapy, whatever.

    I think a little swooning is definitely warranted about the potential of this gene-specific approach to medicine, especially as it applies to rare or orphan diseases that will never have the numbers or R & D backing to go through the traditional clinical trial phases.

  3. Joe Chemler says:

    @ Harriet
    The state of the art omics also now include Epigenomics.
    http://roadmapepigenomics.org/

  4. Bad Science Monkey says:

    Next-generation sequencing (NGS), or ‘deep sequencing,’ can refer to a couple of different things in this context:

    1) Whole genome shotgun sequencing: a DNA sample from the tumor of interest is fragmented into millions of relatively small pieces (75-300 base pairs each) which are then sequenced in parallel. Those short sequences are then computationally aligned (using a reference genome, i.e. the human genome project) to produce a complete, or near complete, genome sequence. Nowadays, a complete human genome sequence can be generated in something like 10 days at a cost of ~$10,000. The near-term goal is the “$1000 genome,” which probably isn’t too far off.

    2) RNA-seq. RNA-seq is a process where the total messenger RNA (mRNA) from the tumor sample is reverse transcribed into DNA and then those transcripts are sequenced. The advantage here is that you know what genes are being expressed, and you have a lot less sequence information to deal with (remember, the vast majority of our genome is non-coding DNA), the disadvantage is that you won’t catch mutations in non-coding regions (such as promoters or other regulatory elements).

    These newer technologies offer a significant advantages over the older microarray/single nucleotide polymorphism (SNP) technologies because they actually read the entire genetic sequence, rather than identifying the presence or absence of specific (known) mutations or markers. In other words they are completely agnostic, and will detect de novo or previously unknown mutations just as easily as common ones.

    If anyone is interested in the technology, there are a lot of youtube videos floating around from some of the big players (Illumina miSeq/HiSeq, Roche 454, PacBio, etc.) that explain the underlying molecular biology pretty well (and have cool animations).

    The big caveat, of course, is that just having the sequence information doesn’t necessarily lead to better treatments. It’s a huge step, but right now we’re in a position where we can collect a lot of information very quickly (and at relatively low cost), but a good portion of that genetic information is still not “actionable.”

    1. Harriet Hall says:

      Thanks for the explanation.

    2. Jen Phillips says:

      “The big caveat, of course, is that just having the sequence information doesn’t necessarily lead to better treatments. It’s a huge step, but right now we’re in a position where we can collect a lot of information very quickly (and at relatively low cost), but a good portion of that genetic information is still not “actionable.”

      Exactly, and that’s where animal and cell culture models come into play. Sometimes it’s not an easy call to say a particular lesion is pathogenic vs. merely polymorphic, especially if the index patient is from a small family. Sometimes two different lesions in the same gene will have different pathogenic outcomes. Being able to model specific mutations and test the molecular impact is a crucial step toward targeted therapies.

  5. PMoran says:

    This is a new field to me, and I can only express confidence that the difficulties in gathering adequate evidence will be overcome somehow, possibly aided by the ease with which massive amounts of patient data might soon be gathered from all over the world, maintained centrally, and easily analysed, using advances in computer technology.

    I am amazed at the progress in medicine in the last half century. Many of the advances have had to await the right technology. The technology enables better understandings of disease as well as massively aiding in diagnosis and improving treatment.

    We like to call the mainstream evidence-based, but it would be at least equally informative to call it “technology based medicine.”

    This is one reason why CAM was never a serious threat to medical science. Understanding that helps me be more relaxed about some matters to with CAM, thinking mainly about how to keep people safe if they choose to use it.

  6. “Maybe not, but when you have no better way to choose between two chemotherapeutic agents, it is certainly reasonable to be guided by these tests. ”

    This is “Pie in the sky!!!”

    You guys are distracted with futuristic concepts of highly technical processes that may never see the office setting due to expense, values and ethics. Yet you can swear beyond doubt that a 5000 y/o discipline is bogus.

    I’m at a lost of words as to how to describe the article’s relevance and your ultimate intentions.

    1. Windriven says:

      “Yet you can swear beyond doubt that a 5000 y/o discipline is bogus.”

      5000 years and the only evidence of effectiveness is the febrile proclamations of a few passionate devotees. Kinda pathetic, don’t you think? Real hard science has been around less than 10% of 5,000 years. Shall we enumerate its many hard, proven achievements?

      I struggle to understand your attachment to this nonsense. I struggle even harder to understand why you think that repeating your earnest (if misplaced) belief in acupuncture will influence anyone here. You offer zero evidence. The books and articles you cite aren’t evidence, they’re how-to manuals and propaganda.

      Yes Steve, bogus. Belly up to the bar with some actual evidence and we’ll have something to talk about. Until then your pleadings are those of an importuning child. Persistence can be a virtue. Also not.

    2. MadisonMD says:

      Yet you can swear beyond doubt that a 5000 y/o discipline is bogus.

      Is astrology bogus Steve? If so, please explain how it can be bogus since it is 5000 years old. If not, tell us why it is true.

    3. WilliamLawrenceUtridge says:

      Yet you can swear beyond doubt that a 5000 y/o discipline is bogus.

      It’s not the 5,000 years old part that makes acupuncture bogus. It’s the 30+ years of inconsistent, borderline, unreliable modern results that makes acupuncture bogus. Something that actually worked 5,000 years ago should still work today – the fact that results are negative now indicates that, like nearly all prescientific medicine, past results were based on placebo and confirmation bias.

      Also, how does modern acupuncture, with silicone-coated filiform steel needles, compare to acupuncture 5,000 years ago, with thick stone needles that had to be hammered into the skin and probably had more to do with bloodletting than modern acupuncture? The technology to create fine steel needles didn’t exist until maybe two hundred years ago. Not to mention the fact that it was mainly practiced in Japan, Chinese (and Tibetan, and Korean) acupuncture involved thicker “needles” that were really closer to knives. You should learn a little history rather than assuming you know what you’re talking about.

      It must be frustrating to be continually confronted by people who know more than you do about what you claim expertise in.

      1. @WilliamLawrenceUtridge
        You are good with your history and knowledge.
        Your use of the knowledge is faulty due to a few flaws in logic.
        The reasons are because you have no experience and a superficial concept of the discipline. Without the experience your opinions are incomplete and invalid.

        Ask Ingraham about muscles, pain, hands-on options and needles, he is the resident expert and has a little more experience.

        For new visitors, Acupuncture and needle therapies work, not so much for the definitions that are published, but for innate, natural and holistic reasons.

        1. n brownlee says:

          “innate, natural and holistic reasons”

          I do not think any of those words mean what you think they mean. Including ‘reasons’. Which you have never given any of. Period.

        2. WilliamLawrenceUtridge says:

          The reasons are because you have no experience and a superficial concept of the discipline. Without the experience your opinions are incomplete and invalid.

          You are failing to mention a point I have brought up repeatedly – that the scientific literature, which is far, far superior to any one or even dozen doctors, fail to find benefit from acupuncture. And for that matter, I have experienced acupuncture and it didn’t do a damned thing for me.

          Thousands of trials have been conducted. They show, in aggregate, that it doesn’t matter where you put the needles, it doesn’t matter if you penetrate the skin, but it does matter if your doctor is enthusiastic or not. The important thing is that patients think they are getting acupuncture, not that they actually get it – and that’s why it is a placebo. Any other drug or treatment with this outcome would have been discarded years ago and derided by you – but because it’s your little pet intervention, you make excuses and willfully ignore the literature.

          Ask Ingraham about muscles, pain, hands-on options and needles, he is the resident expert and has a little more experience.

          I’ve corresponded with Paul, I’ve read his work, I’ve even talked to Paul. And Paul’s assessment matches mine – acupuncture is a placebo.

          Surgeons for years would have invoked their experience as a reason to do knee tissue debridement, or bloodletting, or coronary recathetarization. Research showed them useless, and they were abandoned. Maybe you should look at the acupuncture research.

          innate, natural and holistic reasons

          What’s innate about stabbing people with fine needles? What’s natural about fine needles themselves, let alone stabbing people with them? What’s holistic about stabbing people in specific locations?

          These poor, tortured, misused words you write – they do nothing to justify acupuncture, nor do they make the scientific literature disappear. Rather than marketing acupuncture, perhaps contemplate researching it.

          1. “Paul’s assessment matches mine – acupuncture is a placebo.”
            There no such data that states with absolute certainly!

            I do not think you know what acupuncture or placebo truly means. So to some who is misinformed or have an agenda twisting the concepts is very easy. Your logic is flawed or have an agenda that includes profits, egos or personal gain.

            If that is your belief, that is your person choice. You and anyone here are not allowed (with impunity) to impose you personal beliefs onto unsuspecting readers.

            1. Windriven says:

              “There no such data that states with absolute certainly!”

              Preponderance of evidence. There may not be absolute proof that acupuncture is placebo at best*, but there in NO credible evidence that it is anything more.

              “our logic is flawed or have an agenda that includes profits, egos or personal gain.”

              This is getting really tiresome. You frequently assert that our logic is flawed but you never lay out the case that demonstrates that. And it is absolutely chickensh!t of you to continuously slander those who disagree with you by insisting that they are paid stooges.

              If you want to play with the big dogs you need to up your game. Scrape up some actual evidence. Drop the ad hominem attacks. If acupuncture is more than a way to cheat vulnerable people out of their hard earned money, lay out the evidence.

              *an idiotic and all but impossible bar to clear. That is not Ho’s science works. You claim efficacy for acupuncture. Now all you have to do is prove it.

              1. MadisonMD says:

                agenda that includes profits, egos or personal gain

                The irony is, of course, that SSR has more potential for personal gain by promoting acupuncture than others have in refuting it.

            2. WilliamLawrenceUtridge says:

              There no such data that states with absolute certainly!

              Theoretically there can never be adequate data to know anything with absolute certainty. That’s a basic fact of science, one of many you fail to grasp. Another would be the necessity of changing your mind in the face of evidence. But the preponderance of evidence shows that needling location, depth, penetration and diagnosis do not matter – what matters is that the patient thinks they are getting acupuncture, and that it will help. Which makes it indistinguishable from placebo – an explanation that has an added advantage of not requiring novel anatomical structures or processes.

              I do not think you know what acupuncture or placebo truly means.

              Well I am aware of the conventional explanations, which are nonsense, and I’ll note that your definition seems to be “not any approach that leads to negative study results”. Which is problematic since you just keep moving the goalposts. Which is the real goal of your presence – first, convince others you are right. Failing that – avoid changing your mind, irrespective the evidence. Very human, but very wrong if you want to know whether your knowledge reflects reality.

              So to some who is misinformed or have an agenda twisting the concepts is very easy. Your logic is flawed or have an agenda that includes profits, egos or personal gain.

              All I ask for is some empirical evidence, some well-controlled clinical trials, that show acupuncture is different from placebo. You are unable to present such information, and keep demanding we respect your clinical opinion. So if there’s an ego involved, I think it’s on the side of the person who believes that their opinion is worth more than hundreds of clinical trials.

              You and anyone here are not allowed (with impunity) to impose you personal beliefs onto unsuspecting readers.

              I don’t impose my beliefs on anyone. In addition, the site isn’t censored, bar spam filters. All I ask is that someone provide a reasonable explanation or evidence for their assertions. This is hardly unreasonable. It’s a pretty low bar, and any drug that is currently being sold meets or exceeds it.

              The fact that you are unable to substantiate your claims with anything beyond your personal experience is not my fault or problem, it’s yours.

  7. mho says:

    I think this company is doing something similar, but Its way over my head. I know of a few cancer patients who’ve had these tests done.
    http://www.foundationone.com/learn.php#2

    About FoundationOne
    FoundationOne, the first clinical product from Foundation Medicine, is a fully informative genomic profile that complements traditional cancer treatment decision tools and often expands treatment options by matching each patient with targeted therapies and clinical trials that are relevant to the molecular changes in their tumor based on the most recent scientific and medical research. The test utilizes next-generation sequencing to identify alterations in all genes known to be somatically altered in human solid tumor cancers.

    Test results are provided in a user-friendly interpretive report that highlights the genomic alterations that are relevant to the individual patient and provides information about targeted therapies and clinical trials to inform treatment decisions.

    FoundationOne interrogates the entire coding sequence of 236 cancer-related genes plus 47 introns from 19 genes often rearranged or altered in solid tumor cancers. These genes are known to be somatically altered in solid cancers based on recent scientific and clinical literature and are sequenced at great depth to identify the relevant, actionable somatic alterations, including single base pair change, insertions, deletions, copy number alterations, and selected fusions.

    1. swbarnes2 says:

      Yeah, the FoundationOne is also using Illumina Next Generation “deep sequencing”. For the next few years, that’s pretty much the way to do this. This site has more details about the exact method. You pick your favorite genes, and you use molecular probes specific for those regions of DNA that you care about, so you fish out mostly those parts, instead of having to sequence 3 billion bases. I’m a little surprised that they can claim to see copy number variants with this method, I wouldn’t expect it to be that quantifiable, but if they say they can, then I guess they can.

      And yeah, right now, we can generate a lot of sequence data, and don’t get a whole lot of “this DNA means we should use that drug, not this one” indications, but that should improve over time.

  8. Missmolly says:

    Thanks for posting this, Harriet. It’s easy to get disheartened when we see so many research dollars spent on implausible and anti-scientific ‘therapies’; we can get distracted from the true, plausible, innovative research that continues to be undertaken in real medicine.
    Sure, deep sequencing/targeted therapies/’personalised medicine’ isn’t going to be an instant panacea to everything- science doesn’t work like that. But we can now cure Ph+ leukaemia without transplant (yay, tyrosine kinase inhibitors!). And anti-GD2 monoclonal antibodies increase the 5 year survival of kids with stage 4 neuroblastoma by 20% (data on longer term survival still maturing, but that’s a tonne of preschoolers given years more with their families). And at a European conference last year, I heard about studies currently underway using epigenetics to predict things as varied as risk of cardiotoxicity with anthracyclines and response to different classes of antiemetics.
    So excuse me for ‘swooning’, but precision medicine is pretty exciting stuff. And if it achieves only one one-hundredth of its plausible potential, that’s still an enormous leap forward in our knowledge and ability to treat patients- and a hell of a lot more than we’ll achieve with a million studies on homeopathy.
    I love you, science.

  9. thor says:

    Wow. No other words needed. Dr McCoy “Bones” is getting closer and closer to reality. My only questions/comment would of course be patient cost?

  10. MadisonMD says:

    Since SSR brought up acupuncture–again on an unrelated thread on genomics, I thought I would peruse what NCCAM is doing in this arena. Well, it turns out, that NCCAM spent just about $400K per year for 5 years to learn how acupuncture alters serum proteomics in people with irritable bowel syndrome. Here are the hypotheses:

    (1) Our primary hypothesis is that serum proteins participate directly or indirectly to the brain-gut interactions associated with clinical responses in IBS.
    (2) Our second hypothesis is that patients who clinically respond to placebo or acupuncture treatment have distinct serum protein profiles from those who don’t respond.
    (3) A third hypothesis is that placebo or acupuncture treatment results in changes in the serum proteome.

    So, here is some really, really cool research on precision medicine. Not. You can’t make this stuff up.

  11. Anthony Murawski says:

    I’m afraid your comments about the shortcomings of “one-size fits all” mentality apply remarkably well to your rigid orientation toward Lyme disease. For instance, you cite the CDC for the claim that a positive IgM western blot result obtained more than four weeks after initial infection is by definition a false positive. Making that kind of assertion on the basis of appeal to authority alone is equivalent to endorsing faith healing. Please provide scientific justification as to why B. burgdorferi would be the only microorganism that is curable by definition within a certain time frame, and the only microorganism that sometimes elicits a true positive IgM response during early infection, but then suddenly begins eliciting a nonspecific IgM response on the 29th day of infection. If you actually bothered to educate yourself, you would discover that like several other persistent infections, B. burgdorferi engages in antigenic variation/non-expression when targeted by IgG antibodies. Upon variation and expression of a new outer surface epitope, a renewed IgM response is triggered. I’d be happy to send you an entire treatise (published by informa) on the role of antigenic variation in chronic, persistent infections

    Sincerely,
    Anthony Murawski
    awmurawski@gmail.com

    1. Anthony Murawski says:

      Incidentally, I am not expecting that you publish my remarks, but it was no longer possible to post a response to your original article. Also, I’m not out to offend you. I am merely mimicking your dismissive tone and hoping you may realize that you are not knowledgeable enough concerning Lyme disease to go around publishing such incendiary comments.

      I’m afraid your comments about the shortcomings of “one-size fits all” mentality apply remarkably well to your rigid orientation toward Lyme disease. For instance, you cite the CDC for the claim that a positive IgM western blot result obtained more than four weeks after initial infection is by definition a false positive. Making that kind of assertion on the basis of appeal to authority alone is equivalent to endorsing faith healing. Please provide scientific justification as to why B. burgdorferi would be the only microorganism that is curable by definition within a certain time frame, and the only microorganism that sometimes elicits a true positive IgM response during early infection, but then suddenly begins eliciting a nonspecific IgM response on the 29th day of infection. If you actually bothered to educate yourself, you would discover that like several other persistent infections, B. burgdorferi engages in antigenic variation/non-expression when targeted by IgG antibodies. Upon variation and expression of a new outer surface epitope, a renewed IgM response is triggered. I’d be happy to send you an entire treatise (published by informa) on the role of antigenic variation in chronic, persistent infections

      Sincerely,
      Anthony Murawski
      awmurawski@gmail.com

      1. WilliamLawrenceUtridge says:

        Incidentally, I am not expecting that you publish my remarks, but it was no longer possible to post a response to your original article.

        Oh snap, it must sting that your comments actually appeared. That must interfere with your powerful sense of righteous indignation.

        I’m afraid your comments about the shortcomings of “one-size fits all” mentality apply remarkably well to your rigid orientation toward Lyme disease. For instance, you cite the CDC for the claim that a positive IgM western blot result obtained more than four weeks after initial infection is by definition a false positive. Making that kind of assertion on the basis of appeal to authority alone is equivalent to endorsing faith healing.

        Again, not an appeal to authority as a logical fallacy, it’s an appeal to a legitimate authority in the absence of time and inclination to reinvestigate the topic starting with the primary sources. Which is reasonable I think. Further, the discussions and evidence of Lyme disease are not based on single sources or individuals, it’s based on groups of experts who research the topic as the main part of their professional lives. Amateurs whose interest is sparked by the belief that they are a victim of a fake disease do not make great neutral assessors of the data, since they start from a conclusion and work backwards and systematically through the evidence to justify that conclusion.

        If you actually bothered to educate yourself, you would discover that like several other persistent infections, B. burgdorferi engages in antigenic variation/non-expression when targeted by IgG antibodies.

        Why don’t genuine experts think this? Why hasn’t the relevant scientific community recognize and agree with your assertion? Which incidentally, is you appealing to authority, specifically your own. Despite you being, apparently, a lawyer rather than a doctor or PhD researcher. See, you’re essentially demanding that we believe you are a good-faith interpreter of the evidence despite being a) a sufferer of an alleged and controversial condition known for attracting zealous patients willing to persecute and harass those who disagree with you, and b) invoking a treatise. Why should we?

    2. WilliamLawrenceUtridge says:

      Making that kind of assertion on the basis of appeal to authority alone is equivalent to endorsing faith healing.

      An appeal to authority is appropriate when you are appealing to an actual authority. For instance, claiming one should believe in God because Einstein did is the logical fallacy “appeal to authority”. Claiming one should believe that energy and mass are interchangeable because Einstein did – realistic summary of the opinion of a genius recognized for his contributions to physics – is not an appeal to authority. People simply don’t have the time to become experts or read the primary literature in all fields of endeavors throughout the world, and must delegate to real experts. Like the CDC. Claiming the CDC’s opinion on Lyme disease as Dr. Hall did in her original post that you are trying to resurrect here is a logical fallacy is a failure to understand the appeal to authority, or a bad-faith effort to smear someone with whom you do not agree.

      Please provide scientific justification as to why B. burgdorferi would be the only microorganism that is curable by definition within a certain time frame, and the only microorganism that sometimes elicits a true positive IgM response during early infection, but then suddenly begins eliciting a nonspecific IgM response on the 29th day of infection.

      See this is a logical fallacy, specifically a straw man – the idea that doctors rigidly and dogmatically adhere to the guidelines with no individual assessment or flexibility. The guidelines represent the summary and distillation of the best evidence for treatment options, not an absolute restriction placed on reality.

      If you actually bothered to educate yourself, you would discover that like several other persistent infections, B. burgdorferi engages in antigenic variation/non-expression when targeted by IgG antibodies.

      Here’s another logical fallacy, specifically an ad hominem that Dr. Hall is too ignorant or too biased to have an opinion.

      I’d be happy to send you an entire treatise (published by informa) on the role of antigenic variation in chronic, persistent infections

      Allow me to mock you now. See, lots of people with self- or quack-diagnosed “chronic” “Lyme” disease will adopt their new diagnosis as an identity, ignore contradictory information, see conspiracies of deliberate malice or somehow suggest Big Pharma or some other boogeyman is “keeping the truth down” for…well I’ve never seen a good reason really. The reality is – whatever is causing your symptoms, it probably isn’t Lyme disease anymore. It’s simply not known why you have a vague cluster of symptoms that you do. There’s no good evidence that “chronic” “Lyme” exists. Your activism and belittling, like you did here, do not help your cause – it just makes you look like a zealot and makes you easy to ignore.

      You should see a counselor or therapist – not because your symptoms are somatization (though they might be), but because they can help you adjust to your new limits, understand how they affect your life, and figure out some way of finding something positive in your current circumstances.

      1. Sawyer says:

        “Your activism and belittling, like you did here, do not help your cause – it just makes you look like a zealot and makes you easy to ignore”

        If there was an Olympics for medical activism, the CLD crowd would win gold in this event every time. Unlike the normal parade of quacks insisting mainstream medicine is evil, I suspect some of the questions about Lyme diagnostics are actually worth looking into, and many of the people asking those questions clearly have robust knowledge about biology. The question of whether a Western Blot, immunofluorescence, or PCR test is going to give a reliable result is extremely complicated, and no doubt fascinating for much of this site’s audience. And as recent cases of the Heartland Virus demonstrate, it’s very plausible that unknown infections could be lurking right under our nose. These are real issues, worthy of attention and debate. Yet Chronic Lyme advocates lose all credibility in discussing these topics by employing the worst possible tactics known to man for engaging other scientists, doctors, and journalists.

        In the history of the internet, I have yet to see anyone necro a comment thread that is several months old, completely distort the subject matter, insult the original author, and then turn it into a viable debate about science. Or any topic, for that matter. If I was a CLD proponent, I’d be furious at people like Andrew that keep pulling this crap over and over. It’s a surefire way to prevent anyone ever changing their minds.

        1. WilliamLawrenceUtridge says:

          Unlike the normal parade of quacks insisting mainstream medicine is evil, I suspect some of the questions about Lyme diagnostics are actually worth looking into,

          Certainly, it’s obviously a very complex and novel disease, but it’s unsettled. And the CLD proponents are prematurely proclaiming an unchangeable Truth(TM), which is the problem. The real science is still quite preliminary, it’s far too early to claim to have all the answers, particularly when the treatments make so little sense (and have failed in clinical trials).

          and many of the people asking those questions clearly have robust knowledge about biology.

          I wonder if it’s robust, or if they have an island of knowledge surrounded by a sea of ignorance. The fact that they can rhyme off a dozen specific and complicated flaws in the testing process is less convincing to me than the abilty to say why real experts don’t find these arguments convincing. Every time I’ve looked into these sorts of specific objections for other conditions, I’ve found that not only have they been addressed, but they weren’t flaws in the first place (for instance, do you remember when stan dropped a whole bunch of convincing-seeming bafflegab about vitamin E only to be thoroughly destroyed by Angora Rabbit, an actual expert?). I doubt CLD will be any different.

          If I was a CLD proponent, I’d be furious at people like Andrew that keep pulling this crap over and over. It’s a surefire way to prevent anyone ever changing their minds.

          Indeed, the demand for fast, superficially-pleasing answers does more to hurt those with Lyme Disease and whatever Chronic Lyme Disease than any institutional indifference or even outright malice ever could.

    3. MadisonMD says:

      Anthony, are you aware of how B cells engage in heavy chain class switching from IgM to IgG shortly after antigen stimulation? It seems that you are not understanding basic immunology. This is why IgM late after exposure is more likely a false positive. It should be switched to IgG long before four weeks elapse.

      Even if new antigens were presented later, it would seem irrelevant as the antibody stimulated by the initial antigen–the one for which there is a test–would already be class switched to IgG. If new antigens were presented at a later time then new IgMs would be generated to these antigens.

      In other words I call bull$hit. And like so many other BSers here you provide no cites, but only ask people to email you to see them. I wonder why you all do that.

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