Hello scientists,
When I think about genetic diseases like cystic fibrosis, sickle cell anemia, diabetes, and various forms of cancer I don't imagine that those can be easily treated by surgery because the issue is that the wrong protein(s) are written into a patient's genetic code. I imagine that if one were to look at the protein expression map of a diseased individual and a normal individual there should be statistical differences most of which are insignificant, but one upregulated or downregulated protein in a large pathway has a critical mutation.
So what would be the most efficient means to figure out the culprit protein and the gene that codes for it? I consider myself more proficient in bioinformatics than experimental wet-lab biochemistry. But I'm probably overthinking it as scientists usually collect a crude sample, filter it as much as they can, and send it off for a sequencing lab to analyze, and then collect the results and analyze them, right?
Once the malformed protein and its pathway is discovered, perhaps from biostatistics of control and diseased groups, how does one fix the gene for which bad insertions, deletions, or frameshifts happened in? I know from my reading research papers that viruses often leave fragments of their dna in their host, even if their host's immune system manages to suppress them or wipe them out, so probably the least harmful virus available could function as a vector to fix the point mutation. But how do you know that it will do what you calculate?
Perhaps CRISPR is the best way to go about it. I imagine that correcting the genetic diseases might still be a difficult task given that biochemists often work with cell lysates in vitro, but the cure in vivo isn't supposed to lyse the cells.
Can drugs be used to treat genetic diseases permanently after a few doses? Many drugs are inhibitors of some protein pathway but they are gradually eliminated from the body, but is there any evidence that some drugs can change protein pathways permanently after x number of administration doses? Perhaps they can if drugs change the behavior of immune system cells, and those cells then change other cells' pathways, then there might be a way to treat genetic diseases.
I can sort of imagine solutions on computers. But those solutions have to work in the complicated matrix which is the chambers of the human body.
How do you think we scientists can treat genetic diseases?
Hi Adron,
Reads like a great review of literature (and hope can write one with you!). Excellent questions and no short answers. Hope experts will chip in with great answers to rescue your inquisitive thoughts!
Thanks,
Biswa
These are good questions. There is a great deal of information available about the subject of identifying the causes and the treatment of genetic diseases, both for specialists and in publications for a scientifically-interested general audience. You should have no trouble finding out about these subjects in textbooks, magazines, books, documentaries, on the Internet, etc. Various means are in use or in development for treatment of genetic diseases, including gene therapy, stem cell therapy, enzyme replacement therapy, and drug therapy.
Here is a place to start for scientific information on genetic diseases and genetic associations of diseases:
http://www.disgenet.org/web/DisGeNET/menu;jsessionid=1x51wvmmuepph7xpjm1mdl1qq
You're asking a question that the pharmaceutical industry, and biomedical science in general, has struggled with for decades. Indeed, target discovery and validation is every bit as important as drug discovery when it comes to treating diseases, be they genetically driven or not.
Many people expected the Human Genome Project to essentially answer the questions you're asking - clearly it didn't. While fabulously useful, the HGP resulted in very, very few simple answers or advances. Similarly, to take just cancer: it doesn't have *a* genetic cause, it has a bunch of disparate causes. Consider Weinberg and Hanahan's reviews, where they lay out an argument for cancer being caused by 12 key pathways - that's still 12 genetic pathways, that can be altered at multiple points to offer the same effect. Or Celiac disease: is it caused by a problem with tissue transglutaminase? For some people yes, that seems to play a big role. For others, it's something else entirely.
Regarding drug treatment: curing chronic conditions is difficult to impossible, hence them being chronic conditions. But just because a condition is genetic doesn't make it chronic. Take cancer again as an example: somebody can have a mutation to their Ras gene that normally leads to cancer, but never develop a tumor. So if somebody with that mutation DOES develop a tumor, we imagine we could cure it, and not have the disease come back. We are, frankly, pretty bad at this right now - even the best cancer chemical therapies have low absolute success rates, but we get better each year.
Now, something like, say, celiac disease? Or depression? Or hormonal disorders? It's unlikely those will be curable, at least without constant chemical treatment. It all comes down to what the base state is - is the problem just in a specific place (ie: a tumor) or is it all over (ie: celiac disease and the whole intestine). If you can't imagine just removing a few (or a lot of) cells and having the person both be cured AND still be alive, chances are drugs won't cure them either, since that's metaphorically all drugs do - remove the bad cells from play.
As for CRISPR/Gene editing in general: that's certainly a research track. But it's an incredibly controversial pathway in general too - with a drug, you can wash it out of the system if something goes wrong. But a gene edit? It's very, very hard to undo what you did. And while a protein (again, say Ras) might have a mutation that leads to cancer... what ELSE is that mutation doing? How much of the rest of the host is mutated to work with the mutant protein? What good is it to cure the cancer if the person's skin stops regrowing as it sheds, for instance? But, of course, as you note: a gene edit *could* fix the problem, then and there, simply and safely. Then you've got the issue of what counts as the *correct* form of a protein, and who decides. We've generally hesitated to release genetically modified organisms into the wild in case there are unplanned effects (and there are ALWAYS unplanned effects). Now, we can sterilize corn, or salmon, or whatnot - but we can't ethically sterilize a person for daring to get gene alteration therapy. So we could only alter them to 'normal', right? But what's normal? Who defines it? And if we CAN alter your genes to 'normal', then what's to stop you from altering them to 'better'? If we can equate a gene with height, or high IQ, or blue eyes, or whatever... why shouldn't people be allowed to get cosmetic genetic surgery, if others are allowed healing genetic surgery? It's an ethically difficult field in a way that more traditional drug treatment is not (and even that is changing - I saw a report at one point that there are active levels of Prozac in the Thames. How ethical is it to treat people with drugs if they'll stay in the environment, essentially poisoning other people, for decades?)
But if you want to dig into genetic causes, cancer is probably one of the best places to start. Not that it's intrinsically more genetically based than any other genetic disease, but there are a LOT of publicly available resources out there. In particular, take a look at the Cancer Genome Atlas, and the Cancer Cell Line Encyclopedia. You can get raw data, or use various online tools, to poke around and see if you can find something nobody else has ever noticed.
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