8 ms·

A radically simple idea may open the door to a new world of antibiotics

144 points by obeone 11y ago

joe_the_user 11y ago
The article gives the impression that a lot of biology involves ad-hoc, artisanal techniques that have been somewhat standardized and automated over the years. And that the standardization and automation involved can actually stand in the way of changing an approach. There was an article about the standardization of laboratory mice - it allows large scale, reproducible results but guarantees you won't things that can't be learned from the single, genetically uniform mouse type that is used.
- adrianN 11y ago
  Currently our understanding of biochemistry is so poor that we still have a lot to learn about the very basics. I don't think the diversity of our lab mice is currently a limiting factor.
  - danieltillett 11y ago
    Our understanding of biochemistry is actually quite good, it is our understanding of biochemistry diversity that is poor (i.e. why are you and I different). Using inbred mice does not help solve this problem.
    - adrianN 11y ago
      I'm no expert, but it seems to me that as long as there is still basic research being done on the behavior of very simple proteins, we're a long way from understanding the complex interactions that happen in cells.
      - danieltillett 11y ago
        Yes we have a lot to learn about all the interactions between proteins in a cell, but this typically does not fall under the heading of biochemistry. Slightly off topic the traditional divisions between different areas of biological sciences that built up in the 20th C have all broken down with the rise of molecular biology. Once biochemistry was a different field to say microbiology, now both are part of the super-field of molecular sciences.
  - PeterisP 11y ago
    The important practical results (e.g. many particular drugs) that we get and need are obtained not because of understanding why they work but despite that, empirical testing is a key part of current process. We have considered and discarded a lot of candidate drugs with great potential before starting human testing. As a rule, if some molecule would cure an important disease but for whatever reason doesn't work on the popular strains of mice, then our current process would cause us to discard it.
- danieltillett 11y ago
  I would like to see inbred mice banned from all research not about inbreding. No study should use inbred mice - sure is lets you use less mice, but at the expense of generating results that are limited to one individual. If we can't afford to use outbred mice then we should not have done the experiment.
  - _Wintermute 11y ago
    The use of inbred animals isn't a cost saving technique. Inbred strains are developed over many generations so that individuals are genetically homogeneous. You know that any different results you get are due to different treatments for instance rather than the genetic background of the animals you're using.
    - nonbel 11y ago
      >"You know that any different results you get are due to different treatments for instance rather than the genetic background of the animals you're using." I don't think this is really true. Perhaps that makes it unlikely genetic differences are the cause of a relatively large apparent treatment effect, but not just any difference.
    - danieltillett 11y ago
      Yes it is. Using inbred mice allows you to use fewer mice as the variability due to the genetic background is reduced. The more variability in your system the more individuals you need to see a statistically valid difference due to treatment. The more you have to test the more the cost. None of this would matter if we were developing cures for diseases of C57BL/6 mice [1], but we are actually interested in developing cures for humans who are not inbred (well in most places). We need our animals models to match as closely as possible to humans and using inbred mice is not a good match. 1. https://en.wikipedia.org/wiki/C57BL/6 https://en.wikipedia.org/wiki/C57BL/6
- jkimmel 11y ago
  >guarantees you won't things that can't be learned from the single, genetically uniform mouse type that is used. This is a misrepresentation of the state of mouse biology research. We use many different strains of inbred mice (check out the JAX Labs list of available inbreds)[1]. Inbreeding reduces the genetic variability of our mice, allowing us to control more of the variation in an experiment. This allows us to perform pilot studies with smaller samples sizes while still reaching sufficient statistical power. This is important -- mouse biology is expensive, and we try to discover as much as possible with limited funding. If a result merits generalization to multiple backgrounds, it is often tested in multiple inbred strains and an "outbred" strain that is genetically diverse. [1] - https://www.jax.org/jax-mice-and-services/find-and-order-jax-mice/most-popular-jax-mice-strains https://www.jax.org/jax-mice-and-services/find-and-order-jax...
  - joe_the_user 11y ago
    I think you're confusing my comment, which addresses the inherent limitation of automating particular experimental processes with a criticism about how biological research ought to be conducted. It may well be that uniformity is needed for reproducibility - even adding more controls for the uniformity, biology seems broadly limited by a relatively few particular starting points. As the OP points out, because the vast diversity of biological phenomena, it seems there are variety of things that simply aren't seen with only these starting points (again, not to deny that as practical matter one might still need to limit one's starting points).
danieltillett 11y ago
The problem developing new antibiotics is not the science it is economic and regulatory. Let's say you are crazy enough to pay the enormous cost of bring a new antibiotic through the regulatory process, your new antibiotic doesn't get used by doctors. They put the new antibiotic on the shelf to be used in emergencies when all the other antibiotics haven't worked. Your sales are then near zero. This is why all the major pharmaceutical companies have shut down their antibiotic divisions. What we need to work towards is a large cash payment on approval of each drug or a guaranteed minimium annual payment. Once we have this we will start to get the new antibiotics we need.
- DanBC 11y ago
  There are millions of people in US with anti-biotic resistant illness. There are millions of people in EU with anti-biotic illness. These are serious, life-threatening, life-limiting illnesses where the seller can set high prices. This is far from "near zero" sales. http://www.who.int/mediacentre/news/releases/2014/amr-report/en/ http://www.who.int/mediacentre/news/releases/2014/amr-report...
  - danieltillett 11y ago
    Yes this is because we have not been developing new antibiotics because of the non-use problem. Now of course because all the antibiotic divisions have been shut down we don't have the infrastructure to bring new antibiotics to market at the rate we need. You have to make the decision to develop a new antibiotic 15 years before you need it. We need to develop new antibiotics before we have a problem and where they will sit on the shelf, rather than wait until we have none and then panic.
  - jessriedel 11y ago
    Please give a better cite. Yours does not seem to support your claim. The only part of that link that mentions "millions" is > Treatment failure to the last resort of treatment for gonorrhoea–third generation cephalosporins–has been confirmed in Austria, Australia, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden and the United Kingdom. An estimated 106 million people are infected with gonorrhoea every year (2008 estimates). Only 1,000 people die a year from gonorrhoea worldwide, the vast majority of whom live outside the US and EU. https://en.wikipedia.org/wiki/Gonorrhea https://en.wikipedia.org/wiki/Gonorrhea To the best of my knowledge, the anti-biotic resistant bacteria that currently poses the greatest public health risk is Methicillin-resistant Staphylococcus aureus (MRSA). > Many of these infections are less serious, but the Centers for Disease Control and Prevention (CDC) estimates that there are 80,461 invasive MRSA infections and 11,285 deaths due to MRSA annually https://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureus#US_and_UK https://en.wikipedia.org/wiki/Methicillin-resistant_Staphylo... None of these are millions of people with life-threatening risks in the US.
hyperion2010 11y ago
The ability to culture organisms is the single most important roadblock to understanding. Even if a new culturing technique only enables you to grow .00001 % of the bacterial species out there that is still a 100 fold increase in the number that we can now study at scale. DNA sequencing has made it possible to identify new species by looking at their 16s ribosomal RNA, but if you are looking for small molecules and proteins you have to be able to amplify the whole organism, not just its nucleic acids. Huge deal, expect much more to come from microbiologists using this culturing technique.
- refurb 11y ago
  Why does being able to culture bacterial species matter? We can currently culture anything that infects humans.
  - csours 11y ago
    We need to culture the things that infect the things that infect us.
    - hyperion2010 11y ago
      Pretty much. We are completely blind to the other members of the micro ecosystem that are probably living happily on and around us under non-pathological conditions. There are theories out there that suggest that many infections are caused not by too many bad bacteria but too few or unstable populations of good bacteria (vast over simplification). In addition, we actually have quite a bit of trouble culturing bacteria that might be pathological (our inability to culture them is quite related to our inability to determine their pathological status).
    - refurb 11y ago
      Bacteria that infect other bacteria? Or do you mean bacteria that produce antibacterial compounds that could be used as antibiotics? Didn't most antibiotics come from fungi? All of the -mycins came from fungi.

144 points by obeone 11y ago

The article gives the impression that a lot of biology involves ad-hoc, artisanal techniques that have been somewhat standardized and automated over the years. And that the standardization and automation involved can actually stand in the way of changing an approach. There was an article about the standardization of laboratory mice - it allows large scale, reproducible results but guarantees you won't things that can't be learned from the single, genetically uniform mouse type that is used.

adrianN 11y ago
Currently our understanding of biochemistry is so poor that we still have a lot to learn about the very basics. I don't think the diversity of our lab mice is currently a limiting factor.
- danieltillett 11y ago
  Our understanding of biochemistry is actually quite good, it is our understanding of biochemistry diversity that is poor (i.e. why are you and I different). Using inbred mice does not help solve this problem.
  - adrianN 11y ago
    I'm no expert, but it seems to me that as long as there is still basic research being done on the behavior of very simple proteins, we're a long way from understanding the complex interactions that happen in cells.
    - danieltillett 11y ago
      Yes we have a lot to learn about all the interactions between proteins in a cell, but this typically does not fall under the heading of biochemistry. Slightly off topic the traditional divisions between different areas of biological sciences that built up in the 20th C have all broken down with the rise of molecular biology. Once biochemistry was a different field to say microbiology, now both are part of the super-field of molecular sciences.
- PeterisP 11y ago
  The important practical results (e.g. many particular drugs) that we get and need are obtained not because of understanding why they work but despite that, empirical testing is a key part of current process. We have considered and discarded a lot of candidate drugs with great potential before starting human testing. As a rule, if some molecule would cure an important disease but for whatever reason doesn't work on the popular strains of mice, then our current process would cause us to discard it.
danieltillett 11y ago
I would like to see inbred mice banned from all research not about inbreding. No study should use inbred mice - sure is lets you use less mice, but at the expense of generating results that are limited to one individual. If we can't afford to use outbred mice then we should not have done the experiment.
- _Wintermute 11y ago
  The use of inbred animals isn't a cost saving technique. Inbred strains are developed over many generations so that individuals are genetically homogeneous. You know that any different results you get are due to different treatments for instance rather than the genetic background of the animals you're using.
  - nonbel 11y ago
    >"You know that any different results you get are due to different treatments for instance rather than the genetic background of the animals you're using." I don't think this is really true. Perhaps that makes it unlikely genetic differences are the cause of a relatively large apparent treatment effect, but not just any difference.
  - danieltillett 11y ago
    Yes it is. Using inbred mice allows you to use fewer mice as the variability due to the genetic background is reduced. The more variability in your system the more individuals you need to see a statistically valid difference due to treatment. The more you have to test the more the cost. None of this would matter if we were developing cures for diseases of C57BL/6 mice [1], but we are actually interested in developing cures for humans who are not inbred (well in most places). We need our animals models to match as closely as possible to humans and using inbred mice is not a good match. 1. https://en.wikipedia.org/wiki/C57BL/6 https://en.wikipedia.org/wiki/C57BL/6
jkimmel 11y ago
>guarantees you won't things that can't be learned from the single, genetically uniform mouse type that is used. This is a misrepresentation of the state of mouse biology research. We use many different strains of inbred mice (check out the JAX Labs list of available inbreds)[1]. Inbreeding reduces the genetic variability of our mice, allowing us to control more of the variation in an experiment. This allows us to perform pilot studies with smaller samples sizes while still reaching sufficient statistical power. This is important -- mouse biology is expensive, and we try to discover as much as possible with limited funding. If a result merits generalization to multiple backgrounds, it is often tested in multiple inbred strains and an "outbred" strain that is genetically diverse. [1] - https://www.jax.org/jax-mice-and-services/find-and-order-jax-mice/most-popular-jax-mice-strains https://www.jax.org/jax-mice-and-services/find-and-order-jax...
- joe_the_user 11y ago
  I think you're confusing my comment, which addresses the inherent limitation of automating particular experimental processes with a criticism about how biological research ought to be conducted. It may well be that uniformity is needed for reproducibility - even adding more controls for the uniformity, biology seems broadly limited by a relatively few particular starting points. As the OP points out, because the vast diversity of biological phenomena, it seems there are variety of things that simply aren't seen with only these starting points (again, not to deny that as practical matter one might still need to limit one's starting points).

danieltillett 11y ago

The problem developing new antibiotics is not the science it is economic and regulatory. Let's say you are crazy enough to pay the enormous cost of bring a new antibiotic through the regulatory process, your new antibiotic doesn't get used by doctors. They put the new antibiotic on the shelf to be used in emergencies when all the other antibiotics haven't worked. Your sales are then near zero. This is why all the major pharmaceutical companies have shut down their antibiotic divisions. What we need to work towards is a large cash payment on approval of each drug or a guaranteed minimium annual payment. Once we have this we will start to get the new antibiotics we need.

DanBC 11y ago
There are millions of people in US with anti-biotic resistant illness. There are millions of people in EU with anti-biotic illness. These are serious, life-threatening, life-limiting illnesses where the seller can set high prices. This is far from "near zero" sales. http://www.who.int/mediacentre/news/releases/2014/amr-report/en/ http://www.who.int/mediacentre/news/releases/2014/amr-report...
- danieltillett 11y ago
  Yes this is because we have not been developing new antibiotics because of the non-use problem. Now of course because all the antibiotic divisions have been shut down we don't have the infrastructure to bring new antibiotics to market at the rate we need. You have to make the decision to develop a new antibiotic 15 years before you need it. We need to develop new antibiotics before we have a problem and where they will sit on the shelf, rather than wait until we have none and then panic.
- jessriedel 11y ago
  Please give a better cite. Yours does not seem to support your claim. The only part of that link that mentions "millions" is > Treatment failure to the last resort of treatment for gonorrhoea–third generation cephalosporins–has been confirmed in Austria, Australia, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden and the United Kingdom. An estimated 106 million people are infected with gonorrhoea every year (2008 estimates). Only 1,000 people die a year from gonorrhoea worldwide, the vast majority of whom live outside the US and EU. https://en.wikipedia.org/wiki/Gonorrhea https://en.wikipedia.org/wiki/Gonorrhea To the best of my knowledge, the anti-biotic resistant bacteria that currently poses the greatest public health risk is Methicillin-resistant Staphylococcus aureus (MRSA). > Many of these infections are less serious, but the Centers for Disease Control and Prevention (CDC) estimates that there are 80,461 invasive MRSA infections and 11,285 deaths due to MRSA annually https://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureus#US_and_UK https://en.wikipedia.org/wiki/Methicillin-resistant_Staphylo... None of these are millions of people with life-threatening risks in the US.

hyperion2010 11y ago

The ability to culture organisms is the single most important roadblock to understanding. Even if a new culturing technique only enables you to grow .00001 % of the bacterial species out there that is still a 100 fold increase in the number that we can now study at scale. DNA sequencing has made it possible to identify new species by looking at their 16s ribosomal RNA, but if you are looking for small molecules and proteins you have to be able to amplify the whole organism, not just its nucleic acids. Huge deal, expect much more to come from microbiologists using this culturing technique.

refurb 11y ago
Why does being able to culture bacterial species matter? We can currently culture anything that infects humans.
- csours 11y ago
  We need to culture the things that infect the things that infect us.
  - hyperion2010 11y ago
    Pretty much. We are completely blind to the other members of the micro ecosystem that are probably living happily on and around us under non-pathological conditions. There are theories out there that suggest that many infections are caused not by too many bad bacteria but too few or unstable populations of good bacteria (vast over simplification). In addition, we actually have quite a bit of trouble culturing bacteria that might be pathological (our inability to culture them is quite related to our inability to determine their pathological status).
  - refurb 11y ago
    Bacteria that infect other bacteria? Or do you mean bacteria that produce antibacterial compounds that could be used as antibiotics? Didn't most antibiotics come from fungi? All of the -mycins came from fungi.