I wish it were that simple. :(
Eye color, for example, is influenced by a combination of multiple genes. There’s no straightforward eye color gene. Likewise, it’s especially true for diseases when something like “stomach cancer” is actually a dozen different diseases where each is influenced by dozens of different genes that share symptoms. Combinatorial explosion is a real problem.
As a personal example, a close family member was recently diagnosed with shwachman-diamond syndrome (SDS). I have confirmed with multiple leading physicians (Dana Farber, Mayo Clinic, etc) that all of the tools necessary to cure her are presently available. At a high level, this would involve: 1. Extracting marrow. 2. Isolating blood-cell producing stem cells & amplifying in a dish. 3. Modifying using a product like [A] 4. Validating/re-sequencing to confirm transduction. 5. Re-insert modified cells into patient.
Yet doctors can't engage in this work without going through the lengthy drug trial process. So instead, they recommend much riskier treatment options including some that would complicate future gene-therapy attempts.
[A] - https://crispr.sigmainformatics.com/templates/CRISPR%20Custo...
This is a bit of a leap. In principle (some of) the technology "is there" but there is a huge amount of complexity in the steps 1 through 5!
> Yet doctors can't engage in this work without going through the lengthy drug trial process.
I think it needs to be said that the "lengthy drug trial process" exists for extremely good reasons. Were a treatment to be shown to be so incredibly effective during the trial process, based on pre-defined statistics monitored by an independent data safety monitoring committee, the trial would be stopped as it would be unethical not to provide all patients with the clear benefits. (recent example: https://www.ncbi.nlm.nih.gov/pubmed/29132880)
> So instead, they recommend much riskier treatment options including some that would complicate future gene-therapy attempts.
I believe it is unquestionable that doctors should be advocating treatment based on the best available evidence, and that the process for obtaining said evidence is a thorough and rigorous as possible, otherwise great harm can be done (classic example, thalidomide).
I would question the doctor that routinely recommended an experimental treatment which has not been shown to be efficacious over a "risky procedure" which has been shown to have $X efficacy.
Making patients aware of trials which may be of benefit to them is a valid and valuable part of medical practice, which is not always done very well. This is improving (in the UK at least) with greater numbers of research nurses and the use of databases such as https://www.ukctg.nihr.ac.uk.
Excuse my ignorance here, but has there been a single other drug that the FDA has stopped before it became an issue that a less insanely thorough process wouldn't have? It seems like the FDA was right about thalidomide and has been using that as justification ever since. At this point, clinical trials have become so onerous that the FDA can't even vet them and just trusts the drug companies to be above board.
On the other hand, something which is exceptionally well known to work should also attract huge and immediate capital to do the proper tests. Even for rare diseases, a sure thing would be funded.
I think the difficulty is more about procedural or cell based cures vs. drug-based cures or treatments. The system is set up for the latter, but is not comfortable with the former.
Only if there is a ROI. Which also means that even treatments for not-so-rare diseases don't get funded if the majority of patients won't be able to afford the treatment at a price that provides that ROI. Clinical trials in the US or Europe are insanely expensive and you cannot even budget them: Adverse reactions by "male patients over 45, born on a new moon Tuesday"? In worst case you restart the trial, excluding the problematic group to at least get the proof of safety and effectiveness for some part of the population so you can finally make some money...
On the more consumer side of things, being able to fix some sort of obnoxious but perfectly survivable condition that genetic engineering may be able to solve (say lactose intolerant) may be something that you could sell to a lot of people.
For Medicare or certain people on Medicaid it might be worth it.
Of course, mere and relatively small correlations between disease and genetic traits are extremely common; but there are lots of possible explanations of such findings. In some cases 16 percent of all genes have a small positive correlation to a given disease, and "if everybody is at fault nobody is at fault!"
(+ obvoiusly the stuff from the other comments about how hard it is to determine the cause to begin with)
viruses are useful because they have evolved to insert foreign DNA into host cells. nothing humans can conceivably engineer has come close yet to the ability of viruses to do this
however viruses have also evolved a lot of bad qualities that cause disease. AAV is nice because 1) it is not known to cause disease, 2) only causes a mild immune response (so the body doesnt reject it before it does its work) and 3) is replication defective, so it wont reproduce uncontrollably in your body
all that said, viral vectors are far from perfect. the biggest issue is that you can usually only inject them once. after one injection, the immune system learns to recognize the virus as foreign, and upon subsequent administrations it will kill the virus before it can transfect cells. also, there is some risk that the viral genome can integrate with the host genome in ways that arent ideal.
from what i understand, the liver and the eye are really the only easily targeted specific tissues. the viruses are naturally carried to the liver, and the physiology of the eye enables viruses to get into cells there easily. getting viruses just to the brain, or heart, or pancreas, is much more challenging
aav technology has been around for a while, but there have been many false starts. back in the late 90s there were copmanies delivering genes into the brain with AAVs to treat parkinsons and alzheimers, and the genes got integrated and expressed by the right cells. however, the diseases were too complex for just one gene to cure them. in many ways, the advances in biology are enabling us to find what diseases are "right" for gene therapy, althoguh vector tech has improved as well
As for the CNS - Voyager therapeutics has had some great readouts in September in gene therapy for Parkinson's. More data coming out in Q1 to see second part of study.
its still pretty hard from what i can tell to deliver oligos to specific cells. delivery has been a huge challenge for ASOs, mRNA etc. viral vectors and autologous cell therapies have been used but have limitations, and antibody-tagged "targeted" nanoparticles have also been tried with varying degrees of success.
theres been some really clever developments in delivering oligos with cationic lipid nanoparticles to macrophages. biontech has an approach where theyve made nanoparticles that are naturally taken up by macropinocytosis by dendritic cells and macrophages. if you get the overall charge of the nanoparticle right (net negative i believe), the dendritic cells migrate to the spleen (rather than the lung with positive charge), where they can present antigen encoded with mRNA to t cells. they also have some interesting mRNA tech that increases the transfection efficiency, as it is hard to prevent oligos from getting degraded in lysosomes before they are translated. genentech paid them $310M upfront for a preclinical asset
Also correct about general delivery difficulties. Hadn't heard of Biontech's method - almost sounds like voodoo by your description.
I think there is interesting blocking and tackling happening on an organ-by-organ basis. E.g. GalNAc for liver hepatocytes, LNPs for systemic mRNA therapies, direct injection for eye or CNS (cheating, but still works). I'm partial to exosome hype...
Also no such discussion is complete without saying CRISPR, but the point remains that you can conjugate it targetted vehicles like antibodies. Conjugating to antibodies seemed to work for Stem :p
out of curiousity, what's the exosome hype? ive heard a few strong life sci VCs mention it, but i talked to a ceo of an exosome company and didnt quite understand the specific therapeutic potential
Happy to geek out more offline. Email in my profile.
id imagine the immunosuppressive dose would have to be pretty strong and come with a host of other risks. i know the immunosuppression load for gvhd is pretty heavy, and corticosteroids are not fun drugs
They used AAV (actually, take a look at the article, they give a nice and clear explanation of what modifications they had to make).
Blue eyes are believed to be caused by an isolated, inherited gene, OCA2. This gene is present in all people that have blue eyes. It disables the production of melanin in the iris.
All blue eyed people are believed to have a common ancestor from 6000 to 10,000 years ago, the first person with blue eyes (originally caused by a random mutation). It’s harmless enough that lots of us have it now.
See [1].
[1] https://www.sciencedaily.com/releases/2008/01/080130170343.h...
I ask because my niece had blue eyes as a baby. This didn't make any sense because my sister was Indian, our parents were from India, their parents were from .. well I guess now it's Pakistan, but they migrated during the partition.
My sister married a white dude, but still it seemed very unlikely her daughter wouldn't have brown eyes. That's when we found out my grandmother got her education in Europe, and came back pregnant. Apparently divorces at the time were so shameful that it was better to tell your child their parent died.
My nieces eyes are now a bit hazel/blue-green ish. My grandmother passed away not too long after that, and that secret would have died with her, if it wasn't for the fact that my niece had blue eyes.
I think the other half of this is the microbiome. I have been speaking to physicians about leaky gut recently and a great analogy is the protein genes are like a piano and the microbiome is like the musician.
As you suggest the genes/piano is sort of the hand you are dealt (you have the gene for certain disease or not), but the microbiome is what will typically unlock those diseases or not given the gene set. Another way of explaining this is that humans have about 20,000 genes, the most genes in any animal are about 35,000, and wheat has 164,000-334,000 genes. Obviously we are much more complex with the potential to carry many more diseases which physicians explained to m through humans having a microbiome.
If true, that would be a Nobel-worthy finding. I don't think this is true, but do you have a citation supporting this for the "typical" genetic disease?
> Here are just some of the health conditions that involve our microbes: Acne Antibiotic-associated diarrhea Asthma/allergies Autism Autoimmune diseases Cancer Dental cavities Depression and anxiety Diabetes Eczema Gastric ulcers Hardening of the arteries Inflammatory bowel diseases Malnutrition Obesity
http://learn.genetics.utah.edu/content/microbiome/disease/
>Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome.
https://www.nature.com/articles/nrg.2017.63?WT.feed_name=sub...
>Researchers have discovered that a powerful guardian gene known to protect against a variety of autoimmune diseases, including type 1 diabetes, is triggered by the bacteria in our gut.
https://newatlas.com/guardian-gene-gut-bacteria-diabetes/511...
- You need a combination of genetics + environment to have a phenotype (whether disease or otherwise)
- Several conditions have a relationship with the gut microbiome
Also, I think you will enjoy this absolutely amazing study that found that the gut microbiome drives cerebral cavernous malformations(!!!) by interactions with TLR4: https://www.nature.com/articles/nature22075
So, I just don't think that "typically" the gut microbiome is the driver of disease. In fact, it's a rare enough find that people get Nature papers out of it. But, if it is actually typical, then I stand by my assertion that someone will eventually get a Nobel prize from proving it.
people are studying microbiome therapies for cancer, autoimmune disease, cns disease, etc, but its way too early to tell if any of it is real. there are many challenges: how do you ensure the microbes you administer stay in the body, colonize, and actually produce the molecules you want them to? how do you manage the risk that they interact with other microbe populations in ways that are impossible to predict accurately, but potentially very harmful? how do you manufacture these things in a consistent, high quality way? what is the regulatory path? how do you justify a huge risky r&d investment when you can't patent a microbe? not to mention the biology risk; the "microbiome thesis" sounds nice, but how confident are we that microbes can treat cancer, depression, parkinsons? right now, not very
I have a genetic disorder. Working on my gut health has gone a long way towards reversing my symptoms.
I don't talk about it as much as I used to because it was a constant shit show from people being completely dismissive, outright calling me crazy and asserting utterly illogical things in the name of their "scientific" bias, like "Your 13+ years of steady forward health progress in the face of your degenerative condition is merely wild coincidence and doesn't prove that you know anything at all. Stranger things have happened!"
Cuz, yeah.
People who see themselves as scientific and logical are very often not remotely objective. They just have college degrees or whatever to justify their ugly personal prejudices, and don't confuse them with the facts.
One could just as well argue that because the immune system is so well developed and robust in the gut that it's the last place to look for dysfunction. Or one could argue that a 70% share of immune cells is rather low considering the relative ratio of environmentally-exposed surface area.
We could say all kinds of things if we're free to make unsubstantiated conjectures. But we really can't say anything of substance without context and evidence. The human organism is ridiculously complex and consistently defies intuition.
I don't agree, but I appreciate the expanded perspective.
The way I used to describe it was that your genes are like the blueprints for a house and what you eat is like local building materials. The blueprints may specify 2 bedrooms, one bathroom, but exactly how that will look will depend a lot on the vernacular architecture. Is it adobe brick because you live in the American Southwest? Is it made of blocks of ice because you are an Inuit? Etc.
So, different building materials have different strengths and weaknesses. This will significantly impact things like ceiling height and room size because what shapes the material supports will vary, depending on the material.
I'm sorry some people are reflexively downvoting. I hate it that so many people who imagine themselves to be scientific are so incredibly dismissive of stuff like this.
The virus was deliberately defective and unable to replicate, so the copies made for use in treatment are the only copies that would ever exist. This also ensures that dose control is effective, if the virus could replicate then further copies of the gene would be inserted.
I couldn’t find it on a cursory reading, does anyone know what vector they used to achieve liver sinusoidal cell specificity? My understanding is that many gene therapy studies have used blood cells, which can be pulled out of the body prior to gene therapy, the advances in viral vectors may be just as empowering as the therapy itself. Imagine, in all the irony, getting “vaccines” as a child via viral vectors against common causes of poor health local to your birthplace. An enjoyable quote from a Paul Berg which holds true, of course - “Fears of creating new kinds of plagues or of altering human evolution or of irreversibly altering the environment were only some of the concerns that were rampant”.