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Science News

Patient Outcomes Linked To Biomarker Levels 42

Posted by ScuttleMonkey from the good-science-needs-practice dept.
JonN writes to tell us Science Daily is reporting that researchers at Yale University have discovered that current pathology methods for biomarker detection can be dramatically altered depending on the concentration of antibodies used. From the article: "Biomarkers may have the power to provide diagnostic, therapeutic, and prognostic information for personalized medicine." said Donald Earl Henson, M.D., of the George Washington University Cancer Institute, in "Back to the Drawing Board on Immunohistochemistry and Predictive Factors," an accompanying editorial. "However, immunohistochemistry, a popular technique for evaluating biomarker expression, may contain procedural flaws that jeopardize its promise."
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Patient Outcomes Linked To Biomarker Levels More

Patient Outcomes Linked To Biomarker Levels

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  • Computational Molecular Phenotyping (Score:5, Informative)

    by BWJones ( 18351 ) * on Monday January 02, 2006 @04:33PM (#14380608) Homepage Journal

    I am not surprised as most immunohistochemical approaches to biomarkers are optimized for proteins that have notoriously variable levels depending upon sampling method and analytical method. Most basic scientists have known this for some time, and are very careful about interpretation of immunohistochemical results, but the medical field has been slow to pay attention.

    As an outcome of our work in the visual system, we have been developing a new approach to biomarker analysis based upon quantitative small molecular molecular phenotyping called Computational Molecular Phenotyping (CMP) [utah.edu] that is a much more sensitive and reliable assay for not just eyes, but just about any biological system. Small molecular signals are much more tightly regulated between subjects and even remarkably between species. CMP relies upon 1) quantitative immunohistochemistry 2) computational tools derived from methods originally developed by the CIA and NASA for remote sensing and 3) new technologies developed in-house to assist in the the data processing and analysis.

    Applications are in not just in pathology such as histological analysis of oncological tissues, but also in drug development, pharmacology and basic science. Also, as an interesting aside, I have also looked not only at a variety of vertebrate and invertabrate organ systems, but I am also looking at plant tissues with these technologies and there are some very interesting results that could assist in agronomics and bioencryption.

    • [[ Offtopic, Meta-comment ]]

      You know you've got a jaundiced view on life when you read an interested researcher's real science comments, and instinctively feel disgusted by the blatant PR grab.

      On re-reading the parent comment, I almost feel obliged to visit the web site, to prove to myself that not everyone's just after the PR, but might actually have something relevant to say.

      It's been a tough few weeks for SlashDot readers, full of front-page advertorials. Now the editorial sloppiness is causing me to do
      • You know you've got a jaundiced view on life when you read an interested researcher's real science comments, and instinctively feel disgusted by the blatant PR grab.

        I hear you. I must say though that the link was included, because we really are enthusiastic about our work and the possibilities. Right now, we are totally funded through the NIH via taxpayer dollars and have been sharing any and all technologies gratis. I have even traveled to other labs to help them learn what it is that we do and will be
        • I should have added that ~ScuttleMonkey has been making up for some of the other Slashdot editors lately. His posts of submitted articles have been informative, unique and most welcome in the face of silly submissions and editorial abuses from ~Zonk. If we could get more material via ~ ScuttleMonkey, I would be more inclined to continue to invest time, energy and money in Slashdot.

        • First off, you have to be excited about the science. However, it's not just the science, in this day and age, you have to sell it as well.

          An example:

          The NIH pay line is currently at ~10% - this means that 90 % of grant applications fail to be funded. As anyone who has been a member of a study section can attest, this is not because of a lack of outstanding proposals - instead there is a limit to the level of funding available to support them. You really need a personal connection to crack the funding barr

          • Call it PR if you want, or networking, but without it you cannot succeed in the US as an independent scientist.

            Your point is ownly partially valid. The fact is if you're doing PR you are, literally, not doing science. And the more marketing is done the more science, good and bad, is crowded out.

            Mediocre scientists might not like it but good science can and does sell itself and if my tax dollars are going to be spent on marketing, not science, I would prefer they not be spent at all.

            ---

            The majorit

    • There seems to be great confusion over this topic, so I am going to chime in with a my attempt to clarify.

      Biomarkers in a nutshell: Let's say we believe that there are 6 proteins of interest to some disease. If we find that you have higher than normal levels of proteins A,B, and C and have lower than normal levels of proteins X, Y, and Z then you have a good PROBABILITY of having the disease so we should follow up with imaging or other diagnostic studies. These 6 proteins would be called biomarkers.

      Findi
    • Does your lab hire european (swiss) graduated medical student with ~1 year of cumulated lab experience for PhD thesis ?

      Or, in another way : I love your work, may I work with you ?

      </whoring>

      • Or, in another way : I love your work, may I work with

        Cool. Thanks. We just brought on a medical student, another neuroscience student and two undergraduate students. Our total number of students are two neuroscience students, a medical student, two undergraduate students, and two computer science students. Also, our US legislators seeming inability to do their job screwed just about every NIH funded lab this year by 12-20% of their funding for the year. (they managed to take care of their own salaries

  • hmmmm .... (Score:2, Funny)

    by Anonymous Coward
    Can someone translate this article into English?
    • Can someone translate this article into English?

      What are you talking about? The writeup was perfectly cromulent. It has embiggened all of us.

      • Re:hmmmm .... (Score:5, Informative)

        by Anonymous Coward on Monday January 02, 2006 @05:15PM (#14380810)
        Currently, if someone has a disease, doctors use a variety of pathology techniques to characterize a disease. In the age of molecular medicine, doctors often do biopsies and determine the levels of various important proteins, or "biomarkers," made by the tumor. The level of these different proteins can be used for prognosis or treatment; for example, cancers with high levels of a protein called MMP9 tend to be metastatic and should be treated aggressively.

        The problem comes when trying to measure the amount of protein. Most proteins are measured using immunohistochemistry, which just means that you "stain" the sample's proteins with antibodies specific for that protein. You then measure the amount of antibody through various methods; the antibodies are often attached to a fluorescent tag, and you measure the level of fluorescence and extrapolate the true protein concentration from that. You usually assume that the more antibody that binds, the more protein there is, and the two are related in a linear fashion. This is an important assumption.

        Different pathologists use different concentrations of antibody. The article states that depending on what concentration you use, you can make completely opposite conclusions about the protein levels, and thus about the disease. Essentially, the flaw is that "there is a non-linear relationship between the antibody concentration and its target." In other words, adding a lot of antibody changes the way the antibody binds to the protein, which makes identifying the true protein amount much more difficult.

        I hope that helps.
      • I'd agree with this assessment, and go so far as to say the parent poster is positively nonesevent.

    • Re:hmmmm .... (Score:2, Insightful)

      by kfg ( 145172 )
      What's getting me is that I find this article and the first post more lucid, understandable and plainspoke than the previous article on Ambient Findability.

      KFG
  • I don't know - I still don't trust it ;)
  • The procedural problems will need to be ironed out before we reach "Gattaca"-type analysis of the population. Just watch out- from the time they are born, Big Brother will be predicting the time and cause of your kids' death.
    • Agent: I'm sorry ma'am, but your son seems to have died in a unlicensed fashion.
      Woman: What?
      Agent: Well, you see, he wasn't licensed to die at this time, so I'm afraid we're going to have to level a unlicensed death tax on him, payable by his next of kin.
      Woman: So your trying to tell me my son just died, and your going to charge me for it?
      Agent: Well, yeah, but he should have been more considerate and died when he was supposed to. Now we accept check or...
  • It's made by Sharpie! It sure does smell, though!

  • Oh nooooes. (Score:4, Informative)

    by Number44 ( 41761 ) on Monday January 02, 2006 @04:51PM (#14380699) Homepage
    Coincidentally, I just accepted a job at a company making immunohistochemical staining equipment (Ventana Medical Systems [ventanamed.com]) and all I can say is, look at the stock over the past 5 years [yahoo.com] and tell me this article's prediction holds water.

    Ventana's been making the stuff that runs the staining process for a long time, and has done VERY well by it. Their results are outstanding and have proven to be good medicine!

    • Re:Oh nooooes. (Score:2, Insightful)

      by kfg ( 145172 )
      I can say is, look at the stock over the past 5 years. . .

      All I can say is that I don't consider stock performance scientific data; even with regards to stock performance.

      KFG
    • I hope you enjoy your new job.
      Not wishing to bring your analysis into question but how does five years of (broadly) increasing share price have any relation to "sometimes when one uses high concentrations of the antibody, low HER2 marker levels were associated with decreased survival but if one uses lower concentrations of the antibody then high HER2 levels were associated with decreased survival . If you look for a completely different marker, increased ER levels were associated with increased survi

    • Re:Oh nooooes. (Score:5, Informative)

      by Comatose51 ( 687974 ) on Monday January 02, 2006 @05:31PM (#14380900) Homepage
      I would not trust the stock market to be the expert on science. I work at a finance company. The traders and analysts study companies and their products quite a bit but they don't get any special information nor do they have any special insights. Most of those guys are not scientists (but a few are engineers). They're not much better than you and I (unless you ARE a scientist or more precisely medical doctor, etc.) at knowing if something will work nor not. Remember the dot-com bubble and how those companies were bidded up and later died? Traders and analysts are specialists in their field, but not all fields. This is why people like Buffet prefer traditional business that they can look at the bottom-line or people like Peter Lynch advocates trading in what you know and understand. Lynch, especially, points this out in his famous book, "One Up on Wall Street".
    • Good equipment based on questionable methodology still produces questionable results.

    • Your notion that your company, its profits, and your job could be threatened by this discovery is anti-science and anti-capitalist. In science an unexpected result should be considered an opportunity for discovery and increase of knowledge. With capitalism an unexpected result should be considered a business opportunity for improvement of existing products or the creation of new products. If you are going to be successful then you will have to weigh reality more heavily than stock prices since nature is

  • looks a lot like an "l" causing me to read it as "blomarker". I guess my overall health would be greatly improved if women would help raise my "blomarker" level too :P

  • your personal biomarker assessment (Score:1, Interesting)

    by Anonymous Coward
    Get yours here.. about $3400

    http://www.biophysicalcorp.com/about_assessment.as px [biophysicalcorp.com]

  • Old news (Score:5, Interesting)

    by pugdk ( 697845 ) on Monday January 02, 2006 @05:37PM (#14380930) Homepage
    I work with stuff like this on a daily basis (post doc level) and everyone in biomedical research knows to be highly suspicious of everything that has to do with immunohistochemistry and immunofluorescence. It all comes down to your negative and positive controls - as you can get a very strong signal with more antibody / less washing / longer incubation on a negative control and only a slight signal on a positive sample with less antibody / more washing / shorter incubation....

    When reading research papers containing these images / results you need to trust the research team doing it... its so easy to falsify and way too easy to misread if you mess up your experiment slightly. Also different protocols in different labs will give different results.

    But yeah, lets put obvious and well known stuff on the frontpage of /. :-)


    -pug

    • as you can get a very strong signal with more antibody / less washing / longer incubation

      How could you leave out Tyramide Amplification? That alone gives you enough fudge factor to say that something like GAPDH or b-actin are overexpressed in foo vs bar.

      But yeah, lets put obvious and well known stuff on the frontpage of /. :-)

      Better yet, lets put up obvious and well known stuff that confuses the shit out of people on the frontpage of /.

  • Or is the headline completely misleading? I understand that it's taken from the title of TFA, but out of context what it's saying is basically the opposite of reality.

  • using IHC for quantitation is idiotic (Score:4, Interesting)

    by pinche cabron ( 942185 ) on Monday January 02, 2006 @08:46PM (#14381685)
    And I speak as someone who has developed and extensively tested an immunoassay (ELISA) [wikipedia.org] for a cancer biomarker. IHC is tissue staining (immunohistochemistry), as opposed to ICC (immunocytochemistry, cell staining), and neither of those methods is worth a damn for quantifying protein levels. You would have to homogenize the sample (sonicate it, for example), then do an ELISA with a standard curve. And no, the standard curve doesn't have to be linear, but you do have to fit it to some suitable sigmoidal (S-shaped) model.

    Then there's the problem of quenching. If the protein level is super high, my fluorescent signal will be too high and the dye molecules stack on top of each other, causing quenching (loss of fluorescent signal). The way around that problem is a dilution series (two would be adequate) for each test sample. Quenching is the main reason IHC and ICC suck for quantitation, too. That, and photobleaching, and other microscope artifacts. Anyone with any experience reserves IHC and ICC for qualitative information.

    They mentioned the Yale scientists looked at tissue microarrays, which should not be the standard test. That technology is in its infancy, and most of its successes are either exaggerations or outright lies. Again, I'm speaking as someone in-the-know. I've seen the shiny Powerpoint presentations, and I've seen the shoddy data behind the scenes that they didn't show in the presentation. High-throughput automated microscopy? Hah. Not for another decade will that work as advertised.

    And another thing: standardization of the antibody is not an issue as long as the off-rate is slow enough, and the same antibody is used for test samples and standards. I've had more than adequate experience in this arena as well, using Biacore [biacore.com] Surface Plasmon Resonance to measure antibody on- and off-rates.

    Just goes to show you, never send a doctor to do the job of a molecular biologist or biochemist.

  • Everybody knows that! (Score:3, Insightful)

    by ponos ( 122721 ) on Tuesday January 03, 2006 @12:32PM (#14385291)
    Well, I do IHC as part of my PhD and everybody knows that you have to keep a strict standardised procedure to get comparable results. We routinely "standardise" new antibodies until we get a clean signal and we also use other methods to verify the results (like Western Blot). Anyway, the "research" antibodies are rarely of sufficient quality to rely on them for everyday medical uses, because they need very precise handling (you wouldn't want to rely on an alpha version of something, would you?). On the other hand, most commercial "tested" antibodies that are used in hospitals are very robust and provide consistent results with very slight differences. We jokingly say that "you could spit in the solution and it would still work".

    At a design level, IHC is often problematic because of several key facts, especially the fact that it has to be "evaluated" by someone, using rather lax criteria. As as general rule, most observers obtain widely different results (i.e. 5-10% difference is considered very low, while 20-30% can be quite common).

    I personally don't trust IHC that much, but those applications that make it to medical use have been tested many times and are reliable or at least more reliable than previous methods. In the future, new methods that combine IHC with automated fractal analysis, for example, could improve error margins. The linked article seems to promote an automated type of analysis (didn't read the nasty details) and is naturally expected to "magnify" the shortcomings of traditional IHC. I would welcome this type of technology in my lab (hate to evaluate IHC slides, let the computer do it!).

    P.

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