Another day, another result...

I had the urge to just sit down and type out a long rant, but then common sense kicked in and I realized that no one is really interested in yet another graduate student's rant about their project not working. However, it only took a few minutes for me to figure out why it's relevant to the general world - something that's (unfortunately) missing from most grad student projects.

If you follow along with Daniel McArthur's blog, Genetic Future, you may have caught the announcement that Illumina is getting into the personal genome sequencing game. While I can't admit that I was surprised by the news, I will have to admit that I am somewhat skeptical about how it's going to play out.

If your business is using arrays, then you'll have an easy time sorting through the relevance of the known "useful" changes to the genome - there are only a couple hundred or thousand that are relevant at the moment, and several hundred thousand more that might be relevant in the near future. However, when you're sequencing a whole genome, interpretation becomes a lot more difficult.

Since my graduate project is really the analysis of transcriptome sequencing (a subset of genome sequencing), I know firsthand the frustration involved. Indeed, my project was originally focused on identifying changes to the genome common to several cancer cell lines. Unfortunately, this is what brought on my need to rant: there is vastly more going on in the genome than small sequence changes.

We tend to believe blindly what we were taught as the "central paradigm of molecular biology". Genes are copied to mRNA, mRNA is translated to proteins, and the protein goes off to do it's work. However, cells are infinitely more complex than that. Genes can be inactivated by small changes, can be chopped up and spliced together to become inactivated or even deregulated, interference can be run by distally modified sequences, gene splicing can be completely co-opted by inactivating genes we barely even understand yet and desperately over-expressed proteins can be marked for deletion by over-activating garbage collection systems so that they don't have a chance to get where they were needed in the first place. And here we are, looking for single nucleotide variations, which make up a VERY small portion of the information in a Cell.

I don't have the solution, yet, but whatever we do in the future, it's not going to involve $48,000 genome re-sequencing. That information on it's own is pretty useless - we'll have to study expression (WTSS or RNA-Seq, so figure another $30,000), changes to epigenetics (of which there are many histone marks, so figure 30 x $10,000) and even dna methylation (I don't begin to know what this process costs.)

So, yes, while I'm happy to see genome re-sequencing move beyond the confines of array based SNP testing, I'm pretty confident that this isn't the big step forward it might seem. The early adopters might enjoy having a pretty piece of paper that tells them something unique about their DNA, and I don't begrudge it. (In fact, I'd love to have my DNA sequenced, just for the sheer entertainment value.) Still, I don't think we're seeing a revolution in personal genomics - not quite yet. Various experiments have shown we're on the cusp of a major change, but this isn't the tipping point: we're still going to have to wait for real insight into the use of this information.

When Illumina offers a nice toolkit that allows you to get all of the SNVs, changes in expression and full ChIP-Seq analysis - and maybe even a few mutant transcription factor ChIP-Seq experiments thrown in - and all for $48,000, then we'll have a truly revolutionary system.

In the meantime, I think I'll hold out on buying my genome sequence. $48,000 would buy me a couple more weeks in Tahiti, which would currently offer me a LOT more peace of mind. (=

And on that note, I'd better get back to doing the things I do.... new FindPeaks tag, anyone?

BC Genome Forum 2009

I had a lot of stuff to blog about, but just haven't had the time to write any of it down. I haven't forgotten about any of it, but it's just not going to happen before this weekend. I'm currently bogged down in debugging something that I REALLY want to get working (and mostly is, but still has something slightly fishy going on...), and just too much going on outside of work to get it done otherwise.

Still, I figured I should mention a few things of interest before I forget to discuss them at all.

I attended some of the BC Genome forum lectures on Friday. I skipped the morning, since they seemed mainly irrelevant to anything I do - which was later confirmed - but caught the session on personal medicine. For the most part, it was focused the ethics of personal medicine. I was considering blogging those talks, but they just didn't have enough interest factor, individually.

For the most part, the speakers were caught in a pre-2006 time warp. Everything was about micro-arrays. One of the speakers even said something to the effect of "maybe one day we'll be able to sequence the whole human genome for patients, but we're no where near that yet." Needless to say my coleagues and I all exchanged startled glances.

Still, there were a few things of interest: There was a lot of discussion about what conditions you find in genomic screens that you should feel obligated to discuss with the DNA donor. They gave the example of one volunteer to tested positive for a condition that could be life threatening if they were to undergo surgery for any reason. It's easily treated, and can be easily managed - if you're aware of it. Since the donor was in the healthy control group, they were clearly unaware that they had the condition. In this condition, where the donor was clearly at risk, the penetrance of the gene is 100%, and the patient could clearly do something about the problem, it was "a no-brainer" that the donor should be notified.

However, for most of the information people are pulling from arrays, it's not always clear if the ethics tilt so heavily towards breaking confidentiality and reporting information to the patient. How this type of situation should be managed was touched upon by several of the speakers. The best solution we'd heard during the forum was one group who had set up an advisory board who sits down on a yearly/6-month basis to determine which - if any - conditions should be returned to the donors.

Unfortunately, no one described the criteria used to make that decision, but the concept is pretty solid.

The surprising thing for me was that after several years of using mechanisms like this, only 12-20 conditions were being returned. In the world of genomics, that's a VERY small number, but is probably more representative of the fact that they're using arrays to do genome screens.

And that is one of the reasons why it felt like 2006 all over again. All the mechanisms they've put in place are fine when you're talking about a couple of nnew conditions being screened each year. Within 2 years we'll be routinely doing whole genome sequencing with Pacific Biosciences SMRT (or the equivalent) systems, and whole genome association studies will become vastly more plentiful and powerful. Thus, when your independent board gets 1200 candidate diagnostic genes with actionable outcomes per year, that mechanism won't fly.

What's realy needed (in my humble opinion) is for a national board to be created in each country to determine what gene information should be disseminated as useful and actionable - possibly as part of the FDA in the states. That would also be very useful for reining in companies like 23andMe and the like... but that's another story altogether.

Moving along, there were a few other interesting things at the event. My personal favorite was from the Smit lab in the microbiology & immunology department at UBC, presented by Dr. John Nomelini, who I know from my days in the same department. They have a pretty cool system, based on the caulobacter bacterial system, where they can pull down antibodies (similarly to streptavadin beads) but using a much cheaper and easier system. While I don't know the legal issues around the university's licencing of the technology, Dr Nomelini is trying to find people interested in using the technology for ChIP experiments. I've proposed the idea to a few people here to test it out on ChIP-Seq, which would help bring the cost down by a few $100. We'll see if it gets off the ground.

So, if you've made it this far, hopefully you've gleaned something useful from this rambling post. I have some coding to do before my parents arrive for the easter weekend. Time to get back to debugging...

Personal Medicine... is it worthwhile?

After the symposium yesterday, and several more insightful comments, I thought I should write a couple of quick points.

One of the main issues is penetrance, or how often the disease occurs when you have a given genomic profile. For some diseases, like Huntington's disease, having the particular mutation translates directly into a certainty that you will have the disease. There really isn't much of a chance that you'll somehow avoid developing it. For other diseases, a gene may change your likelihood of developing the disease slightly or in an almost un-noticeable way. In fact, sometimes you may have offsetting changes that negate what would be a risk factor in another person. Genomes are wild and complex data structures, and are definitely not digital in the sense that seeing a particular variation will always give you a certain result.

Mainly, that has to do with the biology of the cell. There are often redundant pathways to accomplish a given task, or several levels of regulation that can be called on to turn genes on or off. Off the top of my head, I can think of several levels of regulation (dna methylation, histone post-translational modifications, enhancers, promotors, microrna, ubiquitination leading to increased degradation, splicing, mis-folding through chaperonin regulation, etc) that can be used to fine tune or throttle the systems in any given cell. At that rate, looking at a single variation seems like it might be an entirely useless venture.

And, in fact, that was the general consensus of the panelists last night: the companies that currently run a microarray on your dna and then report to you some slight changes in risk factors are really a waste of time - they don't begin to compensate for the complexity that is really going on.

However, my contention isn't that we should be doing personal medicine over the whole genome, but that as we move forward, that personal medicine will have a large and growing impact over how healthcare is practiced. I've heard several people talk about Warfarin as an example of this. Warfarin is used to treat hypertension, and is quite effective in most people. However, each person has different dosage requirements - not because they need more to activate the pathway, but because we all degrade it at different rates, depending on which p450 enzymes we have to break it down.



In the above graph, you can see all patients conform to some "normal" distribution, but they're really made up of two subpopulations - one set of fast metabolizers and one set of slow metabolizers, as judged by metabolism of some other drugs. (Yes, I'm way oversimplifying how this works - this is not real warfarin data!) When you look at the spectrum of patients that come in, you see a continuum of patient dosages, but you'd never understand why.

Instead, you could look for markers. In the case of drug metabolism, only one p450 may be responsible for the speed at which the drug is processed, so looking at the same group of patients for that particular trait will give you a completely different graph:



Which means, you can start to figure out what initial dose will be required, and tweak from there.

(If you're wondering why the fast metabolizers and slow metabolizers of the same drug have some overlap in my example, it's just so I'd have an excuse to say there are probably other factors involved: environment, other things interfering with the metabolism, the rate at which the kidneys clear the drugs... and probably many other things I've never considered.)

So what's my point? It's easy. Personal medicine isn't about whole genomics, but rather about finding out what conditions underly the complex behaviours of the body - and then to apply that knowledge as best as we can to treat people. (Whole Genome Studies will be important to learning how these things work though, so without the ability to do whole genome sequencing, we wouldn't have a chance at really making personal medicine effective.) I'll be the first to admit we don't know enough to do this for all diseases, but we certainly do know enough to begin applying it to a few. I've argued that within 5 years, we'll start to really see the effects. It won't be a radical change to all medical care at once, but a slow progression into the clinics.

To narrow my prediction down further, at some point in the next 5 years, it will become routine (~10-20% of patients?) for doctors to start doing genomic tests (not full genome sequencing!) to apply this type of knowledge when they treat their patients with new drugs. (Not every illness will require genomic information, so clearly we'll never reach 100% requirement for it - having a splinter removed in the E.R. won't require the doc to check your genome...) I give it another 10 years before full genome sequencing begins hitting clinics.. and even that will be a gradual change.

Now I've really wandered far outside of my field. I'll let the doctors and physicians handle it from here and try to restrict my comments to the more scientific aspects of it.

Personal Medicine - towards efficient medicine

I've posted a couple of thoughts on Personal Medicine, lately. They've been fairly popular, and obviously controversial enough that people have taken the time to comment. (I really appreciate that, by the way!) Those comments are very useful in giving me an opportunity to think about the subject in ways I hadn't considered. (Thanks, again, to those who chimed in on the last two posts!) So, I have at least two more topics I want to cover. The first one is "efficient medicine."

All this talk about personal medicine is interesting, because it's relatively obvious what everyone means: using a patient's genomic/transcriptomic information to make personal health decisions that are tailored to suit the patient's personal needs. Hence, it's personal medicine. However, the question really has to be asked why we're doing it. I contend that the personal medicine is a technique, but the underlying goal is really "efficient medicine."

By efficient medicine, I really mean efficiency in several ways:

1. More efficient use of medication (1): treating only those people who will benefit from the treatment.
2. More efficient use of time: automate health care so that we can figure out the right treatment more quickly.
   
3. More efficient use of resources: treat people once with the right medication, so that less time needs to be spent in clinics and hospitals
4. More efficient use of medication (2): ensure people treated with medications won't suffer from adverse effects, which has a human cost as well.
5. More efficient use of doctors: Allow doctors to spend less time trying to diagnose problems, and more time trying to figure out how to solve them.

I'm sure I could go on, but by now everyone gets the idea. Efficiency means something different to everyone in the medical chain of command, yet I'd like to think everyone is striving to provide more efficient medical care. Whether the medical funding agency wants to save money by not treating non-responders to a drug, a hospital wants to save resources by pro-actively treating an out-patient (metabolic disease), or whether the doctor wants to spend less time trying to figure out the root cause of a patient's problem (eg. Crone's disease), knowing what's going on at the genomic level will make the medical care more efficient for everyone involved.

So, let me re-iterate my other points from the past few blog items: We are near the tipping point where the cost of personal medicine is becoming sufficiently low that the efficiency benefits from taking advantage of it will have a measurable effect.

Once that takes place, it will be a tide that washes away the in-efficient medical practices of the past. Medical funding agencies won't fund doctors or medical practices that waste time or money, and that will force through changes that make personal medicine the only way to do business.

Again, I'm not arguing that doctors are incompetent, just that personal medicine will change the baseline level of efficiency we demand, and that MDs will need to cope with that change.

And, as a corrolory, that's going to lead to an aweful lot of medical funding agencies to start funding lifestyle changes. (Go to the gym 3 times a week, and save 50% on your insurance....) Change is coming, people... and you don't need to be an MD or a PhD to see it.

And speaking of efficiency, I have a few more things I need to get done this afternoon! Back to the grindstone...

alternative and personal medicines

After my post the other day, on the subject of resistance to personal medicine from doctors, there were a few interesting comments, which I figured merited their own entry.

The first comment, from Will, implied that I think all MD's are idiots - which is far from the truth. I've met idiot doctors before (such as the one that told me a collapsed lung was psychosomatic), and some very bright doctors (such as the one that asked me about 10 questions, listened to my chest, told me I had a collapsed lung and then sent me back to the hospital right away.) Like all professions, there are good ones, and there are bad ones. However, like all professions, the exceptional doctors, by definition, are few and far between.

And, as a scientist, I can appreciate why that is: doctors are to the human body as mechanics are to our cars, and a car is a relatively simple piece of machinery, when compared with the human body. Even more frightening, a lot of the human body is simply a "black box" in the sense that we know what we put in, and we know what comes out, but we rarely understand all of the intricacies of the processes that are occuring. So when it comes to my car, if I had one, I'd trust a guy named Garry who doesn't have a high school education to be able to figure out what went wrong and fix it, but when it comes to my body, I expect the person doing the fixing to have about 10 years of higher-education.

But what is that higher-education? It's not necessarily a biochemistry degree, or even a molecular biology degree - it's typically a higher level overview of how the body works: anatomy, histology, immunology, and the various other "organ-level" subjects. We don't expect the average physician to be able to describe how transcription factors, polymerases, gyrases, ligases or any of the host of other molecular tools work, or what their effect is on the human body. Thus, physicians are handcuffed by their high level view of the complex systems upon which they use.

And, of course, that leads us to the major issue. Dealing with complex systems at a high level can only be done by applying rule based solutions. For instance, if you see a broken leg, you splint it. You don't need to know about osteoblasts and osteoclasts and how they work to rebuild bone. We don't look at the molecular signals that they need, or what to do to encourage them, you just expect the doctor to apply the rule. If something goes wrong and the bone doesn't heal, then (and only then) your doctor starts looking for another rule to apply. That's not a bad thing, really - but that's how we have come to expect modern medicine to work.

The article I linked to in my earlier post wasn't about doctors being idiots or stupid, it was about doctors being influenced in their rules and the application of those rules in ways that aren't productive. When doctors are influenced by other doctors around them (group mentality) to do unnecessary or unproductive treatments, despite the lack of evidence to show the treatment works, that's not a good thing. When doctors use rule based medicine that's outdated, that's also not a good thing.

While I don't have independent stats on it, the article certainly made it seem like those are common occurrences - and that makes it appear that modern science isn't doing a very good job on matching diseases with treatments. When that starts to sink in to a patient's mind, they start looking for alternatives, which leads you to alternative medicines. In my mind, alternative medicines are any form of treatment for which there is no scientific evidence that it works. If you could show me in a properly controlled trial that waving a crystal pyramid over aching joints actually did better than placebo, I'd have no problem considering it a real medical treatment.

So what does alternative medicine have to offer? Hope and faith. Having nothing to believe in is a scary concept, and when science based rules let you down, there's alternative medicine, waiting to lure you in like a cult. Of course, I don't mean to say that alternative medicines have nothing to contribute - but the vast majority of them (in my humble opinion) are complete garbage, made up by people who want to make a living on someone else's misery and doubt.

Of course, our current medical practices aren't much better, in many cases. (See this example for Lipitor's Number Needed To Treat. It's worth a quick read.)

And that's what brings us to personal medicine. Like the rule based approach, personal medicine isn't a huge change, but it does introduce a new layer.



The advantage of he new layer is twofold: The first is that rules that were based on "bad practice" should slowly melt away, and the second is that the number needed to treat should be drastically reduced, since treatments will now be indicated for conditions that can be more closely matched with the cause (not the symptoms.)

And, best of all, it still lets the doctors operate in a rule based environment. The shift may not be as big, after all - it just means retraining all of our MDs. In some countries, that education will be mandated by the organizations that pay them, and the transition will go quickly. Only in the places where no one monitors how treatments are done will the switch be slow.

So really, I think the time is ripe to update the rules, don't you?

We're probably a lot further from personalized medicine than we think...

I keep writing posts about how I think we're closer to personalized medicine than we realize, but I think I might have to change my tune... just by a little bit. This article (Why Doctors Hate Science - Sharon Begley/Newsweek) was linked to from Slashdot today, and caught my eye.

I highly suggest giving the article a quick read, but if you don't, the general summary is that many doctors aren't able to embrace science to find the correct/best diagnosis and treatment option, let alone necessarily provide appropriate care at some level. On the surface, it's a scathing taunt at doctors, although really, I think there are "professionals" in all fields that just don't apply logic. To quote my girlfriend "I hate stupid people." Well, apparently they exist everywhere, even in the medical profession.

Still after reading the article, I have to say that change is coming, and it's going to come quickly. Those doctors who can't cope with it are going to be blown away by the younger ones who are able to deal with it - and who will be able to get the diagnosis right the first time, as well as the treatment. (As personal medicine begins to LOWER the number of errors doctors make in treatment, insurance companies will have to start lowering their premiums compared to the "old school" doctors - or raise the premiums on the ones not using genetic information - and we can all see where that will take the medical profession in the U.S.) In Canada, I guess the federal government will just mandate that the correct tests must be done before doctors are paid for a treatment. Voila.

Anyhow, with doctors actively resisting the application of logic and science to their treatment regiments, I have to wonder how long they'll effectively be able to keep personalized medicine at bay.