7 ms·

I work at a medium-sized pharmaceutical company as a computational biologist. Diseases like KS sometimes come up as potential repurposing targets (or novel drug

by biols 5y ago

I work at a medium-sized pharmaceutical company as a computational biologist. Diseases like KS sometimes come up as potential repurposing targets (or novel drug targets), but we get a LOT of pushback from finance / leadership because we're unlikely to turn a profit working on ultra-rare indications. It is a deeply frustrating position to be in, wanting to work on these rare diseases and help this rarified patient population and not being able to, even though me and my colleagues are poised to do so. I often get maligned for being a scientist in pharma; laypeople often assert that I "don't want to treat cancer / rare genetic disease / etc; because then I'd be out of business." I can assure those reading that all of us DESPERATELY would like to work in these indications, and often times it's tragically finance that dictates whether we are able to or not. The system feels broken.

netizen-936824 5y ago
Sounds like you and your colleagues could start your own company, there may be enough people. I wonder if a nonprofit pharma company is viable.
- codekilla 5y ago
  I have been reading a book recently: The Story of Taxol: Nature and Politics in the Pursuit of an Anti-Cancer Drug, and one of the most fascinating parts was the way they discovered this molecule. Long story short, Taxol is a molecule they isolated from the bark of the Pacific Yew. The interesting part for me was learning about the Cancer Chemotherapy National Service Center [1]. They went around collecting samples of random plants, then tested them for anti-cancer properties very systematically. So in the U.S., at one point, we had a publicly funded drug discovery program targeted at a specific disease, and this is what jump started Pharma research in anti-cancer drugs. I would say we need to restart a program like this, and of course we should also focus on rare diseases--we stand to learn a tremendous amount, and it's difficult to convince industry to do it. Personally, I'm a computational/mathematical biologist and I work on single cell data targeting multiple myeloma, I'd really like to see serious non-profit Pharma. Drug repurposing seems like the most feasible avenue. What I know of right now is open Pharma [2]. [1] https://dtp.cancer.gov/timeline/flash/milestones/M3_CCNSC.htm https://dtp.cancer.gov/timeline/flash/milestones/M3_CCNSC.ht... [2] https://www.ospfound.org https://www.ospfound.org
  - netizen-936824 5y ago
    Out of curiosity, what does your work entail with single cell stuff from a computational perspective? I've been doing some research into molecular docking as a drug discovery method, but its all single protein.
    - codekilla 5y ago
      There are a lot of modalities being integrated, things like spatial/temporal, ADT/protein, etc. Integrating all of this data is a computational challenge, and of course there are lots of methods for analyzing it that vary in computational demands. It's not simulation, but still a lot of processing.
      - netizen-936824 5y ago
        So you're taking all wet bench data and analyzing or integrating it rather than modeling? That's interesting! Are there any possibilities that you see from your experience in using modeling or other in silico methods to reduce time in the lab, find new leads in drug development, or otherwise enhance research capabilities?
        codekilla 5y ago
        Yes, essentially, though you may create models of interactions etc., but the main idea is to extract information from various aspects of the cell. As far as in silico, I think absolutely there are probably opportunities here. Generative models might be useful for some type of counterfactual (automated) reasoning with respect to disease course/treatment. I think we're in the relatively early days of collecting high resolution cellular data, so I think in silico approaches like this will be more and more relevant.
  - biols 5y ago
    The Broad Institute hosts a very interesting transcriptomic dataset called CMap [1] that was intended to facilitate rapid drug repurposing. Having studied this dataset and worked with the data generators and software teams, I can say that drug repurposing is NOT as straightforward as people think. However, I agree that as a strategy drug repurposing is a useful tool in the arsenal generally. [1] https://clue.io https://clue.io
- t3po7re5 5y ago
  I wish there was a way to crowd fund or crowd source a push for new therapeutics. I have a rare cancer at the moment and the overwhelming majority of drugs used for it were developed for other cancers. I wish there was a way we could establish an open source community or project around creating novel drug targets as a small moon shot funded by donations from the lives that it effects.
  - halukakin 5y ago
    From a software developer perspective: A github like service where every incremental research step is recorded&visible. A build management system like travis where each experiment is built and held accountable to unit tests. Something like github actions where you can trigger an automated lab trial instantly. Somehow opensource SW development communities have so much they can teach to medical researchers in terms of how to scale development.
    - gardenfelder 5y ago
      Sage Bionetworks Synapse https://www.synapse.org/ https://www.synapse.org/ was conceived as a github-based research collaboration ecosystem.
    - biols 5y ago
      This is what I'd like to see. There should be some kind of system where in-progress research being done by pharma companies can be published. This would reduce the massively redundant amount of studies (e.g. CRISPR screens, xenograft studies, etc.) and help scientists more quickly converge on the mechanistic underpinnings of disease and how best to address them therapeutically. Obviously this can't work in the current pharma industry configuration; what financial incentive is there for big pharma companies to publish their results for another company to beat them to a new drug? I don't have a solution to this problem, but I hope someday we as a society can find one. This would absolutely revolutionize biopharmaceutical science.
      - codekilla 5y ago
        I've thought about things like the patent/ip problem, the structure of biomedical research, Pharma research, etc. This is an area where I don't actually see competition as a net benefit, however....it's the reality. The only thing I can come up with is a version of 'data rental'. Rather than Pharma companies locking this data away from others indefinitely, is there a way they could profit from it somehow, while still retaining ownership and not divulging trade secrets? Maybe not. I've thought that a type of cryptographic data commons based on multi-party communication [1] could possibly be deployed with some effect. Basically you need algorithms that can compute on encrypted data, and a way to securely communicate encrypted data. There might not be huge incentive to use something like this, but maybe a version of this idea could work. [1] https://en.wikipedia.org/wiki/Secure_multi-party_computation https://en.wikipedia.org/wiki/Secure_multi-party_computation
halukakin 5y ago
I hope one-day things would turn around. If the regulators asked pharmaceutical companies to study for these drugs on the side so much could change. Probably less than 1% of their R&D budget would be enough to move things.
- ImaCake 5y ago
  Absolutely. A lot of funding gets poured into dead end alzheimers research or similar that will never work. A fraction of that redirected to rare diseases that get zero funding will do wonders. It is a shame that academia and research are so burdened with graft and politics.
WalterBright 5y ago
If you could do research that will save 10 lives, vs research that will save 1 life, which would you choose? I understand that there are no easy choices here, and having to make a choice will always be heartbreaking. May I suggest contacting MacKenzie Scott (Jeff Bezos' ex) who seems to be looking for worthwhile endeavors to finance. (I have no connection to Ms Scott, I just read articles about her charitable activities in the newspaper.)
- halukakin 5y ago
  I first heard about her efforts when she donated $40M to UCF. https://www.ucf.edu/news/scott-40-million-transformational-investment-in-ucf/ https://www.ucf.edu/news/scott-40-million-transformational-i... I hope we can get in touch somehow. Thank you.
- biols 5y ago
  Major pharma companies are all constantly competing, and very often are duplicating work because they are not sharing major experimental results. The way it feels is that there's already "too many people" working in certain areas (e.g. in cancer), while almost no attention is paid to these rare diseases. I think that more people studying rare diseases would result in a net gain of lives saved; I don't think it's as zero-sum as "either 1 person's life is saved or 10 are" in this instance. Research also cross pollinates across disease areas. For example, understanding altered metabolism in cancer can yield insights for non-oncological metabolic disorders. Oftentimes, though, nobody's working on translating that work out of a cancer model, because the financial incentives are not there.
  - WalterBright 5y ago
    On the other hand, competition has given us what, 6 covid vaccines of varying effectiveness, and in record time. What if only the least effective one was developed, and took 18 months? The 1962 FDA effectiveness mandates have had the side effect of increasing drug development costs enormously, and that shuts down development of treatments for rare disorders.
anyfactor 5y ago
I want to preface this by saying I am not providing an opinion rather I am genuinely curious. When Martin Shkreli bought the rights to Daraprim, some of his rhetoric about pharmaceutical industry sounded fair. He said that he is willing to send the drug for free to anyone who wrote to the company and he was essentially making the insurance companies pay the absurd price of the drug. He claimed no patient would ever financially suffer for the drug. He said the needed the money to pay for new research and better drugs and it was one of of lesser of evil thing he can do to R&D. Ignoring the trickle down effect, if the government and Insurance companies in most cases ultimately pay for the price of medication wouldn't it be valid motivator to research rare diseases?
- jmcgough 5y ago
  Zolgensma comes to mind - one time gene therapy treatment for a rare disease (tens of thousands), billed at $2M. Not sure if there's as viable for OP since only a few hundred people have been diagnosed.
- obilgic 5y ago
  not providing an opinion on your suggestion but there is no such a thing as "government and Insurance companies paying" though, It's taxpayers.
  - djbusby 5y ago
    Always has been. Through insurance, cost-pass-thru, taxes, direct medication purchase, etc. So, now that it's established that it's always the individual paying into...which is the most efficient way of allocating funds out of the system? Profit? Lives saved? Less acne?
- not2b 5y ago
  Insurance companies get their money from people, companies, or governments that pay for insurance. To get him an absurd amount of money, ultimately we (individuals, companies, taxpayers) have to provide it.
  - 5y ago
fartcannon 5y ago
Just the fact that you get push back on work like that suggests to me that these companies will never cure anything. They will treat absolutely disease, but cure nothing.
- robotresearcher 5y ago
  Have you not had a family member or close friend cured of disease that would have killed them a hundred years ago, thanks to modern pharma drug? I sure have.
  - fartcannon 5y ago
    No, not personally, I do have 2 on life long treatments. But I was being too hyperbolic and I don't doubt your story. I'm just extrapolating incentives. Is there any incentive to cure (invoice once), when they can treat (life long invoices)? Certainly scorn is irrelevant as OPs comment suggests they're unwilling to work on rare diseases. And these companies are public. They have shareholders that expect them to constantly grow. I don't believe it's a stretch to say, at the very least, the incentive is there.
    - bluGill 5y ago
      competion provides the incentive, a cure will put all your treatment competitors out of business as you get everything from everyone who doesn't like treatment. You know many people who would have died of smallpox,measles, polio, and the like 100 years ago, you just have no idea who those people are.
      - fartcannon 5y ago
        That is a reassuring perspective. To be clear, I still think this conversation goes on in the background. Bill Gates famously convinced Oxford not to give the covid vaccine IP away thus preventing poorer countries from creating their own vaccines. The deaths from this act alone should be enough to convince you that money makes medicine murkier than you clearly want to believe.
giantg2 5y ago
It would be cool if pharma companies had charitable rotation program for researchers to volunteer to research these types of things. So the researchers could still get paid and the company could claim the costs as a write-off (not sure if they actually need one) with the results being public use.
wxnx 5y ago
Thanks for your comment. I'm also a computational biologist by training, but have never worked in the private sector. I'm familiar with the idea of re-purposing drugs for rare disease treatments (most of my adjacent work has been in very early-stage academic research), but I'm curious about the financials here. Could some of the financial risk here be minimized by aggregating multiple groups of patients, all suffering from different rare diseases? From what I know about the process, the answer is yes, but I'd be curious to hear from somebody closer to the process.
webmaven 5y ago
How do you (eventually) do phase 2 and 3 trials for an ultra rare disease that only has hundreds of patients?

by biols 5y ago

netizen-936824 5y ago

Sounds like you and your colleagues could start your own company, there may be enough people. I wonder if a nonprofit pharma company is viable.

codekilla 5y ago
I have been reading a book recently: The Story of Taxol: Nature and Politics in the Pursuit of an Anti-Cancer Drug, and one of the most fascinating parts was the way they discovered this molecule. Long story short, Taxol is a molecule they isolated from the bark of the Pacific Yew. The interesting part for me was learning about the Cancer Chemotherapy National Service Center [1]. They went around collecting samples of random plants, then tested them for anti-cancer properties very systematically. So in the U.S., at one point, we had a publicly funded drug discovery program targeted at a specific disease, and this is what jump started Pharma research in anti-cancer drugs. I would say we need to restart a program like this, and of course we should also focus on rare diseases--we stand to learn a tremendous amount, and it's difficult to convince industry to do it. Personally, I'm a computational/mathematical biologist and I work on single cell data targeting multiple myeloma, I'd really like to see serious non-profit Pharma. Drug repurposing seems like the most feasible avenue. What I know of right now is open Pharma [2]. [1] https://dtp.cancer.gov/timeline/flash/milestones/M3_CCNSC.htm https://dtp.cancer.gov/timeline/flash/milestones/M3_CCNSC.ht... [2] https://www.ospfound.org https://www.ospfound.org
- netizen-936824 5y ago
  Out of curiosity, what does your work entail with single cell stuff from a computational perspective? I've been doing some research into molecular docking as a drug discovery method, but its all single protein.
  - codekilla 5y ago
    There are a lot of modalities being integrated, things like spatial/temporal, ADT/protein, etc. Integrating all of this data is a computational challenge, and of course there are lots of methods for analyzing it that vary in computational demands. It's not simulation, but still a lot of processing.
    - netizen-936824 5y ago
      So you're taking all wet bench data and analyzing or integrating it rather than modeling? That's interesting! Are there any possibilities that you see from your experience in using modeling or other in silico methods to reduce time in the lab, find new leads in drug development, or otherwise enhance research capabilities?
      - codekilla 5y ago
        Yes, essentially, though you may create models of interactions etc., but the main idea is to extract information from various aspects of the cell. As far as in silico, I think absolutely there are probably opportunities here. Generative models might be useful for some type of counterfactual (automated) reasoning with respect to disease course/treatment. I think we're in the relatively early days of collecting high resolution cellular data, so I think in silico approaches like this will be more and more relevant.
- biols 5y ago
  The Broad Institute hosts a very interesting transcriptomic dataset called CMap [1] that was intended to facilitate rapid drug repurposing. Having studied this dataset and worked with the data generators and software teams, I can say that drug repurposing is NOT as straightforward as people think. However, I agree that as a strategy drug repurposing is a useful tool in the arsenal generally. [1] https://clue.io https://clue.io
t3po7re5 5y ago
I wish there was a way to crowd fund or crowd source a push for new therapeutics. I have a rare cancer at the moment and the overwhelming majority of drugs used for it were developed for other cancers. I wish there was a way we could establish an open source community or project around creating novel drug targets as a small moon shot funded by donations from the lives that it effects.
- halukakin 5y ago
  From a software developer perspective: A github like service where every incremental research step is recorded&visible. A build management system like travis where each experiment is built and held accountable to unit tests. Something like github actions where you can trigger an automated lab trial instantly. Somehow opensource SW development communities have so much they can teach to medical researchers in terms of how to scale development.
  - gardenfelder 5y ago
    Sage Bionetworks Synapse https://www.synapse.org/ https://www.synapse.org/ was conceived as a github-based research collaboration ecosystem.
  - biols 5y ago
    This is what I'd like to see. There should be some kind of system where in-progress research being done by pharma companies can be published. This would reduce the massively redundant amount of studies (e.g. CRISPR screens, xenograft studies, etc.) and help scientists more quickly converge on the mechanistic underpinnings of disease and how best to address them therapeutically. Obviously this can't work in the current pharma industry configuration; what financial incentive is there for big pharma companies to publish their results for another company to beat them to a new drug? I don't have a solution to this problem, but I hope someday we as a society can find one. This would absolutely revolutionize biopharmaceutical science.
    - codekilla 5y ago
      I've thought about things like the patent/ip problem, the structure of biomedical research, Pharma research, etc. This is an area where I don't actually see competition as a net benefit, however....it's the reality. The only thing I can come up with is a version of 'data rental'. Rather than Pharma companies locking this data away from others indefinitely, is there a way they could profit from it somehow, while still retaining ownership and not divulging trade secrets? Maybe not. I've thought that a type of cryptographic data commons based on multi-party communication [1] could possibly be deployed with some effect. Basically you need algorithms that can compute on encrypted data, and a way to securely communicate encrypted data. There might not be huge incentive to use something like this, but maybe a version of this idea could work. [1] https://en.wikipedia.org/wiki/Secure_multi-party_computation https://en.wikipedia.org/wiki/Secure_multi-party_computation

halukakin 5y ago

I hope one-day things would turn around. If the regulators asked pharmaceutical companies to study for these drugs on the side so much could change. Probably less than 1% of their R&D budget would be enough to move things.

ImaCake 5y ago
Absolutely. A lot of funding gets poured into dead end alzheimers research or similar that will never work. A fraction of that redirected to rare diseases that get zero funding will do wonders. It is a shame that academia and research are so burdened with graft and politics.

WalterBright 5y ago

If you could do research that will save 10 lives, vs research that will save 1 life, which would you choose? I understand that there are no easy choices here, and having to make a choice will always be heartbreaking. May I suggest contacting MacKenzie Scott (Jeff Bezos' ex) who seems to be looking for worthwhile endeavors to finance. (I have no connection to Ms Scott, I just read articles about her charitable activities in the newspaper.)

halukakin 5y ago
I first heard about her efforts when she donated $40M to UCF. https://www.ucf.edu/news/scott-40-million-transformational-investment-in-ucf/ https://www.ucf.edu/news/scott-40-million-transformational-i... I hope we can get in touch somehow. Thank you.
biols 5y ago
Major pharma companies are all constantly competing, and very often are duplicating work because they are not sharing major experimental results. The way it feels is that there's already "too many people" working in certain areas (e.g. in cancer), while almost no attention is paid to these rare diseases. I think that more people studying rare diseases would result in a net gain of lives saved; I don't think it's as zero-sum as "either 1 person's life is saved or 10 are" in this instance. Research also cross pollinates across disease areas. For example, understanding altered metabolism in cancer can yield insights for non-oncological metabolic disorders. Oftentimes, though, nobody's working on translating that work out of a cancer model, because the financial incentives are not there.
- WalterBright 5y ago
  On the other hand, competition has given us what, 6 covid vaccines of varying effectiveness, and in record time. What if only the least effective one was developed, and took 18 months? The 1962 FDA effectiveness mandates have had the side effect of increasing drug development costs enormously, and that shuts down development of treatments for rare disorders.

anyfactor 5y ago

I want to preface this by saying I am not providing an opinion rather I am genuinely curious. When Martin Shkreli bought the rights to Daraprim, some of his rhetoric about pharmaceutical industry sounded fair. He said that he is willing to send the drug for free to anyone who wrote to the company and he was essentially making the insurance companies pay the absurd price of the drug. He claimed no patient would ever financially suffer for the drug. He said the needed the money to pay for new research and better drugs and it was one of of lesser of evil thing he can do to R&D. Ignoring the trickle down effect, if the government and Insurance companies in most cases ultimately pay for the price of medication wouldn't it be valid motivator to research rare diseases?

jmcgough 5y ago
Zolgensma comes to mind - one time gene therapy treatment for a rare disease (tens of thousands), billed at $2M. Not sure if there's as viable for OP since only a few hundred people have been diagnosed.
obilgic 5y ago
not providing an opinion on your suggestion but there is no such a thing as "government and Insurance companies paying" though, It's taxpayers.
- djbusby 5y ago
  Always has been. Through insurance, cost-pass-thru, taxes, direct medication purchase, etc. So, now that it's established that it's always the individual paying into...which is the most efficient way of allocating funds out of the system? Profit? Lives saved? Less acne?
not2b 5y ago
Insurance companies get their money from people, companies, or governments that pay for insurance. To get him an absurd amount of money, ultimately we (individuals, companies, taxpayers) have to provide it.
- 5y ago

fartcannon 5y ago

Just the fact that you get push back on work like that suggests to me that these companies will never cure anything. They will treat absolutely disease, but cure nothing.

robotresearcher 5y ago
Have you not had a family member or close friend cured of disease that would have killed them a hundred years ago, thanks to modern pharma drug? I sure have.
- fartcannon 5y ago
  No, not personally, I do have 2 on life long treatments. But I was being too hyperbolic and I don't doubt your story. I'm just extrapolating incentives. Is there any incentive to cure (invoice once), when they can treat (life long invoices)? Certainly scorn is irrelevant as OPs comment suggests they're unwilling to work on rare diseases. And these companies are public. They have shareholders that expect them to constantly grow. I don't believe it's a stretch to say, at the very least, the incentive is there.
  - bluGill 5y ago
    competion provides the incentive, a cure will put all your treatment competitors out of business as you get everything from everyone who doesn't like treatment. You know many people who would have died of smallpox,measles, polio, and the like 100 years ago, you just have no idea who those people are.
    - fartcannon 5y ago
      That is a reassuring perspective. To be clear, I still think this conversation goes on in the background. Bill Gates famously convinced Oxford not to give the covid vaccine IP away thus preventing poorer countries from creating their own vaccines. The deaths from this act alone should be enough to convince you that money makes medicine murkier than you clearly want to believe.

giantg2 5y ago

It would be cool if pharma companies had charitable rotation program for researchers to volunteer to research these types of things. So the researchers could still get paid and the company could claim the costs as a write-off (not sure if they actually need one) with the results being public use.

wxnx 5y ago

Thanks for your comment. I'm also a computational biologist by training, but have never worked in the private sector. I'm familiar with the idea of re-purposing drugs for rare disease treatments (most of my adjacent work has been in very early-stage academic research), but I'm curious about the financials here. Could some of the financial risk here be minimized by aggregating multiple groups of patients, all suffering from different rare diseases? From what I know about the process, the answer is yes, but I'd be curious to hear from somebody closer to the process.

webmaven 5y ago

How do you (eventually) do phase 2 and 3 trials for an ultra rare disease that only has hundreds of patients?