Hey everyone! We’re Juliana and Robert, co-founders of Parallel Bio. We're improving drug discovery by replacing animal models, in the hope of making cures for humans, not mice.
The biggest reason why 92% of new drugs fail is that drugs are currently discovered in mice, which are not realistic models of human disease but are used due to the challenges of working in humans. We've created a human ‘immune system in a dish’ to discover drugs more likely to work in patients.
Robert has a PhD in immunology and is intimately familiar with the ways in which people are failing to recognize the importance of the immune system in diseases and the failures of trying to model it adequately. Juliana has a MSc in bioengineering and for the last 5 years has been working on developing mini-organ models in an effort to more accurately model human disease.
Both of us have always recognized a gap in the pharmaceutical industry that everyone seems to acknowledge exists, but few people are working to fill, which is using humans and human systems to treat disease. Since it is not always possible to test drugs directly in patients, there is a critical need for human systems to test drugs on that will predict downstream success in the patient.
Our immune organoid is a 3D system that has all of the features of a human secondary lymphoid organ. It contains all of the cells (B cells, T cells, NK cells, etc), structures (germinal centers, LZ/DZ, etc), and function (somatic hypermutation, antibody and cellular response, etc) that you would expect to see in a secondary lymphoid organ. It matches the genetic background of the patient from which it’s derived, meaning it also models diseases that patients have. And because it exhibits the same functions as a human immune system, you can test drugs and vaccines as if you were testing them in actual patients from the start. It's also easier to work with than mice.
People are currently using our platform as a new way to produce antibody therapies, to test vaccine candidates, and to test new treatments for diseases like multiple sclerosis.
Very cool and promising. Is there any literature on this "immune system in a dish", or is it ,understandably, proprietary?
Three main Q:
* How's reception been with med chemists?
* How do you expect cost to compare with some of the individual existing immunological wet lab screens? No individual numbers, just comparative would be interesting to know.
* How granular is data collection for this kinda all-in-one system, and is throughput high enough to collect data and build predictive models alongside it?
I used to work in the earlier stages of drug discovery and advances in these assays are fascinating. Really exciting work, guys!
There are some reviews on immune organoids that I posted below. This is the first human one though able to recapitulate these features at a commercial scale.
We haven't gotten any feedback from med chemists yet!
The cost is comparable to other in vitro systems and is cheaper than using animals.
*The data collection can be very granular. You can use single cell techniques like flow and RNA-seq to generate high resolution data. You can also use high resolution imaging techniques like CODEX. Moving into high throughput and building predictive models is exactly where we want to go. Currently, we can generate 7500 organoids from a single donor and screen them in the thousands. We're working on building a ML pipeline along with automation so that we can screen in the hundreds of thousands if not more. Key to this though is that we have designed a platform that is amenable to this kind of automation and scale.
Oh wow, your upcoming plans sound great. Keep up the good work guys!
And I highly recommend reaching out to a med chemist for some input. There's a lot of veteran retirees specializing in spaces adjacent to this who are open to consulting here and there. They're generally quite kind.
On behalf of all the mice, thank you very much for doing this. I'm all for modern medicine but the number of mice, primates and other mammals that we kill in the name of science every year does not sit right with me.
I’ve always felt that if there was _any_ morally acceptable reason to harm and kill animals it is for the sake of (reasonable) medical research. In principle the ethics board is there to make sure this is true but in practice they rarely do anything about it. Perhaps the real way to solve that problem is hold the IrBs to a higher standard and make them do their job?
I always try to reverse a situation to see if it makes sense, and then I ask myself: what would we think if aliens came to earth to experiment on us with untested medicine, kill us afterwards and only when it is perfectly safe on us they would apply it to themselves. I believe a large fraction of humanity would say that that is unethical and they'd have all kinds of cognitive dissonance to deal with (and associated reasons why this is different) to explain why what we do is ok.
I personally don't think it is ok, but it apparently is a necessity, at the same time if this can be stopped then that would be great.
We feel exactly the same way. Not only is it unacceptable that over 110 million animals a year are sacrificed for research, but these models do a terrible job of translating to humans and in most cases cannot even model the disease of interest but are used regardless. I used to work in tuberculosis where mice are predominantly used even though they do not get the disease and the disease they do get has the exact opposite pathology as a human.
We agree that this would be an important step. That being said, there is a paucity of models that would make suitable replacements to animal models. People are working on this issue, but many more people need to be working on developing better in vitro systems. Even with our platform, animal models still have to be used for certain assays (e.g. ADME) but we hope that one day this will not be the case.
- They're derived from secondary lymphoid tissue. We're trying to biobank as broadly as we can to capture sex, age, race, HLA, genetics, and other characteristics in a wide net.
- These are not iPSC-derived organoids.
- This depends on the readout but workup post treatment so far has included histology, immunofluorescence, serology (ELISA, SPR, etc.), CyTOF and other flow, broad RNA-seq, bulk and single cell repertoire sequencing for B and T cells, and MSD/Luminex.
- We haven't looked for mutations from drug and vaccine treatment. We'd love to know more about what you're thinking there.
This is a moonshot if I ever saw one. Exciting stuff.
Does your system also have epithelial lining, with all of the components of innate immunity which integrate with the adaptive immune system?
The role of the nervous system is more and more recognized as being integrated within the immune system - is there any way you can somehow include that in your system as well in the future?
Exciting to hear this! Do you have any references to the type of work (if your own isn’t published) that closely resembles the organoid models you use?
How finicky are these organoids to maintain? It used to be true that organoids are harder to maintain than super large mouse colonies by a long shot!
What validation are you doing on your immune organoid to confirm they work correctly for the assay you’re trying to do?
How do you emulate the various ailments in these organoids? You mentioned MS, are you able to emulate MS like conditions (or even EAE) in these systems?
The organoids are incredibly finicky until you figure out a culture system they like. Then it is actually very easy to maintain them. This allows us defensibility as it's hard for others to figure out but easier for us now that we have.
We've used the organoid to test 12 immunomodulators and confirmed they matched human clinical data. We also vaccinated the organoids against 8 infectious diseases and they produced a full immune response with class switching, germinal center formation, somatic hypermutation, etc. We're also in the process of using more historical controls to show that immune reactions that were missed in mice and other animals are captured in our system (e.g. there are highly inflammatory drugs that were safe in mice but deadly in people once they got to clinical trials).
By biobanking on diverse patient backgrounds, diseases are emulated in these organoids naturally. Immune disease is typically a function of dysfunctional cells that exist in a patient. By capturing an immune niche that has those cells, we have the disease-causing cells. We can confirm they emulate a disease by demonstrating a phenotype on a tissue of interest (e.g. we can make an MS immune organoid from a patient with MS and then show that the immune cells from the organoid demyelinate neurons). This should be the same for any immune disease as we continue to generate proof of concept.
Heads up I went to email you a congratulatory email at hello@parallel.bio but my email was rejected. Might want to double check your google groups settings.
The biggest reason why 92% of new drugs fail is that drugs are currently discovered in mice, which are not realistic models of human disease but are used due to the challenges of working in humans. We've created a human ‘immune system in a dish’ to discover drugs more likely to work in patients.
Robert has a PhD in immunology and is intimately familiar with the ways in which people are failing to recognize the importance of the immune system in diseases and the failures of trying to model it adequately. Juliana has a MSc in bioengineering and for the last 5 years has been working on developing mini-organ models in an effort to more accurately model human disease.
Both of us have always recognized a gap in the pharmaceutical industry that everyone seems to acknowledge exists, but few people are working to fill, which is using humans and human systems to treat disease. Since it is not always possible to test drugs directly in patients, there is a critical need for human systems to test drugs on that will predict downstream success in the patient.
Our immune organoid is a 3D system that has all of the features of a human secondary lymphoid organ. It contains all of the cells (B cells, T cells, NK cells, etc), structures (germinal centers, LZ/DZ, etc), and function (somatic hypermutation, antibody and cellular response, etc) that you would expect to see in a secondary lymphoid organ. It matches the genetic background of the patient from which it’s derived, meaning it also models diseases that patients have. And because it exhibits the same functions as a human immune system, you can test drugs and vaccines as if you were testing them in actual patients from the start. It's also easier to work with than mice.
People are currently using our platform as a new way to produce antibody therapies, to test vaccine candidates, and to test new treatments for diseases like multiple sclerosis.