6 ms·

Your links are talking about preclinical trials and attempts to replicate specific high profile, controversial studies from specific subfields. We're talking a

Your links are talking about preclinical trials and attempts to replicate specific high profile, controversial studies from specific subfields. We're talking about the entirety of basic research. The "evidence" for this is the incredible advances in our understanding of how the cell and the molecules of life work in the last 50 years. Every single experiment done in the modern life sciences would not be even possible to contemplate doing if all of the molecular biology it is based on was not extremely reproducible. Entire fields of modern biology like genomics, structural biology, genome editing, and more could not even be fathomed to exist if this were not true. Nobody tallies up how often biology "works", only how often a few experiments attempting to prove specific hypotheses don't work. Basic science in molecular biology and microbiology are extremely reproducible most of the time and nobody writing these articles questions that. No offense, but this is some creationist-tier science denial you have going on if you don't believe this, and it isn't the responsibility of the scientific community to educate people who've read one time many articles about reproducibility that science works.

nonbel 10y ago
>"Entire fields of modern biology like genomics, structural biology, genome editing, and more could not even be fathomed to exist if this were not true." Yes, everything needs to be redone since at least the 1980s, and probably the 1940s (whenever NHST became the primary method of assessing what is correct or not). We have no idea what is actually going on. It is scary, I know. It took me years to accept. >"this is some creationist-tier science denial you have going on if you don't believe this" Ok, link to a specific paper and I will discuss it with you. In my experience, if it is biomed, no one will have ever published a replication of any results it contains. There will be no model capable of quantitative prediction of anything, and conclusions drawn will also almost certainly be fatally flawed due to the vagueness of their explanation.
- tstactplsignore 10y ago
  Lol, I just realized you were that guy who denies CRISPR-Cas9 genome editing really works. It may be against the rules, but I just have to tell you that you are an insufferable idiot who brings down the quality of discourse on this site with your bizarro pseudoscience nonsense.
  - nonbel 10y ago
    This is a strawman. What I have seen in the data presented by the CRISPR-Cas9 researchers seems consistent with the idea that ~1% to 0.1% of cells in culture are mutants at any given site, the treatment selectively kills or growth arrests the non-mutants (at that site), and then the surviving (because they lacked the target sequence) pre-existing mutants divide and multiply to take over the population. I believe this may account for the vast majority of the "editing" they are measuring, and claims of increased efficiency over earlier methods (eg TALEN) are due to this mechanism. They have not done proper due diligence of ruling out other explanations and prematurely starting running with their favorite, most hype-able, hypothesis. Can you find one paper where they report the efficiency of inserting a cassette via HDR, or do they all only look at NHEJ when talking about that? I have only seen the latter. Also, this alternative explanation has real-life consequences. If correct, the very mechanism via which CRISPR-Cas9 works is toxic, meaning all the hundreds of millions of dollars (billions?) currently being spent trying to make it less toxic will be wasted.
    - toufka 10y ago
      You do realize that the power of Cas9 is not it's ability to cut or even induce non-homologous-end-joining, but rather to co-localize with an exact sequence of DNA (that can be changed in a day for a few dollars). Cutting DNA is certainly a great self-defense mechanism used by the bacteria that causes strep throat to attack other bacteria. But in the ways that Cas9 will eventually be used, likely its entire endonuclease activity will be stripped, leaving only its homing ability. And for that you can swap in any other useful protein functions that now happen at a particular sequence location. And that is what makes Cas9 so exciting. That NHEJ works at all is just a bonus to get us to some early results quickly. fCas9 or dCas9, or a nickase (different endonuclease, and endonuclease-dead respectively) as well as a host of other variants actually hold great promise precisely and solely in their ability to locate a sequence.
      - nonbel 10y ago
        That may be. My explanation also requires relatively precise co-localization. Assuming the toxicity is only due to the endonuclease activity, those plans shouldn't be affected either way.
- tstactplsignore 10y ago
  This is ridiculous. Your views on NHST are extremist, absurd, and are not shared by pretty much all real statisticians, even those who are critical of frequentist methods. Secondly, many biological findings are not quantitative or statistical in nature- they simply are observations that have been repeated tens of thousands of times. Honestly I don't really care enough to respond over something that nobody else in the world really believes. Your claim that you were "trained in biomedicine" is cute but difficult to take seriously. It isn't worth my or anyone else's time to fight your bizarre and excessive ignorance on this topic. I just think it is important to point out to the community that you have zero credibility on this issue and are spouting nonsense that real statisticians, scientists, and computational biologists would laugh at.
  - nonbel 10y ago
    Of course I have zero credibility, I am a random person on the internet. But since you know I am so wrong, it should have taken less effort for you to link a paper than to write that post... Anyway, I agree it is pointless to continue a discussion at this level, which is why I tried to guide us to talking about specific findings (of your choice).

nonbel 10y ago

>"Entire fields of modern biology like genomics, structural biology, genome editing, and more could not even be fathomed to exist if this were not true." Yes, everything needs to be redone since at least the 1980s, and probably the 1940s (whenever NHST became the primary method of assessing what is correct or not). We have no idea what is actually going on. It is scary, I know. It took me years to accept. >"this is some creationist-tier science denial you have going on if you don't believe this" Ok, link to a specific paper and I will discuss it with you. In my experience, if it is biomed, no one will have ever published a replication of any results it contains. There will be no model capable of quantitative prediction of anything, and conclusions drawn will also almost certainly be fatally flawed due to the vagueness of their explanation.

tstactplsignore 10y ago
Lol, I just realized you were that guy who denies CRISPR-Cas9 genome editing really works. It may be against the rules, but I just have to tell you that you are an insufferable idiot who brings down the quality of discourse on this site with your bizarro pseudoscience nonsense.
- nonbel 10y ago
  This is a strawman. What I have seen in the data presented by the CRISPR-Cas9 researchers seems consistent with the idea that ~1% to 0.1% of cells in culture are mutants at any given site, the treatment selectively kills or growth arrests the non-mutants (at that site), and then the surviving (because they lacked the target sequence) pre-existing mutants divide and multiply to take over the population. I believe this may account for the vast majority of the "editing" they are measuring, and claims of increased efficiency over earlier methods (eg TALEN) are due to this mechanism. They have not done proper due diligence of ruling out other explanations and prematurely starting running with their favorite, most hype-able, hypothesis. Can you find one paper where they report the efficiency of inserting a cassette via HDR, or do they all only look at NHEJ when talking about that? I have only seen the latter. Also, this alternative explanation has real-life consequences. If correct, the very mechanism via which CRISPR-Cas9 works is toxic, meaning all the hundreds of millions of dollars (billions?) currently being spent trying to make it less toxic will be wasted.
  - toufka 10y ago
    You do realize that the power of Cas9 is not it's ability to cut or even induce non-homologous-end-joining, but rather to co-localize with an exact sequence of DNA (that can be changed in a day for a few dollars). Cutting DNA is certainly a great self-defense mechanism used by the bacteria that causes strep throat to attack other bacteria. But in the ways that Cas9 will eventually be used, likely its entire endonuclease activity will be stripped, leaving only its homing ability. And for that you can swap in any other useful protein functions that now happen at a particular sequence location. And that is what makes Cas9 so exciting. That NHEJ works at all is just a bonus to get us to some early results quickly. fCas9 or dCas9, or a nickase (different endonuclease, and endonuclease-dead respectively) as well as a host of other variants actually hold great promise precisely and solely in their ability to locate a sequence.
    - nonbel 10y ago
      That may be. My explanation also requires relatively precise co-localization. Assuming the toxicity is only due to the endonuclease activity, those plans shouldn't be affected either way.
tstactplsignore 10y ago
This is ridiculous. Your views on NHST are extremist, absurd, and are not shared by pretty much all real statisticians, even those who are critical of frequentist methods. Secondly, many biological findings are not quantitative or statistical in nature- they simply are observations that have been repeated tens of thousands of times. Honestly I don't really care enough to respond over something that nobody else in the world really believes. Your claim that you were "trained in biomedicine" is cute but difficult to take seriously. It isn't worth my or anyone else's time to fight your bizarre and excessive ignorance on this topic. I just think it is important to point out to the community that you have zero credibility on this issue and are spouting nonsense that real statisticians, scientists, and computational biologists would laugh at.
- nonbel 10y ago
  Of course I have zero credibility, I am a random person on the internet. But since you know I am so wrong, it should have taken less effort for you to link a paper than to write that post... Anyway, I agree it is pointless to continue a discussion at this level, which is why I tried to guide us to talking about specific findings (of your choice).