DSeid: Thanks for clarifying, but still I must disagree. Molecular genetic labs are churning out data on physiology and pathophysiology of disease. Genomics is the tool that allows us to go from human to model organism back to human. Actual treatment options are just around the corner.
Just because we pick the rarest of the rare zebras to research doesn’t mean that we only end up with usable data on the rarest of the rare zebras. Think of these disorders – familial forms of common sporadic disease – as the tips of icebergs.
Look at cancer. Research on familial polyposis coli reveals defects in DNA repair enzymes. BRCA1 and BRCA2 are also thought to be involved in DNA repair. As are the genes mutated in Bloom syndrome and Werner syndrome. These are all rare syndromes, but we take the information and look in sporadic cancers. Presto, huge numbers of cancers have mutations in the DNA repair pathways, including in the APC, BRCA1, BRCA2, BLM, WER genes, etc. etc. Now, it is becoming more routine to look at DNA repair enzymes in sporadic colon cancer, and tailoring chemotherapy around a particular cancer’s DNA repair deficits.
Same goes with neurodegeneration. Genetics is letting us pour information into our knowledge of why particular sets of neurons degenerate. Familial ALS is linked often to mutations in superoxide dismutase, which eliminates free radicals. Familial Parkinson Disease in protein degradation machinery, and Alzheimer Disease in cholesterol and protein processing. I’ll let you conclude where the targets for the next generations of drugs for sporadic ALS, PD, and AD are.
Patience, my young padwan. Large scale genomic sequencing began in the mid 80s, and never picked up steam until about 7 years ago. Most of the computational techniques we use for population analysis are less than 10 years old. The molecular genetics of human disease is a field primarily of the last 10 years. The money going into this has not been wasted. The basic science labs are pumping out research – there are whole conferences devoted to this stuff. A PubMed search of mouse AND parkinson pulls up 1168 articles, 880 of which have been published since 1990. It has entered the slow pipeline of pharmaceutical companies and FDA approval, and we should start to see results in a few years. The past 10 years have given us insights into the molecular pathogenesis of nearly every major disease. It will all be worth it very soon.
Who you calling young, you whippersnapper! I was Golgi staining rat brains and counting dendritic bifurcations when you were in diapers. (Presuming that you are the usual early twenty mudphud.)
We shall see …
(I hope that I am wrong.)
Enjoy your career! And allow me to pass on advice from my mudphud buddies - don’t forget that you will be leaving your PhD work behind for at least five years (two years of clinical rotations and a residency of three minimium) … you will not be getting a research position based on your PhD thesis … get it done in three years max and don’t sweat it if the straight up PhDs say it isn’t “a real PhD”, you’ll still have an easier time swinging funding than they will! … I’ve seen too many 5 year PhD MDPhDs whose technical expertise and research was still obsolete by the time they were ready to go back to the labs. FWIW.
Tars, are you specifically looking at the markers of the regulators of T cell development? (I presume that you are familiar with the whole TH1/TH2 balance work … the so-called “hygiene hypothesis”?) Asthma is a great example of the kind of complex multifactorial phenotype that I have been talking about. The “both ends” is exactly the approach that I think is most likely to be most productive. (And a medical scientist with the ability to help integrate divergent types of research into clinical relevance is what edwino, and other MDPhDs to be should be aspiring to become.)
I’m not the one in the lab who’s gonna handle this project, but i believe we are looking at T cells. Is the hygiene hypothesis you refer to the one that says children who are exposed to more dirty environments at an earlier age are less likely to develop asthma do to their immune system being more practiced at recognizing real invaders? (i didn’t study asthma much in school, but IIRC the IgE antibodies are the ones that go haywire. IgE also works against parasites as well, but i believe it was identified with asthma first) An increase in allergies in general seems to also come from our more sterile environment. I wouldn’t be surprised if one day we inject newborns with weakened diseases just to give their immune systems practice to reduce allergies.
That’s the gist of it. One version posits a balance between the types of T helper cells … that if they do not get recruited to fight of bacterial and viral infections (TH1) then they’ll develop into allergy responsive cells (TH2). Another version (gaining credence) notes that children with high IgE to Ascaris (a parasitic roundworm) and tenfold higher total IgE, do not have skin test positivity or asthma compared to similar kids in nearby towns where Ascaris infestation is less (although hardly “clean” places to live either). In these African towns asthma is not a common problem and, interestingly, kids with Ascaris IgE who did have bronchial reactivity did not have it associated with allergies, whereas those without Ascaris who had brochial reactivity did have it associated with allergies (similar to the typical Western pattern). It is unclear if it helminth exposure or other features that travel with such exposure that is the significant factor. They conclude that the greater exposure to infections leads to a more experienced network that is able to respond with more subtlety than a network with less experience. Both versions have a lot of loose ends, IMHO, but clearly some kids have something(s) that predisposes them to develop certain kinds of T cell developmental responses given a certain environmental exposure or lack thereof and others are genetically less likely to do so.
And to use this as an illustration - the ideal would be to function on communicating parallel paths. Use this phenotypic knowledge to guide the search for genetic markers while continuing to unravel more specifically what happens to the T-cell networks when. As haplotypes or SNPs associated with asthma are identified, use the knowledge of those products to better undestand what is happening in the network. Recognize that many different “lesions” in the network and of exposure may be working independently and in conjuction with each other to result in the asthma phenotype and make the goal not to identify “the asthma gene” but to understand the complexity of the system enough to intervene intelligently. (Yes, perhaps with certain kinds of exposures introduced at particular developmental stages)
Never mind designer babies with higher IQ, what about designer babies with that gene for bioluminescence that they spliced into those monkeys a couple years ago?