Gene expression data
Close to one million gene-expression data sets are now publicly accessible. This can help researchers to identify disease trends and identify new drug targets.
Norman Swan: There’s a relatively new area of medical research that’s growing fast, it’s called Systems Medicine which uses the massive amount of genetic and clinical information available on more and more of us to find new and better treatments. It’s also and amazingly finding old treatments for new diseases. Visiting Australia last week as the guest of the Cancer Institute NSW was a leader in this field; Dr Atul Butte of Stanford University in California.
Atul Butte: Increasingly in health care we are able to make a lot of measurements and act on them so at the molecular level we have all the products of the genome that we can measure onward to the health system level where, especially in the United States, we are moving to electronic health records and ideally we’ll be able to keep track of all the different pieces and make these catalogues. And something like Systems Medicine the idea is to put it altogether to try to reach a better optimum to where we are today.
Norman Swan: And so what you’re doing at the moment is combining clinical information with genes, chromosomes and what’s going on at the molecular level?
Atul Butte: That’s exactly right and what’s amazing to me is that we are very good at making these measurements and even saving them in data bases. Where we really need a lot of new thinking is in making use of the data.
Norman Swan: So give me an example of some of the work you have done.
Atul Butte: My favourite example is looking at products of the genome project. The genome project was a multi-national collaboration and it took about 13 years and about US $3 billion to complete. Today we can now measure the entire genome of an individual for about US $1,000 and people are getting it down to about 27 hours instead of the 13 years. And because of that people are making all sorts of measurements on human genomes and the blueprints that come out of those genomes. We have so many of these measurements now that scientists are now asked to share that data on the internet. The journal editors require it, funding agencies require that.
Norman Swan: So if you’ve mapped a part of a gene or mapped a gene and it’s publicly funded it goes into a publicly funded data base which has benefits in that it’s hard for somebody else to patent that area because it now becomes public property.
Atul Butte: Exactly, at least the raw data has to be made publicly available. The interpretation of that for example, its utility in actual medicine and medical care could perhaps still be patented and that’s a legal determination.
Norman Swan: Give me examples of how you are making these correlations so far.
Atul Butte: For example think of a disease like breast cancer. To date more than 30,000 digital samples of breast cancer are available on the internet.
Norman Swan: You’re kidding.
Atul Butte: 30,000 such samples.
Norman Swan: So these are like the biopsies correlated with the molecular analysis?
Atul Butte: Exactly, some patient somewhere gave a biopsy. they were consented so these are all people who agreed to this or these were samples .......
Norman Swan: So it’s a tissue bank.
Atul Butte: It’s a tissue bank, the samples were run on the types of gene chips or erased to measure every gene in the genome and then......
Norman Swan: And just to explain these are like slides where you can measure 30,000 genes or 10,000 genes at a time and see what the pattern of genetic expression is.
Atul Butte: That’s exactly right, this is radio so I can’t show you what one of these looks like, these are chips that otherwise look at DNA now, they are about the size of a thumb nail but scientists have been using these for almost a decade.
Norman Swan: And of course in good tissue banks which we’re trying to develop and have already in Australia not only do you have the biopsy and the genetic information you actually have very good clinical information, you know what happened to this woman in her life, you know she’s still alive but she had three courses of chemotherapy.
Atul Butte: Believe it or not that is the hardest part now; figuring out what happened to the patient is actually the difficult part.
Norman Swan: And the most important part.
Atul Butte: That is the most important part, especially after they’ve left the Health Care Institution, so we can know that biopsy went along with someone who actually did well with this disease.
Norman Swan: And you’re discovering what from when you start these mass correlations?
Atul Butte: The idea is well if 100 people or 1,000 researchers have studied the same disease again and again what’s simply in common. So there are scientists that use mice to study diseases, some use cell lines, or cells in a dish, others use human biopsies – what’s in common between the 1,000 ways of looking at this disease and increasingly we’re finding what’s in common seems to be actually the key points, or the key molecules that seem to be triggering these diseases amenable to drugs.
Norman Swan: And of course what’s happening now, which is almost mind boggling is people like you are saying it doesn’t matter where in fact you have had the cancer, what matters is what it looks like when you’ve done the genetic analysis and then some tumours from very different parts of the body start to look the same.
Atul Butte: Yes, it’s actually amazing that we classify diseases today according to where in the body these diseases happen. It’s a tradition we’ve had going back...
Norman Swan: Naive and old-fashioned.
Atul Butte: Call it naive, because it goes back to the 1860s. William Farr, the Royal College of Physicians actually started what we now call the International Classification of Disease or the ICD System. Instead we should really be thinking about what does the disease look like at a molecular level, not necessarily what kind of doctor takes care of those diseases.
Norman Swan: And you’ve been doing a study looking -- there are all these old drugs on the shelves which people have either discarded or they’re using for one thing or they’re out of patent but they may have uses when you actually look at what they do.
Atul Butte: Precisely, there is a number of different diseases that actually at a molecular level are similar to each other. We heard about two particular successes over the past year one where we took an ulcer drug known as cimetidine, it’s available over the counter...
Norman Swan: This was one of the first effective ulcer drugs on the market.
Atul Butte: Absolutely, one of the best ones.
Norman Swan: Now out of patent.
Atul Butte: Pretty safe too which is why you don’t need a prescription long off patent and we showed how that works on lung cancer.
Norman Swan: Lung cancer?
Atul Butte: Lung cancer.
Norman Swan: What happened?
Atul Butte: We are just starting human trials on this and similar drugs. When you put the lung cancer into a mouse model give the mouse the cimetidine, it slows the growth of the tumours. So we would imagine it could be used in combination with other different types of medications.
Norman Swan: And what was the clue that you might be able to match cimetidine with the lung cancer?
Atul Butte: We started with just publicly available data. In this particular form of lung cancer some genes go up and some genes go down, we had equivalent data on the drug, so we actually just did a match.
Norman Swan: So essentially it’s like a mass fishing trip where you’re throwing out millions of lines and you see what you hook back rather than starting with a hypothesis. I think it might be cimetidine and I think it might be lung cancer, you’re actually trawling.
Atul Butte: You’ve got it.
Norman Swan: I mixed a couple of my fishing metaphors up there.
Atul Butte: You did mix a couple up there but we do have a lot of different baits that a graded for different types of fish and we just have to try them all and see what actually match.
Norman Swan: You said you had a second example?
Atul Butte: Yes the second example we had was an epilepsy drug known as topiramate, also off patent. Topiramate has been an effective drug for a lot of different indications and we showed actually how that would work on Crohn’s disease, a particular nasty disease known as an inflammatory bowel disease, the body starts to attack its own intestinal system. There’s a well known rat model for Crohn’s disease. The rat has Crohn’s disease, we give it topiramate, and I’m famous for showing these rat colonoscopies where you can see yourself...
Norman Swan: Too much information at this time of day.
Atul Butte: A little too much. You can imagine what you see in a colonoscopy of a rat but you can clearly see actually that Crohn’s disease is getting better.
Norman Swan: Again because of a receptor interaction. What’s going on here?
Atul Butte: We find the science after we know the drug works, it’s actually kind of reverse from how traditional drug discovery is done, but literally what we see is that the drug has certain effects, this gene goes up, this gene goes down, we notice that’s the opposite of what happens in Crohn’s disease and we just try to match opposite effects.
Norman Swan: How often does the match work and not work?
Atul Butte: That’s a great question and it’s always hard to test the negatives here but so far we’ve tried it 6 or 7 times and 6 or 7 times it’s worked, we’ve never had a failure.
Norman Swan: Unless something turns up.
Atul Butte: Of course something can always fail so we can’t be too cocky.
Norman Swan: And the pharmaceutical industry has come together on this because they’ve got these things on the shelf and here’s this new life for an old drug.
Atul Butte: Absolutely, in fact they’ve even come together for the same molecule so topiramate just two days ago in the United States was approved for another indication for obesity so that drug topiramate, probably cimetidine and many others have many other uses out there. If we don’t look for them we’re not going to find them.
Norman Swan: And of course you don’t need to go through the safety trials, they’ve been done 20 years ago.
Atul Butte: At the very least we know what the safety profile is for these drugs and we have some experience but still we can’t just take a cancer drug and think it could be used for a particular disease, we still have to consider some safety here.
Norman Swan: Australia wants to develop tissue banks like this and is doing so. The conversation that cancer researchers have is how expensive this is because there’s a lot of surgeons who have like their own amateur bank, they are trying to do their best, they keep the tissues they know it’s important but it’s not fully annotated as they say which is what we’ve been discussing about the genes with the clinical story and so on. It becomes quite expensive to have one of these banks if you’re going to do it properly.
Atul Butte: That’s right, I tend to be a little bit more of a pragmatist, I remember the Voltaire quote 'that perfection is the enemy of the good'. The idea is to start from somewhere and then proceed from there. The other danger of tissue banks though is that sometimes the individuals who run tissue banks are often so protective of those banks...
Norman Swan: They don’t want to share.
Atul Butte: They don’t want to share, think of the big city library that doesn’t want to let their books out, so I think the real danger of a tissue bank really is that not enough people use it or even have training to know what they can do with those samples.
Norman Swan: And what gets you over that hurdle?
Atul Butte: What gets you over that hurdle is successful case examples showing what people can find that they otherwise could never have found.
Norman Swan: And how much computer grunt do you need?
Atul Butte: We use a lot of computers. For example a graduate student of mine the other day needed to have a computer with half a terabyte of RAM. He was able to provision himself a virtual computer like this, used it for about six hours and disbanded it for a couple of hundred dollars.
Norman Swan: So that’s why my computer ran slow that day is it?
Atul Butte: Perhaps the internet went slower that day. I think what I’m trying to draw a picture of here is a new way to think about these types of investigators and computational scientists. Remember I can start an experiment with breast cancer already with 30,000 samples, that’s more than any breast cancer researcher will ever have in their lab.
Norman Swan: Who doesn’t need a wet lab, doesn’t need laboratory benches with all these chemicals on it, you can sit in a room with nice air conditioning and get on with it.
Atul Butte: We are able to get a lot of biology done through good collaborations or an increasing new trend is the ability to get biological experiments done with a credit card. There are companies that are called contract research organisations or CROs, the pharmaceutical companies are well known for using these. Well actually nobody ever said we in academia couldn’t use some of those services as well, so for a couple of thousand dollars now we can actually get that drug tested.That epilepsy drug we wanted to test for Crohn’s disease, we actually picked two contract research organisations to test that in. How else could we get those rat colonoscopies -- we found a company that knew exactly how to do that.
Norman Swan: Some odd individual who got their jollies doing it.
Atul Butte: As I joke that is precisely the kind of thing you want to outsource. The last thing I always have to say is some of these drugs, the public has the ability to go to a pharmacy to get those drugs and I often have to caution them, until we have shown that these drugs actually work in human trials please don't go and get those ulcer drugs if you have lung cancer. Talk to your doctor; wait for the right human trials to be done before we actually try these for your own case.
Norman Swan: Atul, thanks for coming in.
Atul Butte: Thanks for having me.
Norman Swan: Atul Butte is Chief of Systems Medicine at Stanford University in California.
Monya Baker Gene data to hit milestone. Nature, 487;282-283 (19 July 2012)
- Associate Professor Atul Butte
- Chief and Associate Professor of Systems Medicine
Department of Pediatrics
- Dr Norman Swan
- Brigitte Seega