Print BCTV: Gene Sequencing -- The world's neglected diseases; Profiles in Innovation: gene sequencing

Gene Sequencing

Transcript of BioCentury This Week TV Episode 192



Dr. Mary Moran, Executive Director, Policy Cures

Dr. Svante Pääbo, Director, Department of Evolutionary Genetics, Max Planck Institute



Bill & Melinda Gates Foundation

Wellcome Trust

World Health Organization

Kary Mullis

Frederick Sanger

Francis Crick

James Watson

Applied BioSystems

Illumina Inc.




Steve Usdin, Senior Editor




STEVE USDIN: Governments and foundations are pouring billions into research for neglected diseases that destroy lives in the world's poorest countries. Is it enough? And is the investment producing results? We'll ask a leading global health analyst. And in profiles in innovation, how gene sequencing technology has changed our understanding of what it means to be human. I'm Steve Usdin. Welcome to BioCentury This Week.


NARRATOR: Connecting patients, scientists, innovators, and policymakers to the future of medicine, BioCentury This Week.


STEVE USDIN: More than one billion of the world's poorest are afflicted by diseases that aren't major problems in the developed world. Sleeping sickness, Chagas disease, hook worms, schistosomiasis, malaria, tuberculosis, and AIDS. These neglected diseases shorten lives and sap the strength of individuals, tear communities apart, mire whole countries in poverty.


Over the last decade, there's been a revolution in approaches to neglected diseases. Complacency has been replaced by an urgent search for new treatments. Led by the US, tens of billions of dollars have been invested. Results have been impressive. But progress has been limited by a lack of coordination. To help steer neglected disease R&D, Policy Cures an independent research and consulting group studies and reports on funding flows.


To discuss efforts to accelerate the development of therapies for neglected diseases, we're joined by Mary Moran, executive director of Policy Cures. So, Mary, to start with, what is a neglected disease?


MARY MORAN: Well, there's really two kind of diseases, Steve. There's diseases that affect rich countries. They're the market diseases.


Now, once a disease like TB or malaria recedes from rich countries, you're left with a vacuum. And that disease becomes neglected. And that's when the public, or philanthropy, needs to step in and start making those products.


STEVE USDIN: And you've been tracking investments in R&D for neglected diseases for a while. And one of the stories has been a tremendous increase in investment by governments, by philanthropies. Can you give us an idea kind of what's the scale per year? How much money is invested in it? And what's being produced as a result of it?


MARY MORAN: Sure, actually it's probably one of the most remarkable things I've seen in four decades. So pre-2000, there was really very little investment in making products for these diseases. They had no market. And no one was clear who should do it.


And now the investment is it about $3.5 billion US dollars a year. It's pretty remarkable. All this has happened since probably about 2000.


The pipeline has over 350 products in it. And there's over 44 products that have been registered. That's really amazing.


STEVE USDIN: So there's about $3.5 billion per year that's going into R&D for neglected diseases. But it's not evenly distributed across the board, right?




STEVE USDIN: There are a couple kind of marquee diseases that are getting the money, right?


MARY MORAN: Yeah, there are. I mean, the big three are the obvious ones. So AIDS get about a third of that. TB and malaria share another third. And then the other third, the other 28 diseases have to split that up between them. So they're not so well-funded.


STEVE USDIN: You do an annual survey of R&D funding for neglected tropical diseases. And the last one you did, you said there's good news and bad news. What was the good? What was the bad?


MARY MORAN: I think the good news is that you've got all these billions. I mean, no one will quibble about that. Some of the bad was probably a few things I would highlight. The first is that unevenness across diseases. So some diseases clearly aren't getting enough to make the products they need. So they're still neglected.


The second thing is, well it's good news for the US. The US is actually been the country that's really holding the line on funding. So if we look at all the other countries together, they've actually cut their funding by about 20%. And the US is putting in now 70% of government funding globally, which is just a remarkable effort, near 70%.


STEVE USDIN: That's a remarkable effort. But I guess it also suggests that other countries aren't really pulling their weight.


MARY MORAN: Yeah, actually, you know, if anyone wants to become very famous, for $20 million, you can be a top 10 funder in this field. Isn't that remarkable? $20 million, you can't buy a house for that in some places.


STEVE USDIN: So we're talking about it's $3.5 billion. But just $20 million would make you a top-10 funder.


MARY MORAN: Would make you a top-10 funder. So really the US is the big one. UK, European Commission, Germany, France, Australia, India, and then you're getting to tiny little amounts like $13 million.


STEVE USDIN: And then you've also got a disparity between government funding and funding from philanthropy. So there's two or three philanthropies that kind of dominate the whole landscape, aren't there?


MARY MORAN: Yeah, but I think the mix of funding is not bad. So governments provide about two thirds. But this kind of is a public responsibility. Then your philanthropies -- I mean, philanthropy means the Gates Foundation and the Wellcome Trust.


They put in a good chunk, maybe about 20%. And then industry philanthropy is about 17%. So that's big drug companies mostly putting in a really substantial effort to help make these products.


STEVE USDIN: So we're going to come in just a moment. I want to talk to you more about the role of industry, and this interface between industry and government. First, in the US government is the largest funder of neglected diseases R&D. Here are the numbers.


NARRATOR: You're watching BioCentury This Week.




STEVE USDIN: We're back with Mary Moran talking about research and development for neglected diseases. Mary, you kind of made a splash a while back with the commentary that was in Nature, criticizing in the World Health Organization, its approach for R&D for neglected diseases. Can you tell us a little bit about what that's all about?


MARY MORAN: Sure, I suppose the first thing I'd say up front is I think this the World Health Organization, the WHO, is very, very well meaning. But I think they've been captured by one idea. And it's an idea that doesn't work.


So what happened was they said, we want to get better, more affordable medicines for the world's poor. Everyone would agree with that. And that means two things. That means getting more affordable commercial medicines. And then it means making nonprofit medicines for neglected diseases.


But the WHO decided that the approach they would focus on was changing the way we manage intellectual property. In a sense, removing private intellectual property rights, or shifting them into the public sector. So, naturally, a lot of people became extremely upset.


It was very hard to push this idea through. But the WHO spent the best part of a decade, actually more than a decade, focusing just on this one approach. It doesn't work for commercial diseases because no one will sign up to it.


And now what provoked me to write the Nature article was that they're now testing out some of these kind of anti-IP ideas in the nonprofit area, and saying we should come up with a new model. And I think I said earlier, we've just developed this new way of doing nonprofit diseases.


We're putting in money. And we've got a pipeline. It's really working. And I thought it was quite dangerous to have WHO now saying, let's deconstruct that. And let's come up with a new model that's focused on intellectual property, which isn't even the problem for nonprofit diseases, by definition. You don't have profits. That's why they're neglected.


STEVE USDIN: So what's been your response to your commentary, to your criticism of the WHO on this? And do you think that anything's moving in the direction that you'd like to see it? Or are they just going to keep on going down that path?


MARY MORAN: In terms of the response publicly, there was a fair bit of criticism from supporters of the kind of anti-IP position. Privately, surprisingly, I got a lot of letters, actually unanimous supportive letters from -- well, I hesitate to say it. But even people inside government, and senior people inside WHO saying, we agree.


What's to happen? Obviously, I can't dictate the direction of it, nor should I. But I actually think they're just going to keep going down the same path. I would love to see them say, this was a good idea at the time. We've given it a good go.


But after 10 years it hasn't worked. And we need to start saving lives. We need these affordable medicines. So we're going to look at a different idea. I think that would be a much more productive approach.


STEVE USDIN: And what are some of the ideas that you've looked into that you think would be more productive, innovative funding ideas, or other models for developing drugs for neglected diseases?


MARY MORAN: Well, I think the drugs for neglected diseases are kind of pretty well taken care of because the pipeline that's there is very good. It just needs a bit more public funding, as we said, or philanthropic funding, some of those non-contributing countries.


There's a few obvious names missing from the list. You don't see Japan there. You don't see Italy there. Brazil's a pretty small funder given its size. So if some of those countries started chipping in more I think a lot of that would be improved.


On the commercial side, I can't believe we couldn't come up with a solution, Steve. You've got three billion people in poor countries saying, we want to buy medicines at a price that suits us. And you've got a bunch of drug companies saying, we really want to sell to those three billion people at a price that they will buy at. Now, it seems to me you ought to be able to put those two things together.


STEVE USDIN: And so is part of that solution figuring out ways to have differential pricing of the same drugs in developing countries and poor countries, and in developed, wealthier countries?


MARY MORAN: Yeah, I think tiered pricing, even within countries. So wealthy people in Brazil don't pay the same price as poor people in Brazil. And I know there's been real push back from, well, I suppose from some of the IP groups against this idea of tiered pricing.


But it seems to make common sense. Rich people should pay more than poor people. I don't have any problem with that.


STEVE USDIN: Great, well, we're going to talk about that and some other ideas right when we come back. There's scores of neglected diseases. But most of the funding goes to three, as we've said, HIV, malaria, and tuberculosis. Here are the numbers.






NARRATOR: Now, back to BioCentury This Week.


STEVE USDIN: We're back with Mary Moran talking about R&D for neglected diseases. Mary, we've been talking about funding and some of these kind of abstract things. But I want to make it much more concrete an example. And I think one of the more interesting examples is to talk about the progress in TB.


MARY MORAN: Oh, I'm so glad you picked TB, Steve because there's -- actually, the Gates Foundation made an announcement about a very promising new TB drug. And just so your viewers get a picture, our TB tools are ancient.


Our TB diagnostic is from 1896. Queen Victoria would have used it. Our vaccine is from 1921.


STEVE USDIN: And it doesn't work.


MARY MORAN: Yeah, it's pretty -- everyone with adult TB had the vaccine when they're a baby. So does it work? Probably not.


But the TB drugs are all from around World War II, so 1940's to 1960's. So we've had a real problem managing TB. Now, one of these groups that I talked about before that have these new pipeline of products, they've just made the first -- or they're making the first TB regimen for over 50 years.


And to give you an idea of how good it is the current treatment for drug resistant TB is two years. It costs an average $5,000, up to $10,000. And the failure rate's about 40%, which is pretty terrible. But if you use an old, weak drug, that's what you get.


Now, the new regimen that's just going now into its final stage trials it's $50 to $90 instead of $10,000. It's got 100%, we think, effectiveness rate so far instead of 60%. And the treatment is reduced from two years for drug resistant TB to 16 weeks. Isn't that amazing?


STEVE USDIN: That is impressive.


MARY MORAN: So you get a lot more for a lot less.


STEVE USDIN: And can you talk about who developed this? And what's the name of the new drug?


MARY MORAN: Sure, the new drug's called PaMZ, P-A-M-Z. Scientists aren't very good at naming things. And it's been developed by one of these product development partnerships called the TB Alliance. And what they do is they partner with industry, and academic, and public and philanthropic funding. And they make all this nonprofit.


So huge savings of money in actual the drug costs. But in the treatment costs. So instead of two years in a developing country, trying to -- and the patients were managed. They had to be hospitalized and have injections daily for six months. So all of this is now tablets. Revolution.


STEVE USDIN: So that's going to have a revolution both in terms of treatment and adherence. But also probably dealing with drug resistant tuberculosis, which is an enormous problem also.


MARY MORAN: Yeah, well, the new regimen, the beauty of it is it's effective against drug-sensitive TB, and also probably somewhere between a third and a half of drug resistant TB as well, just with a single medication. So it's exactly the kind of thing we've been looking for.


STEVE USDIN: Go on to some other diseases, sleeping sickness, for example.


MARY MORAN: Yeah, sleeping sickness has been such a sad story. It's a classic neglected disease. If you got sleeping sickness, it was very hard to diagnose.


You would have a spinal tap, take out spinal fluid and look at it. And in the wilds of Africa this is difficult and dangerous. Then the treatment, you had to be hospitalized and have injections which killed between 5% and 10% of the patients you gave them to it's so toxic.


You couldn't even give it in a plastic syringe. It would melt the syringe. It was an arsenic derivative.


So what's happening now is that, again from one of these product development partnerships, they're developing a new test which can be done without a lumbar puncture, just a normal blood test. And they've got a new drug which will be an oral tablet instead of attempting to find a hospital, and putting a drip, and give someone two weeks of infusions.


STEVE USDIN: And how far along is that one?


MARY MORAN: That, again, that's in the very final stages of clinical trials. So trials take a long time. And it's in the final part of them, the big ones where you actually measure the impact of the medicine.


STEVE USDIN: Mary, I want to ask you about another trend that you've highlighted in your annual report this year, which is a shift in the focus of funding from product development partnerships to basic research. How big a shift is it? And what are the implications?


MARY MORAN: It's a huge shift. So I should explain, there's two kinds. Basic research is that kind of laboratory research, looking down a microscope. When you make a discovery, then product development turns that discovery into a medicine that saves lives. So clearly you need both.


But what we've seen since the financial crisis is actually a 28% increase in funding going to basic research. That's $3 billion. That's a big shift. And a 2% decrease in product development.


STEVE USDIN: That's kind of underwater isn't it? It should be the other way around given 10 years of research that's been going on now?


MARY MORAN: That's right. You've got all this stuff that's ready to come out of the pipeline, and be trialed, and get to patients. You should be seeing the opposite.


But what it seems to be is that in response to the financial crisis, a lot of funders have said, I'd really like to keep the money at home and fund my own academic institutions rather than giving it to -- the groups that do this product development are often based overseas. So they might be in New York. Or they might be in Geneva. They might be in London.


And what they do is they look across the whole world and say, I'm picking the best projects from anywhere. And I'm going to turn them into a drug. Some of them might be from -- if it's malaria, some of them are from the US. Some of them are from Australia, some from UK. Whereas, if you fund basic research, you can give it all to your own guys.


STEVE USDIN: But then I guess the question is, are you funding the research as an economic development tool for your own country? Or are you funding it to actually try to make a difference in the world?


MARY MORAN: Yeah, mixed motives, you never achieve either of the things you're trying for. So if you want to fund at home, fund at home. But if you want products that are going to save lives and save aid dollars, you've got to fund product development.


STEVE USDIN: Is part of the issue also that there's a lack of coordination among the funders?


MARY MORAN: Steve, you're too good. You should be in charge of the World Health Organization. Yeah, because what this is -- is each individual funder just makes their own little shift. But when you add it up, we measure what happens across the whole world, when you add it all up, that's when you get this 28%.


So one of the things we would like to say is more funding from governments that at the moment do underfund. And better coordination, they could just sit down, talk to each other, say, this is what we're all doing. I think some of those unproductive changes would start to wind back.


STEVE USDIN: Well, thanks, Mary. We've been talking about technology innovations and how they've improve the lives of patients in developing countries with neglected diseases. Next we're going to talk about technology innovations in gene sequencing, and how it's redrawn the map of human origins. Just a moment in this month's Profiles in Innovation.


NARRATOR: Now in its 22nd year, visit for the most in-depth biotech news and analysis. And visit for exclusive free content.




STEVE USDIN: Advances in gene sequencing have fueled explosive growth in the understanding of biology. From personalized medicine to the foods we eat, gene sequencing has made advances possible that were unimaginable when Francis Crick and James Watson discovered the structure of DNA.


The first breakthrough came in 1977 when Frederick Sanger developed a technique for sequencing DNA. Sanger's sequencing starts by making pieces of DNA in a test tube reaction. Chemical markers make it possible to copy sections of DNA code ending with one of the chemicals that comprise DNA. This process is carried out for all four of the DNA building blocks.


By chopping the genome into small pieces, scientists can analyze chunks of the genome simultaneously in separate reactions. These puzzle pieces can be reassembled to form a genome. At first, this was done by hand. Eventually, the process was automated, making large-scale sequencing possible.


Six years after Sanger's invention, in 1983, Kary Mullis develop the Polymerase Chain Reaction, PCR, a simple, cheap technique to make billions of copies of DNA segments. PCR is critically important because it makes it possible to assemble sequences using only minuscule amounts of DNA.


The combination of Sanger sequencing and PCR made it possible to conceive of an audacious plan, to sequence the complete human genome. Planning started in 1990. And sequencing started in 1996 using sequencers built by Applied Biosystems that automated Sanger's technique, reducing to minutes a manual process that formerly took hours to days.


The first draft human genome sequence was released in 2001. It cost about $3 billion. The race to create faster and cheaper sequencing capabilities started immediately. That competition produced one of the most startling and rapid technological advances in human experience.


Newer technologies that use advanced optics and electronics have greatly increased sequencing speed. Techniques have been created to sequence DNA during the process of DNA synthesis. Costs have plummeted, making it possible to deploy the technology more broadly.


This year, Illumina announced it had passed a critical milestone by creating a machine that can sequence an entire human genome in a day for less than $1,000. Just as microscopes led to the germ theory of disease, and telescopes changed conceptions of humanity's place in the universe, and then provided insights into the origins of the universe, gene sequencing technology is creating new knowledge about the human body and making it possible to peer into the origins of humanity.


Next generation sequencing is just starting to change medicine. It has already transformed other scientific disciplines from agriculture to forensics. The technology has created an entirely new field, paleogenomics. Recently, gene sequencing solved a mystery about the origins of Native Americans. And paleogenomics pioneer Svante Pääbo has used the technology to sequence the genomes of Neanderthals and other early humans.


SVANTE PÄÄBO: So it was really high throughput DNA sequencing that came around in the early 2000s that made it possible to leave - earlier, we had only used PCR to try to amplify particular small fragments of DNA you were interested in. And now one could just go and sequence all the DNA in a fossil and sort out in a computer what came from the species in question, and what were bacterial contaminants.


STEVE USDIN: Pääbo's work has created a completely new understanding of modern human origins.


SVANTE PÄÄBO: It's resolved a long-standing fight in paleontology, over 30 years at least, where there were two camps. One that suggested that, for example, Neanderthals in Europe and other forms in Asia were the direct ancestors Neanderthals of Europeans. And other forms in Asia are present-day Asians.


And another sort of camp that said modern humans evolved in Africa, came out of Africa, and replaced these forms. We have no mixing whatsoever. So there's no special relationship between Neanderthals and present-day humans.


And the Neanderthal genome then really resolved this thing and showed that neither side was totally right really. The big picture is that ancestors of modern human came out of Africa. They eventually replaced these other forms. But they mixed a little bit.


So there is a contribution from Neanderthals. They live on in people today, if you like, by 1% or 2% of the DNA of people outside Africa.


STEVE USDIN: Pääbo's work tells us where we come from and how we got here.


SVANTE PÄÄBO: In some sense, it has showed us the genetic recipe of being a modern human. It has showed what in our genome are the changes that are typical of present-day humans, where we're different from Neanderthals. And another set of changes where we and Neanderthals differ from the apes.


So we have these catalogues now of these changes. So it opens up. It's a tool for trying to elucidate the biology of these changes in the future.


STEVE USDIN: Gene sequencing technology is certain to hold the keys to unlocking even more secrets about human origins.


SVANTE PÄÄBO: I think we now have studied two complete genomes of extinct forms of humans. We found a new form of extinct humans. I think we will probably find other groups in the future, perhaps in China. Probably those groups may also have contributed, to some extent, to present-day humans.


And I hope very much that one will be able to go back further in time. We have just succeeded in retrieving 400,000 year old DNA, a little bit of it, from what is probably ancestors of Neanderthals. So one might be able to go back in the future and find, for example, late surviving Homo erectus in Asia, and sequence their genomes, and find other divergences along the human lineage. We can really time what changes happened early, later, and in the very last part.


It is certainly like discovering the telescope. To be able to look out in space and see other planets and stars that you could not see before, we are now able to look into our genome, and look at our inheritance, and the sort of basis of our biology in a way you could not imagine to do before.


On the one hand, you can infer what happened in the past. But now with these techniques, one can actually go back and study ancient DNA. We can actually go back in time. And if you like, catch evolution red-handed.


STEVE USDIN: Gene sequencing technology is a fundamental tool for exploration. Like the microscope and the telescope, it's just changed our conception of what it means to be human and our relationship with the past. For an extended interview with Svante Pääbo, log on to BioCenturytv/innovation. To discuss this week's show, join the conversation on Twitter. Use the hashtag #BioCenturyTV. I'm Steve Usdin. Thanks for watching.